**Orthopedics**

**Chapter 5**

**Provisional chapter**

**Macroscopic Anatomy, Histopathology, and Image**

**Macroscopic Anatomy, Histopathology, and Image** 

DOI: 10.5772/intechopen.70374

© 2016 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution,

© 2018 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

and reproduction in any medium, provided the original work is properly cited.

Aging populations and rising life expectancy have become a global trend. Developing countries have been living with a growing change in the health profile of the population due to the greater

**Keywords:** diagnostic imaging, arthropathies, technologies, treatments, joint

Joints are physiological connections formed by the association of two or more bones that confer mobility to the skeleton of vertebrates. Composed of several structures, these are often related to pathologies of varied origins, which determine symptomatology of varying degrees of intensity and impairment, responsible for the decrease in life expectancy and the well-being of affected populations. Most of the time, the treatment for these diseases is only symptomatic, aiming at the relief of pain and the return of the patient to daily activities. Thus, there has been an increasing interest in the search for new knowledge about the mechanisms that lead to joint disorders and effective therapeutic resources that may contribute to the fight against pain and to the definitive treatment of joint dysfunctions. To this aim, the knowledge of diagnostic methods, especially imaging methods, is of fundamental importance for the recognition of articular affections, enabling a targeted and effective treatment. Among these auxiliary exams currently used to evaluate the joints, the noninvasive ones are the first choice, where radiography, ultrasonography, magnetic resonance imaging (MRI), computed tomography, and arthroscopy are inserted.

**Diagnosis of Joints and Synovial Cartilages**

**Diagnosis of Joints and Synovial Cartilages**

Flávio Ribeiro Alves,

**Abstract**

**1. Introduction**

Renan Paraguassu de Sá Rodrigues, Andrezza Braga Soares da Silva,

Jacyara de Jesus Rosa Pereira Alves,

http://dx.doi.org/10.5772/intechopen.70374

Kássio Vieira Macedo and Robson Giglio

Additional information is available at the end of the chapter

Additional information is available at the end of the chapter

Gerson Tavares Pessoa, Laecio da Silva Moura,

Flávio Ribeiro Alves, Renan Paraguassu de Sá Rodrigues, Andrezza Braga Soares da Silva, Gerson Tavares Pessoa, Laecio da Silva Moura, Jacyara de Jesus Rosa Pereira Alves, Kássio Vieira Macedo and Robson Giglio

**Provisional chapter**

## **Macroscopic Anatomy, Histopathology, and Image Diagnosis of Joints and Synovial Cartilages Macroscopic Anatomy, Histopathology, and Image Diagnosis of Joints and Synovial Cartilages**

DOI: 10.5772/intechopen.70374

Flávio Ribeiro Alves, Renan Paraguassu de Sá Rodrigues, Andrezza Braga Soares da Silva, Gerson Tavares Pessoa, Laecio da Silva Moura, Jacyara de Jesus Rosa Pereira Alves, Kássio Vieira Macedo and Robson Giglio Flávio Ribeiro Alves, Renan Paraguassu de Sá Rodrigues, Andrezza Braga Soares da Silva, Gerson Tavares Pessoa, Laecio da Silva Moura, Jacyara de Jesus Rosa Pereira Alves, Kássio Vieira Macedo and Robson Giglio Additional information is available at the end of the chapter

Additional information is available at the end of the chapter

http://dx.doi.org/10.5772/intechopen.70374

#### **Abstract**

Joints are physiological connections formed by the association of two or more bones that confer mobility to the skeleton of vertebrates. Composed of several structures, these are often related to pathologies of varied origins, which determine symptomatology of varying degrees of intensity and impairment, responsible for the decrease in life expectancy and the well-being of affected populations. Most of the time, the treatment for these diseases is only symptomatic, aiming at the relief of pain and the return of the patient to daily activities. Thus, there has been an increasing interest in the search for new knowledge about the mechanisms that lead to joint disorders and effective therapeutic resources that may contribute to the fight against pain and to the definitive treatment of joint dysfunctions. To this aim, the knowledge of diagnostic methods, especially imaging methods, is of fundamental importance for the recognition of articular affections, enabling a targeted and effective treatment. Among these auxiliary exams currently used to evaluate the joints, the noninvasive ones are the first choice, where radiography, ultrasonography, magnetic resonance imaging (MRI), computed tomography, and arthroscopy are inserted.

**Keywords:** diagnostic imaging, arthropathies, technologies, treatments, joint

## **1. Introduction**

Aging populations and rising life expectancy have become a global trend. Developing countries have been living with a growing change in the health profile of the population due to the greater

© 2016 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. © 2018 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

life expectancy. Associated with this, the problems related to chronic degenerative and autoimmune diseases arise, which, if not properly treated and followed over the years, can result in serious health problems, compromising the independence and autonomy of patients affected, especially the elderly. In these countries, chronic diseases have caused important and costly demands on health systems and have interfered in qualitative aspects of life [13].

Currently, treatments for these diseases have as main objective the relief of pain and the reduction of functional disability, enabling the development of routine activities and suspension of disease progression. To that aim, several techniques have been proposed, such as pharmacological and nonpharmacological, surgical, and alternative treatments, such as the use of platelet-rich plasma for pain and joint function improvement in osteoarthritis [15, 35], aquatic and nonaquatic exercises [40], and nonsteroidal anti-inflammatory thera-

Macroscopic Anatomy, Histopathology, and Image Diagnosis of Joints and Synovial Cartilages

http://dx.doi.org/10.5772/intechopen.70374

81

More recently, cell therapies have been proposed, such as the use of stem cells, which consist of a nonspecialized cell category, that is, they have no tissue-specific structure that allows them to perform individual functions of other cells. These are capable of dividing and renewing themselves over long periods and also of differentiating themselves into specialized cell types. Unlike other cells, such as those of the muscular and nervous tissues, which do not normally replicate, they can replicate several times in a process called proliferation. In this context, the possibility of using stem cells for cellular therapies has become a very coveted area and is the target of several studies, attracting the attention of researchers from all over

Primordial germ cell therapies have also been studied for the formation of hyaline articular cartilage due to its regenerative characteristic. Diseases such as traumatic chondral lesions, dissecting osteochondritis, patellar chondromalacia, and osteoarthrosis are targets of therapy

Traumatic chondral injuries, when moderate and in areas of low mechanical stress, are usually treated by conservative methods that include dietary reduction for weight reduction, analgesics, anti-inflammatories, and physiotherapy. When extensive, more complex treatments are stipulated as autologous or homologous osteochondral grafts, replacement arthroplasty using

The importance of stem cells as a new treatment method in chondral lesions is due to the fact that articular cartilage has little repair capacity. However, the autologous chondrocyte culture transplant technique in chondral defects is still restricted to small lesions and in young patients. In contrast, recent studies have shown that mesenchymal progenitor cells can repair major defects regardless of age. The great difficulty is still the culture, induction of differentia-

In addition to stem cells, growth factors are also required to determine proliferation and differentiation in cartilaginous tissue both during in vitro cultures and in implantation. These factors include prolactin, which induces cell proliferation and the synthesis of proteoglycans. Other factors that determine chondrogenesis are insulin-like growth factor 1

With the advent of this new technique, it is expected that donor area morbidity can be reduced in cases of allografts where small fragments of cartilage are removed from an area of lower load to another with osteochondral defect and reduce contamination and deterioration of these areas, avoiding lesions inherent to more invasive techniques such as release and wear of

tion, and adhesion at the lesion site, which often do not respond as expected [17].

(IGF-1) and transforming growth factor beta 1 (TGFβ1) [49, 69].

pies [20], among others.

the world [51].

with these cells [46].

partial or total prostheses and arthrodesis [17].

material, in the cases of joint prostheses [55].

Noncommunicable chronic diseases and autoimmune diseases are one of the main factors responsible for the decrease in the life expectancy and the well-being of the populations affected. Its prevalence is elevated in elderly patients, where osteoarticular diseases predominate, which account for a significant portion of these [26].

The concept of degenerative osteoarticular disease presupposes hyaline cartilage abnormalities, which determine symptomatology of variable intensity and impairment of function. The clinical picture is called arthrosis, osteoarthrosis, or osteoarthritis. Osteoarthritis is a degenerative condition of articular hyaline cartilage, difficult to diagnose and treat, which affects older patients more frequently, manifested by pain, stiffness, and functional impairment of the affected joint. The degenerative or degradative process of articular cartilage may be primary or secondary to different causes, such as hereditary diseases, endocrine diseases, joint disorders, and inflammatory diseases [28, 53].

Among autoimmune diseases, rheumatoid arthritis, a complex etiology characterized by symmetrical peripheral polyarthritis, which leads to deformity and destruction of the joints due to erosion of bones and cartilage, also presenting a higher incidence in elderly patients stands out. In general, it affects large and small joints in association with systemic manifestations such as stiffness, fatigue, and weight loss. When it involves other organs, the morbidity and severity of the disease are greater and may decrease life expectancy in 5–10 years. With the progression of the disease, the patients develop incapacity to the development of their activities, which generates social and economic impacts [1].

Degenerative joint disease is another arthropathy characterized by a noninflammatory disorder of mobile joints, being considered as a group of disorders defined by the progressive deterioration of articular cartilage, accompanied by bone and soft tissue alterations [11, 59, 63]. This is a chronic condition leading to degeneration of adjacent structures and thickening of the joint capsule. Different factors are identified as the cause of this disease, such as trauma, intra-articular fractures, subluxations or joint dislocations, conformation defects, and angular deformity [37].

Degenerative joint disease manifests initially with mild lameness, which progresses with the development of the disease [34]. In large-moving joints, initial changes are manifested by acute synovitis and capsulitis [56] or muscle atrophies [41], as well as joint capsule distension with an increase in adjacent soft tissue volume [34]. The predominant symptom is pain sensitivity, which may originate from different intra-articular or extra-articular structures, such as capsule, articular cartilage, synovium, periosteum, bones, tendons, bursae, ligaments, or menisci [47].

These data justify an increasing interest in the search for new knowledge about the mechanisms that lead to joint disorders and effective therapeutic resources that can contribute to the fight against pain and to the definitive treatment of joint dysfunctions, preventing the degeneration of structures until irreversible states.

Currently, treatments for these diseases have as main objective the relief of pain and the reduction of functional disability, enabling the development of routine activities and suspension of disease progression. To that aim, several techniques have been proposed, such as pharmacological and nonpharmacological, surgical, and alternative treatments, such as the use of platelet-rich plasma for pain and joint function improvement in osteoarthritis [15, 35], aquatic and nonaquatic exercises [40], and nonsteroidal anti-inflammatory therapies [20], among others.

life expectancy. Associated with this, the problems related to chronic degenerative and autoimmune diseases arise, which, if not properly treated and followed over the years, can result in serious health problems, compromising the independence and autonomy of patients affected, especially the elderly. In these countries, chronic diseases have caused important and costly

Noncommunicable chronic diseases and autoimmune diseases are one of the main factors responsible for the decrease in the life expectancy and the well-being of the populations affected. Its prevalence is elevated in elderly patients, where osteoarticular diseases predominate, which

The concept of degenerative osteoarticular disease presupposes hyaline cartilage abnormalities, which determine symptomatology of variable intensity and impairment of function. The clinical picture is called arthrosis, osteoarthrosis, or osteoarthritis. Osteoarthritis is a degenerative condition of articular hyaline cartilage, difficult to diagnose and treat, which affects older patients more frequently, manifested by pain, stiffness, and functional impairment of the affected joint. The degenerative or degradative process of articular cartilage may be primary or secondary to different causes, such as hereditary diseases, endocrine diseases, joint

Among autoimmune diseases, rheumatoid arthritis, a complex etiology characterized by symmetrical peripheral polyarthritis, which leads to deformity and destruction of the joints due to erosion of bones and cartilage, also presenting a higher incidence in elderly patients stands out. In general, it affects large and small joints in association with systemic manifestations such as stiffness, fatigue, and weight loss. When it involves other organs, the morbidity and severity of the disease are greater and may decrease life expectancy in 5–10 years. With the progression of the disease, the patients develop incapacity to the development of their

Degenerative joint disease is another arthropathy characterized by a noninflammatory disorder of mobile joints, being considered as a group of disorders defined by the progressive deterioration of articular cartilage, accompanied by bone and soft tissue alterations [11, 59, 63]. This is a chronic condition leading to degeneration of adjacent structures and thickening of the joint capsule. Different factors are identified as the cause of this disease, such as trauma, intra-articular fractures, subluxations or joint dislocations, conformation defects, and angular deformity [37].

Degenerative joint disease manifests initially with mild lameness, which progresses with the development of the disease [34]. In large-moving joints, initial changes are manifested by acute synovitis and capsulitis [56] or muscle atrophies [41], as well as joint capsule distension with an increase in adjacent soft tissue volume [34]. The predominant symptom is pain sensitivity, which may originate from different intra-articular or extra-articular structures, such as capsule, articular cartilage, synovium, periosteum, bones, tendons, bursae, ligaments, or menisci [47].

These data justify an increasing interest in the search for new knowledge about the mechanisms that lead to joint disorders and effective therapeutic resources that can contribute to the fight against pain and to the definitive treatment of joint dysfunctions, preventing the

demands on health systems and have interfered in qualitative aspects of life [13].

account for a significant portion of these [26].

80 Cartilage Repair and Regeneration

disorders, and inflammatory diseases [28, 53].

activities, which generates social and economic impacts [1].

degeneration of structures until irreversible states.

More recently, cell therapies have been proposed, such as the use of stem cells, which consist of a nonspecialized cell category, that is, they have no tissue-specific structure that allows them to perform individual functions of other cells. These are capable of dividing and renewing themselves over long periods and also of differentiating themselves into specialized cell types. Unlike other cells, such as those of the muscular and nervous tissues, which do not normally replicate, they can replicate several times in a process called proliferation. In this context, the possibility of using stem cells for cellular therapies has become a very coveted area and is the target of several studies, attracting the attention of researchers from all over the world [51].

Primordial germ cell therapies have also been studied for the formation of hyaline articular cartilage due to its regenerative characteristic. Diseases such as traumatic chondral lesions, dissecting osteochondritis, patellar chondromalacia, and osteoarthrosis are targets of therapy with these cells [46].

Traumatic chondral injuries, when moderate and in areas of low mechanical stress, are usually treated by conservative methods that include dietary reduction for weight reduction, analgesics, anti-inflammatories, and physiotherapy. When extensive, more complex treatments are stipulated as autologous or homologous osteochondral grafts, replacement arthroplasty using partial or total prostheses and arthrodesis [17].

The importance of stem cells as a new treatment method in chondral lesions is due to the fact that articular cartilage has little repair capacity. However, the autologous chondrocyte culture transplant technique in chondral defects is still restricted to small lesions and in young patients. In contrast, recent studies have shown that mesenchymal progenitor cells can repair major defects regardless of age. The great difficulty is still the culture, induction of differentiation, and adhesion at the lesion site, which often do not respond as expected [17].

In addition to stem cells, growth factors are also required to determine proliferation and differentiation in cartilaginous tissue both during in vitro cultures and in implantation. These factors include prolactin, which induces cell proliferation and the synthesis of proteoglycans. Other factors that determine chondrogenesis are insulin-like growth factor 1 (IGF-1) and transforming growth factor beta 1 (TGFβ1) [49, 69].

With the advent of this new technique, it is expected that donor area morbidity can be reduced in cases of allografts where small fragments of cartilage are removed from an area of lower load to another with osteochondral defect and reduce contamination and deterioration of these areas, avoiding lesions inherent to more invasive techniques such as release and wear of material, in the cases of joint prostheses [55].

However, the literature has shown in several studies that this topic is one of the most promising fields of medicine, with the potential to provide the resolution of pathologies previously limited to symptomatic treatments [16, 38].

and can be of three types: sutures, syndesmosis, and gomphosis. The sutures are joints present mainly in the bones of the skull and are characterized by a small amount of fibrous tissue. In syndesmosis, the bone surfaces are joined by a fibrous substance in a tape or ligament aspect that limits the movement of the articular parts, as in the tibiofibular joint. In the gomphosis, the bony structures are irregular, and the pattern is the one of the inserted teeth in

Macroscopic Anatomy, Histopathology, and Image Diagnosis of Joints and Synovial Cartilages

http://dx.doi.org/10.5772/intechopen.70374

83

Unlike the fibrous ones, in the cartilaginous joints, the interposed tissue is cartilaginous in nature and can be subdivided into synchondrosis and symphysis. Synchondrosis is a provisory or temporary joint, in which the cartilage has a limited life, disappearing soon after the individual reaches adulthood, a situation found in the epiphyseal disks. The symphysis is permanent, commonly present in the intervertebral disks and the pubic symphysis

Unlike fibrous and cartilaginous, the synovial joints allow wide movements, being structurally complex, characterized by the presence of synovial membrane which internally coats the joint space and is responsible for the production of synovial fluid. Other elements participate in the constitution of the synovial joints as the joint cavity, articular bone surfaces, articular

Synovial or diarthrosis cartilages are present in most joints and are capable of flexion and extension movements, adduction and abduction, rotation (around the cerebrum-podalic axis, can be medial and lateral), pronation (medial rotation of the forearm), supination (lateral rotation of the forearm), and circumference (joint movement of adduction, flexion, abduction,

The characteristics found in the articular bone surfaces also allow defining the movements performed by the joint, so these structures can be called flat, seal, ellipsoid, and condylar. The flat surfaces allow sliding movements corresponding to the joints of the carpus or tarsus. In sealing the surfaces that resemble a knight in a saddle, it can be found in the carpometacarpal joint of the thumb. The articulation with ellipsoid surfaces has an elliptical shape, not allowing rotation movements, like the car rim. The condylar, in turn, presents the prominent bone surface appearing a condyle, found in the temporomandibular and metacarpophalangeal [39]. The occurrence of joints involving two distinct natures is possible, as is the case of fibrocartilaginous, which act as shock absorbers, enabling the joint movements. As a way of increasing the contact area of the articular surfaces, the lips (or borders) are examples of joints in which the interposed tissue is fibrocartilaginous in nature. These act as frames and are found in the shoulder joint (glenoid lip). Other examples are disks and menisci. The first, found in the union of the clavicle with the sternum, stabilizes one bony part allowing the other to perform complex movements, as it is also seen in the temporomandibular joint (TMJ). The meniscus, resembling disks, however, is incomplete, acquiring "crescent" form, and is present in the knee joint [66]. Externally, there are elements that reinforce the cohesion between the articular parts, which is the case of the ligaments that can be found internal to the articular or extra-articular cavity and to the physical forces exerted: cohesive force, atmospheric pressure, transition of the

cartilage, and articular capsule described previously [32].

coapted bones, and muscular tension [39].

their alveoli [12, 32].

and extension) [32].

[12, 70].

## **2. Anatomy of the joints**

The word articulation originates from the Latin "articulatio" which means rigidity, that is, structure that derives from a cartilaginous bone set of consistent architecture. Physiologically, it is the connection between bones which gives mobility to the skeleton. The joints are formed by the association of two or more bones with the aid of skeletal muscles, ligaments, and joint capsule. The functional activity of the joints depends essentially on the shape of the joint surfaces and the union means, which may limit it [29, 61].

The articular joints are formed by the joint activity of the following structures: bones, articular surface, articular cartilage, joint space, joint capsule, and synovial fluid. Each of these structures plays an important role in the joint [64].

The bones, rigid structures that serve as support and skeleton forming the joints, communicate by favoring the mobility of the body. Depending on the location, the bones may present different anatomical dispositions and therefore infer in the shape and classification of the joints [68].

The articular surfaces are the regions of bone surface that maintain contact for formation of the articular region. These surfaces correspond to the place of insertion of the articular cartilage serving as the base. The latter is the layer of cartilaginous tissue that covers the articular surfaces, absorbing compressive impacts and assisting in the development of the other constituent structures of the joint [39, 68].

The joint capsule is a fibrous sheath that covers the space belonging to the joint while holding the bone structures together. This structure plays the germinative function for the synovial fluid and provides stability to the joints, thus contributing to the creation of an internal portion, of reduced pressure, favoring a better coaptation [8, 29].

Synovial fluid is an aqueous substance secreted by the joint capsule that fills the joint space and ensures lubrication, allowing the stability and distribution of the loads on the surfaces, reducing the stresses of contact. Synovial fluid is a parameter for many articular anomalies, which can be evaluated by means of arthrocentesis (collection of the joint fluid) and by examining the color, appearance, and viscosity of this material [29, 59].

The joints can be classified according to their structure and mobility in fibrous (synarthroses) or immotile movements, cartilaginous (amphiarthroses) or with limited movements, and synovial (diarthroses) or with ample movements. Another type of classification is with regard to the continuity of the bone pieces, which may be continuous (with bone pieces closely connected to each other) and contiguous (where there is a joint cavity) [12].

The fibrous joints, in which the interposed elements between the bony structures are of fibrous nature, called synarthroses (syn: together, arthro: articulation), are immobile joints and can be of three types: sutures, syndesmosis, and gomphosis. The sutures are joints present mainly in the bones of the skull and are characterized by a small amount of fibrous tissue. In syndesmosis, the bone surfaces are joined by a fibrous substance in a tape or ligament aspect that limits the movement of the articular parts, as in the tibiofibular joint. In the gomphosis, the bony structures are irregular, and the pattern is the one of the inserted teeth in their alveoli [12, 32].

However, the literature has shown in several studies that this topic is one of the most promising fields of medicine, with the potential to provide the resolution of pathologies previously

The word articulation originates from the Latin "articulatio" which means rigidity, that is, structure that derives from a cartilaginous bone set of consistent architecture. Physiologically, it is the connection between bones which gives mobility to the skeleton. The joints are formed by the association of two or more bones with the aid of skeletal muscles, ligaments, and joint capsule. The functional activity of the joints depends essentially on the shape of the joint sur-

The articular joints are formed by the joint activity of the following structures: bones, articular surface, articular cartilage, joint space, joint capsule, and synovial fluid. Each of these struc-

The bones, rigid structures that serve as support and skeleton forming the joints, communicate by favoring the mobility of the body. Depending on the location, the bones may present different anatomical dispositions and therefore infer in the shape and classification of the joints [68]. The articular surfaces are the regions of bone surface that maintain contact for formation of the articular region. These surfaces correspond to the place of insertion of the articular cartilage serving as the base. The latter is the layer of cartilaginous tissue that covers the articular surfaces, absorbing compressive impacts and assisting in the development of the other con-

The joint capsule is a fibrous sheath that covers the space belonging to the joint while holding the bone structures together. This structure plays the germinative function for the synovial fluid and provides stability to the joints, thus contributing to the creation of an internal por-

Synovial fluid is an aqueous substance secreted by the joint capsule that fills the joint space and ensures lubrication, allowing the stability and distribution of the loads on the surfaces, reducing the stresses of contact. Synovial fluid is a parameter for many articular anomalies, which can be evaluated by means of arthrocentesis (collection of the joint fluid) and by exam-

The joints can be classified according to their structure and mobility in fibrous (synarthroses) or immotile movements, cartilaginous (amphiarthroses) or with limited movements, and synovial (diarthroses) or with ample movements. Another type of classification is with regard to the continuity of the bone pieces, which may be continuous (with bone pieces closely con-

The fibrous joints, in which the interposed elements between the bony structures are of fibrous nature, called synarthroses (syn: together, arthro: articulation), are immobile joints

limited to symptomatic treatments [16, 38].

faces and the union means, which may limit it [29, 61].

tion, of reduced pressure, favoring a better coaptation [8, 29].

ining the color, appearance, and viscosity of this material [29, 59].

nected to each other) and contiguous (where there is a joint cavity) [12].

tures plays an important role in the joint [64].

stituent structures of the joint [39, 68].

**2. Anatomy of the joints**

82 Cartilage Repair and Regeneration

Unlike the fibrous ones, in the cartilaginous joints, the interposed tissue is cartilaginous in nature and can be subdivided into synchondrosis and symphysis. Synchondrosis is a provisory or temporary joint, in which the cartilage has a limited life, disappearing soon after the individual reaches adulthood, a situation found in the epiphyseal disks. The symphysis is permanent, commonly present in the intervertebral disks and the pubic symphysis [12, 70].

Unlike fibrous and cartilaginous, the synovial joints allow wide movements, being structurally complex, characterized by the presence of synovial membrane which internally coats the joint space and is responsible for the production of synovial fluid. Other elements participate in the constitution of the synovial joints as the joint cavity, articular bone surfaces, articular cartilage, and articular capsule described previously [32].

Synovial or diarthrosis cartilages are present in most joints and are capable of flexion and extension movements, adduction and abduction, rotation (around the cerebrum-podalic axis, can be medial and lateral), pronation (medial rotation of the forearm), supination (lateral rotation of the forearm), and circumference (joint movement of adduction, flexion, abduction, and extension) [32].

The characteristics found in the articular bone surfaces also allow defining the movements performed by the joint, so these structures can be called flat, seal, ellipsoid, and condylar. The flat surfaces allow sliding movements corresponding to the joints of the carpus or tarsus. In sealing the surfaces that resemble a knight in a saddle, it can be found in the carpometacarpal joint of the thumb. The articulation with ellipsoid surfaces has an elliptical shape, not allowing rotation movements, like the car rim. The condylar, in turn, presents the prominent bone surface appearing a condyle, found in the temporomandibular and metacarpophalangeal [39].

The occurrence of joints involving two distinct natures is possible, as is the case of fibrocartilaginous, which act as shock absorbers, enabling the joint movements. As a way of increasing the contact area of the articular surfaces, the lips (or borders) are examples of joints in which the interposed tissue is fibrocartilaginous in nature. These act as frames and are found in the shoulder joint (glenoid lip). Other examples are disks and menisci. The first, found in the union of the clavicle with the sternum, stabilizes one bony part allowing the other to perform complex movements, as it is also seen in the temporomandibular joint (TMJ). The meniscus, resembling disks, however, is incomplete, acquiring "crescent" form, and is present in the knee joint [66].

Externally, there are elements that reinforce the cohesion between the articular parts, which is the case of the ligaments that can be found internal to the articular or extra-articular cavity and to the physical forces exerted: cohesive force, atmospheric pressure, transition of the coapted bones, and muscular tension [39].

## **3. Histology of joints**

The study of the joints allows inferring about the mechanism of locomotion of the organism, being a content that involves the anatomical part and the ultrastructure of the articular elements. Thus, histology as an important segment in this study defines the tissue characteristics of the joint as well as the importance of its cells for the performance of joint physiology [31].

and the tibia, ranging from 2 to 4 mm. From this thickness, four distinct layers are divided according to the cellular morphology and structure of the extracellular matrix in a superficial, transient, deep, and calcified cartilage zone. The arrangement of chondrocytes and collagen fibers varies between layers, increasing cell density as it approaches the articular surface [62]. The superficial or tangential layer is responsible for the slip of the movement of the bony parts and lubrication, composing about 20–30% of the articular cartilage. This zone is composed of two layers, a thin fibrillar lamina without cells (located in the bed more superficial or distal to the articular surface) and another layer of flat chondrocytes and collagen fibers oriented

Macroscopic Anatomy, Histopathology, and Image Diagnosis of Joints and Synovial Cartilages

http://dx.doi.org/10.5772/intechopen.70374

85

The transitional or intermediate layer is responsible for the transition between the shear forces of the articular parts, still corresponding to about 60–70% of the cartilage; this layer is composed of relatively larger round chondrocytes and immersed in an extracellular matrix. In this area, the collagen fibers are thick and randomly arranged, with a high content of proteoglycan with the presence of spherical chondrocytes. Finally, the calcified or deep layer establishes an intimate relation with the articular surface, corresponding to the smaller percentage in the

The cartilaginous matrix is constantly subjected to external forces due to movement and the load imposed on the joints, which impose the need to maintain high resistance and flexibility. These characteristics are conferred by the collagen fibrils and the amorphous intercellular substance, which are inserted in their constitution permeated by a collagen network composed of water, proteoglycans, and hyaluronic acid. Water is the most abundant element in the matrix, and its high content in the cartilage favors the absorption of impacts, giving the articular cartilage the deformity necessary to withstand the compressive forces to which it is normally subjected. In addition, the cartilage matrix contains electrolytes such

, and K, in concentrations higher than those found in synovial fluid [67].

Chondrocytes are the main cellular elements found in the articular cartilage and produce different collagen molecules, type II collagen being the most abundant in the joints. This collagen is characterized by three α1 chains of type II and organized in fibrils that give a threedimensional network shape to the matrix allowing a certain degree of deformity when it is

In addition to water and hyaluronic acid, the matrix consists of proteoglycans, complex molecules composed of glycosaminoglycans, which are polysaccharides made up of sulfated disaccharide units that repeat themselves in relatively short and unbranched chains. The proteoglycans bind to hyaluronic acid forming chains of multi-molecules favoring the cellular

When synthesized and secreted by the chondrocytes, the hyaluronate-proteoglycan complexes and the collagen cluster themselves, resulting in perfectly structured complexes adapted to withstand the compression and traction forces to which the joint is subjected. Once the cartilage is subjected to compressive forces, the water retained by the proteoglycans is released proportionally to the force exerted, being recovered when that force is ceased. However, the amount of water that proteoglycans can expel upon being compressed is limited and determined by

tangentially to the articular surface, having low proteoglycan content [62].

constitution of the cartilage [52, 72].

subjected to compressive or tensile forces [31].

organization of the matrix [31].

as Ca2+, Na+

The component elements of the joints present distinct histological characteristics, where the bone and cartilage tissues are most abundant. The articular surfaces are covered by articular cartilage of the hyaline type. The articular cartilage comprises a highly specialized surface connection fabric that provides a lubricated surface for moving joints and facilitates the transmission and distribution of the loads with a low coefficient of friction [29, 59].

Hyaline cartilage consists of the following cellular elements: chondrocytes, type 2 collagen, and extracellular matrix, as well as important microelements such as water, proteoglycans, glycoproteins, and lipids. Chondrocytes are the most abundant cells in this tissue, which present in their cytoplasm glycogen, lipids, well-developed endoplasmic reticulum, and Golgi complex. These tend to occupy small spaces within the extracellular matrix of the cartilage, called gaps, in which they can be found individually or contain two or more cells by gaps (**Figure 1**) [71].

The hyaline articular cartilage does not present vascularization, and the chondrocytes are nourished by constituents present in the synovial fluid provided by diffusion. The thickness and density of the cartilage vary from joint, and in humans, it is thicker on the end of the femur

**Figure 1.** Photomicrograph of hyaline cartilage from a CAE model (caprine arthritis and encephalitis model) of an infected goat. (A) Affected SHJ (humerus head surface). Note the irregular joint surface with loss of cartilage integrity and heterogeneous chondrocyte distribution that are seen flattened on every surface aspect (arrows) and focal degeneration with cartilage fibrillation (wide arrows). (B) Carpal joint (carpal radial bone). Note the irregular perichondrium surface with spaced and little evident chondroblasts. The chondrocytes wrapped in matrix (\*) are also seen in fewer quantities and spaces on the surface and deep layers. Bars: (a) 10 μm and (b) 10 μm (image gentile provided by Professor Flavio Alves, Specialized Veterinary Diagnostic Imaging Laboratory (LABDIVE), Federal University of Piauí, Teresina, Piauí, Brazil).

and the tibia, ranging from 2 to 4 mm. From this thickness, four distinct layers are divided according to the cellular morphology and structure of the extracellular matrix in a superficial, transient, deep, and calcified cartilage zone. The arrangement of chondrocytes and collagen fibers varies between layers, increasing cell density as it approaches the articular surface [62].

The superficial or tangential layer is responsible for the slip of the movement of the bony parts and lubrication, composing about 20–30% of the articular cartilage. This zone is composed of two layers, a thin fibrillar lamina without cells (located in the bed more superficial or distal to the articular surface) and another layer of flat chondrocytes and collagen fibers oriented tangentially to the articular surface, having low proteoglycan content [62].

The transitional or intermediate layer is responsible for the transition between the shear forces of the articular parts, still corresponding to about 60–70% of the cartilage; this layer is composed of relatively larger round chondrocytes and immersed in an extracellular matrix. In this area, the collagen fibers are thick and randomly arranged, with a high content of proteoglycan with the presence of spherical chondrocytes. Finally, the calcified or deep layer establishes an intimate relation with the articular surface, corresponding to the smaller percentage in the constitution of the cartilage [52, 72].

The cartilaginous matrix is constantly subjected to external forces due to movement and the load imposed on the joints, which impose the need to maintain high resistance and flexibility. These characteristics are conferred by the collagen fibrils and the amorphous intercellular substance, which are inserted in their constitution permeated by a collagen network composed of water, proteoglycans, and hyaluronic acid. Water is the most abundant element in the matrix, and its high content in the cartilage favors the absorption of impacts, giving the articular cartilage the deformity necessary to withstand the compressive forces to which it is normally subjected. In addition, the cartilage matrix contains electrolytes such as Ca2+, Na+ , and K, in concentrations higher than those found in synovial fluid [67].

Chondrocytes are the main cellular elements found in the articular cartilage and produce different collagen molecules, type II collagen being the most abundant in the joints. This collagen is characterized by three α1 chains of type II and organized in fibrils that give a threedimensional network shape to the matrix allowing a certain degree of deformity when it is subjected to compressive or tensile forces [31].

In addition to water and hyaluronic acid, the matrix consists of proteoglycans, complex molecules composed of glycosaminoglycans, which are polysaccharides made up of sulfated disaccharide units that repeat themselves in relatively short and unbranched chains. The proteoglycans bind to hyaluronic acid forming chains of multi-molecules favoring the cellular organization of the matrix [31].

When synthesized and secreted by the chondrocytes, the hyaluronate-proteoglycan complexes and the collagen cluster themselves, resulting in perfectly structured complexes adapted to withstand the compression and traction forces to which the joint is subjected. Once the cartilage is subjected to compressive forces, the water retained by the proteoglycans is released proportionally to the force exerted, being recovered when that force is ceased. However, the amount of water that proteoglycans can expel upon being compressed is limited and determined by

**Figure 1.** Photomicrograph of hyaline cartilage from a CAE model (caprine arthritis and encephalitis model) of an infected goat. (A) Affected SHJ (humerus head surface). Note the irregular joint surface with loss of cartilage integrity and heterogeneous chondrocyte distribution that are seen flattened on every surface aspect (arrows) and focal degeneration with cartilage fibrillation (wide arrows). (B) Carpal joint (carpal radial bone). Note the irregular perichondrium surface with spaced and little evident chondroblasts. The chondrocytes wrapped in matrix (\*) are also seen in fewer quantities and spaces on the surface and deep layers. Bars: (a) 10 μm and (b) 10 μm (image gentile provided by Professor Flavio Alves, Specialized Veterinary Diagnostic Imaging Laboratory (LABDIVE), Federal University of Piauí, Teresina, Piauí,

The study of the joints allows inferring about the mechanism of locomotion of the organism, being a content that involves the anatomical part and the ultrastructure of the articular elements. Thus, histology as an important segment in this study defines the tissue characteristics of the joint as well as the importance of its cells for the performance of joint physiology [31]. The component elements of the joints present distinct histological characteristics, where the bone and cartilage tissues are most abundant. The articular surfaces are covered by articular cartilage of the hyaline type. The articular cartilage comprises a highly specialized surface connection fabric that provides a lubricated surface for moving joints and facilitates the trans-

Hyaline cartilage consists of the following cellular elements: chondrocytes, type 2 collagen, and extracellular matrix, as well as important microelements such as water, proteoglycans, glycoproteins, and lipids. Chondrocytes are the most abundant cells in this tissue, which present in their cytoplasm glycogen, lipids, well-developed endoplasmic reticulum, and Golgi complex. These tend to occupy small spaces within the extracellular matrix of the cartilage, called gaps, in which they can be found individually or contain two or more cells by gaps

The hyaline articular cartilage does not present vascularization, and the chondrocytes are nourished by constituents present in the synovial fluid provided by diffusion. The thickness and density of the cartilage vary from joint, and in humans, it is thicker on the end of the femur

mission and distribution of the loads with a low coefficient of friction [29, 59].

Brazil).

**3. Histology of joints**

84 Cartilage Repair and Regeneration

(**Figure 1**) [71].

their charge [68, 72]. Thus, the ability of articular cartilage to withstand compressive forces is directly proportional to the concentration of proteoglycans in the matrix and depends on the maintenance of its integrity, which at times may subject it to ruptures [29].

**4.1. Radiography**

capture of the images [10].

Radiography is the most common imaging technique, based on imaging by X-ray transmission over a target tissue. The rays that go beyond the body reach a film, sensitizing it. After the revelation, the rays that are absorbed in the body do not sensitize the film, and the corresponding areas will be white (radiopaque). On the other hand, the sensitized areas make the regions in the film black (radiolucent). In the analysis of the film, a variation of shades from white to black denominated radiological density is observed. The contrast between the light and dark areas in the radiography depends on the technical and physical conditions in the

Macroscopic Anatomy, Histopathology, and Image Diagnosis of Joints and Synovial Cartilages

http://dx.doi.org/10.5772/intechopen.70374

87

Like other techniques that expose the body to radiation, X-rays are harmful, requiring the adoption of procedures aimed at protecting exposed professionals and patients. The damage caused by ionizing radiation is cumulative, which means that the harm is caused by repeated doses of radiation that accumulate in the tissues. In order to minimize these risks, collimators, radiation dosage control, plumb protection, screens, and individual monitors (dosimeter) are

After the technical adjustments and taking into account the biosafety tools, the region to be analyzed in the radiography must be properly positioned so that favorable images are acquired for its evaluation. Thus, it is fundamental that incidences are made in different posi-

In the attempt to improve differentiation between structures of similar density, such as those found in the abdomen, contrast media are used which may be either natural (air) or artificial (barium based and iodine based). These solutions are mainly used in the study of digestive,

Radiography is an important diagnostic method for the study of joint changes. However, fractures in rigid structures, neoplasias, growth and posture disorders, traumatic and inflammatory changes, deposition of substances, and problems of calcification, among others, can be diagnosed. It has a high interest in the evaluation of the progression of rheumatic diseases and in the diagnosis of their complications. The radiographic changes found will vary according to the type of lesion and the time of evolution, keeping the clinician informed about the

The radiographic analysis of the joints should take into account the joint space, its dimensions, and regularities. The thickness of the joint space consists of the joint dimension of the cartilages of both bone structures. Any interference in this space can be represented in the radiographic image and indicate inflammatory changes as in the cases of arthritis. The space may be diminished in the case of advanced arthropathies, which may be asymmetric or localized, depending on the pathology, or it may occur that a loss of space is generalized [65].

Synovium, synovial fluid, and articular capsule, because they have the same radiodensity as adjacent soft tissues and cartilage, are only seen if they are contoured by a radiant layer. For this reason, it is often necessary to complement the simple X-ray with the use of articular

used for professionals who deal daily with this type of examination [22].

tions, determining opposite and/or complementary planes [6].

contrast media, known as arthrography (**Figure 2**) [10, 48].

urinary, biliary, vascular, and joint studies [10].

severity of the condition [24].

In addition to the articular cartilage, other elements are involved in the ultrastructure of the joints as the synovial fluid and the joint capsule. The intra-articular space, located between two opposite bone ends, contains the synovial fluid, which lubricates the articular surfaces, reducing friction, and serves as a vehicle for the diffusion of nutrients from the blood vessels of the synovial membrane to the articular cartilage chondrocytes. The elimination of the end products of the cellular metabolism occurs through mechanisms of diffusion, through the cartilage, to the blood and lymphatic vessels of the bone and the synovial membrane [30].

The synovial membrane that coats the articular capsule internally lies close to the surface of the cartilage, separated only by the synovial fluid, and is composed of two leaflets: the first (internal) is the synovial intima, devoid of basement membrane, and composed of one to four layers of cells. The second (more external) connects the outer wall of the fibrous capsule with the synovial intima, which is formed by loose connective tissue with fenestrated capillaries [5, 31].

The synovial intima is composed of two cell types: the "A"-type cells, similar to macrophages (because they have the same derivation of monocytic cells from the bone marrow), and the "B"-type cells, called synoviocytes, which have characteristic fibroblasts. This membrane covering the synovial fluid functions as a dialysis membrane, which, due to the increased capillary hydrostatic pressure, allows the ultrafiltration of the blood, the synovial fluid being constituted by the ultrafiltrate that passes from the synovial capillaries to the joint cavity. The articulation presents microelements essential for its activity in the midst of external and internal compressive forces, as well as assisting in the renewal and integrity of the tissues that compose them [31].

## **4. Diagnostic methods in articulation**

Often, the joints are affected by inflammatory, infectious, or degenerative conditions that can reach the cartilage, bones, and adjacent structures or a combination of these, causing serious damage to the patient. The treatment of these pathologies is elaborated through the definitive diagnosis, which usually relies on the accomplishment of complementary exams, especially the imaging [57].

Imaging methods are essential in the diagnosis of bone and joint changes. Among the auxiliary examinations currently used to evaluate the joints, the noninvasive ones are the first ones of choice, where radiography, ultrasonography, magnetic resonance imaging, computed tomography, and arthroscopy are inserted. Usually, the evaluation begins with the radiological examination, capable of providing essential information about the bony and articular cartilaginous structures. The imaging tests are used to evaluate the integrity of the articular components and the relationship between them, confirm the extent or stage of disease progression, and evaluate the effects of the treatments performed [57].

## **4.1. Radiography**

their charge [68, 72]. Thus, the ability of articular cartilage to withstand compressive forces is directly proportional to the concentration of proteoglycans in the matrix and depends on the

In addition to the articular cartilage, other elements are involved in the ultrastructure of the joints as the synovial fluid and the joint capsule. The intra-articular space, located between two opposite bone ends, contains the synovial fluid, which lubricates the articular surfaces, reducing friction, and serves as a vehicle for the diffusion of nutrients from the blood vessels of the synovial membrane to the articular cartilage chondrocytes. The elimination of the end products of the cellular metabolism occurs through mechanisms of diffusion, through the cartilage, to the blood and lymphatic vessels of the bone and the synovial membrane [30].

The synovial membrane that coats the articular capsule internally lies close to the surface of the cartilage, separated only by the synovial fluid, and is composed of two leaflets: the first (internal) is the synovial intima, devoid of basement membrane, and composed of one to four layers of cells. The second (more external) connects the outer wall of the fibrous capsule with the synovial intima, which is formed by loose connective tissue with fenestrated capillaries

The synovial intima is composed of two cell types: the "A"-type cells, similar to macrophages (because they have the same derivation of monocytic cells from the bone marrow), and the "B"-type cells, called synoviocytes, which have characteristic fibroblasts. This membrane covering the synovial fluid functions as a dialysis membrane, which, due to the increased capillary hydrostatic pressure, allows the ultrafiltration of the blood, the synovial fluid being constituted by the ultrafiltrate that passes from the synovial capillaries to the joint cavity. The articulation presents microelements essential for its activity in the midst of external and internal compressive forces, as well as assisting in the renewal and integrity of the tissues that

Often, the joints are affected by inflammatory, infectious, or degenerative conditions that can reach the cartilage, bones, and adjacent structures or a combination of these, causing serious damage to the patient. The treatment of these pathologies is elaborated through the definitive diagnosis, which usually relies on the accomplishment of complementary exams, especially

Imaging methods are essential in the diagnosis of bone and joint changes. Among the auxiliary examinations currently used to evaluate the joints, the noninvasive ones are the first ones of choice, where radiography, ultrasonography, magnetic resonance imaging, computed tomography, and arthroscopy are inserted. Usually, the evaluation begins with the radiological examination, capable of providing essential information about the bony and articular cartilaginous structures. The imaging tests are used to evaluate the integrity of the articular components and the relationship between them, confirm the extent or stage of disease progression, and evaluate

maintenance of its integrity, which at times may subject it to ruptures [29].

[5, 31].

compose them [31].

86 Cartilage Repair and Regeneration

the imaging [57].

**4. Diagnostic methods in articulation**

the effects of the treatments performed [57].

Radiography is the most common imaging technique, based on imaging by X-ray transmission over a target tissue. The rays that go beyond the body reach a film, sensitizing it. After the revelation, the rays that are absorbed in the body do not sensitize the film, and the corresponding areas will be white (radiopaque). On the other hand, the sensitized areas make the regions in the film black (radiolucent). In the analysis of the film, a variation of shades from white to black denominated radiological density is observed. The contrast between the light and dark areas in the radiography depends on the technical and physical conditions in the capture of the images [10].

Like other techniques that expose the body to radiation, X-rays are harmful, requiring the adoption of procedures aimed at protecting exposed professionals and patients. The damage caused by ionizing radiation is cumulative, which means that the harm is caused by repeated doses of radiation that accumulate in the tissues. In order to minimize these risks, collimators, radiation dosage control, plumb protection, screens, and individual monitors (dosimeter) are used for professionals who deal daily with this type of examination [22].

After the technical adjustments and taking into account the biosafety tools, the region to be analyzed in the radiography must be properly positioned so that favorable images are acquired for its evaluation. Thus, it is fundamental that incidences are made in different positions, determining opposite and/or complementary planes [6].

In the attempt to improve differentiation between structures of similar density, such as those found in the abdomen, contrast media are used which may be either natural (air) or artificial (barium based and iodine based). These solutions are mainly used in the study of digestive, urinary, biliary, vascular, and joint studies [10].

Radiography is an important diagnostic method for the study of joint changes. However, fractures in rigid structures, neoplasias, growth and posture disorders, traumatic and inflammatory changes, deposition of substances, and problems of calcification, among others, can be diagnosed. It has a high interest in the evaluation of the progression of rheumatic diseases and in the diagnosis of their complications. The radiographic changes found will vary according to the type of lesion and the time of evolution, keeping the clinician informed about the severity of the condition [24].

The radiographic analysis of the joints should take into account the joint space, its dimensions, and regularities. The thickness of the joint space consists of the joint dimension of the cartilages of both bone structures. Any interference in this space can be represented in the radiographic image and indicate inflammatory changes as in the cases of arthritis. The space may be diminished in the case of advanced arthropathies, which may be asymmetric or localized, depending on the pathology, or it may occur that a loss of space is generalized [65].

Synovium, synovial fluid, and articular capsule, because they have the same radiodensity as adjacent soft tissues and cartilage, are only seen if they are contoured by a radiant layer. For this reason, it is often necessary to complement the simple X-ray with the use of articular contrast media, known as arthrography (**Figure 2**) [10, 48].

The arthrography corresponds to the contrasted representation of the joint space, and the viability of using the technique with a positive (iodized) contrast is injected directly into the joint. Unlike the simple radiography, the arthrography should be performed with the patient in sedation due to the discomfort in the application of the contrasts. This technique is performed to demonstrate and assess arthropathies and associated soft tissue structures [36, 65]. There are indications of arthrography when there is suspicion of soft tissue ruptures present in the joint space, which are not adequately visualized in the simple radiography, due to the minimal differentiation of radiological density. However, many contrasts may trigger undesirable reactions, so this technique is infeasible in case of patients allergic to contrast or

Macroscopic Anatomy, Histopathology, and Image Diagnosis of Joints and Synovial Cartilages

http://dx.doi.org/10.5772/intechopen.70374

89

Currently, double-contrast arthrography in the joints has been used in humans both in radiology and associated to computed tomography, in order to identify lesions on joint surfaces and in nonbone structures, which has shown great advantages when compared to arthrography

Ultrasonography presents as a consolidated and sensitive examination for the observation of periarticular soft tissue alterations of the articular surfaces, besides being able to diagnose the morphological changes promoted by various arthropathies early [60]. This is due, in large part, to the improvement in the image quality of the equipment, due to the improvement of the imaging technology and the manufacture of transducers with increasing resolution, in

This technique presents some advantages compared to the radiography because it is a noninvasive examination, able to detect early changes, besides providing details of the tissue parenchyma and evidencing structures that do not appreciate the radiographic examination [21].

Such information can be seen by means of the changes that occur in the synovial membrane, joint capsule, as well as periarticular volume increase. This technique allows direct visualization of the joint space, besides being able to guide needles in real time, in cases of treatments with intra-articular drug infusions. Furthermore, it can guide treatments according to signs of inflammation and allows the visualization of the appropriate distribution of medication

In general, it is not necessary to pre-prepare the patient for ultrasonographic joint examination, only the application of a thick layer of acoustic gel between the transducer and the ultra-

Lately, ultrasound examination has been gaining space as a complementary diagnostic method in the therapeutic follow-up of several joint diseases such as rheumatoid arthritis, synovitis, bone erosions, mainly psoriatic arthritis, and systemic lupus erythematosus. The great advantage of the sonographic study is its ability to detect changes such as synoves and bone erosion early on radiography, which has been increasingly valued in the prevention of

addition to the relative decrease in the price of the equipment (**Figure 2**) [21].

sound window to reduce the interference of the layer of air on the skin [21].

solutions used in sedation [10].

with positive contrast medium [50].

**4.2. Ultrasonography**

within the joint space [7, 58].

late and definitive structural damage [3].

**Figure 2.** Radiographic and ultrasound imaging of a normal equine knee joint. (A) Note the smooth surface of the joint (femoral head and tibial plateau), with the discreet presence of the patellar ligament (b), due to the high incidence of X-ray bundles. (B and C) The normal ultrasonographic pattern of the patellar ligament, showing homogeneous echotexture and habitual echogenicity. Note the parallel arrangement of the tendon fibers and the normal hyperechogenic appearance of the infrapatellar fat pad (\*). (D) Proximal insertion of the patellar tendon (h). (a) Patella, (b) patellar ligament, (c) joint space, (d) fibula, (e and f) patellar ligament echotexture, (g) infrapatellar fat pad, (h) proximal insertion of the patellar tendon, and (i) joint space. (Image gentile provided by the Diagnostic Imaging Services, Federal University of Piauí, Teresina, Brazil).

The arthrography corresponds to the contrasted representation of the joint space, and the viability of using the technique with a positive (iodized) contrast is injected directly into the joint. Unlike the simple radiography, the arthrography should be performed with the patient in sedation due to the discomfort in the application of the contrasts. This technique is performed to demonstrate and assess arthropathies and associated soft tissue structures [36, 65].

There are indications of arthrography when there is suspicion of soft tissue ruptures present in the joint space, which are not adequately visualized in the simple radiography, due to the minimal differentiation of radiological density. However, many contrasts may trigger undesirable reactions, so this technique is infeasible in case of patients allergic to contrast or solutions used in sedation [10].

Currently, double-contrast arthrography in the joints has been used in humans both in radiology and associated to computed tomography, in order to identify lesions on joint surfaces and in nonbone structures, which has shown great advantages when compared to arthrography with positive contrast medium [50].

## **4.2. Ultrasonography**

**Figure 2.** Radiographic and ultrasound imaging of a normal equine knee joint. (A) Note the smooth surface of the joint (femoral head and tibial plateau), with the discreet presence of the patellar ligament (b), due to the high incidence of X-ray bundles. (B and C) The normal ultrasonographic pattern of the patellar ligament, showing homogeneous echotexture and habitual echogenicity. Note the parallel arrangement of the tendon fibers and the normal hyperechogenic appearance of the infrapatellar fat pad (\*). (D) Proximal insertion of the patellar tendon (h). (a) Patella, (b) patellar ligament, (c) joint space, (d) fibula, (e and f) patellar ligament echotexture, (g) infrapatellar fat pad, (h) proximal insertion of the patellar tendon, and (i) joint space. (Image gentile provided by the Diagnostic Imaging Services, Federal University of Piauí,

Teresina, Brazil).

88 Cartilage Repair and Regeneration

Ultrasonography presents as a consolidated and sensitive examination for the observation of periarticular soft tissue alterations of the articular surfaces, besides being able to diagnose the morphological changes promoted by various arthropathies early [60]. This is due, in large part, to the improvement in the image quality of the equipment, due to the improvement of the imaging technology and the manufacture of transducers with increasing resolution, in addition to the relative decrease in the price of the equipment (**Figure 2**) [21].

This technique presents some advantages compared to the radiography because it is a noninvasive examination, able to detect early changes, besides providing details of the tissue parenchyma and evidencing structures that do not appreciate the radiographic examination [21].

Such information can be seen by means of the changes that occur in the synovial membrane, joint capsule, as well as periarticular volume increase. This technique allows direct visualization of the joint space, besides being able to guide needles in real time, in cases of treatments with intra-articular drug infusions. Furthermore, it can guide treatments according to signs of inflammation and allows the visualization of the appropriate distribution of medication within the joint space [7, 58].

In general, it is not necessary to pre-prepare the patient for ultrasonographic joint examination, only the application of a thick layer of acoustic gel between the transducer and the ultrasound window to reduce the interference of the layer of air on the skin [21].

Lately, ultrasound examination has been gaining space as a complementary diagnostic method in the therapeutic follow-up of several joint diseases such as rheumatoid arthritis, synovitis, bone erosions, mainly psoriatic arthritis, and systemic lupus erythematosus. The great advantage of the sonographic study is its ability to detect changes such as synoves and bone erosion early on radiography, which has been increasingly valued in the prevention of late and definitive structural damage [3].

Depending on the frequency used in the transducers, it is possible to evaluate most joints by means of ultrasonography. With it, one can investigate structures such as tendons, brackets, cartilage, and bone surface, making it possible to search for erosions in inflammatory diseases in general. The possibility of evaluating numerous structures in a single study extends its application in several rheumatologic pathologies, such as rheumatoid arthritis, spondylarthritis, arthritis by microcrystals, osteoarthritis, collagenosis, and systemic vasculitis. The use of ultrasound is effective for the determination of the presence or absence of lesions in tendons and should be considered as a first line of diagnostic tool [25].

With the development of this technique, associated with the discovery of predisposing factors to various arthropathies, restoration of function through minimally invasive procedures, essentially eliminating lesions and helping patients return to normal activities, was even more

Macroscopic Anatomy, Histopathology, and Image Diagnosis of Joints and Synovial Cartilages

http://dx.doi.org/10.5772/intechopen.70374

91

Arthroscopy is indicated for the diagnosis of joint affections, for the follow-up of treatments and evolution of diseases and in cases of intra-articular alterations not diagnosed by conventional imaging techniques. Arthroscopy of hip-like joints offers minimally invasive surgery for procedures that would require hip dislocation, a more complicated technique. In this joint, the most commonly treated pathologies are femoroacetabular impacts, which are closely associated with demanding activities in hip flexion and internal rotation, common in

Diagnostic indications involve the evaluation of cartilage in osteonecrosis or in conjunction with osteotomies and painful arthroplasties and the collection of tissues for culture. Moreover, synovial diseases such as chondromatosis, pigmented villonodular synovitis, and rheumatoid arthritis are a good indication for this procedure, as well as the treatment of deep gluteal pain [9].

New indications for arthroscopy are being tested, such as round ligament reconstruction, capsulorrhaphy in cases of instability, and repair of tendinous lesions. It is not recommended, however, in cases where there is an infectious process installed in the joint or active skin infections, except when this procedure has the objective of draining secretions resulting from

In general, the preparation for the arthroscopy exam is similar to any other surgical procedure. The physician should have all clinical data on the patient as well as information on hypersensitivity reactions to any medication, including anesthetics, the use of medications, associated health problems, vascular problem such as thrombosis or bleeding, and the possibility of gestation. In addition, general and specific preoperative examinations should be

The procedure is performed with the anesthetized patient, which will depend on the structure to be manipulated, ranging from epidural or spinal anesthesia, for procedures in the pelvic limbs, to general anesthesia for shoulder or hip interventions. Sedative drugs are usually given, and the patient sleeps during the examination, however, can be performed with the patient awake. The patient remains monitored by the anesthesiologist until the end of the procedure, being evaluated the parameters such as heart rate, blood pressure, respiration, body

For the realization of the technique, two small accesses are realized in the articulation: the first one where the arthroscope will be introduced and the second to direct the necessary instruments for the operation, if necessary. In general, a certain amount of saline is inserted into the joint so that it is inflated and becomes clearer, thus allowing a better visualization. Also, tourniquets can be performed to temporarily reduce blood flow, which could hamper visualization. Thus, therapeutic procedures such as removal, reconstruction or repair of menisci or ligaments, removal of loose bone fragments, or cartilage within a joint or inflamed synovial tissue are possible [14].

sports such as golf, baseball, ice hockey, and soccer [7, 18, 43, 54].

septic arthritis or evaluation of the degree of infection in prostheses [9].

temperature, and cardiac electrical activity, among others [14].

performed for a safer procedure [14].

safe and effective [18].

In articulations, ultrasonography is used to evaluate the response to treatment, aiming to reduce the degree of synovitis by examining gray scales and/or synovial vascularization using the Doppler technique in its various modalities. Several ultrasonographic degrees of synovial involvement are proposed in the literature, which have as main objective the detection of possible alteration of the inflammatory activity, analyzing the smallest number of joints possible, to reduce the time of the exam execution [4].

Ultrasonography has a good correlation with magnetic resonance imaging (MRI) in the detection of synovitis and erosions. However, although MRI is considered the gold standard for detection of joint changes, this examination is often uncomfortable for patients besides being contraindicated in the holders of metallic prostheses due to the possibility of physical damages. Also, it is a time-consuming, expensive exam that requires the use of a contrast medium, making evaluation of many joints in a single moment impossible. Thus, ultrasound has assumed an important advantage as a highly feasible method in the diagnostic and sequential treatment of patients with various arthropathies. This can be done more frequently, allowing the evaluation of the progress of the treatment and allowing real-time and dynamic analysis, with the joint in motion.

Recent studies with ultrasound of the ankle joint in patients with Chikungunya, despite the limitations of this study, have made possible the characterization and quantification of the sonographic alterations related to this disease, highlighting the role that the method plays in the diagnosis of such complications. The predominant findings in this study were effusion and tenosynovitis, mainly fibular and posterior tibial, and the most common musculoskeletal comorbidity was the involvement of the calcaneus tendon [44].

## **4.3. Arthroscopy**

Although arthroscopy is a surgical procedure, it is a minimally invasive technique, with a relatively fast execution and good postsurgical recovery, allowing the observation of the interior of a joint through the use of a device called an arthroscope. The arthroscope is an endoscope-like apparatus, consisting of a thin rigid cylindrical tube, the thickness of a pencil, containing a microcamera coupled to the end, carrying optical fibers, which transmit images to a TV monitor, allowing the visualization of the inner face of the joint. The evaluation of the articular surface through arthroscopy solves the limitations of the traditional methods of the examinations like the radiography and ultrasonography, allowing the precise diagnosis of articular alterations [9].

With the development of this technique, associated with the discovery of predisposing factors to various arthropathies, restoration of function through minimally invasive procedures, essentially eliminating lesions and helping patients return to normal activities, was even more safe and effective [18].

Depending on the frequency used in the transducers, it is possible to evaluate most joints by means of ultrasonography. With it, one can investigate structures such as tendons, brackets, cartilage, and bone surface, making it possible to search for erosions in inflammatory diseases in general. The possibility of evaluating numerous structures in a single study extends its application in several rheumatologic pathologies, such as rheumatoid arthritis, spondylarthritis, arthritis by microcrystals, osteoarthritis, collagenosis, and systemic vasculitis. The use of ultrasound is effective for the determination of the presence or absence of lesions in ten-

In articulations, ultrasonography is used to evaluate the response to treatment, aiming to reduce the degree of synovitis by examining gray scales and/or synovial vascularization using the Doppler technique in its various modalities. Several ultrasonographic degrees of synovial involvement are proposed in the literature, which have as main objective the detection of possible alteration of the inflammatory activity, analyzing the smallest number of joints possible,

Ultrasonography has a good correlation with magnetic resonance imaging (MRI) in the detection of synovitis and erosions. However, although MRI is considered the gold standard for detection of joint changes, this examination is often uncomfortable for patients besides being contraindicated in the holders of metallic prostheses due to the possibility of physical damages. Also, it is a time-consuming, expensive exam that requires the use of a contrast medium, making evaluation of many joints in a single moment impossible. Thus, ultrasound has assumed an important advantage as a highly feasible method in the diagnostic and sequential treatment of patients with various arthropathies. This can be done more frequently, allowing the evaluation of the progress of the treatment and allowing real-time and dynamic analysis,

Recent studies with ultrasound of the ankle joint in patients with Chikungunya, despite the limitations of this study, have made possible the characterization and quantification of the sonographic alterations related to this disease, highlighting the role that the method plays in the diagnosis of such complications. The predominant findings in this study were effusion and tenosynovitis, mainly fibular and posterior tibial, and the most common musculoskeletal

Although arthroscopy is a surgical procedure, it is a minimally invasive technique, with a relatively fast execution and good postsurgical recovery, allowing the observation of the interior of a joint through the use of a device called an arthroscope. The arthroscope is an endoscope-like apparatus, consisting of a thin rigid cylindrical tube, the thickness of a pencil, containing a microcamera coupled to the end, carrying optical fibers, which transmit images to a TV monitor, allowing the visualization of the inner face of the joint. The evaluation of the articular surface through arthroscopy solves the limitations of the traditional methods of the examinations like the radiography and ultrasonography, allowing the precise diagnosis of

dons and should be considered as a first line of diagnostic tool [25].

comorbidity was the involvement of the calcaneus tendon [44].

to reduce the time of the exam execution [4].

with the joint in motion.

90 Cartilage Repair and Regeneration

**4.3. Arthroscopy**

articular alterations [9].

Arthroscopy is indicated for the diagnosis of joint affections, for the follow-up of treatments and evolution of diseases and in cases of intra-articular alterations not diagnosed by conventional imaging techniques. Arthroscopy of hip-like joints offers minimally invasive surgery for procedures that would require hip dislocation, a more complicated technique. In this joint, the most commonly treated pathologies are femoroacetabular impacts, which are closely associated with demanding activities in hip flexion and internal rotation, common in sports such as golf, baseball, ice hockey, and soccer [7, 18, 43, 54].

Diagnostic indications involve the evaluation of cartilage in osteonecrosis or in conjunction with osteotomies and painful arthroplasties and the collection of tissues for culture. Moreover, synovial diseases such as chondromatosis, pigmented villonodular synovitis, and rheumatoid arthritis are a good indication for this procedure, as well as the treatment of deep gluteal pain [9].

New indications for arthroscopy are being tested, such as round ligament reconstruction, capsulorrhaphy in cases of instability, and repair of tendinous lesions. It is not recommended, however, in cases where there is an infectious process installed in the joint or active skin infections, except when this procedure has the objective of draining secretions resulting from septic arthritis or evaluation of the degree of infection in prostheses [9].

In general, the preparation for the arthroscopy exam is similar to any other surgical procedure. The physician should have all clinical data on the patient as well as information on hypersensitivity reactions to any medication, including anesthetics, the use of medications, associated health problems, vascular problem such as thrombosis or bleeding, and the possibility of gestation. In addition, general and specific preoperative examinations should be performed for a safer procedure [14].

The procedure is performed with the anesthetized patient, which will depend on the structure to be manipulated, ranging from epidural or spinal anesthesia, for procedures in the pelvic limbs, to general anesthesia for shoulder or hip interventions. Sedative drugs are usually given, and the patient sleeps during the examination, however, can be performed with the patient awake. The patient remains monitored by the anesthesiologist until the end of the procedure, being evaluated the parameters such as heart rate, blood pressure, respiration, body temperature, and cardiac electrical activity, among others [14].

For the realization of the technique, two small accesses are realized in the articulation: the first one where the arthroscope will be introduced and the second to direct the necessary instruments for the operation, if necessary. In general, a certain amount of saline is inserted into the joint so that it is inflated and becomes clearer, thus allowing a better visualization. Also, tourniquets can be performed to temporarily reduce blood flow, which could hamper visualization. Thus, therapeutic procedures such as removal, reconstruction or repair of menisci or ligaments, removal of loose bone fragments, or cartilage within a joint or inflamed synovial tissue are possible [14].

Studies with high-performance soccer athletes have shown that hip arthroscopy for the assessment of pathologies of this joint, such as the femoral acetabular impact (FAI), has been shown to be a safe procedure with satisfactory results regarding the return of the athlete to sporty activities. Hip arthroscopy in athletes with symptomatic FAI and labral pathology allowed for complete rehabilitation, earlier than those undergoing open surgery.

the absence or low density of mobile protons in the tissue, there will be a zero or very small

Macroscopic Anatomy, Histopathology, and Image Diagnosis of Joints and Synovial Cartilages

http://dx.doi.org/10.5772/intechopen.70374

93

All soft bodies can be seen in MRI; however, the cortical bone and air do not produce signal in the images because of the inability of the protons to relax in the dense bone matrix and the relative lack of hydrogen nuclei in the air. Thus, due to the low density of mobile protons, the lenses do not show any signal in any sequence used. All other structures are visible in varying degrees from gray to white because of variations in signal strength. This differentiation between proton densities in tissues defines, in medical terms, the occurrence of tissue changes, as it increases the difference between a lesion and a surrounding

In general, MR imaging is based on the relationship between the equipment and the living tissue so that the patient's atomic nuclei align along the applied magnetic field, generating a magnetization vector. Subsequently, sequential magnetic field gradients are applied to the spatial location of the signals to be acquired; thus, the excitation pulses are applied, and the nuclei absorb energy. After the excitation pulses are applied, the relaxation phenomena begin, and the nuclei begin to induce the MRI signal in the receiver coils. This signal is acquired and processed by means of the transformed Fourier, where the image is formed point to point in

However, for the execution of the examination, the anatomical and clinical prior knowledge of the radiologist technician is still necessary. In the sequence, it is of great value to obtain the best images, as well as to minimize artifacts of techniques. Choosing the appropriate coil for the study region that provides a better signal for exam quality and proper patient positioning

According to the indication, specific protocols are established for the region to be examined and can be divided into the regions: central nervous system, thorax, abdomen, pelvis, and musculoskeletal system. In general, it is indicated that the patient is placed in dorsal decubitus with the head resting on the appropriate coil (quadrature) with the region of interest straight and in the center of the magnet, upper limbs extended on the side of the body and support for the legs in order to promote alignment of column cur-

In order to evaluate joints, magnetic resonance imaging becomes an excellent diagnostic modality, since it allows identification of not only bone and cartilage structures but also soft tissues such as meniscus, ligaments, cortical and medullary bone compartment, muscles, tendons, and

It is believed that the greatest advantage of this technique for joint evaluation is the detection of the disease by the investigation of alterations in the articular components, such as the thickening and enhancement of the synovial membrane, a situation found in rheumatoid arthritis and easily demonstrated by the intravenous injection of paramagnetic contrast (gadolinium). In addition, MRI stands out as a noninvasive method, useful as a complement to clinical

value capable of overriding the evaluation parameters at resonance [27, 42].

tissue [27, 42].

a matrix [2].

vatures [2].

fat (**Figure 3**) [33].

are imperative items in the MRI [23].

Hip arthroscopy is a safe treatment method for a majority of hip pathologies that were unknown until the last decade. The instruments and surgical technique of hip arthroscopy continue to evolve. Better and better results and fewer complications should be expected according to the learning curve.

## **4.4. Magnetic resonance imaging**

Discovered in 1946 by researchers at Stanford University, magnetic resonance imaging (MRI) has been implanted in medicine by Purcell at Harvard years later. In medicine, the first images were obtained from 1972 and advances provided by the application of the technique provided the nomination of Paul Lauterbur and Peter Mansfield to the Nobel Prize of Medicine. In Brazil, the technique was first implanted in the Albert Einstein Hospital of São Paulo in 1986 [27].

MRI is a diagnostic imaging method that uses a magnetic field and radiofrequency waves to obtain images of the interior of the objects in the form of tomes or cuts, without the availability of ionizing radiation. For this, it is necessary to understand physical principles related to the acquisition of images, among them, subjects about electromagnetism, superconductivity, and signal processing [19, 27]. In the clinical setting, MRI aims to complement the diagnostic conclusion given by conventional imaging tests [42].

The formation of the MR image is the result of the interaction of the strong magnetic field produced by the equipment with the hydrogen protons of the living tissue, formulating a condition so that a pulse of radiofrequency can be sent and after collecting the differentiated radiofrequency through a receiving instrument. The signal encoded due to a magnetic field gradient is collected, processed, and converted into an image or information [42].

Hydrogen is the chemical element with the highest concentration in the tissues and with the greatest magnetic moment (the capacity to produce the highest radio signal of all the stable nuclei). Therefore, it is used as the signal source in most magnetic resonance imaging tests. Once a tissue is subjected to a magnetic field and left long enough, the tissue magnetization (name given to the process of interaction of the equipment with the hydrogen protons of the tissue) reaches an equilibrium value that is proportional in intensity to the external magnetic field [45].

Some organs produce a stronger or weaker signal than others, going according to the density of hydrogen present in that tissue, for example, adipose tissue, cerebrospinal fluid, blood, and other body fluids that produce a strong signal due to high density of protons. In contrast, in the absence or low density of mobile protons in the tissue, there will be a zero or very small value capable of overriding the evaluation parameters at resonance [27, 42].

Studies with high-performance soccer athletes have shown that hip arthroscopy for the assessment of pathologies of this joint, such as the femoral acetabular impact (FAI), has been shown to be a safe procedure with satisfactory results regarding the return of the athlete to sporty activities. Hip arthroscopy in athletes with symptomatic FAI and labral pathology allowed for complete rehabilitation, earlier than those undergoing open

Hip arthroscopy is a safe treatment method for a majority of hip pathologies that were unknown until the last decade. The instruments and surgical technique of hip arthroscopy continue to evolve. Better and better results and fewer complications should be expected according to the

Discovered in 1946 by researchers at Stanford University, magnetic resonance imaging (MRI) has been implanted in medicine by Purcell at Harvard years later. In medicine, the first images were obtained from 1972 and advances provided by the application of the technique provided the nomination of Paul Lauterbur and Peter Mansfield to the Nobel Prize of Medicine. In Brazil, the technique was first implanted in the Albert Einstein Hospital of São Paulo in 1986 [27].

MRI is a diagnostic imaging method that uses a magnetic field and radiofrequency waves to obtain images of the interior of the objects in the form of tomes or cuts, without the availability of ionizing radiation. For this, it is necessary to understand physical principles related to the acquisition of images, among them, subjects about electromagnetism, superconductivity, and signal processing [19, 27]. In the clinical setting, MRI aims to complement the diagnostic

The formation of the MR image is the result of the interaction of the strong magnetic field produced by the equipment with the hydrogen protons of the living tissue, formulating a condition so that a pulse of radiofrequency can be sent and after collecting the differentiated radiofrequency through a receiving instrument. The signal encoded due to a magnetic field

Hydrogen is the chemical element with the highest concentration in the tissues and with the greatest magnetic moment (the capacity to produce the highest radio signal of all the stable nuclei). Therefore, it is used as the signal source in most magnetic resonance imaging tests. Once a tissue is subjected to a magnetic field and left long enough, the tissue magnetization (name given to the process of interaction of the equipment with the hydrogen protons of the tissue) reaches an equilibrium value that is proportional in intensity to the external magnetic

Some organs produce a stronger or weaker signal than others, going according to the density of hydrogen present in that tissue, for example, adipose tissue, cerebrospinal fluid, blood, and other body fluids that produce a strong signal due to high density of protons. In contrast, in

gradient is collected, processed, and converted into an image or information [42].

surgery.

learning curve.

92 Cartilage Repair and Regeneration

field [45].

**4.4. Magnetic resonance imaging**

conclusion given by conventional imaging tests [42].

All soft bodies can be seen in MRI; however, the cortical bone and air do not produce signal in the images because of the inability of the protons to relax in the dense bone matrix and the relative lack of hydrogen nuclei in the air. Thus, due to the low density of mobile protons, the lenses do not show any signal in any sequence used. All other structures are visible in varying degrees from gray to white because of variations in signal strength. This differentiation between proton densities in tissues defines, in medical terms, the occurrence of tissue changes, as it increases the difference between a lesion and a surrounding tissue [27, 42].

In general, MR imaging is based on the relationship between the equipment and the living tissue so that the patient's atomic nuclei align along the applied magnetic field, generating a magnetization vector. Subsequently, sequential magnetic field gradients are applied to the spatial location of the signals to be acquired; thus, the excitation pulses are applied, and the nuclei absorb energy. After the excitation pulses are applied, the relaxation phenomena begin, and the nuclei begin to induce the MRI signal in the receiver coils. This signal is acquired and processed by means of the transformed Fourier, where the image is formed point to point in a matrix [2].

However, for the execution of the examination, the anatomical and clinical prior knowledge of the radiologist technician is still necessary. In the sequence, it is of great value to obtain the best images, as well as to minimize artifacts of techniques. Choosing the appropriate coil for the study region that provides a better signal for exam quality and proper patient positioning are imperative items in the MRI [23].

According to the indication, specific protocols are established for the region to be examined and can be divided into the regions: central nervous system, thorax, abdomen, pelvis, and musculoskeletal system. In general, it is indicated that the patient is placed in dorsal decubitus with the head resting on the appropriate coil (quadrature) with the region of interest straight and in the center of the magnet, upper limbs extended on the side of the body and support for the legs in order to promote alignment of column curvatures [2].

In order to evaluate joints, magnetic resonance imaging becomes an excellent diagnostic modality, since it allows identification of not only bone and cartilage structures but also soft tissues such as meniscus, ligaments, cortical and medullary bone compartment, muscles, tendons, and fat (**Figure 3**) [33].

It is believed that the greatest advantage of this technique for joint evaluation is the detection of the disease by the investigation of alterations in the articular components, such as the thickening and enhancement of the synovial membrane, a situation found in rheumatoid arthritis and easily demonstrated by the intravenous injection of paramagnetic contrast (gadolinium). In addition, MRI stands out as a noninvasive method, useful as a complement to clinical

**Figure 3.** (A–C) Magnetic resonance of a normal canine shoulder joint. (j) Subscapularis tendon, (l) joint space, (m) greater tubercle, (n) biceps tendon, (o) humeral head, (p) supraspinatus tendon, (q and r) cranial joint space, (s) cartilage surface, (t) subchondral bone, and (u) caudal joint space (image gentile provided by Professor Robson Giglio, Department of Small Animal Clinical Sciences, College of Veterinary Medicine, University of Florida).

**Figure 4.** (A–C) Magnetic resonance of a normal canine knee joint. (v) Patellar ligament, (x) cranial cruciate ligament, (y and z) meniscus, joint surface (arrowhead), and (\*) cranial cruciate ligament (image gentile provided by Professor Robson Giglio, Department of Small Animal Clinical Sciences, College of Veterinary Medicine, University of Florida).

Macroscopic Anatomy, Histopathology, and Image Diagnosis of Joints and Synovial Cartilages

http://dx.doi.org/10.5772/intechopen.70374

95

**Figure 5.** (A and B) Magnetic resonance of a normal canine shoulder joint *versus* osteoarthrosis. (z) Biceps tendon and (\*) osteophyte. Note the reduction of joint space and discrete synovial edema, associated with irregularity of articular cartilage (image gentile provided by Professor Robson Giglio, Department of Small Animal Clinical Sciences, College of

Veterinary Medicine, University of Florida).

joint assessment, not only for detection of early disease changes but also for its evolutionary control, treatment monitoring, and differential diagnosis with other diseases (**Figure 4**) [27].

In addition, MRI allows measurement of the extent of joint and extra-articular involvement and evaluation of complications due to disease time, with a higher sensitivity for the evaluation of tendon and ligament injuries, involvement of the tendon sheath (tenosynovitis), trochanteric pouch, bone lesions (subchondral erosions, cysts) that initially may not be seen by conventional radiography, changes in bone marrow, chondral lesions, and in the differentiation between joint effusion and synovitis, using paramagnetic contrast that does not pose risks to the patient (**Figure 5**) [42].

However, in spite of the high cost and its limitations for its execution, magnetic resonance imaging in general still constitutes the best imaging method for joint evaluation, standing out for the other examinations due to its advantages of noninvasiveness, the absence of ionizing radiation, not the use of iodinated contrast (potentially nephrotoxic and allergenic), and ability to better anatomical detail, both by the multiplanar nature of acquisition and by the high contrast between different body tissues [27].

Macroscopic Anatomy, Histopathology, and Image Diagnosis of Joints and Synovial Cartilages http://dx.doi.org/10.5772/intechopen.70374 95

**Figure 4.** (A–C) Magnetic resonance of a normal canine knee joint. (v) Patellar ligament, (x) cranial cruciate ligament, (y and z) meniscus, joint surface (arrowhead), and (\*) cranial cruciate ligament (image gentile provided by Professor Robson Giglio, Department of Small Animal Clinical Sciences, College of Veterinary Medicine, University of Florida).

**Figure 3.** (A–C) Magnetic resonance of a normal canine shoulder joint. (j) Subscapularis tendon, (l) joint space, (m) greater tubercle, (n) biceps tendon, (o) humeral head, (p) supraspinatus tendon, (q and r) cranial joint space, (s) cartilage surface, (t) subchondral bone, and (u) caudal joint space (image gentile provided by Professor Robson Giglio, Department of

joint assessment, not only for detection of early disease changes but also for its evolutionary control, treatment monitoring, and differential diagnosis with other diseases (**Figure 4**) [27]. In addition, MRI allows measurement of the extent of joint and extra-articular involvement and evaluation of complications due to disease time, with a higher sensitivity for the evaluation of tendon and ligament injuries, involvement of the tendon sheath (tenosynovitis), trochanteric pouch, bone lesions (subchondral erosions, cysts) that initially may not be seen by conventional radiography, changes in bone marrow, chondral lesions, and in the differentiation between joint effusion and synovitis, using paramagnetic contrast that does not pose risks to the patient (**Figure 5**) [42].

However, in spite of the high cost and its limitations for its execution, magnetic resonance imaging in general still constitutes the best imaging method for joint evaluation, standing out for the other examinations due to its advantages of noninvasiveness, the absence of ionizing radiation, not the use of iodinated contrast (potentially nephrotoxic and allergenic), and ability to better anatomical detail, both by the multiplanar nature of acquisition and by the high

Small Animal Clinical Sciences, College of Veterinary Medicine, University of Florida).

contrast between different body tissues [27].

94 Cartilage Repair and Regeneration

**Figure 5.** (A and B) Magnetic resonance of a normal canine shoulder joint *versus* osteoarthrosis. (z) Biceps tendon and (\*) osteophyte. Note the reduction of joint space and discrete synovial edema, associated with irregularity of articular cartilage (image gentile provided by Professor Robson Giglio, Department of Small Animal Clinical Sciences, College of Veterinary Medicine, University of Florida).

## **5. Conclusion**

Advances in technologies related to research on the diagnosis and treatment of joint diseases have demonstrated excellent results, contributing to the quality of life of patients affected and their return to daily activities. The improvement in the quality of the imaging equipment, combined with the various works in the area of rheumatology, has contributed to a better clinical management of patients, allowing a more conclusive diagnosis and, consequently, the implementation of effective treatments.

[2] Amaro Junior E, Yamashita H. Aspectos básicos de tomografia computadorizada e ressonância magnética. Revista Brasileira de Psiquiatria. 2001;**23**:2-3. DOI: 10.1590/

Macroscopic Anatomy, Histopathology, and Image Diagnosis of Joints and Synovial Cartilages

http://dx.doi.org/10.5772/intechopen.70374

97

[3] Arend CF. Ultrassonografia em portadores de artrite reumatoide: o que o reumatologista clínico deve saber. Revista Brasileira de Reumatologia. 2013;**53**(1):1-6. DOI: 10.1590/

[4] Backhaus M, Burmester GR, Sandrock D, Loreck D, Hess D, Scholz A, Blind S, Hamm B, Bollow M. Prospective two year follow up study comparing novel and conventional imaging procedures in patients with arthritic finger joints. Annals of the Rheumatic Diseases.

[5] Bari C, Dell'Accio F, Tylzanowski P, Luyten FP. Multipotent mesenchymal stem cells from adult human synovial membrane. Arthritis and Rheumatism. 2001;**8**(44):1928-1942.

[6] Bontrager KL, Lampignano JP. Tratado de posicionamento radiográfico e anatomia

[7] Bruyn G, Schmidt W. How to perform ultrasound-guided injections. Best Practice & Research. Clinical Rheumatology. 2009;**23**(1):269-279. DOI: 10.1016/j.berh.2008.11.001 [8] Buckwalter JA, Mankin HJ, Grodzinsky AJ. Articular cartilage and osteoarthritis. Instructional Course Lectures-American Academy of Orthopaedic Surgeons. 2005;**54**:465.

[9] Byrd JW, Jones KS. Artroscopia de quadril em atletas: seguimento de 10 anos. American Journal of Sports Medicine. 2009;**37**(11):2140-2143. DOI: 10.1590/S0102-36162009000100004

[10] Canevaro L. Aspectos físicos e técnicos da radiologia intervencionista. Revista Brasileira

[11] Caron JP. Osteoarthritis. In: Roos MW, Dyson SJ, editors. Diagnosis and Management of

[12] Carrere MTA. Biomecánica clínica. Biomecánica articular. REDUCA (Enfermería,

[13] Chaimowicz F. A saúde dos idosos brasileiros às vésperas do século XXI: Problemas, projeções e alternativas. Revista de Saúde Pública. 1997;**31**:184-200. DOI: 10.1590/

[14] Chokshi BV, Rosen JE. Diagnostic arthroscopy of the knee. In: Koval KJ, Zuckerman JD. Atlas of Orthopedic Surgery: A Multimedia Reference. Lippincott Williams and

[15] Coimbra IB, Pastor EH, Greve JMD, Puccinelli MLC, Fuller R, Cavalcanti FS, Maciel FMB, Honda E. Osteoartrite (artrose): tratamento. Revista Brasileira de Reumatologia.

Lameses in the Horse. Philadelphia: Saunders Company; 2003. p. 594

2004;**6**(44):450-453. DOI: 10.1590/S0482-50042004000600009

DOI: 10.1002/1529-0131(200108)44:8<1928:AID-ART331>3.0.CO;2-P

S1516-44462001000500002

S0482-50042013000100009

associada. Brasil: Elsevier; 2005

DOI: 10.1007/s11420-011-9250-z

de Física Médica. 2009;**1**(3):101-115

Fisioterapia y Podología). 2010;**3**(2):14-31

S0034-89101997000200014

Wilkins: Philadelphia. 2004. 554 p

2002;**61**(10):895-904. DOI: 10.1136/ard.61.10.895

## **Acknowledgements**

Our thanks go to Professor Robson Giglio of the University of Florida for the granting of illustration images of magnetic resonance. In addition, we thank the Diagnostic Imaging Services of the University Veterinary Hospital of the Federal University of Piauí (UFPI) for the concession of the images of articular ultrasonography.

## **Author details**

Flávio Ribeiro Alves<sup>1</sup> \*, Renan Paraguassu de Sá Rodrigues<sup>1</sup> , Andrezza Braga Soares da Silva<sup>1</sup> , Gerson Tavares Pessoa<sup>2</sup> , Laecio da Silva Moura<sup>1</sup> , Jacyara de Jesus Rosa Pereira Alves<sup>3</sup> , Kássio Vieira Macedo<sup>4</sup> and Robson Giglio<sup>5</sup>

\*Address all correspondence to: flavioribeiro@ufpi.edu.br

1 Department of Morphophysiology, Federal University of Piauí, Teresina, Brazil

2 Veterinary Diagnostic Imaging Residency, Veterinary Hospital, Federal University of Piauí, Teresina, Brazil

3 Coloproctology and Colorectal Surgery Service of the University Hospital, Federal University of Piauí, Teresina, Piauí, Brazil

4 Postgraduate Dentistry, Federal University of Piauí, Teresina, Brazil

5 Department of Small Animal Clinical Sciences, College of Veterinary Medicine, University of Florida, Gainesville, Florida, USA

## **References**

[1] Albers JM, Paimela L, Kurki P, Eberhardt K, Emery P, Hof M, Avan't Schreuder F, Leirisalorepo M, Van Riel PLCM. Treatment strategy, disease activity, and outcome in four cohorts of patients with early rheumatoid arthritis. Annals of the Rheumatic Diseases. 2001;**60**:453-458

[2] Amaro Junior E, Yamashita H. Aspectos básicos de tomografia computadorizada e ressonância magnética. Revista Brasileira de Psiquiatria. 2001;**23**:2-3. DOI: 10.1590/ S1516-44462001000500002

**5. Conclusion**

96 Cartilage Repair and Regeneration

implementation of effective treatments.

sion of the images of articular ultrasonography.

**Acknowledgements**

**Author details**

Flávio Ribeiro Alves<sup>1</sup>

Gerson Tavares Pessoa<sup>2</sup>

Kássio Vieira Macedo<sup>4</sup>

Piauí, Teresina, Brazil

**References**

University of Piauí, Teresina, Piauí, Brazil

of Florida, Gainesville, Florida, USA

Advances in technologies related to research on the diagnosis and treatment of joint diseases have demonstrated excellent results, contributing to the quality of life of patients affected and their return to daily activities. The improvement in the quality of the imaging equipment, combined with the various works in the area of rheumatology, has contributed to a better clinical management of patients, allowing a more conclusive diagnosis and, consequently, the

Our thanks go to Professor Robson Giglio of the University of Florida for the granting of illustration images of magnetic resonance. In addition, we thank the Diagnostic Imaging Services of the University Veterinary Hospital of the Federal University of Piauí (UFPI) for the conces-

, Andrezza Braga Soares da Silva<sup>1</sup>

, Jacyara de Jesus Rosa Pereira Alves<sup>3</sup>

,

,

\*, Renan Paraguassu de Sá Rodrigues<sup>1</sup>

1 Department of Morphophysiology, Federal University of Piauí, Teresina, Brazil

2 Veterinary Diagnostic Imaging Residency, Veterinary Hospital, Federal University of

3 Coloproctology and Colorectal Surgery Service of the University Hospital, Federal

5 Department of Small Animal Clinical Sciences, College of Veterinary Medicine, University

[1] Albers JM, Paimela L, Kurki P, Eberhardt K, Emery P, Hof M, Avan't Schreuder F, Leirisalorepo M, Van Riel PLCM. Treatment strategy, disease activity, and outcome in four cohorts of patients with early rheumatoid arthritis. Annals of the Rheumatic Diseases. 2001;**60**:453-458

, Laecio da Silva Moura<sup>1</sup>

and Robson Giglio<sup>5</sup>

4 Postgraduate Dentistry, Federal University of Piauí, Teresina, Brazil

\*Address all correspondence to: flavioribeiro@ufpi.edu.br


[16] Cristante AF, Barros-filho TE, Tatsui N, Mendrone A, Caldas JG, Camargo A, Alexandre A, Teixeira WG, Oliveira RP, Marcon RM. Stem cells in the treatment of chronic spinal cord injury: Evaluation of somatosensitive evoked potentials in 39 patients. Spinal Cord. 2009;**47**(10):733-738. DOI: 10.1038/sc.2009.24

[30] Hyc A, Osiecka-Iwan A, Jóźwiak J, Moskalewski S. The morphology and selected biological properties of articular cartilage. Ortopedia, Traumatologia, Rehabilitacja. 2001;**2**(3):151-162

Macroscopic Anatomy, Histopathology, and Image Diagnosis of Joints and Synovial Cartilages

http://dx.doi.org/10.5772/intechopen.70374

99

[31] Junqueira LC, Carneiro J. Tecido cartilaginoso. In: Junqueira LC, Carneiro J. Histologia

[32] Khan IM, Willams R, Redman SN, Archer CW. The development of synovial joints. Current Topics in Developmental Biology. 2007;**79**:1-36. DOI: 10.1002/bdrc.10015

[33] Khanna AJ, Cosgarea AJ, Mont MA, Andres BM, Domb BG, Evans PJ, Bluemke DA, Frassica FJ. Magnetic resonance imaging of the knee. Journal of Bone and Joint Surgery.

[34] Kidd JA, Fuller C, Barr ARS. Osteoarthritis in the horse. Equine Veterinary Education.

[35] Knop PE, Paula LE, Fuller R. Plasma rico em plaquetas no tratamento da osteoartrite.

[36] Laredo FJ, Lederman HM, Ihsida A. Doença de Legg-Calvé-Perthes. I-Técnica da artro-

[37] Loeser RF. The biology of osteoarthritis. In: Annual, Meeting of the American College of Veterinary Pathologistis, Annual Meeting of the American Society for Veterinary Clinical

[38] Lu P, Kadoya K, Tuszynski MH. Axonal growth and connectivity from neural stem cell grafts in models of spinal cord injury. Current Opinion in Neurobiology. 2014;**1**(27):

[40] Mattos F, Leitea N, Pittab A, Bentoa PCB. Effects of aquatic exercise on muscle strength and functional performance of individuals with osteoarthritis: A systematic review. Revista Brasileira de Reumatologia. 2016;**56**(6):530-542. DOI: 10.1016/j.rbre.2016.09.003

[41] May SA. Radiological aspects of degenerative joint disease. Equine Veterinary Education.

[42] Mazzola AA. Ressonância magnética: princípios de formação da imagem e aplicações em imagem funcional. Revista Brasileira de Física Médica. 2009;**1**(3):117-129

[43] McDonald J, Herzog MM, Philippon MJ. Performance outcomes in professional hockey players following arthroscopic treatment of FAI and microfracture of the hip. Knee Surgery, Sports Traumatology, Arthroscopy. 2014;**22**(4):915-919. DOI: 10.1007/s00167-013-2691-9

[44] Mogami R, JLP V, YFB C, Torezani RS, Vieira AA, ACB K, Barbosa YB, Abreu MM.Ultrasound of ankles in the diagnosis of complications of chikungunya fever. Radiologia Brasileira.

[39] Magee DJ. Avaliação Musculoesquelética. 5a ed. São Paulo:Manole; 2010. p. 1228

básica. 9a ed. Rio de Janeiro: Guanabara Koogan; 2008. 135 p

2001;**13**(3):160-168. DOI: 10.1111/j.2042-3292.2001.tb00082.x

Revista Brasileira de Reumatologia. 2016;**56**(2):152-164

grafia. Revista Brasileira de Ortopedia. 1992;**1**(27):3-6

Pathology. Proceedings. v.40: Boston, MA, USA; 2005

1999;**8**(2):140-120. DOI: 10.1111/j.2042-3292.1996.tb01861.x

2017;**50**(2):71-75. DOI: 10.1590/0100-3984.2017.50.2e1

2001;**83**:128-141 PMID: 11712834

103-109

Epub 2016 Oct 4


[30] Hyc A, Osiecka-Iwan A, Jóźwiak J, Moskalewski S. The morphology and selected biological properties of articular cartilage. Ortopedia, Traumatologia, Rehabilitacja. 2001;**2**(3):151-162

[16] Cristante AF, Barros-filho TE, Tatsui N, Mendrone A, Caldas JG, Camargo A, Alexandre A, Teixeira WG, Oliveira RP, Marcon RM. Stem cells in the treatment of chronic spinal cord injury: Evaluation of somatosensitive evoked potentials in 39 patients. Spinal Cord.

[17] Cristante FA, Narazaki DK. Avanços no uso de células-tronco em ortopedia. Revista Brasilira de Ortopedia. 2011;**46**(4):1-8. DOI: 10.1590/S0102-36162011000400003

[18] Domb BG, Dunne KF, Martin TJ, Gui C, Finch NA, Vemula SP, Redmond JM. Patient reported outcomes for patients who returned to sport compared with those who did not after hip arthroscopy: Minimum 2-year follow-up. Journal of Hip Preservation Surgery.

[19] Doyon D, Cabanis EA. Diagnóstico por Imagem em Ressonância Magnética. Rio de

[20] Erbas M, Simsek T, Kiraz HA, Sahin H, Toman H. Comparação da eficácia de tenoxicam administrado por via oral e intra-articular a pacientes com osteoartrite de joelhos. Revista Brasileira de Anestesiologia. 2015;**65**(5):333-337. DOI: 10.1016/j.bjan.2013.12.003

[21] Feliciano MAR, Canola JC, Vicente WRR. Diagnóstico por imagem em cães e gatos. 1st

[22] Fernandes GS, Carvalho ACP, Azevedo ACP. Avaliação dos riscos ocupacionais de trabalhadores de serviços de radiologia. Radiologia Brasileira. 2005;**4**(38):279-281. DOI:

[23] Gattass R, Moll J, Andreiuolo PA, Farias MF, Feitosa PH. Fundamentos da ressonância magnética Funcional. Vol. 13. Cérebro e Mente; 2001 Disponível em:<http://www.epub.

[24] Gonçalves M, Sannomyia EK, Nakazone N, Andréa G. Avaliaçäo de métodos de local-

[25] Grant TH, Kelikian AS, Jereb SE. Diagnóstico por ultra-sonografia das rupturas do tendão peroneo. Uma correlação cirúrgica. Journal of Bone and Joint Surgery (American).

[26] Grundy EMD. The epidemiology of aging. In: Tallis RC, Fillit HW, editors. Brocklehurst's Textbook of Geriatric Medicine and Gerontology. Philadelphia: Elsevier Science Ltd.; 2003.

[27] Hage MC, Ferrarini NS, Iwasaki M. Imagem por ressonância magnética: princípios básicos. Ciência Rural. 2009;**4**(39):1275-1283. DOI: 10.1590/S0103-84782009005000041 [28] Hochberg M, Lixing L, Bansell B, Langenberg P, Berman B. Traditional Chinese acupuncture is effective as adjunctive therapy in patients with osteoarthritis of the knee.

[29] Huber M, Trattnig S, Lintner F. Anatomy, biochemistry, and physiology of articular cartilage. Investigative Radiology. 2000;**10**(35):573-580. DOI: 10.1097/00004424-200010000-00003

izaçäo radiográfica para o clínico geral: Parte I. RFO UPF. 2001;**1**(6):45-51

2009;**47**(10):733-738. DOI: 10.1038/sc.2009.24

2016;**3**(2):124-131. DOI: 10.1093/jhps/hnv078

ed. São Paulo:MedVet; 2015. p. 768

10.1590/S0100-39842005000400009

2005;**87**(8):1788-1794. DOI: 10.2106/JBJS.D.02450

Arthritis Rheumatology. 2004;**50**(1):1-6

Janeiro: Medsi; 2000

98 Cartilage Repair and Regeneration

org.br/cm

p. 3-20


[45] Moonen CT, Van Zijl PC, Frank JA, Le Bihan D, Becker ED. Functional magnetic resonance imaging in medicine and physiology. Science. 1990;**250**(4977):53-61

[59] Schmitz N, Laverty S, Kraus VB, Aigner T. Basic methods in histopathology of joint tissues. Osteoarthritis and Cartilage. 2010;**1**(18):113-116. DOI: 10.1016/j.joca.2010.05.026.

Macroscopic Anatomy, Histopathology, and Image Diagnosis of Joints and Synovial Cartilages

http://dx.doi.org/10.5772/intechopen.70374

101

[60] Siems JJ, Breur GJ, Blevins WE, Cornell KK. Use of two-dimensional realtime ultrasonography for diagnosing contracture and strain of the infraspinatus muscle in a dog. Journal of the American Veterinary Medical Association. 1998;**212**:77-80 PMID:

[61] Sobotta J. Sobotta Atlas de Anatomia Humana. 23th ed. Rio de Janeiro: Guanabara

[62] Sophia FAJ, Bedi A, Rodeo SA. The basic science of articular cartilage: Structure, composition, and function. Sports Health. 2009;**1**(6):461-468. DOI: 10.1177/1941738109350438

[63] Souza ANA, Saladino AO, Biasi C, Matera JM. Uso dos condroprotetores na afecção articular degenerativa: revisão. Revista Acadêmica: Ciências Agrárias e Ambientais.

[64] Standring S. Osteology. Gray's Anatomy; the Anatomical Basis of Clinical Practice. 40th

[65] Thrall DE. Diagnóstico de Radiologia Veterinaria. 6th ed. São Paulo: Elsevier; 2015. p. 848 [66] Tong AC, Tideman H. The microanatomy of the rhesus monkey temporomandibular joint. Journal of Oral and Maxillofacial Surgery. 2001;**59**(1):46-52. DOI: 10.1053/

[67] Werner PR, Susko I, Prantoni GA. Regeneração da cartilagem articular lesada experimentalmente em cães em crescimento. Revista do Centro de Ciências Rurais. 2008;**1**(14):59-72

[68] White TD, Black MT, Folkens PA. Human Osteology. 3th ed. Massachusetts:Academic

[69] Wight TN. Versican: A versatile extracellular matrix proteoglycan in cell biology. Current Opinion in Cell Biology. 2002;**14**(5):617-623. DOI: 10.1016/S0955-0674(02)00375-7

[70] Witter K, Patulova P, Egerbacher M, Paral V. Morphology of the junction between rib bone and rib cartilage-a discussion of the terms "synchondrosis" and "symphysis".

[71] Zhang Z, McCaffery JM, Spencer RGS, Francomano CA. Hyaline cartilage engineered by chondrocytes in pellet culture: Histological, immunohistochemical and ultrastructural analysis in comparison with cartilage explants. Journal of Anatomy. 2004;**205**(3):229-237.

[72] Zhou S, Cui Z, Urban JP. Factors influencing the oxygen concentration gradient from the synovial surface of articular cartilage to the cartilage-bone interface: A modeling study.

Arthritis and Rheumatism. 2004;**50**(12):3915-3924. DOI: 10.1002/art.20675

ed. London: Elsevier Churchill Livingstone; 2010. p. 1433-1439

Wiener Tierärztliche Monatsschrift. 2004;**8**(91):214-221

DOI: 10.1111/j.0021-8782.2004.00327.x

9426783

Koogan; 2012

2010;**3**(8):281-289

joms.2001.19284

Press; 2011. p. 662


[59] Schmitz N, Laverty S, Kraus VB, Aigner T. Basic methods in histopathology of joint tissues. Osteoarthritis and Cartilage. 2010;**1**(18):113-116. DOI: 10.1016/j.joca.2010.05.026.

[45] Moonen CT, Van Zijl PC, Frank JA, Le Bihan D, Becker ED. Functional magnetic reso-

[46] Nagase T, Muneta T, Ju YJ, Hara K, Morito T, Koga H, Nimura A, Mochizuki T, Sekiya I. Analysis of the chondrogenic potential of human synovial stem cells according to harvest site and culture parameters in knees with medial compartment osteoarthritis. Arthritis and Rheumatism. 2008;**58**(5):389-1398. DOI: 10.1002/art.23418 [47] Naredo E, Cabero F, Palop MJ, Collado P, Cruz A, Crespo M. Ultrasonographic findings in knee osteoarthritis: A comparative study with clinical and radiographic assessment.

Osteoarthritis and Cartilage. 2005;**13**(7):568-574. DOI: 10.1016/j.joca.2005.02.008

Paulo; 2006

100 Cartilage Repair and Regeneration

1993;**2**(26):91-97

j.csm.2005.12.006

10.1097/BRS.0b013e31819403ce

Williams &Wilkins; 2001. p. 2195-2215

Revista de Medicina. 2011;**90**(4):185-194

2007;**56**(3):882-891. DOI: 10.1002/art.22446

[48] Nobrega AI. Tecnologia radiológica e diagnóstico por Imagem. Editora Difusão: São

[49] Ogueta S, Muñoz J, Obregon E, Delgado-baeza E, García-Ruiz JP. Prolactin is a component of the human synovial liquid and modulates the growth and chondrogenic differentiation of bone marrow-derived mesenchymal stem cells. Molecular and Cellular

[50] Oliveira S. Princípios da artrografia com duplo contraste do joelho. Radiologia Brasileira.

[51] Paul C, Samdani AF, Betz RR, et al. Grafting of human bone marrow stromal cells into spinal cord injury: A comparison of delivery methods. Spine. 2009;**34**(4):328-334. DOI:

[52] Pearle AD, Warren RF, Rodeo SA. Basic science of articular cartilage and osteoarthritis.

[53] Pelletier JP, Martel-Pelletier J, Howell DS. Etiopathogenesis of osteoarthritis. In: Koopman WJ, editor. Arthritis and Allied Conditions. 14th ed. Philadelphia: Lippincott

[54] Philippon MJ, Schenker ML. Arthroscopy for the treatment of Femoroacetabular impingement in the athlete. Clinics in Sports Medicine. 2006;**25**(2):299-308. DOI: 10.1016/

[55] Rahaman MN, Mao JJ. Stem cell-based composite tissue constructs for regenerative medicine. Biotechnology and Bioengineering. 2005;**91**(3):261-284. DOI: 10.1002/bit.20292

[56] Riggs CM. Osteochondral injury and joint disease in the athletic horse. Equine Veterinary

[57] Rodrigues MB. Diagnostic imaging in musculoskeletal trauma—general principles.

[58] Schmidt TA, Gastelum NS, Nguyen QT, Schumacher BL, Sah RL. Boundary lubrication of articular cartilage: Role of synovial fluid constituents. Arthritis & Rheumatology.

Education. 2006;**18**(2):100-112. DOI: 10.1111/j.2042-3292.2006.tb00426.x.

Endocrinology. 2002;**190**(1-2):51-63. DOI: 10.1016/S0303-7207(02)00013-8

Clinical Sports Medicine. 2005;**24**(1):1-12. DOI: 10.1016/j.csm.2004.08.007

nance imaging in medicine and physiology. Science. 1990;**250**(4977):53-61


**Chapter 6**

**Provisional chapter**

**Chondral Lesion in the Hip Joint and Current Chondral**

This chapter gives a detailed review of the composition, structure and biomechanics of articular cartilage in the joint. W have looked at the most common types of cartilage lesions and at the existing methods of articular cartilage repair techniques in the hip joint. Articular cartilage is specialized hyaline cartilage which makes a firm, smooth and slippery surface that resists plastic deformation. It has a unique structure and mechanical properties that provide joints with a surface that combines low friction, shock absorption and wear resistance, while bearing large repetitive loads throughout an individual's lifetime. Cartilage lesions in the hip are most common on the acetabular side and typically present as focal area of delamination or chondral flap. Joint preserving techniques are becoming increasingly common. The spectrum of options includes palliative procedures such as joint lavage and chondral debridement, reparative procedures such as microfracture and direct chondral repair, and restorative procedures such as mosaicoplasty. Preservation of the host tissue is most attractive solution to cartilage damage, particularly in young active individuals. Tissue engineering offers one solution but many problems

have to be overcome before these techniques become a reality.

**Keywords:** chondral repair, mosaicoplasty, ACI, MACI, hip joint

**Chondral Lesion in the Hip Joint and Current Chondral** 

DOI: 10.5772/intechopen.70261

© 2016 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution,

© 2018 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

and reproduction in any medium, provided the original work is properly cited.

Sports injuries or trauma are a common cause of chondral injuries resulting in joint pain, limitation of function and disability [1]. Articular cartilage is avascular and has very limited capacity for repair [2]. In view of this, chondral lesions that do not penetrate the subchondral bone

**Repair Techniques**

Mulhall

**Repair Techniques**

Adrian J. Cassar-Gheiti, Neil G. Burke,

Adrian J. Cassar-Gheiti, Neil G. Burke, Theresa M. Cassar-Gheiti and Kevin J.

http://dx.doi.org/10.5772/intechopen.70261

**Abstract**

**1. Introduction**

Theresa M. Cassar-Gheiti and Kevin J. Mulhall

Additional information is available at the end of the chapter

Additional information is available at the end of the chapter

**Provisional chapter**

## **Chondral Lesion in the Hip Joint and Current Chondral Repair Techniques Repair Techniques**

**Chondral Lesion in the Hip Joint and Current Chondral** 

DOI: 10.5772/intechopen.70261

Adrian J. Cassar-Gheiti, Neil G. Burke, Theresa M. Cassar-Gheiti and Kevin J. Mulhall Theresa M. Cassar-Gheiti and Kevin J. Mulhall

Adrian J. Cassar-Gheiti, Neil G. Burke,

Additional information is available at the end of the chapter Additional information is available at the end of the chapter

http://dx.doi.org/10.5772/intechopen.70261

#### **Abstract**

This chapter gives a detailed review of the composition, structure and biomechanics of articular cartilage in the joint. W have looked at the most common types of cartilage lesions and at the existing methods of articular cartilage repair techniques in the hip joint. Articular cartilage is specialized hyaline cartilage which makes a firm, smooth and slippery surface that resists plastic deformation. It has a unique structure and mechanical properties that provide joints with a surface that combines low friction, shock absorption and wear resistance, while bearing large repetitive loads throughout an individual's lifetime. Cartilage lesions in the hip are most common on the acetabular side and typically present as focal area of delamination or chondral flap. Joint preserving techniques are becoming increasingly common. The spectrum of options includes palliative procedures such as joint lavage and chondral debridement, reparative procedures such as microfracture and direct chondral repair, and restorative procedures such as mosaicoplasty. Preservation of the host tissue is most attractive solution to cartilage damage, particularly in young active individuals. Tissue engineering offers one solution but many problems have to be overcome before these techniques become a reality.

**Keywords:** chondral repair, mosaicoplasty, ACI, MACI, hip joint

## **1. Introduction**

Sports injuries or trauma are a common cause of chondral injuries resulting in joint pain, limitation of function and disability [1]. Articular cartilage is avascular and has very limited capacity for repair [2]. In view of this, chondral lesions that do not penetrate the subchondral bone

© 2016 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. © 2018 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

(partial thickness) do not heal and usually progress to the degeneration of the articular surface [2]. The most common joint affected with chondral injuries is the knee joint [3]. The knee joint accounts for approximately 75% of all reported chondral lesions [4]. In a bibliometric analysis for the most cited topics of arthroscopic procedures, cartilage repair techniques accounted for 53% of all citations, making this the most cited topic in arthroscopic orthopedic surgery and second most cited topic in orthopedics [5]. Cartilage lesions in the hip joint can be due to either traumatic or atraumatic pathologies, these can be associated with labral tears [6, 7], femoroacetabular impingement (FAI) [8], arthritis [9], osteonecrosis and dysplasia [10]. A direct association between acetabular labral injuries and chondral lesions of the femoral head and acetabulum has been reported by various authors [11, 12]. Hip morphology makes chondral injuries in the hip joint difficult to manage, but with recent advances and increased availability of hip arthroscopy over the past years [13], repair techniques commonly applied to the knee joint are being transferred to the hip [14]. Although, in the current literature there is no evidence, early detection and management of chondral lesion may pre-empt degeneration of the entire joint, making hip preserving techniques particularly useful in young active patients.

is divided into six zones. Zone 6 corresponds to the fovea on the acetabulum and to the area around the insertion of ligamentum teres on the femoral head. Zone 1 corresponds to the anteroinferior region, Zone 2 to the anterosuperior region, Zone 3 to the central superior region, Zone 4 to the posterosuperior region, Zone 5 to the posteroinferior region on both acetabulum and femoral head while Zone 6 corresponds to the fovea on the acetabulum and the corresponding area around the insertion of ligamentum teres on the femur [15]. This geographical zone method of describing pathology in the hip joint has been used and validated by many authors [6, 16–26].

Chondral Lesion in the Hip Joint and Current Chondral Repair Techniques

http://dx.doi.org/10.5772/intechopen.70261

105

The spectrum of cartilage damage varies from mild to severe. It is essential to have a reliable classification system for chondral lesion seen during surgery in the hip joint. Most classification for chondral lesions are based on classification used in any other joint [27, 28] but lately new classification are being developed to describe various chondral lesions specific to the hip joint [9, 24]. The most common classification used in the literature is the Outerbridge classification (**Figure 2**) [28] which was described in 1961 and cited 914 times [29] and the second most common classification is the one developed by the International Cartilage Repair Society (ICRS) [27] which was described in 2003 and cited 169 times [29]. **Figure 3** demonstrates the

The Outerbridge classification categorizes chondral injury into four grades from I (slight) to IV (severe) (**Figures 2** and **3**). It is simple and reproducible and new classification systems for the hip joint are based on it [9, 24]. In a Grade I cartilage lesion there is softening or oedema, Grade II there is less than 1.3 cm cartilage fragmentation or tear, Grade III if fragmentation or tear of cartilage is more than 1.3 cm and Grade IV if subchondral bone is visible and breached. New classification systems for the hip joint have taken this further and have described the amount of delamination in the cartilage [9, 24]. For the purpose of this study the Outerbridge

Non-arthritic cartilage injuries in the hip refer to focal chondral defects on either the femoral or the acetabular side of the joint. Cartilage lesions in the hip are most common on the

**Figure 2.** Outerbridge classification during hip arthroscopy. (A)—Grade I, (B)—Grade II, (C)—Grade III, and (D)—

**2.1. Classification for chondral lesions**

differences between the two classifications.

**2.2. Type of chondral lesions**

Grade IV.

classification [28] has been used to describe cartilage injury.

## **2. Describing chondral lesion in the hip joint**

The hip joint is roughly spherical in shape, but its orientation does not fit exactly. This makes documentation of intra-articular hip lesion challenging. Traditionally a clock face method has been used to topographically report the focus of damage in the hip joint. Although practical the clock face method becomes confusing during arthroscopy and on changing sides. Ilizaliturri et al. [15] have developed and validated an alternative method which is based on anatomical landmarks easily recognizable during arthroscopy (**Figure 1**).

The geographical zone method divides both the acetabulum and the femoral head into six corresponding zones (Zones 1–6) [15]. The acetabulum is divided by two imaginary vertical lines that follow the anterior and posterior limits of the acetabular fossa, which divide it into three sections. A horizontal line perpendicular to the previous lines is placed at the superior limit of the fossa dividing the acetabulum into a superior and inferior part. As a result the acetabulum

**Figure 1.** Modified geographical zone mapping system for right acetabulum and right femoral head. Zones A acetabular zones, Zones L—labral zones, and Zones F—femoral head zones. Adopted from Ilizaliturri et al. [15].

is divided into six zones. Zone 6 corresponds to the fovea on the acetabulum and to the area around the insertion of ligamentum teres on the femoral head. Zone 1 corresponds to the anteroinferior region, Zone 2 to the anterosuperior region, Zone 3 to the central superior region, Zone 4 to the posterosuperior region, Zone 5 to the posteroinferior region on both acetabulum and femoral head while Zone 6 corresponds to the fovea on the acetabulum and the corresponding area around the insertion of ligamentum teres on the femur [15]. This geographical zone method of describing pathology in the hip joint has been used and validated by many authors [6, 16–26].

## **2.1. Classification for chondral lesions**

(partial thickness) do not heal and usually progress to the degeneration of the articular surface [2]. The most common joint affected with chondral injuries is the knee joint [3]. The knee joint accounts for approximately 75% of all reported chondral lesions [4]. In a bibliometric analysis for the most cited topics of arthroscopic procedures, cartilage repair techniques accounted for 53% of all citations, making this the most cited topic in arthroscopic orthopedic surgery and second most cited topic in orthopedics [5]. Cartilage lesions in the hip joint can be due to either traumatic or atraumatic pathologies, these can be associated with labral tears [6, 7], femoroacetabular impingement (FAI) [8], arthritis [9], osteonecrosis and dysplasia [10]. A direct association between acetabular labral injuries and chondral lesions of the femoral head and acetabulum has been reported by various authors [11, 12]. Hip morphology makes chondral injuries in the hip joint difficult to manage, but with recent advances and increased availability of hip arthroscopy over the past years [13], repair techniques commonly applied to the knee joint are being transferred to the hip [14]. Although, in the current literature there is no evidence, early detection and management of chondral lesion may pre-empt degeneration of the entire joint, making hip preserving techniques particularly useful in young active patients.

The hip joint is roughly spherical in shape, but its orientation does not fit exactly. This makes documentation of intra-articular hip lesion challenging. Traditionally a clock face method has been used to topographically report the focus of damage in the hip joint. Although practical the clock face method becomes confusing during arthroscopy and on changing sides. Ilizaliturri et al. [15] have developed and validated an alternative method which is based on

The geographical zone method divides both the acetabulum and the femoral head into six corresponding zones (Zones 1–6) [15]. The acetabulum is divided by two imaginary vertical lines that follow the anterior and posterior limits of the acetabular fossa, which divide it into three sections. A horizontal line perpendicular to the previous lines is placed at the superior limit of the fossa dividing the acetabulum into a superior and inferior part. As a result the acetabulum

**Figure 1.** Modified geographical zone mapping system for right acetabulum and right femoral head. Zones A acetabular zones, Zones L—labral zones, and Zones F—femoral head zones. Adopted from Ilizaliturri et al. [15].

**2. Describing chondral lesion in the hip joint**

104 Cartilage Repair and Regeneration

anatomical landmarks easily recognizable during arthroscopy (**Figure 1**).

The spectrum of cartilage damage varies from mild to severe. It is essential to have a reliable classification system for chondral lesion seen during surgery in the hip joint. Most classification for chondral lesions are based on classification used in any other joint [27, 28] but lately new classification are being developed to describe various chondral lesions specific to the hip joint [9, 24]. The most common classification used in the literature is the Outerbridge classification (**Figure 2**) [28] which was described in 1961 and cited 914 times [29] and the second most common classification is the one developed by the International Cartilage Repair Society (ICRS) [27] which was described in 2003 and cited 169 times [29]. **Figure 3** demonstrates the differences between the two classifications.

The Outerbridge classification categorizes chondral injury into four grades from I (slight) to IV (severe) (**Figures 2** and **3**). It is simple and reproducible and new classification systems for the hip joint are based on it [9, 24]. In a Grade I cartilage lesion there is softening or oedema, Grade II there is less than 1.3 cm cartilage fragmentation or tear, Grade III if fragmentation or tear of cartilage is more than 1.3 cm and Grade IV if subchondral bone is visible and breached. New classification systems for the hip joint have taken this further and have described the amount of delamination in the cartilage [9, 24]. For the purpose of this study the Outerbridge classification [28] has been used to describe cartilage injury.

## **2.2. Type of chondral lesions**

Non-arthritic cartilage injuries in the hip refer to focal chondral defects on either the femoral or the acetabular side of the joint. Cartilage lesions in the hip are most common on the

**Figure 2.** Outerbridge classification during hip arthroscopy. (A)—Grade I, (B)—Grade II, (C)—Grade III, and (D)— Grade IV.

lesions with a chondral flap (62%), (ii) localized full-thickness chondral wear without an associated flap (38%), (iii) global degenerative joint disease with areas of full-thickness cartilage loss (6%) (**Figure 4**) [39]. They have also reported that most Grade IV anterior lesions consisted of a chondral flap in continuity with a tear of the articular margin of the labrum.

Chondral Lesion in the Hip Joint and Current Chondral Repair Techniques

http://dx.doi.org/10.5772/intechopen.70261

107

Cartilage lesions on the femoral head are less common, but typically occur from impact loading across the hip joint [33, 40]. Lesions on the femoral head can present as shear injuries, delamination, chondral flaps, fissuring, fractures and impaction injuries. The type and degree of injury depends on the amount and direction of the impact load [33, 38, 40, 41]. Fissuring of cartilage is reported to occur at 25% strain of articular cartilage specimens and the extent of damage to chondrocytes depends on the quality of the underlying bone [42]. In a recent study by Philippon et al. all patients sustained a labral tear and chondral defect following a traumatic hip dislocation. In 14% of the cases an isolated femoral head lesion was observed. Avascular necrosis (AVN) is another known cause of focal cartilage injury to the femoral head, and is secondary to loss of structural integrity of subchondral bone [42]. A wide spectrum of chondral

The current goal for surgical intervention is to correct the cause of injury and address the associated chondral pathology. The cause of chondral damage is mostly due to abnormal morphology either the acetabulum or the femoral head and surgery is tailored to the underlying anatomical abnormality. Femoroacetabular impingement is the most common cause of chondral injury in the acetabulum, osteochondroplasty of the femoral neck is one technique used to address this abnormality. Osteochondroplasty only addresses the abnormality on the femoral neck while other techniques are required to repair the associated chondral injury in the acetabulum. Joint-preserving techniques traditionally used in the treatment of cartilage lesions in the knee

**Figure 4.** Three different patterns of Grade IV lesions. (A)—Wave sign, (B)—Carpet, and (C)—Global degeneration.

This region was termed the 'watershed zone' by McCarthy et al. [39].

lesions is associated with AVN from mild delamination to complete collapse.

**3. Current articular repair techniques**

**Figure 3.** ICRS classification. Adopted from www.cartilage.com.

acetabular side and typically present as focal area of delamination or chondral flap (carpet type lesion). The most common condition resulting in these type of lesions is femoroacetabular impingement (FAI) [30–36]. Most acetabular cartilage lesions are localized to the anterior and anterosuperior region of the acetabulum, present in 59–88% of cases and in the posterior or posterosuperior acetabulum in 25–55% of cases [37]. Lesions on the posterior aspect are commonly related to repetitive posterior loading of the posterior rim of the acetabulum or by axial impact in high energy contact sports [38]. Cartilage lesions on the anterior and anterosuperior aspect are more common in FAI as described by Ganz et al. in both Cam and Pincer type impingement [30–32]. In a series of 273 patients who underwent hip arthroscopy, McCarthy et al. reported that 26% of patient had and Outerbridge IV chondral lesion. They have also reported three distinct patterns Outerbridge IV chondral lesions: (i) isolated lesions with a chondral flap (62%), (ii) localized full-thickness chondral wear without an associated flap (38%), (iii) global degenerative joint disease with areas of full-thickness cartilage loss (6%) (**Figure 4**) [39]. They have also reported that most Grade IV anterior lesions consisted of a chondral flap in continuity with a tear of the articular margin of the labrum. This region was termed the 'watershed zone' by McCarthy et al. [39].

Cartilage lesions on the femoral head are less common, but typically occur from impact loading across the hip joint [33, 40]. Lesions on the femoral head can present as shear injuries, delamination, chondral flaps, fissuring, fractures and impaction injuries. The type and degree of injury depends on the amount and direction of the impact load [33, 38, 40, 41]. Fissuring of cartilage is reported to occur at 25% strain of articular cartilage specimens and the extent of damage to chondrocytes depends on the quality of the underlying bone [42]. In a recent study by Philippon et al. all patients sustained a labral tear and chondral defect following a traumatic hip dislocation. In 14% of the cases an isolated femoral head lesion was observed. Avascular necrosis (AVN) is another known cause of focal cartilage injury to the femoral head, and is secondary to loss of structural integrity of subchondral bone [42]. A wide spectrum of chondral lesions is associated with AVN from mild delamination to complete collapse.

**Figure 4.** Three different patterns of Grade IV lesions. (A)—Wave sign, (B)—Carpet, and (C)—Global degeneration.

## **3. Current articular repair techniques**

acetabular side and typically present as focal area of delamination or chondral flap (carpet type lesion). The most common condition resulting in these type of lesions is femoroacetabular impingement (FAI) [30–36]. Most acetabular cartilage lesions are localized to the anterior and anterosuperior region of the acetabulum, present in 59–88% of cases and in the posterior or posterosuperior acetabulum in 25–55% of cases [37]. Lesions on the posterior aspect are commonly related to repetitive posterior loading of the posterior rim of the acetabulum or by axial impact in high energy contact sports [38]. Cartilage lesions on the anterior and anterosuperior aspect are more common in FAI as described by Ganz et al. in both Cam and Pincer type impingement [30–32]. In a series of 273 patients who underwent hip arthroscopy, McCarthy et al. reported that 26% of patient had and Outerbridge IV chondral lesion. They have also reported three distinct patterns Outerbridge IV chondral lesions: (i) isolated

**Figure 3.** ICRS classification. Adopted from www.cartilage.com.

106 Cartilage Repair and Regeneration

The current goal for surgical intervention is to correct the cause of injury and address the associated chondral pathology. The cause of chondral damage is mostly due to abnormal morphology either the acetabulum or the femoral head and surgery is tailored to the underlying anatomical abnormality. Femoroacetabular impingement is the most common cause of chondral injury in the acetabulum, osteochondroplasty of the femoral neck is one technique used to address this abnormality. Osteochondroplasty only addresses the abnormality on the femoral neck while other techniques are required to repair the associated chondral injury in the acetabulum. Joint-preserving techniques traditionally used in the treatment of cartilage lesions in the knee joint are becoming increasingly utilized in the hip joint. The experience in the hip is limited at this point, but the spectrum of options includes palliative procedures such as joint lavage and chondral debridement, reparative procedures such as microfracture of subchondral bone and recently combined with direct chondral repair [43–47], and restorative procedures such as mosaicoplasty [48], autologous chondrocyte implantation (ACI) [32, 34, 35, 49–59].

one patient progressing to generalized osteoarthritis [55]. Although there are no published long term studies on microfracture in the hip join, studies with good long term results exist for microfracture of the knee [71, 72, 77–79]. Lodhia et al. concluded that microfractures in the hip helps patients to achieve favorable outcomes of their hip with similar results to a matched cohort of patients, who may have a chondral lesion that did not warrant microfracture [46]. Even with meticulous surgical technique and proper patient selection, the results of microfracture appear to deteriorate over time [80]. Although microfracture is an easy reproducible technique that is commonly employed as a first line treatment the results are not as good in

Chondral Lesion in the Hip Joint and Current Chondral Repair Techniques

http://dx.doi.org/10.5772/intechopen.70261

109

Direct chondral repair refers to techniques in which a full-thickness chondral flap is repaired back to the subchondral bone rather than debrided. The most recent reported direct chondral repairs are techniques using suture repair [47] and fibrin adhesive [43, 44] in combination

This technique describe by Sekiya et al. is used to repair, a chondral flap, where microfractures are applied under the chondral flap. An anchor loaded with absorbable sutures is than fixed in the perilabral sulcus, the suture is passed over the labrum and through the chondral flap, back through the labrum to tie it in the perilabral sulcus [47]. This allows initially stability until the chondral flap heals back in place through fibrosis stimulated by the microfractures. This technique has been only reported by Sekiya et al. and at 2 years follow-up, the patient reported to feel 95% normal, with a Harris Hip Score of 93 and Hip Outcome Score Sports subscale of 81. There are no large studies on this technique available to date and further research is warranted.

Fibrin adhesive is a biological compound, which has been used in many fields of surgery. The haemostatic and adhesive properties of fibrin glue are well known to neurosurgeons [81], ophthalmologists [82, 83], otolaryngologists [84], general [85, 86] and orthopedic surgeons [87, 88]. In orthopedics fibrin adhesive can be used to reattach native hyaline cartilage to the underlying subchondral bone to create an anatomical and durable repair [89]. In the hip joint, Tzaveas et al. reported repair of a chondral flap by using a combination of microfracture and fibrin adhesive under the chondral flap. Follow-up of 43 patients for 1–3 years showed significant improvement in modified Harris Hip Scores with this technique [43]. No randomized control studies of this technique with microfracture or any other technique exists and further

Cyanoacrylates are a class of synthetic glues that rapidly solidify upon contact with weak basis, such as water or blood [90]. Compared with other tissue adhesives cyanoacrylates

with microfracture. These techniques are used on the acetabular side of the hip joint.

older patients and tend to deteriorate over time.

**3.3. Direct chondral repair**

*3.3.1. Suture repair*

*3.3.2. Fibrin adhesive repair*

studies are required.

*3.3.3. Cyanoacrylate*

## **3.1. Arthroscopic lavage and debridement**

Arthroscopic washout or lavage has been the primary treatment for chondral lesions for the past 24 years [60]. During arthroscopic lavage, inflammatory mediators, loose cartilage and any cartilaginous debris residing in the joint causing synovial inflammation, effusion and bio-mechanical obstruction is washed out. Jackson has reported symptomatic improvement in 45% of patients at 3.5 years and measurable improvement in 80% of patients after arthroscopic lavage [61] with similar results reported by other authors [62, 63]. Most commonly debridement of chondral debris is carried out with arthroscopic lavage. McLaren et al. reported excellent control of pain in 38% of patients and improved function 22% of cases after arthroscopic debridement and lavage [64], similar results were also reported by Gibson et al. [65]. Sözen et al. have reported improvement in Harris Hip Scores (HHS) in 62% of patients after arthroscopic debridement and lavage in osteoarthritis of the hip joint [66]. Arthroscopic lavage and debridement only addresses the patients' symptoms and slow further degeneration by reducing chondral debris in the joint but it does not facilitate defect repair nor does prevent future defect enlargement. Moseley et al. reported no improvement in symptoms or function when arthroscopic lavage and debridement when compared with placebo arthroscopy [67].

#### **3.2. Bone marrow stimulation**

Bone marrow stimulation is the most frequent used technique for treating small symptomatic lesions of the articular cartilage in both knee and hip joint. The most common bone marrow stimulation technique is microfracture. This procedure is straightforward and the costs are low compared with other treatment modalities. Microfracture has become increasingly popular among orthopedic surgeons as preferred treatment for chondral defects [45, 50, 68–72].

When subchondral bone is perforated during microfracture it brings undifferentiated stem cells into the defect from the marrow. A marrow clot is established within the microfractured area [68]. The newly formed clot provides an environment for both pluripotent marrow cells and mesenchymal stem cells to differentiate into stable tissue within the base of the lesion [68]. Histological evaluation indicates that fibrocartilaginous tissue is the final product covering the previous lesion [73]. However the overall concentration of mesenchymal stem cells is quite low and declines with age [74]. Reparative fibrocartilage consists of Type-I, Type-II and Type-III in varying amounts and does not resemble the surrounding hyaline cartilage with less Type-II collagen [75, 76].

Phillippon et al. reported that eight of nine patients had 95–100% coverage of an isolated acetabular chondral lesion or acetabular lesion associated with a femoral head lesion, with Grade I or II appearance of the repair product at an average of 20 months follow-up with only one patient progressing to generalized osteoarthritis [55]. Although there are no published long term studies on microfracture in the hip join, studies with good long term results exist for microfracture of the knee [71, 72, 77–79]. Lodhia et al. concluded that microfractures in the hip helps patients to achieve favorable outcomes of their hip with similar results to a matched cohort of patients, who may have a chondral lesion that did not warrant microfracture [46]. Even with meticulous surgical technique and proper patient selection, the results of microfracture appear to deteriorate over time [80]. Although microfracture is an easy reproducible technique that is commonly employed as a first line treatment the results are not as good in older patients and tend to deteriorate over time.

## **3.3. Direct chondral repair**

Direct chondral repair refers to techniques in which a full-thickness chondral flap is repaired back to the subchondral bone rather than debrided. The most recent reported direct chondral repairs are techniques using suture repair [47] and fibrin adhesive [43, 44] in combination with microfracture. These techniques are used on the acetabular side of the hip joint.

## *3.3.1. Suture repair*

joint are becoming increasingly utilized in the hip joint. The experience in the hip is limited at this point, but the spectrum of options includes palliative procedures such as joint lavage and chondral debridement, reparative procedures such as microfracture of subchondral bone and recently combined with direct chondral repair [43–47], and restorative procedures such as

Arthroscopic washout or lavage has been the primary treatment for chondral lesions for the past 24 years [60]. During arthroscopic lavage, inflammatory mediators, loose cartilage and any cartilaginous debris residing in the joint causing synovial inflammation, effusion and bio-mechanical obstruction is washed out. Jackson has reported symptomatic improvement in 45% of patients at 3.5 years and measurable improvement in 80% of patients after arthroscopic lavage [61] with similar results reported by other authors [62, 63]. Most commonly debridement of chondral debris is carried out with arthroscopic lavage. McLaren et al. reported excellent control of pain in 38% of patients and improved function 22% of cases after arthroscopic debridement and lavage [64], similar results were also reported by Gibson et al. [65]. Sözen et al. have reported improvement in Harris Hip Scores (HHS) in 62% of patients after arthroscopic debridement and lavage in osteoarthritis of the hip joint [66]. Arthroscopic lavage and debridement only addresses the patients' symptoms and slow further degeneration by reducing chondral debris in the joint but it does not facilitate defect repair nor does prevent future defect enlargement. Moseley et al. reported no improvement in symptoms or function when arthroscopic lavage and debridement when compared with placebo arthroscopy [67].

Bone marrow stimulation is the most frequent used technique for treating small symptomatic lesions of the articular cartilage in both knee and hip joint. The most common bone marrow stimulation technique is microfracture. This procedure is straightforward and the costs are low compared with other treatment modalities. Microfracture has become increasingly popular among orthopedic surgeons as preferred treatment for chondral defects [45, 50, 68–72].

When subchondral bone is perforated during microfracture it brings undifferentiated stem cells into the defect from the marrow. A marrow clot is established within the microfractured area [68]. The newly formed clot provides an environment for both pluripotent marrow cells and mesenchymal stem cells to differentiate into stable tissue within the base of the lesion [68]. Histological evaluation indicates that fibrocartilaginous tissue is the final product covering the previous lesion [73]. However the overall concentration of mesenchymal stem cells is quite low and declines with age [74]. Reparative fibrocartilage consists of Type-I, Type-II and Type-III in varying amounts and does not resemble the surrounding hyaline cartilage with

Phillippon et al. reported that eight of nine patients had 95–100% coverage of an isolated acetabular chondral lesion or acetabular lesion associated with a femoral head lesion, with Grade I or II appearance of the repair product at an average of 20 months follow-up with only

mosaicoplasty [48], autologous chondrocyte implantation (ACI) [32, 34, 35, 49–59].

**3.1. Arthroscopic lavage and debridement**

108 Cartilage Repair and Regeneration

**3.2. Bone marrow stimulation**

less Type-II collagen [75, 76].

This technique describe by Sekiya et al. is used to repair, a chondral flap, where microfractures are applied under the chondral flap. An anchor loaded with absorbable sutures is than fixed in the perilabral sulcus, the suture is passed over the labrum and through the chondral flap, back through the labrum to tie it in the perilabral sulcus [47]. This allows initially stability until the chondral flap heals back in place through fibrosis stimulated by the microfractures. This technique has been only reported by Sekiya et al. and at 2 years follow-up, the patient reported to feel 95% normal, with a Harris Hip Score of 93 and Hip Outcome Score Sports subscale of 81. There are no large studies on this technique available to date and further research is warranted.

## *3.3.2. Fibrin adhesive repair*

Fibrin adhesive is a biological compound, which has been used in many fields of surgery. The haemostatic and adhesive properties of fibrin glue are well known to neurosurgeons [81], ophthalmologists [82, 83], otolaryngologists [84], general [85, 86] and orthopedic surgeons [87, 88]. In orthopedics fibrin adhesive can be used to reattach native hyaline cartilage to the underlying subchondral bone to create an anatomical and durable repair [89]. In the hip joint, Tzaveas et al. reported repair of a chondral flap by using a combination of microfracture and fibrin adhesive under the chondral flap. Follow-up of 43 patients for 1–3 years showed significant improvement in modified Harris Hip Scores with this technique [43]. No randomized control studies of this technique with microfracture or any other technique exists and further studies are required.

## *3.3.3. Cyanoacrylate*

Cyanoacrylates are a class of synthetic glues that rapidly solidify upon contact with weak basis, such as water or blood [90]. Compared with other tissue adhesives cyanoacrylates are easier to use, have quicker polymerization and guarantee higher bonding strength. The use of cyanoacrylate tissue adhesive is well described in the literature for closure of skin wounds [91–93]. Cyanoacrylates is a generic name for a group of tissue adhesives such as ethyl-2-cyanoacrylate, *n*-butyl-2-cyanoacrylate and 2-octyl cyanoacrylate distributed under various names like Histoacryl®, Indermil®, Dermabond® or Glubran®. All cyanoacrylate bond body tissue and show a bacteriostatic effect. In medical practice, *n*-butyl- and octyl-cyanoacrylate are most commonly used. Both biomechanical [94, 95] and cytotoxic [96–98] properties of cyanoacrylate have been tested extensively. *n*-Butyl-2-cyanoacrylate have been approved for internal use including atriovenous embolization [99], endoscopic treatment of bleeding ulcers [100, 101], occlusion of biliary [102] and pancreatic fistulas [103], fixation of polypropylene mesh in open [104, 105] and laparoscopic hernia repair [106]. In orthopedic literature, cyanoacrylate (Dermabond®) has been used for skin closure with excellent result when compared with staples after total joint arthroplasty. A biomechanical study on the use of cyanoacrylate (Histoacryl®) for meniscal repair, reported decrease failure rates when compared to vertical suture repair [95] but no *in vivo* study is yet available. Octyl-cyanoacrylate was used to fix meniscal transplant in a rabbit model, the authors had to sacrifice all animals earlier than planned due to severe inflammatory reaction with caseous necrosis in the operated joint and they have recommended against the use of octyl-cyanoacrylate to fix transplanted menisci [107]. A new cyanoacrylate, 'Glubran 2' (GEM Srl, Viareggio, Italy) is authorized for surgical use and with a CE mark for 'internal use'. Glubran 2 is different to other cyanoacrylates as it has a different chemical composition making it a co-monomer rather than a simple monomer and is composed of *n*-butyl-2-cyanoacrylate and methacryloxysulfolane monomer [104]. The difference in compositions, allows polymerization at lower temperatures and reduced inflammatory reaction when compared to other cyanoacrylates [97, 108]. In recent years a number of clinical studies in general surgery have reported good results when 'Glubran 2' has been used *in vivo* [104–106]. At this stage there is no clinical study evaluating the use of cyanoacrylate intraarticularly.

osteochondral plugs harvested from a non-weight or less weight bearing areas of the articular surface in the joint and transferred to create a congruent and durable area in the defect. Koh et al. assessed contact pressures on a swine knee model and reported that flush or slightly sunk grafts could restore contact pressures to nearly normal levels, but elevated angled grafts adversely increased contact pressures [116]. However, they used only one plug, which does not correlate with clinical practice. Kock et al. reported reduction in contact pressures after OATS to be 30% less than contact pressures before the procedure with an empty defect in a human cadaveric knee [117]. The outcomes of autologous mosaicoplasty are promising, Hangody and Füles evaluated the largest series of mosaicoplasty performed for localized Outerbridge Grade III or IV lesions and reported good to excellent results for 92% of the femoral lesions, 87% of tibial lesions and 79% of patellofemoral lesions [118]. Ollat et al. reported satisfactory results in 72.5% of the patients at 8 years of follow-up and that the largest defects with the longest follow-up have the worst prognosis [111]. Osteochondral mosaicoplasty of the femoral head has mixed prognosis; Rittmeister et al. reported that four out of five hips had unsatisfactory results after 5 years follow-up and underwent total hip arthroplasty [119], while Girard et al. reported satisfactory improvements in Postel Merle d'Aubingé Score and global range of motion in the hip joint at an average follow-up of 30 months [120]. Nam et al. reported on two cases that underwent OATS combined with osteochondral fragment fixation after traumatic anterior dislocation of the hip joints [121]. They showed good clinical outcomes and graft incorporation using magnetic resonance imaging (MRI) [121]. Emre et al. have reported good, pain free results a 3 years after surgery [122]. Good clinical outcomes were also reported for fragment fixation combined with OATS for the treatment of osteochondral defects after posterior fracture-dislocation of the hip joint [123]. Recently, good results have been reported from arthroscopic OATS procedure in one patients with 2 year follow-up [48, 124]. Arthroscopic OATS procedures for treating osteochondral lesions of the femoral head are promising but more studies with more patients and longer follow-up periods are

Chondral Lesion in the Hip Joint and Current Chondral Repair Techniques

http://dx.doi.org/10.5772/intechopen.70261

111

required to fully understand the benefits of mosaicoplasty in the hip joint.

Osteochondral allograft transplantation is chondral surface reconstruction that involves transplantation of a cadaveric graft consisting of intact, viable articular cartilage and its underlying subchondral bone into the defect. Currently fresh osteochondral allografts are utilized to treat a broad spectrum of articular cartilage pathology, from focal chondral defects to joints with established osteoarthritis in the hip, knee and ankle joint [125–127]. Advantages to the use of osteochondral allografts include the ability to achieve precise surface architecture, immediate transplantation of viable hyaline cartilage, the potential to replace large defects and no donor site morbidity. Like any allograft transplantation, limitations include; limited graft availability, high cost, risk of immunological reactions and rejections, potential for disease transmission and technically demanding aspect of machining and sizing the allograft [128]. A number of retrospective studies have been performed to assess the outcomes of osteochondral allograft transplantation for the treatment of focal osteochondral defects of the knee, and they have demonstrated good-to-excellent results [129–132]. Krych et al. have reported improvement in Harris Hip Score at 2 and 3 year follow-up in two cases that underwent osteochondral allograft of the acetabulum [113]. Gross et al. reported survival rates for osteochondral allografts of 95% at five years, 85% at 10 years and 73% at fifteen years for posttraumatic femoral condylar lesions [133].

Biomechanical data published on chondral repair techniques has shown improve resistance to shear forces across the chondral surface when compared to fibrin adhesive repair in cadaveric models [109]. Furthermore we have identified early biomechanical failure in fibrin adhesive repair, which failed at only 50 cycles, while suture of chondral flaps were more biomechanically stable throughout the 1500 cycle testing [109]. The small number of reported outcomes and early laboratory failure may limit fibrin glue clinical use, however, both fibrin glue, suture and cyanoacrylate repair warrant further investigation.

#### **3.4. Whole tissue transplantation**

The use of whole tissue chondral transplantation using either an autograft or an allograft is well known in the orthopedics [56, 110–115].

In autologous osteochondral transplantation, occasionally referred as osteoarticular transfer system (OATS), is an effective method for resurfacing osteochondral defects and most commonly used in the knee joint. This technique involves transplantation of multiple cylindrical osteochondral plugs harvested from a non-weight or less weight bearing areas of the articular surface in the joint and transferred to create a congruent and durable area in the defect. Koh et al. assessed contact pressures on a swine knee model and reported that flush or slightly sunk grafts could restore contact pressures to nearly normal levels, but elevated angled grafts adversely increased contact pressures [116]. However, they used only one plug, which does not correlate with clinical practice. Kock et al. reported reduction in contact pressures after OATS to be 30% less than contact pressures before the procedure with an empty defect in a human cadaveric knee [117]. The outcomes of autologous mosaicoplasty are promising, Hangody and Füles evaluated the largest series of mosaicoplasty performed for localized Outerbridge Grade III or IV lesions and reported good to excellent results for 92% of the femoral lesions, 87% of tibial lesions and 79% of patellofemoral lesions [118]. Ollat et al. reported satisfactory results in 72.5% of the patients at 8 years of follow-up and that the largest defects with the longest follow-up have the worst prognosis [111]. Osteochondral mosaicoplasty of the femoral head has mixed prognosis; Rittmeister et al. reported that four out of five hips had unsatisfactory results after 5 years follow-up and underwent total hip arthroplasty [119], while Girard et al. reported satisfactory improvements in Postel Merle d'Aubingé Score and global range of motion in the hip joint at an average follow-up of 30 months [120]. Nam et al. reported on two cases that underwent OATS combined with osteochondral fragment fixation after traumatic anterior dislocation of the hip joints [121]. They showed good clinical outcomes and graft incorporation using magnetic resonance imaging (MRI) [121]. Emre et al. have reported good, pain free results a 3 years after surgery [122]. Good clinical outcomes were also reported for fragment fixation combined with OATS for the treatment of osteochondral defects after posterior fracture-dislocation of the hip joint [123]. Recently, good results have been reported from arthroscopic OATS procedure in one patients with 2 year follow-up [48, 124]. Arthroscopic OATS procedures for treating osteochondral lesions of the femoral head are promising but more studies with more patients and longer follow-up periods are required to fully understand the benefits of mosaicoplasty in the hip joint.

are easier to use, have quicker polymerization and guarantee higher bonding strength. The use of cyanoacrylate tissue adhesive is well described in the literature for closure of skin wounds [91–93]. Cyanoacrylates is a generic name for a group of tissue adhesives such as ethyl-2-cyanoacrylate, *n*-butyl-2-cyanoacrylate and 2-octyl cyanoacrylate distributed under various names like Histoacryl®, Indermil®, Dermabond® or Glubran®. All cyanoacrylate bond body tissue and show a bacteriostatic effect. In medical practice, *n*-butyl- and octyl-cyanoacrylate are most commonly used. Both biomechanical [94, 95] and cytotoxic [96–98] properties of cyanoacrylate have been tested extensively. *n*-Butyl-2-cyanoacrylate have been approved for internal use including atriovenous embolization [99], endoscopic treatment of bleeding ulcers [100, 101], occlusion of biliary [102] and pancreatic fistulas [103], fixation of polypropylene mesh in open [104, 105] and laparoscopic hernia repair [106]. In orthopedic literature, cyanoacrylate (Dermabond®) has been used for skin closure with excellent result when compared with staples after total joint arthroplasty. A biomechanical study on the use of cyanoacrylate (Histoacryl®) for meniscal repair, reported decrease failure rates when compared to vertical suture repair [95] but no *in vivo* study is yet available. Octyl-cyanoacrylate was used to fix meniscal transplant in a rabbit model, the authors had to sacrifice all animals earlier than planned due to severe inflammatory reaction with caseous necrosis in the operated joint and they have recommended against the use of octyl-cyanoacrylate to fix transplanted menisci [107]. A new cyanoacrylate, 'Glubran 2' (GEM Srl, Viareggio, Italy) is authorized for surgical use and with a CE mark for 'internal use'. Glubran 2 is different to other cyanoacrylates as it has a different chemical composition making it a co-monomer rather than a simple monomer and is composed of *n*-butyl-2-cyanoacrylate and methacryloxysulfolane monomer [104]. The difference in compositions, allows polymerization at lower temperatures and reduced inflammatory reaction when compared to other cyanoacrylates [97, 108]. In recent years a number of clinical studies in general surgery have reported good results when 'Glubran 2' has been used *in vivo* [104–106]. At this stage there is no clinical study

Biomechanical data published on chondral repair techniques has shown improve resistance to shear forces across the chondral surface when compared to fibrin adhesive repair in cadaveric models [109]. Furthermore we have identified early biomechanical failure in fibrin adhesive repair, which failed at only 50 cycles, while suture of chondral flaps were more biomechanically stable throughout the 1500 cycle testing [109]. The small number of reported outcomes and early laboratory failure may limit fibrin glue clinical use, however, both fibrin glue, suture and cyanoacrylate repair warrant further investigation.

The use of whole tissue chondral transplantation using either an autograft or an allograft is

In autologous osteochondral transplantation, occasionally referred as osteoarticular transfer system (OATS), is an effective method for resurfacing osteochondral defects and most commonly used in the knee joint. This technique involves transplantation of multiple cylindrical

evaluating the use of cyanoacrylate intraarticularly.

**3.4. Whole tissue transplantation**

110 Cartilage Repair and Regeneration

well known in the orthopedics [56, 110–115].

Osteochondral allograft transplantation is chondral surface reconstruction that involves transplantation of a cadaveric graft consisting of intact, viable articular cartilage and its underlying subchondral bone into the defect. Currently fresh osteochondral allografts are utilized to treat a broad spectrum of articular cartilage pathology, from focal chondral defects to joints with established osteoarthritis in the hip, knee and ankle joint [125–127]. Advantages to the use of osteochondral allografts include the ability to achieve precise surface architecture, immediate transplantation of viable hyaline cartilage, the potential to replace large defects and no donor site morbidity. Like any allograft transplantation, limitations include; limited graft availability, high cost, risk of immunological reactions and rejections, potential for disease transmission and technically demanding aspect of machining and sizing the allograft [128]. A number of retrospective studies have been performed to assess the outcomes of osteochondral allograft transplantation for the treatment of focal osteochondral defects of the knee, and they have demonstrated good-to-excellent results [129–132]. Krych et al. have reported improvement in Harris Hip Score at 2 and 3 year follow-up in two cases that underwent osteochondral allograft of the acetabulum [113]. Gross et al. reported survival rates for osteochondral allografts of 95% at five years, 85% at 10 years and 73% at fifteen years for posttraumatic femoral condylar lesions [133].

### **3.5. Cell based and scaffold treatment**

Autologous chondrocyte implantation (ACI) was originally described by Brittberg et al. [134]. ACI is an innovative technique to restore cartilage cells into full-thickness chondral defects. In ACI there is development of hyaline like cartilage rather than fibrocartilage in the defect, leading to better long term outcomes and longevity of the healing tissue. Good out comes have been reported by various authors. ACI involves two surgical procedures, the first operation is used to harvest the tissue required and the second procedure is required to implant the chondrocytes in the defect. During the second procedure periosteal is also harvested from a different site and used to contain the chondrocytes in the chondral defect. ACI is not without limitations; not many patients are willing to undergo two procedures and there is a risk of donor site morbidity at the periosteal harvest site. Adverse events after ACI have been reported in 46% of patients undergoing the procedure, with graft failure accounting for 25%, delamination accounting for 22% and tissue hypertrophy occurred in about 18% of cases [135]. Peterson et al. reported 52 adverse events, including 26 instances of periosteal hypertrophy and seven graft failure in 101 patients [136].

**4. Conclusion**

lesions in the hip.

**Author details**

**References**

Management of chondral lesion the hip joint to preserve the native joint in young active patients with chondral lesion is challenging for the orthopedic surgeon. Joint-preserving technique in the hip joint continue to evolve with recent reports showing promising results. Indications for these techniques continue to expand and a simplified algorithm was proposed by El Bitar et al. for join preserving management of articular cartilage lesions in the hip joint [14]. The literature so far is limited to low evidence studies with lack of control groups making comparison of different treatment options difficult. Further research in these different modalities is required to formulate a best treatment practice guidelines in the treatment of chondral

Chondral Lesion in the Hip Joint and Current Chondral Repair Techniques

http://dx.doi.org/10.5772/intechopen.70261

113

Adrian J. Cassar-Gheiti\*, Neil G. Burke, Theresa M. Cassar-Gheiti and Kevin J. Mulhall

[1] Peters CL, Erickson J. The etiology and treatment of hip pain in the young adult. Journal

[2] Rolauffs B, et al. Vulnerability of the superficial zone of immature articular cartilage to

[3] Flanigan DC, et al. Prevalence of chondral defects in athletes' knees: A systematic review.

[4] Obedian RS, Grelsamer RP. Osteochondritis dissecans of the distal femur and patella.

[5] Cassar Gheiti AJ, et al. The 25 most cited articles in arthroscopic orthopaedic surgery.

[6] Sampson TG. Arthroscopic treatment for chondral lesions of the hip. Clinics in Sports

[7] Guanche CA, Sikka RS. Acetabular labral tears with underlying chondromalacia: A pos-

[8] Bare AA, Guanche CA. Hip impingement: The role of arthroscopy. Orthopedics.

sible association with high-level running. Arthroscopy. 2005;**21**(5):580-585

of Bone & Joint Surgery – American Volume. 2006;**88**(Suppl 4):20-26

compressive injury. Arthritis & Rheumatology. 2010;**62**(10):3016-3027

Medicine & Science in Sports & Exercise. 2010;**42**(10):1795-1801

\*Address all correspondence to: adriancassargheiti@gmail.com

Cappagh National Orthopaedic Hospital, Dublin, Ireland

Clinics in Sports Medicine. 1997;**16**(1):157-174

Arthroscopy. 2012;**28**(4):548-564

Medicine. 2011;**30**(2):331-348

2005;**28**(3):266-273

In second generation or scaffold based ACI, harvested chondrocytes are delivered on an absorbable scaffold that supports the cells preimplantation culturing and postoperative healing process. In matrix-associated chondrocyte implantation (MACI) procedure chondrocytes are incorporated into various types of tissue engineered scaffolds. Various tissueengineered compounds are being used as scaffolds including hyaluronan, alginates, agarose hydrogels and gelatin scaffolds [137–140]. The results from MACI to treat chondral defects have been encouraging, Behrens et al. reported substantial improvement in clinical outcome scores in 35% of patients at 5 year follow-up [141]. Marcacci et al. reported improvement in quality of life as assessed by the EuroQol - Visual Analogue Scale (EQ-VAS) in 93% of patient at 2 year follow-up after hyaluronan-based scaffold MACI, with resumption of sports at same or slightly lower level in 56.7% of patients at 12 months [142]. Although promising results are being reported after MACI, long term clinical outcomes associated with this procedure are still limited.

The autologous matrix-induced chondrogenesis (AMIC), further develops the scaffold technique in combination with micro-fracturing [59]. It is a one-step procedure that involves microfracturing of the debrided cartilage lesion and a commercially available collagen I/III matrix for covering the blood clot and its MSCs. Fixation is with partial autologous fibrin glue in which the thrombin part is yielded from the patient's serum. The indications of AMIC are symptomatic full-thickness chondral and subchondral defects in the major joints, maximum size of 2–4 cm2 , posttraumatic or osteochondrosis dissecans, and location in the main weight bearing area of the joint or maximum area of pain [59, 143]. In one study, patients with large Grade IV chondral lesions experienced significant improvement up to 24 months after the AMIC procedure [144]. Recently, Fontana has reported on the 5 year follow-up of 201 patients treated with AMIC in the hip joint. This study reported continuous improvement with respect to each evaluation time point in modified Harris Hip Scores peaking at 3 years follow-up [59]. The AMIC technique is further beneficial because it eliminates the need for specialized centers and laboratory support to cultivate cells, in turn reducing total therapy time and overall cost, compared to twostage procedures such as MACI.

## **4. Conclusion**

**3.5. Cell based and scaffold treatment**

112 Cartilage Repair and Regeneration

with this procedure are still limited.

compared to twostage procedures such as MACI.

size of 2–4 cm2

Autologous chondrocyte implantation (ACI) was originally described by Brittberg et al. [134]. ACI is an innovative technique to restore cartilage cells into full-thickness chondral defects. In ACI there is development of hyaline like cartilage rather than fibrocartilage in the defect, leading to better long term outcomes and longevity of the healing tissue. Good out comes have been reported by various authors. ACI involves two surgical procedures, the first operation is used to harvest the tissue required and the second procedure is required to implant the chondrocytes in the defect. During the second procedure periosteal is also harvested from a different site and used to contain the chondrocytes in the chondral defect. ACI is not without limitations; not many patients are willing to undergo two procedures and there is a risk of donor site morbidity at the periosteal harvest site. Adverse events after ACI have been reported in 46% of patients undergoing the procedure, with graft failure accounting for 25%, delamination accounting for 22% and tissue hypertrophy occurred in about 18% of cases [135]. Peterson et al. reported 52 adverse events, including 26 instances

In second generation or scaffold based ACI, harvested chondrocytes are delivered on an absorbable scaffold that supports the cells preimplantation culturing and postoperative healing process. In matrix-associated chondrocyte implantation (MACI) procedure chondrocytes are incorporated into various types of tissue engineered scaffolds. Various tissueengineered compounds are being used as scaffolds including hyaluronan, alginates, agarose hydrogels and gelatin scaffolds [137–140]. The results from MACI to treat chondral defects have been encouraging, Behrens et al. reported substantial improvement in clinical outcome scores in 35% of patients at 5 year follow-up [141]. Marcacci et al. reported improvement in quality of life as assessed by the EuroQol - Visual Analogue Scale (EQ-VAS) in 93% of patient at 2 year follow-up after hyaluronan-based scaffold MACI, with resumption of sports at same or slightly lower level in 56.7% of patients at 12 months [142]. Although promising results are being reported after MACI, long term clinical outcomes associated

The autologous matrix-induced chondrogenesis (AMIC), further develops the scaffold technique in combination with micro-fracturing [59]. It is a one-step procedure that involves microfracturing of the debrided cartilage lesion and a commercially available collagen I/III matrix for covering the blood clot and its MSCs. Fixation is with partial autologous fibrin glue in which the thrombin part is yielded from the patient's serum. The indications of AMIC are symptomatic full-thickness chondral and subchondral defects in the major joints, maximum

bearing area of the joint or maximum area of pain [59, 143]. In one study, patients with large Grade IV chondral lesions experienced significant improvement up to 24 months after the AMIC procedure [144]. Recently, Fontana has reported on the 5 year follow-up of 201 patients treated with AMIC in the hip joint. This study reported continuous improvement with respect to each evaluation time point in modified Harris Hip Scores peaking at 3 years follow-up [59]. The AMIC technique is further beneficial because it eliminates the need for specialized centers and laboratory support to cultivate cells, in turn reducing total therapy time and overall cost,

, posttraumatic or osteochondrosis dissecans, and location in the main weight

of periosteal hypertrophy and seven graft failure in 101 patients [136].

Management of chondral lesion the hip joint to preserve the native joint in young active patients with chondral lesion is challenging for the orthopedic surgeon. Joint-preserving technique in the hip joint continue to evolve with recent reports showing promising results. Indications for these techniques continue to expand and a simplified algorithm was proposed by El Bitar et al. for join preserving management of articular cartilage lesions in the hip joint [14]. The literature so far is limited to low evidence studies with lack of control groups making comparison of different treatment options difficult. Further research in these different modalities is required to formulate a best treatment practice guidelines in the treatment of chondral lesions in the hip.

## **Author details**

Adrian J. Cassar-Gheiti\*, Neil G. Burke, Theresa M. Cassar-Gheiti and Kevin J. Mulhall

\*Address all correspondence to: adriancassargheiti@gmail.com

Cappagh National Orthopaedic Hospital, Dublin, Ireland

## **References**


[9] Beck M, et al. Hip morphology influences the pattern of damage to the acetabular cartilage: Femoroacetabular impingement as a cause of early osteoarthritis of the hip. Journal of Bone & Joint Surgery – British Volume. 2005;**87**(7):1012-1018

[25] Sendtner E, Winkler R, Grifka J. Femoroacetabular impingement: Minimally invasive

Chondral Lesion in the Hip Joint and Current Chondral Repair Techniques

http://dx.doi.org/10.5772/intechopen.70261

115

[26] Gerhardt M, et al. Characterisation and classification of the neural anatomy in the human

[27] Brittberg M, Winalski CS. Evaluation of cartilage injuries and repair. Journal of Bone &

[28] Outerbridge RE. The etiology of chondromalacia patellae. Journal of Bone & Joint

[30] Beck M, et al. Anterior femoroacetabular impingement: Part II. Midterm results of surgi-

[31] Ganz R, et al. Femoroacetabular impingement: A cause for osteoarthritis of the hip.

[32] Lavigne M, et al. Anterior femoroacetabular impingement: Part I. Techniques of joint preserving surgery. Clinical Orthopaedics and Related Research. 2004;**418**:6166

[33] Philippon MJ, et al. Arthroscopic findings following traumatic hip dislocation in 14 pro-

[34] Clohisy JC, et al. AOA symposium. Hip disease in the young adult: Current concepts of etiology and surgical treatment. Journal of Bone & Joint Surgery – American Volume.

[35] Shindle MK, et al. Hip arthroscopy in the athletic patient: Current techniques and spectrum of disease. Journal of Bone & Joint Surgery – American Volume. 2007;**89**(Suppl 3):29-43

[36] Singh PJ, O'Donnell JM. The outcome of hip arthroscopy in Australian football league

[37] Schmid MR, et al. Cartilage lesions in the hip: Diagnostic effectiveness of MR arthrogra-

[38] Moorman 3rd CT, et al. Traumatic posterior hip subluxation in American football. Journal of Bone & Joint Surgery – American Volume. 2003;**85-A**(7):1190-1196

[39] McCarthy JC, et al. The watershed labral lesion: Its relationship to early arthritis of the

[40] Byrd JW. Lateral impact injury. A source of occult hip pathology. Clinics in Sports

[41] Schmitt KU, Schlittler M, Boesiger P. Biomechanical loading of the hip during side jumps

by soccer goalkeepers. Journal of Sports Sciences. 2010;**28**(1):53-59

hip surgery. Orthopade. 2011;**40**(3):261-270; quiz 271

Joint Surgery – American Volume. 2003;**85-A**(Suppl 2):58-69

Clinical Orthopaedics and Related Research. 2003;**417**:112-120

players: A review of 27 hips. Arthroscopy. 2010;**26**(6):743-749

hip. Journal of Arthroplasty. 2001;**16**(8 Suppl 1):81-87

fessional athletes. Arthroscopy. 2009;**25**(2):169-174

2008;**90**(10):2267-2281

phy. Radiology. 2003;**226**(2):382-386

Medicine. 2001;**20**(4):801-815

[29] ISI Web Of Knowledge. 2012, Thomas Reuters. www.webofknowledge.com

cal treatment. Clinical Orthopaedics and Related Research. 2004;**418**:67-73

hip joint. HIP International. 2012;**22**(1):75-81

Surgery – British Volume. 1961;**43-B**:752-757


[9] Beck M, et al. Hip morphology influences the pattern of damage to the acetabular cartilage: Femoroacetabular impingement as a cause of early osteoarthritis of the hip. Journal

[10] Reijman M, et al. Acetabular dysplasia predicts incident osteoarthritis of the hip: The

[11] Byrd JW. Labral lesions: An elusive source of hip pain case reports and literature review.

[12] McCarthy JC, et al. The Otto E. Aufranc Award: The role of labral lesions to development of early degenerative hip disease. Clinical Orthopaedics and Related Research. 2001;**393**:25-37

[13] Colvin AC, Harrast J, Harner C. Trends in hip arthroscopy. Journal of Bone & Joint

[14] El Bitar YF, et al. Joint-preserving surgical options for management of chondral injuries of the hip. Journal of the American Academy of Orthopaedic Surgeons. 2014;**22**(1):46-56

[15] Ilizaliturri Jr VM, et al. A geographic zone method to describe intra-articular pathology in hip arthroscopy: Cadaveric study and preliminary report. Arthroscopy. 2008;**24**(5):534-539

[16] Shindle MK, et al. Arthroscopic management of labral tears in the hip. Journal of Bone &

[17] Larson CM, Giveans MR. Arthroscopic debridement versus refixation of the acetabular labrum associated with femoroacetabular impingement. Arthroscopy. 2009;**25**(4):369-376

[18] Sampatchalit S, et al. Changes in the acetabular fossa of the hip: MR arthrographic findings correlated with anatomic and histologic analysis using cadaveric specimens.

[19] Ruiz-Suarez M, Aziz-Jacobo J, Barber FA. Cyclic load testing and ultimate failure strength of suture anchors in the acetabular rim. Arthroscopy. 2010;**26**(6):762-768 [20] Blankenbaker DG, et al. MR arthrography of the hip: Comparison of IDEAL-SPGR volume sequence to standard MR sequences in the detection and grading of cartilage

[21] Colvin AC, Koehler SM, Bird J. Can the change in center-edge angle during pincer trimming be reliably predicted? Clinical Orthopaedics and Related Research. 2011;**469**(4):1071-1074

[22] Cross MB, et al. Impingement (acetabular side). Clinics in Sports Medicine. 2011;**30**(2):379-390 [23] Ilizaliturri Jr VM, et al. Hip arthroscopy after traumatic hip dislocation. The American

[24] Konan S, et al. Validation of the classification system for acetabular chondral lesions identified at arthroscopy in patients with femoroacetabular impingement. Journal of

of Bone & Joint Surgery – British Volume. 2005;**87**(7):1012-1018

Rotterdam study. Arthritis & Rheumatology. 2005;**52**(3):787-793

Arthroscopy. 1996;**12**(5):603-612

114 Cartilage Repair and Regeneration

Surgery – American Volume. 2012;**94**(4):e23

lesions. Radiology. 2011;**261**(3):863-871

Journal of Sports Medicine. 2011;**39**(Suppl):50S-57S

Bone & Joint Surgery – British Volume. 2011;**93**(3):332-336

Joint Surgery – American Volume, 2008;**90**(Suppl 4):2-19

American Journal of Roentgenology. 2009;**193**(2):W127-W133


[42] Krueger JA, et al. The extent and distribution of cell death and matrix damage in impacted chondral explants varies with the presence of underlying bone. Journal of Biomechanical Engineering. 2003;**125**(1):114-119

[58] Knutsen G, et al. A randomized multicenter trial comparing autologous chondrocyte implantation with microfracture: Long-term follow-up at 14 to 15 years. Journal of Bone

Chondral Lesion in the Hip Joint and Current Chondral Repair Techniques

http://dx.doi.org/10.5772/intechopen.70261

117

[59] Fontana A. Autologous Membrane Induced Chondrogenesis (AMIC) for the treatment of acetabular chondral defect. Muscles, Ligaments and Tendons Journal. 2016;**6**(3):

[60] Bauer M, Jackson RW. Chondral lesions of the femoral condyles: A system of arthroscopic

[61] Jackson RW. Arthroscopic Treatment of degenerative Arthritis, In: McGinty JB, editor.

[62] Chang RW, et al. A randomized, controlled trial of arthroscopic surgery versus closedneedle joint lavage for patients with osteoarthritis of the knee. Arthritis & Rheumatology.

[63] Livesley PJ, et al. Arthroscopic lavage of osteoarthritic knees. Journal of Bone & Joint Surgery –

[64] McLaren AC, et al. Arthroscopic debridement of the knee for osteoarthrosis. Canadian

[65] Gibson JN, et al. Arthroscopic lavage and debridement for osteoarthritis of the knee.

[66] Sozen YV, et al. The effectiveness of arthroscopic debridement and lavage treatment in osteoarthritis of the hip: Preliminary results. Acta Orthopaedica et Traumatologica Turcica.

[67] Moseley JB, et al. A controlled trial of arthroscopic surgery for osteoarthritis of the knee.

[68] Steadman JR, Rodkey WG, Rodrigo JJ. Microfracture: Surgical technique and rehabilitation to treat chondral defects. Clinical Orthopaedics and Related Research. 2001;**391**(Suppl):

[69] Steadman JR, et al. The microfracture technic in the management of complete cartilage

[70] Steadman JR, Rodkey WG, Briggs KK. Microfracture: Its history and experience of the

[71] Steadman JR, et al. Outcomes of microfracture for traumatic chondral defects of the

[72] Knutsen G, et al. Autologous chondrocyte implantation compared with microfracture in the knee. A randomized trial. Journal of Bone & Joint Surgery – American Volume.

knee: Average 11-year follow-up. Arthroscopy. 2003;**19**(5):477-484

Journal of Bone & Joint Surgery – British Volume. 1992;**74**(4):534-537

& Joint Surgery – American Volume. 2016;**98**(16):1332-1339

classification. Arthroscopy. 1988;**4**(2):97-102

Operative Arhroscopy. New York: Raven press; 1991

New England Journal of Medicine. 2002;**347**(2):81-88

defects in the knee joint. Orthopade. 1999;**28**(1):26-32

developing surgeon. Cartilage. 2010;**1**(2):78-86

367-371

1993;**36**(3):289-296

2004;**38**(2):96-103

S362-S369

2004;**86-A**(3):455-464

British Volume. 1991;**73**(6):922-926

Journal of Surgery. 1991;**34**(6):595-598


[58] Knutsen G, et al. A randomized multicenter trial comparing autologous chondrocyte implantation with microfracture: Long-term follow-up at 14 to 15 years. Journal of Bone & Joint Surgery – American Volume. 2016;**98**(16):1332-1339

[42] Krueger JA, et al. The extent and distribution of cell death and matrix damage in impacted chondral explants varies with the presence of underlying bone. Journal of

[43] Stafford GH, Bunn JR, Villar RN. Arthroscopic repair of delaminated acetabular articular cartilage using fibrin adhesive. Results at one to three years. HIP International.

[44] Tsaveas AP, Villar RN, Arthroscopic repair of acetabular chondral delamination with

[45] McGill KC, Bush-Joseph CA, Nho SJ. Hip microfracture: Indications, technique, and out-

[46] Lodhia P, et al. Microfracture in the hip: A matched-control study with average 3-year

[47] Sekiya JK, Martin RL, Lesniak BP. Arthroscopic repair of delaminated acetabular articular cartilage in femoroacetabular impingement. Orthopedics. 2009;**32**(9). DOI:

[48] Kubo T, et al. Hip arthroscopic osteochondral autologous transplantation for treating osteochondritis dissecans of the femoral head. Arthroscopy Techniques. 2015;**4**(6):

[49] Akimau P, et al. Autologous chondrocyte implantation with bone grafting for osteochondral defect due to posttraumatic osteonecrosis of the hip – A case report. Acta

[50] Crawford K, et al. Microfracture of the hip in athletes. Clinics in Sports Medicine.

[51] Hart R, et al. Mosaicplasty for the treatment of femoral head defect after incorrect resorb-

[52] Millis MB, Kim YJ. Rationale of osteotomy and related procedures for hip preservation:

[53] Nousiainen MT, et al. The use osteochondral allograft in the treatment of a severe femo-

[54] Parvizi J, et al. Management of arthritis of the hip in the young adult. Journal of Bone &

[55] Philippon MJ, et al. Can microfracture produce repair tissue in acetabular chondral

[56] Williams RJ, editor. Cartilage Repair Strategies. Totowa, NJ: Humana Press; 2007. xvii,

[57] Fontana A, et al. Arthroscopic treatment of hip chondral defects: Autologous chondrocyte transplantation versus simple debridement – A pilot study. Arthroscopy. 2012;**28**(3):322-329

A review. Clinical Orthopaedics and Related Research. 2002;**405**:108-121

ral head fracture. Journal of Orthopaedic Trauma. 2010;**24**(2):120-124

Biomechanical Engineering. 2003;**125**(1):114-119

fibrin adhesive. HIP International. 2010;**20**(1):115-119

able screw insertion. Arthroscopy. 2003;**19**(10):E1-E5

Joint Surgery – British Volume. 2006;**88**(10):1279-1285

defects? Arthroscopy. 2008;**24**(1):46-50

follow-up. Journal of Hip Preservation Surgery. 2015;**2**(4):417-427

comes. Cartilage. 2010;**1**(2):127-136

10.3928/01477447-20090728-44

Orthopaedica. 2006;**77**(2):333-336

2006;**25**(2):327-335, x

e675-e680

374 p

2011;**21**(6):744-750

116 Cartilage Repair and Regeneration


[73] Frisbie DD, et al. Early events in cartilage repair after subchondral bone microfracture. Clinical Orthopaedics and Related Research. 2003;**407**:215-227

[86] Fortelny RH, et al. Use of fibrin sealant (Tisseel/Tissucol) in hernia repair: A systematic

Chondral Lesion in the Hip Joint and Current Chondral Repair Techniques

http://dx.doi.org/10.5772/intechopen.70261

119

[87] Massin P, et al. Does fibrin sealant use in total knee replacement reduce transfusion rates? A non-randomised comparative study. Orthopaedics & Traumatology: Surgery &

[88] Bekkers JE, et al. Quality of scaffold fixation in a human cadaver knee model. Osteo-

[89] Shah MA, Ebert AM, Sanders WE. Fibrin glue fixation of a digital osteochondral fracture: Case report and review of the literature. Journal of Hand Surgery American

[90] Esposito C, et al. Experience with the use of tissue adhesives in pediatric endoscopic

[91] Quinn J, et al. A randomized trial comparing octylcyanoacrylate tissue adhesive and sutures in the management of lacerations. Journal of the American Medical Association.

[92] Qureshi A, et al. n-Butyl cyanoacrylate adhesive for skin closure of abdominal wounds: Preliminary results. Annals of the Royal College of Surgeons of England. 1997;**79**(6):414-415

[93] Liebelt EL. Current concepts in laceration repair. Current Opinion in Pediatrics.

[94] Kull S, et al. Glubran 2 surgical glue: In vitro evaluation of adhesive and mechanical

[95] Ayan I, et al. Histoacryl glue in meniscal repairs (a biomechanical study). International

[96] Papatheofanis FJ. Cytotoxicity of alkyl-2-cyanoacrylate adhesives. Journal of Biomedical

[97] Montanaro L, et al. Cytotoxicity, blood compatibility and antimicrobial activity of two

[98] Evans CE, Lees GC, Trail IA. Cytotoxicity of cyanoacrylate adhesives to cultured tendon cells. Journal of Hand Surgery: British & European Volume. 1999;**24**(6):658-661

[99] n-BCA Trial Investigtors. N-butyl cyanoacrylate embolization of cerebral arteriovenous malformations: Results of a prospective, randomized, multi-center trial. American

[100] Dhiman RK, et al. Endoscopic sclerotherapy of gastric variceal bleeding with N-butyl-

[101] Seewald S, et al. Cyanoacrylate glue in gastric variceal bleeding. Endoscopy. 2002;**34**(11):

2-cyanoacrylate. Journal of Clinical Gastroenterology. 2002;**35**(3):222-227

properties. Journal of Surgical Research. 2009;**157**(1):e15-e21

cyanoacrylate glues for surgical use. Biomaterials. 2001;**22**(1):59-66

review. Surgical Endoscopy. 2012;**26**(7):1803-1812

arthritis and Cartilage. 2010;**18**(2):266-272

surgery. Surgical Endoscopy. 2004;**18**(2):290-292

Research. 2012;**98**(2):180-185

Society. 2002;**27**(3):464-469

1997;**277**(19):1527-1530

1997;**9**(5): 459-464

926-932

Orthopaedics. 2007;**31**(2):241-246

Materials Research. 1989;**23**(6):661-668

Journal of Neuroradiology. 2002;**23**(5):748-755


[86] Fortelny RH, et al. Use of fibrin sealant (Tisseel/Tissucol) in hernia repair: A systematic review. Surgical Endoscopy. 2012;**26**(7):1803-1812

[73] Frisbie DD, et al. Early events in cartilage repair after subchondral bone microfracture.

[74] Tran-Khanh N, et al. Aged bovine chondrocytes display a diminished capacity to produce a collagen-rich, mechanically functional cartilage extracellular matrix. Journal of

[75] Frisbie DD, et al. Arthroscopic subchondral bone plate microfracture technique augments healing of large chondral defects in the radial carpal bone and medial femoral

[76] Bae DK, Yoon KH, Song SJ. Cartilage healing after microfracture in osteoarthritic knees.

[77] Saris DB, et al. Characterized chondrocyte implantation results in better structural repair when treating symptomatic cartilage defects of the knee in a randomized controlled trial versus microfracture. The American Journal of Sports Medicine. 2008;**36**(2):235-246

[78] Gudas R, et al. A prospective randomized clinical study of mosaic osteochondral autologous transplantation versus microfracture for the treatment of osteochondral defects in

[79] Gobbi A, Nunag P, Malinowski K. Treatment of full thickness chondral lesions of the knee with microfracture in a group of athletes. Knee Surgery, Sports Traumatology, Arthroscopy.

[80] Mithoefer K, et al. High-impact athletics after knee articular cartilage repair: A prospective evaluation of the microfracture technique. The American Journal of Sports Medicine.

[81] Jankowitz BT, et al. Effect of fibrin glue on the prevention of persistent cerebral spinal fluid leakage after incidental durotomy during lumbar spinal surgery. European Spine

[82] Lagoutte FM, Gauthier L, Comte PR. A fibrin sealant for perforated and preperforated

[83] Shehadeh-Mashor R, et al. Management of recurrent pterygium with intraoperative mitomycin C and conjunctival autograft with fibrin glue. American Journal of

[84] Hobbs CG, Darr A, Carlin WV. Management of intra-operative cerebrospinal fluid leak following endoscopic trans-sphenoidal pituitary surgery. Journal of Laryngology & Otology.

[85] Campanelli G, et al. Randomized, controlled, blinded trial of Tisseel/Tissucol for mesh fixation in patients undergoing Lichtenstein technique for primary inguinal hernia

repair: Results of the TIMELI trial. Annals of Surgery. 2012;**255**(4):650-657

corneal ulcers. British Journal of Ophthalmology. 1989;**73**(9):757-761

the knee joint in young athletes. Arthroscopy. 2005;**21**(9):1066-1075

Clinical Orthopaedics and Related Research. 2003;**407**:215-227

condyle of horses. Veterinary Surgery. 1999;**28**(4):242-255

Orthopaedic Research. 2005;**23**(6):1354-1362

Arthroscopy. 2006;**22**(4):367-374

2005;**13**(3):213-221

118 Cartilage Repair and Regeneration

2006;**34**(9):1413-1418

2011;**125**(3):311-313

Journal. 2009;**18**(8):1169-1174

Ophthalmology. 2011;**152**(5):730-732


[102] Seewald S, et al. Endoscopic treatment of biliary leakage with n-butyl-2 cyanoacrylate. Gastrointestinal Endoscopy. 2002;**56**(6):916-919

[116] Koh JL, et al. The effect of graft height mismatch on contact pressure following osteochondral grafting: A biomechanical study. The American Journal of Sports Medicine.

Chondral Lesion in the Hip Joint and Current Chondral Repair Techniques

http://dx.doi.org/10.5772/intechopen.70261

121

[117] Kock NB, et al. A cadaveric analysis of contact stress restoration after osteochondral transplantation of a cylindrical cartilage defect. Knee Surgery, Sports Traumatology,

[118] Hangody L, Füles P. Autologous osteochondral mosaicplasty for the treatment of full-thickness defects of weight-bearing joints: Ten years of experimental and clinical experience. Journal of Bone & Joint Surgery – American Volume. 2003;**85-A**(Suppl 2):

[119] Rittmeister M, et al. Five-year results following autogenous osteochondral transplanta-

[120] Girard J, et al. Osteochondral mosaicplasty of the femoral head. HIP International.

[121] Nam D, et al. Traumatic osteochondral injury of the femoral head treated by mosaicplasty: A report of two cases. The Musculoskeletal Journal of Hospital for Special Surgery.

[122] Emre TY, et al. Mosaicplasty for the treatment of the osteochondral lesion in the femoral head. Bulletin of the NYU Hospital for Joint Diseases. 2012;**70**(4):288-290

[123] Gagala J, Tarczynska M, Gaweda K, Fixation of femoral head fractures with autologous osteochondral transfer (mosaicplasty). Journal of Orthopaedic Trauma. 2014;**28**(9):e226-e230

[124] Cetinkaya S, Toker B, Taser O. Arthroscopic retrograde osteochondral autologous transplantation to chondral lesion in femoral head. Orthopedics. 2014;**37**(6):

[125] Evans KN, Providence BC. Case report: Fresh-stored osteochondral allograft for treatment of osteochondritis dissecans the femoral head. Clinical Orthopaedics and Related

[126] Aubin PP, et al. Long-term followup of fresh femoral osteochondral allografts for posttraumatic knee defects. Clinical Orthopaedics and Related Research. 2001;**391**(Suppl):S318-S327

[127] Kim CW, et al. Treatment of post-traumatic ankle arthrosis with bipolar tibiotalar osteochondral shell allografts. Foot & Ankle International. 2002;**23**(12):1091-1102 [128] Bugbee WD. Fresh osteochondral allografts. Journal of Knee Surgery. 2002;**15**(3):191-195 [129] Chu CR, et al. Articular cartilage transplantation. Clinical results in the knee. Clinical

[130] Ghazavi MT, et al. Fresh osteochondral allografts for post-traumatic osteochondral defects of the knee. Journal of Bone & Joint Surgery – British Volume. 1997;**79**(6):

Orthopaedics and Related Research. 1999;**360**:159-168

tion to the femoral head. Orthopade. 2005;**34**(4):320, 322-326

2004;**32**(2):317-320

2011;**21**(5):542-548

2010;**6**(2):228-234

e600-e604

1008-1013

Research. 2010;**468**(2):613-618

25-32

Arthroscopy. 2008;**16**(5):461-468


[116] Koh JL, et al. The effect of graft height mismatch on contact pressure following osteochondral grafting: A biomechanical study. The American Journal of Sports Medicine. 2004;**32**(2):317-320

[102] Seewald S, et al. Endoscopic treatment of biliary leakage with n-butyl-2 cyanoacrylate.

[103] Mutignani M, et al. External pancreatic fistulas resistant to conventional endoscopic therapy: Endoscopic closure with N-butyl-2-cyanoacrylate (Glubran 2). Endoscopy.

[104] Testini M, et al. A single-surgeon randomized trial comparing sutures, N-butyl-2 cyanoacrylate and human fibrin glue for mesh fixation during primary inguinal hernia

[105] Paajanen H, et al. Randomized clinical trial of tissue glue versus absorbable sutures for mesh fixation in local anaesthetic Lichtenstein hernia repair. British Journal of Surgery.

[106] Kukleta JF, Freytag C, Weber M. Efficiency and safety of mesh fixation in laparoscopic inguinal hernia repair using n-butyl cyanoacrylate: Long-term biocompatibility in over

[107] Reckers LJ, Fagundes DJ, Cohen M. The ineffectiveness of fibrin glue and cyanoacrylate

[108] Levrier O, et al. Efficacy and low vascular toxicity of embolization with radical versus anionic polymerization of n-butyl-2-cyanoacrylate (NBCA). An experimental study in

[109] Cassar-Gheiti AJ, et al. Comparison of four chondral repair techniques in the hip joint: A biomechanical study using a physiological human cadaveric model. Osteoarthritis

[110] Krusche-Mandl I, et al. Long-term results 8 years after autologous osteochondral transplantation: 7 T gagCEST and sodium magnetic resonance imaging with morphological

[111] Ollat D, et al. Mosaic osteochondral transplantations in the knee joint, midterm results of the SFA multicenter study. Orthopaedics & Traumatology: Surgery & Research. 2011;

[112] Robert H. Chondral repair of the knee joint using mosaicplasty. Orthopaedics &

[113] Krych AJ, Lorich DG, Kelly BT. Treatment of focal osteochondral defects of the acetabulum with osteochondral allograft transplantation. Orthopedics. 2011;**34**(7):e307-e311

[114] Scully WF, Parada SA, Arrington ED. Allograft osteochondral transplantation in the knee in the active duty population. Military Medicine. 2011;**176**(10):1196-1201

[115] Krych AJ, et al. Return to athletic activity after osteochondral allograft transplantation in the knee. The American Journal of Sports Medicine. Am J Sports Med. 2012

and clinical correlation. Osteoarthritis and Cartilage. 2012;**20**(5):357-363

on fixation of meniscus transplants in rabbits. Knee. 2009;**16**(4):290-294

Gastrointestinal Endoscopy. 2002;**56**(6):916-919

repair. Canadian Journal of Surgery. 2010;**53**(3):155-160

1300 mesh fixations. Hernia. 2012;**16**(2):153-162

and Cartilage. 2015;**23**(6):1018-1025

**97**(8 Suppl):S160-S166

May;**40**(5):1053-9

the swine. Journal of Neuroradiology. 2003;**30**(2):95-102

Traumatology: Surgery & Research. 2011;**97**(4):418-429

2004;**36**(8):738-742

120 Cartilage Repair and Regeneration

2011;**98**(9):1245-1251


[131] Bugbee WD, Convery FR. Osteochondral allograft transplantation. Clinics in Sports Medicine. 1999;**18**(1):67-75

**Chapter 7**

**Provisional chapter**

**Osteochondritis Dissecans of the Knee**

**Osteochondritis Dissecans of the Knee**

DOI: 10.5772/intechopen.70275

Osteochondritis dissecans (OCD) is a common but poorly understood source of knee pain and dysfunction. It is a condition primarily affecting the subchondral bone, with secondary effects on the articular cartilage surface. A large amount of research over the past two decades has produced many valuable insights into the condition, but further study and elucidation are still needed. The goal of this chapter will be to serve as a general overview of osteochondritis dissecans as it is understood today, including the etiology, clinical pre-

**Keywords:** osteochondritis dissecans, knee, cartilage injury, OCD treatment, OCD outcomes

Osteochondritis dissecans (OCD) has become a well-recognized, but still poorly understood source of knee pain and dysfunction. It is a condition primarily affecting the subchondral bone, with secondary effects on the articular cartilage surface. A large amount of research over the last two decades has produced many valuable insights into the condition, but further study and elucidation are still needed. The goal of this chapter will be to serve as a general overview of osteochondritis dissecans as it is understood today, including the etiology, clini-

The term osteochondritis dissecans was first documented in the literature in 1887 by Franz Konig, who described a presumed inflammatory process leading to loose bodies in the elbow and knee joints in young, atraumatic patients [1]. This theory was ultimately disproved as histological studies began to support findings of necrosis rather than inflammation in OCD lesions [2–6]. Many other theories and descriptions of osteochondritis dissecans have subsequently been proposed, but a definitive understanding remains elusive. The current working

cal presentation, diagnosis, treatment options, outcomes, and future research aims.

sentation, diagnosis, treatment options, outcomes, and future research aims.

© 2016 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution,

© 2018 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

and reproduction in any medium, provided the original work is properly cited.

Anthony C. Egger and Paul Saluan

Anthony C. Egger and Paul Saluan

http://dx.doi.org/10.5772/intechopen.70275

**Abstract**

**1. Introduction**

Additional information is available at the end of the chapter

Additional information is available at the end of the chapter


**Provisional chapter**

## **Osteochondritis Dissecans of the Knee**

**Osteochondritis Dissecans of the Knee**

## Anthony C. Egger and Paul Saluan Anthony C. Egger and Paul Saluan Additional information is available at the end of the chapter

Additional information is available at the end of the chapter

http://dx.doi.org/10.5772/intechopen.70275

#### **Abstract**

[131] Bugbee WD, Convery FR. Osteochondral allograft transplantation. Clinics in Sports

[132] Emmerson BC, et al. Fresh osteochondral allografting in the treatment of osteochondritis dissecans of the femoral condyle. The American Journal of Sports Medicine.

[133] Gross AE, et al. Fresh osteochondral allografts for posttraumatic knee defects: Longterm followup. Clinical Orthopaedics and Related Research. 2008;**466**(8):1863-1870

[134] Brittberg M, et al. Treatment of deep cartilage defects in the knee with autologous chondrocyte transplantation. New England Journal of Medicine. 1994;**331**(14):889-895 [135] Wood JJ, et al. Autologous cultured chondrocytes: Adverse events reported to the United States Food and Drug Administration. Journal of Bone & Joint Surgery – American

[136] Peterson L, et al. Two- to 9-year outcome after autologous chondrocyte transplantation of the knee. Clinical Orthopaedics and Related Research, 2000;**374**:212-234

[137] Awad HA, et al. Chondrogenic differentiation of adipose-derived adult stem cells in agarose, alginate, and gelatin scaffolds. Biomaterials. 2004;**25**(16):3211-3222

[138] Guo JF, Jourdian GW, MacCallum DK. Culture and growth characteristics of chondrocytes encapsulated in alginate beads. Connective Tissue Research. 1989;**19**(2-4):277-297

[139] Pettersson S, et al. Cell expansion of human articular chondrocytes on macroporous gelatine scaffolds-impact of microcarrier selection on cell proliferation. Biomedical

[140] Marmotti A, et al. One-step osteochondral repair with cartilage fragments in a composite scaffold. Knee Surgery, Sports Traumatology, Arthroscopy. 2012;**20**(12):2590-2601

[141] Behrens P, et al. Matrix-associated autologous chondrocyte transplantation/implanta-

[142] Marcacci M, et al. In: Williams RJ, editor, Cell-Based Cartilage Repair Using the Hyalograft Transplant. Cartilage Repair Strategies Totowa, NJ: Humana Press; 2007.

[143] Benthien JP, Behrens P. Autologous Matrix-Induced Chondrogenesis (AMIC): Combining microfracturing and a collagen I/III matrix for articular cartilage resurfac-

[144] Gille J, et al. Outcome of Autologous Matrix-Induced Chondrogenesis (AMIC) in cartilage knee surgery: Data of the AMIC registry. Archives of Orthopaedic and Trauma Surgery.

tion (MACT/MACI) – 5-year follow-up. Knee. 2006;**13**(3):194-202

Medicine. 1999;**18**(1):67-75

Volume. 2006;**88**(3):503-507

Materials. 2011;**6**(6):065001

ing. Cartilage. 2010;**1**(1):65-68

pp. 207-218

2013;**133**(1):87-93

2007;**35**(6):907-914

122 Cartilage Repair and Regeneration

Osteochondritis dissecans (OCD) is a common but poorly understood source of knee pain and dysfunction. It is a condition primarily affecting the subchondral bone, with secondary effects on the articular cartilage surface. A large amount of research over the past two decades has produced many valuable insights into the condition, but further study and elucidation are still needed. The goal of this chapter will be to serve as a general overview of osteochondritis dissecans as it is understood today, including the etiology, clinical presentation, diagnosis, treatment options, outcomes, and future research aims.

DOI: 10.5772/intechopen.70275

**Keywords:** osteochondritis dissecans, knee, cartilage injury, OCD treatment, OCD outcomes

## **1. Introduction**

Osteochondritis dissecans (OCD) has become a well-recognized, but still poorly understood source of knee pain and dysfunction. It is a condition primarily affecting the subchondral bone, with secondary effects on the articular cartilage surface. A large amount of research over the last two decades has produced many valuable insights into the condition, but further study and elucidation are still needed. The goal of this chapter will be to serve as a general overview of osteochondritis dissecans as it is understood today, including the etiology, clinical presentation, diagnosis, treatment options, outcomes, and future research aims.

The term osteochondritis dissecans was first documented in the literature in 1887 by Franz Konig, who described a presumed inflammatory process leading to loose bodies in the elbow and knee joints in young, atraumatic patients [1]. This theory was ultimately disproved as histological studies began to support findings of necrosis rather than inflammation in OCD lesions [2–6]. Many other theories and descriptions of osteochondritis dissecans have subsequently been proposed, but a definitive understanding remains elusive. The current working

© 2016 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. © 2018 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

definition of OCD as developed by the leading collaborative research group on the topic is as follows: a focal, idiopathic alteration of subchondral bone with risk for instability and disruption of adjacent articular cartilage that result in premature osteoarthritis [7].

Histology of necrotic bone has been shown to be consistent with vascular occlusions, and it has been proposed that insufficient arterial branching could lead to subchondral bone infarction and subsequent OCD [21, 22]. The presence of an ischemic zone in the lateral aspect of the medial femoral condyle has been questioned, although particularly in young patients who

Osteochondritis Dissecans of the Knee http://dx.doi.org/10.5772/intechopen.70275 125

Repetitive microtrauma has become the most accepted cause of OCD, mainly due to the rising incidence of the disorder among athletes [27]. The theory states that an initial stress reaction occurs in the subchondral bone of the knee and with further loading a true stress fracture is generated. Repetitive, progressive loading prevents the stress fracture from healing and eventually the subchondral bone becomes necrotic [2]. The fragment begins to dissect and ultimately separate from the fracture bed leading to an unstable OCD lesion. In this theory, bone necrosis is seen as secondary to trauma rather than to a primary lack of vascularity. Mechanical axis alignment has also been associated with OCD, with aberrant mechanical pressures on the condyles potentially leading to the formation of an OCD [28]. The true etiology of OCD is most likely multi-factorial and a combination of the currently proposed

The clinical presentation of OCD lesions can be quite variable and often differs depending on the stability and severity of the lesion. Stable lesions, as are frequently seen in juvenile OCD, often present with complaints of nonspecific and poorly localized knee pain which is exacerbated by exercise, particularly when climbing stairs or hills [10]. Unstable lesions are commonly seen in adult OCD and present with more mechanical symptoms like swelling,

On physical examination, both stable and unstable lesions may present with an antalgic gait. An external rotation of the tibia during gait can be seen as compensation for impingement of the tibial eminence on an OCD lesion of the medial femoral condyle [29]. This can be tested clinically with the Wilson test, which elicits pain when the tibia is internally rotated during extension of the knee between 90 and 30°. Pain is relieved with tibial external rotation as it moves the eminence away from the lesion. Ligamentous stability and overall alignment must also be assessed to allow for concomitant pathology to be appropriately addressed. Muscle strength testing is also important as significant dynamic strength deficits of the quadriceps

Plain radiographs and magnetic resonance imaging (MRI) are the two most commonly used imaging modalities in evaluating knee OCD. Radiographs are commonly used for the initial diagnosis and assessment of skeletal maturity, whereas MRI highlights changes in the articu-

have good distal femoral blood supply [23–26].

**4. Clinical presentation and physical examination**

and core may warrant rehabilitation attempts prior to surgery [30].

theories.

**5. Imaging**

stiffness, locking, and catching.

lar cartilage and subchondral bone.

Traditionally, OCD had been subclassified into two groups based on the status of the distal femoral physis. Juvenile OCD occurs in those with an open distal femoral physis, whereas adult OCD is found in skeletally mature patients [8]. Previously, the etiology of OCD in skeletally immature individuals was thought to be from a fundamental disturbance in epiphyseal development. The adult form, on the other hand, was believed to be associated with more direct traumatic causation [9]. However, many experts now currently feel adult OCD is in the majority of cases not a distinct entity, but instead the natural progression of juvenile OCD missed in adolescence [10–12]. While the nomenclature is no longer as critical, the distinction between "juvenile" and "adult" OCD as based on presentation and timing of diagnosis is still important in regards to prognosis. Multiple studies have shown that juvenile OCD lesions to be more stable in appearance and to have a better prognosis than those diagnosed in adulthood [8, 10, 13–15].

## **2. Epidemiology**

The presence of articular cartilage pathology is found in greater than 60% of patients undergoing knee arthroscopies, with focal chondral defects of all varieties found in 20% of these patients [16–18]. As a subset of these lesions, osteochondritis dissecans of the knee remains a relatively uncommon condition. In the pediatric population aged 6–19 years, the incidence of OCD lesions of the knee was found to be 9.5 per 100,000. There is a strong predilection for males versus females with an incidence of 15.4 and 3.3 per 100,000, respectively. Patients aged 12–19 years have an over three times risk of OCD than those aged 6–11 years. In terms of race and ethnicity, African Americans have double the risk of OCD of the knee compared to non-Hispanic whites, and at least 4 times the risk of disease as all other races and ethnicities [19].

The most common location for OCD lesions to occur is in the medial femoral condyle, which accounts for 70–85% of all lesions. The majority of these lesions occur in the posterolateral aspect of the medial femoral condyle [19]. The next most frequent location is the lateral femoral condyle, and the lesions in this location are often found to be larger and more advanced. OCD lesions are also rarely found on the patella, trochlea, and tibial plateau [11].

## **3. Etiology**

Starting with Konig's inflammatory theory, numerous hypotheses regarding the true pathophysiology behind the formation and progression of OCD lesions of the knee have been proposed, but no one theory has gained uniform consensus. In histologic review of OCD lesions, necrosis of the subchondral bone is often identified but it remains unclear if the presence of the necrosis is primary or secondary to the pathogenesis of OCD [3–6, 20]. The vascularity of the subchondral bone has been described as an end arterial arcade with poor anastomoses. Histology of necrotic bone has been shown to be consistent with vascular occlusions, and it has been proposed that insufficient arterial branching could lead to subchondral bone infarction and subsequent OCD [21, 22]. The presence of an ischemic zone in the lateral aspect of the medial femoral condyle has been questioned, although particularly in young patients who have good distal femoral blood supply [23–26].

Repetitive microtrauma has become the most accepted cause of OCD, mainly due to the rising incidence of the disorder among athletes [27]. The theory states that an initial stress reaction occurs in the subchondral bone of the knee and with further loading a true stress fracture is generated. Repetitive, progressive loading prevents the stress fracture from healing and eventually the subchondral bone becomes necrotic [2]. The fragment begins to dissect and ultimately separate from the fracture bed leading to an unstable OCD lesion. In this theory, bone necrosis is seen as secondary to trauma rather than to a primary lack of vascularity. Mechanical axis alignment has also been associated with OCD, with aberrant mechanical pressures on the condyles potentially leading to the formation of an OCD [28]. The true etiology of OCD is most likely multi-factorial and a combination of the currently proposed theories.

## **4. Clinical presentation and physical examination**

The clinical presentation of OCD lesions can be quite variable and often differs depending on the stability and severity of the lesion. Stable lesions, as are frequently seen in juvenile OCD, often present with complaints of nonspecific and poorly localized knee pain which is exacerbated by exercise, particularly when climbing stairs or hills [10]. Unstable lesions are commonly seen in adult OCD and present with more mechanical symptoms like swelling, stiffness, locking, and catching.

On physical examination, both stable and unstable lesions may present with an antalgic gait. An external rotation of the tibia during gait can be seen as compensation for impingement of the tibial eminence on an OCD lesion of the medial femoral condyle [29]. This can be tested clinically with the Wilson test, which elicits pain when the tibia is internally rotated during extension of the knee between 90 and 30°. Pain is relieved with tibial external rotation as it moves the eminence away from the lesion. Ligamentous stability and overall alignment must also be assessed to allow for concomitant pathology to be appropriately addressed. Muscle strength testing is also important as significant dynamic strength deficits of the quadriceps and core may warrant rehabilitation attempts prior to surgery [30].

## **5. Imaging**

definition of OCD as developed by the leading collaborative research group on the topic is as follows: a focal, idiopathic alteration of subchondral bone with risk for instability and disrup-

Traditionally, OCD had been subclassified into two groups based on the status of the distal femoral physis. Juvenile OCD occurs in those with an open distal femoral physis, whereas adult OCD is found in skeletally mature patients [8]. Previously, the etiology of OCD in skeletally immature individuals was thought to be from a fundamental disturbance in epiphyseal development. The adult form, on the other hand, was believed to be associated with more direct traumatic causation [9]. However, many experts now currently feel adult OCD is in the majority of cases not a distinct entity, but instead the natural progression of juvenile OCD missed in adolescence [10–12]. While the nomenclature is no longer as critical, the distinction between "juvenile" and "adult" OCD as based on presentation and timing of diagnosis is still important in regards to prognosis. Multiple studies have shown that juvenile OCD lesions to be more stable in appearance and to have a better prognosis than those diagnosed in adult-

The presence of articular cartilage pathology is found in greater than 60% of patients undergoing knee arthroscopies, with focal chondral defects of all varieties found in 20% of these patients [16–18]. As a subset of these lesions, osteochondritis dissecans of the knee remains a relatively uncommon condition. In the pediatric population aged 6–19 years, the incidence of OCD lesions of the knee was found to be 9.5 per 100,000. There is a strong predilection for males versus females with an incidence of 15.4 and 3.3 per 100,000, respectively. Patients aged 12–19 years have an over three times risk of OCD than those aged 6–11 years. In terms of race and ethnicity, African Americans have double the risk of OCD of the knee compared to non-Hispanic whites, and at least 4 times the risk of disease as all other races and ethnicities [19]. The most common location for OCD lesions to occur is in the medial femoral condyle, which accounts for 70–85% of all lesions. The majority of these lesions occur in the posterolateral aspect of the medial femoral condyle [19]. The next most frequent location is the lateral femoral condyle, and the lesions in this location are often found to be larger and more advanced.

OCD lesions are also rarely found on the patella, trochlea, and tibial plateau [11].

Starting with Konig's inflammatory theory, numerous hypotheses regarding the true pathophysiology behind the formation and progression of OCD lesions of the knee have been proposed, but no one theory has gained uniform consensus. In histologic review of OCD lesions, necrosis of the subchondral bone is often identified but it remains unclear if the presence of the necrosis is primary or secondary to the pathogenesis of OCD [3–6, 20]. The vascularity of the subchondral bone has been described as an end arterial arcade with poor anastomoses.

tion of adjacent articular cartilage that result in premature osteoarthritis [7].

hood [8, 10, 13–15].

124 Cartilage Repair and Regeneration

**2. Epidemiology**

**3. Etiology**

Plain radiographs and magnetic resonance imaging (MRI) are the two most commonly used imaging modalities in evaluating knee OCD. Radiographs are commonly used for the initial diagnosis and assessment of skeletal maturity, whereas MRI highlights changes in the articular cartilage and subchondral bone.

Radiographs are relatively inexpensive and easy to obtain, making it the initial imaging choice for evaluation of suspected OCD. Radiographs evaluating for OCD lesions often include anteroposterior, lateral, sunrise, and tunnel/notch views. The characteristic appearance of an OCD lesion of the knee consists of a well-circumscribed lucent defect in the subchondral bone [31]. The notch view, which is obtained with a posterior to anterior beam at approximately 30° of flexion, is particularly helpful for evaluating the posterior aspects of the femoral condyles [8]. Evaluating for potential lesions in boys younger than 13 and girls younger than 11 requires caution as they may develop secondary ossifications that can resemble OCD lesions and MRI is often needed for clarification [10]. Given the limitations of radiographs in assessing an OCD lesion, MRI is often used to evaluate the true size and stability in order to determine an appropriate surgical plan.

an offloader brace [40]. The goal of conservative management is to eliminate pain and repeti-

Osteochondritis Dissecans of the Knee http://dx.doi.org/10.5772/intechopen.70275 127

Overall, successful healing rates >50% have been shown for stable juvenile OCD lesions treated nonoperatively. However, this has not been replicated in the adult population, with poor results seen without surgical intervention for adult OCD lesions [4, 8, 41]. Adult OCD lesions have little capacity for healing with nonoperative means, but an unloader brace is a potential temporary option to allow an athlete to finish their season prior to operative intervention [40]. Complete resolution of symptoms takes time, patience, and compliance, which

In those patients who have failed nonoperative treatment or have large, unstable, or unsalvageable lesions, surgical intervention is often required. Cartilage treatment strategies can be characterized as palliation (debridement), repair [drilling and microfracture (MF)], or restoration [osteochondral autograft transfer (OAT), osteochondral allograft (OCA), and autologous chondrocyte implantation (ACI)] [42]. One of the most important determinations to be made prior to surgical intervention is the stability of the OCD lesion. The stability relates to the mechanical integrity of the subchondral lesion [43]. A lesion which is immobile and resting in situ is considered to be stable, whereas a lesion which is mobile, fragmented, or ex situ is considered unstable. The distinction is important for determining the appropriate surgical plan.

Subchondral drilling is the initial standard of care operative procedure for stable OCD lesions. There are two main types of drilling, transarticular and retroarticular, but the principle behind each technique is the same. The goal of subchondral drilling is to use a Kirschner wire to disrupt the sclerotic margin of the lesion to establish channels between the necrotic subchondral bone and the healthy cancellous bone in order to promote revascularization, osseous bridging,

Transarticular drilling is done from inside the joint and penetrates the articular cartilage through at least one site to create subchondral penetrations. The main concern with this technique is related to the uncertain long-term implications of disrupting the articular cartilage with the drill sites. Retroarticular drilling avoids this concern by sparing the articular surface and physes with drilling through the affected femoral condyle into the lesion under fluoroscopy. Aside from the added radiation risk, this technique is also more technically demanding and risks incomplete lesion drilling, lesion displacement, or inadvertent soft tissue injury [10]. Neither technique has clearly demonstrated superior patient-orientated outcomes or radiographic healing. Transarticular drilling demonstrated an average healing rate of 91% with a mean healing time of 4.5 months with retroarticular just behind at 86% at 5.6 months [44].

and healing [11]. The average time to healing is around 4–6 months after surgery.

tive loading to help promote healing of OCD lesions.

is important to stress to patients early in the process.

**8. Operative treatment**

**9. Subchondral drilling**

## **6. Classification systems**

The most commonly used classification system for OCD lesions is based on MRI findings. The Hefti system divides lesions into five different stages and differentiates between stable (stages 1 and 2) and unstable (stages 3, 4, and 5) lesions with progressive pathology noted [13].

The MRI classification has been shown to be accurate to divide lesions into stable and unstable categories, but ultimately arthroscopic evaluation provides the best assessment of the OCD lesion [32]. Multiple arthroscopic systems have been proposed to classify lesions during surgery, but no comprehensive system to describe the full complement of OCD lesions has been accepted [32–37]. The Research in OsteoChondritis of the Knee (ROCK) group developed a novel classification system to provide a common language in describing these lesions [38]. To optimize comprehensibility and applicability, each type was described with a memorable name. The classification divides lesions into immobile and mobile lesions. The "cue ball" (no detectable abnormality), "shadow" (cartilage intact but subtly demarcated), and "wrinkle in the rug" (cartilage is demarcated with a fissure or wrinkle) are in the immobile category. The mobile lesions consist of the "locked door" (cartilage fissuring at periphery but unable to hinge open), "trap door" (able to hinge open the fissure), and "crater" (exposed subchondral bone defect). This classification system has been shown to have very good inter-observer reliability and should be used to facilitate a common language which is crucial for future collaborative research.

## **7. Nonoperative treatment**

Nonoperative management is the appropriate first line of treatment for stable juvenile OCD lesions. Juvenile OCD lesions have a higher healing potential than adult lesions, and an open distal femoral physis has been shown as one of the best predictors for successful nonoperative management [39]. Conservative management is usually attempted for a minimum of 3 months to allow for potential healing. Most current nonoperative treatment plans focus on activity modification with cessation of impact activities and protected weight bearing with crutches or an offloader brace [40]. The goal of conservative management is to eliminate pain and repetitive loading to help promote healing of OCD lesions.

Overall, successful healing rates >50% have been shown for stable juvenile OCD lesions treated nonoperatively. However, this has not been replicated in the adult population, with poor results seen without surgical intervention for adult OCD lesions [4, 8, 41]. Adult OCD lesions have little capacity for healing with nonoperative means, but an unloader brace is a potential temporary option to allow an athlete to finish their season prior to operative intervention [40]. Complete resolution of symptoms takes time, patience, and compliance, which is important to stress to patients early in the process.

## **8. Operative treatment**

Radiographs are relatively inexpensive and easy to obtain, making it the initial imaging choice for evaluation of suspected OCD. Radiographs evaluating for OCD lesions often include anteroposterior, lateral, sunrise, and tunnel/notch views. The characteristic appearance of an OCD lesion of the knee consists of a well-circumscribed lucent defect in the subchondral bone [31]. The notch view, which is obtained with a posterior to anterior beam at approximately 30° of flexion, is particularly helpful for evaluating the posterior aspects of the femoral condyles [8]. Evaluating for potential lesions in boys younger than 13 and girls younger than 11 requires caution as they may develop secondary ossifications that can resemble OCD lesions and MRI is often needed for clarification [10]. Given the limitations of radiographs in assessing an OCD lesion, MRI is often used to evaluate the true size and stability in order to deter-

The most commonly used classification system for OCD lesions is based on MRI findings. The Hefti system divides lesions into five different stages and differentiates between stable (stages 1 and 2) and unstable (stages 3, 4, and 5) lesions with progressive pathology noted [13].

The MRI classification has been shown to be accurate to divide lesions into stable and unstable categories, but ultimately arthroscopic evaluation provides the best assessment of the OCD lesion [32]. Multiple arthroscopic systems have been proposed to classify lesions during surgery, but no comprehensive system to describe the full complement of OCD lesions has been accepted [32–37]. The Research in OsteoChondritis of the Knee (ROCK) group developed a novel classification system to provide a common language in describing these lesions [38]. To optimize comprehensibility and applicability, each type was described with a memorable name. The classification divides lesions into immobile and mobile lesions. The "cue ball" (no detectable abnormality), "shadow" (cartilage intact but subtly demarcated), and "wrinkle in the rug" (cartilage is demarcated with a fissure or wrinkle) are in the immobile category. The mobile lesions consist of the "locked door" (cartilage fissuring at periphery but unable to hinge open), "trap door" (able to hinge open the fissure), and "crater" (exposed subchondral bone defect). This classification system has been shown to have very good inter-observer reliability and should be used to facilitate a common language which is crucial for future col-

Nonoperative management is the appropriate first line of treatment for stable juvenile OCD lesions. Juvenile OCD lesions have a higher healing potential than adult lesions, and an open distal femoral physis has been shown as one of the best predictors for successful nonoperative management [39]. Conservative management is usually attempted for a minimum of 3 months to allow for potential healing. Most current nonoperative treatment plans focus on activity modification with cessation of impact activities and protected weight bearing with crutches or

mine an appropriate surgical plan.

**6. Classification systems**

126 Cartilage Repair and Regeneration

laborative research.

**7. Nonoperative treatment**

In those patients who have failed nonoperative treatment or have large, unstable, or unsalvageable lesions, surgical intervention is often required. Cartilage treatment strategies can be characterized as palliation (debridement), repair [drilling and microfracture (MF)], or restoration [osteochondral autograft transfer (OAT), osteochondral allograft (OCA), and autologous chondrocyte implantation (ACI)] [42]. One of the most important determinations to be made prior to surgical intervention is the stability of the OCD lesion. The stability relates to the mechanical integrity of the subchondral lesion [43]. A lesion which is immobile and resting in situ is considered to be stable, whereas a lesion which is mobile, fragmented, or ex situ is considered unstable. The distinction is important for determining the appropriate surgical plan.

## **9. Subchondral drilling**

Subchondral drilling is the initial standard of care operative procedure for stable OCD lesions. There are two main types of drilling, transarticular and retroarticular, but the principle behind each technique is the same. The goal of subchondral drilling is to use a Kirschner wire to disrupt the sclerotic margin of the lesion to establish channels between the necrotic subchondral bone and the healthy cancellous bone in order to promote revascularization, osseous bridging, and healing [11]. The average time to healing is around 4–6 months after surgery.

Transarticular drilling is done from inside the joint and penetrates the articular cartilage through at least one site to create subchondral penetrations. The main concern with this technique is related to the uncertain long-term implications of disrupting the articular cartilage with the drill sites. Retroarticular drilling avoids this concern by sparing the articular surface and physes with drilling through the affected femoral condyle into the lesion under fluoroscopy. Aside from the added radiation risk, this technique is also more technically demanding and risks incomplete lesion drilling, lesion displacement, or inadvertent soft tissue injury [10].

Neither technique has clearly demonstrated superior patient-orientated outcomes or radiographic healing. Transarticular drilling demonstrated an average healing rate of 91% with a mean healing time of 4.5 months with retroarticular just behind at 86% at 5.6 months [44]. No complications were noted throughout a review of all studies on drilling, making the technique not only effective but also safe option. Poorer results have been noted in older patients with closed physes, fissures of the articular cartilage, and lesions located outside the traditional posterolateral medial condyle [45–47].

with successful results; however, the major drawback is the concern for increased articular cartilage morbidity due to screw prominence on the articular surface [63, 64]. Cannulated headless compression screws have now been developed as an alternative, which theoretically

Bioabsorbable screws, pins, tacks, and darts have been designed and utilized with overall good results [66–69]. The main advantages of bioabsorbable fixation are the lack of metal artifact on postoperative MRI as well as theoretically no subsequent surgery needed for implant removal [66]. Bioabsorbable implants can fail though due to screw breakage, screw back out, reactive synovitis, and loss of compressive force over time [70–73]. These implant failures often lead to refractory mechanical symptoms and need for revision surgery. Despite these potential risks, unstable lesions should still be fixed instead of excised when technically feasible. As there has been no significant difference noted in comparison of bioabsorbable pins and tacks, variable pitch screws, and partially threaded screws with regard to clinical and radiographic healing, the choice of fixation is surgeon dependent [69]. The most frequently used techniques among surgeons are bioabsorbable screws and metal headless variable pitch

Microfracture is a marrow stimulation technique that was developed and implemented in the early 1980s to allow for cartilage repair. The goal of the procedure is to create microfractures in the subchondral bone perpendicular to the surface to create a surface rough enough to hold the generated marrow clot. The pluripotent cells of the clot proliferate and differentiate into cells with morphological features similar to chondrocytes. These cells then produce a cartilaginous repair tissue to fill the chondral defect [75]. The fibrocartilage which matures though is often predominately type 1 collagen, a structurally different entity from hyaline cartilage [76]. Indications for microfracture include smaller partial and full-thickness cartilage defects in patients with acceptable knee alignment. The greatest improvement occurs with the treatment of acute lesions less than 4 cm in size in patients under 35 years old [77]. Younger patients have better results with microfracture as it is crucial to have adequate height of cartilage on the lesion rim to hold the clot in place, which is difficult in degenerative lesions where the

Early results of microfracture are positive with clear improvement in knee function noted throughout the literature at 2 years, particularly in smaller lesions. Despite good midterm results published by the developer of the technique, the longevity and durability of microfracture have been questioned [78–80]. When compared to other cartilage procedures like OAT and ACI, the results are mixed, although no study showed superior results for microfracture [81–83]. Microfracture has been found to have a significantly higher failure rate and need for

) and at greater than 5 years post-

Osteochondritis Dissecans of the Knee http://dx.doi.org/10.5772/intechopen.70275 129

) has been shown for microfracture to

reoperation than OAT or ACI with larger lesions (>4.5 cm<sup>2</sup>

be successful in the demanding athletic population [81, 85].

operatively [84]. An even smaller size threshold (<2 cm<sup>2</sup>

combines the advantages of both techniques [65].

screws [74].

**12. Microfracture**

cartilage is thinner [75].

## **10. Debridement**

The simplest solution to the management of an unstable OCD lesion is excision of the fragment with debridement of the remaining chondral defect. As the painful and limiting mechanical symptoms of an unstable OCD are due to these loose fragments, excision has been correlated with good short-term clinical results [48, 49]. However, as excision and debridement alone leads to a loss of articular cartilage with subsequent degenerative changes, the longer term imaging and knee function scores deteriorate [50, 51]. Even while patients maintain good clinical knee scores, evidence of early degenerative changes can be seen on radiographs at midterm follow up after excision and debridement [52, 53]. The results of these studies further reinforce that every attempt should be made to preserve, repair, or replace the native bone and cartilage that is damaged in an OCD lesion.

## **11. Lesion fixation**

For unstable lesions or stable lesions that have failed a drilling procedure, the next surgical option is often fixation of the osteochondral lesion. The general principles of lesion fixation are to attempt to restore the articular surface, enhance the blood supply of the osseous interface, and initiate early range of motion postoperatively [8].

Historically, after lesions were debrided and bone grafted, they were pinned in place with Kirschner wires; after, the lesion had been debrided and bone grafting had been applied [54]. However, this technique has largely been abandoned due to K-wire bending and inability to hold and provide an adequate compressive force to the lesion. K-wires were replaced by the use of rigid metal screw fixation, either with variable pitch or cannulated partially threaded screws. Most recently, bioabsorbable implants designed as screws or pins have become popularized for fixation. Fixation is again particularly important given the poor results seen with detached fragment removal, especially in weight-bearing areas of the femoral condyles [49, 51, 55].

Variable pitch headless screws were initially described for use in scaphoid fixation, but indications spread to include fixation of OCD lesions [56–58]. The goal of fixation with these screws is to achieve compression encouraging bony union of the subchondral fractures. The main advantage of variable pitch headless screws (Herbert screws) lies in their ability to provide strong compression and be sunk completely under the articular surface to prevent protrusion. The rigid fixation also allows early joint motion due to anatomic restoration of the joint surface [59]. The majority of patients undergoing this technique report good to excellent results without major complications [60–62]. The use of cannulated screws has also been described with successful results; however, the major drawback is the concern for increased articular cartilage morbidity due to screw prominence on the articular surface [63, 64]. Cannulated headless compression screws have now been developed as an alternative, which theoretically combines the advantages of both techniques [65].

Bioabsorbable screws, pins, tacks, and darts have been designed and utilized with overall good results [66–69]. The main advantages of bioabsorbable fixation are the lack of metal artifact on postoperative MRI as well as theoretically no subsequent surgery needed for implant removal [66]. Bioabsorbable implants can fail though due to screw breakage, screw back out, reactive synovitis, and loss of compressive force over time [70–73]. These implant failures often lead to refractory mechanical symptoms and need for revision surgery. Despite these potential risks, unstable lesions should still be fixed instead of excised when technically feasible. As there has been no significant difference noted in comparison of bioabsorbable pins and tacks, variable pitch screws, and partially threaded screws with regard to clinical and radiographic healing, the choice of fixation is surgeon dependent [69]. The most frequently used techniques among surgeons are bioabsorbable screws and metal headless variable pitch screws [74].

## **12. Microfracture**

No complications were noted throughout a review of all studies on drilling, making the technique not only effective but also safe option. Poorer results have been noted in older patients with closed physes, fissures of the articular cartilage, and lesions located outside the tradi-

The simplest solution to the management of an unstable OCD lesion is excision of the fragment with debridement of the remaining chondral defect. As the painful and limiting mechanical symptoms of an unstable OCD are due to these loose fragments, excision has been correlated with good short-term clinical results [48, 49]. However, as excision and debridement alone leads to a loss of articular cartilage with subsequent degenerative changes, the longer term imaging and knee function scores deteriorate [50, 51]. Even while patients maintain good clinical knee scores, evidence of early degenerative changes can be seen on radiographs at midterm follow up after excision and debridement [52, 53]. The results of these studies further reinforce that every attempt should be made to preserve, repair, or replace the native bone

For unstable lesions or stable lesions that have failed a drilling procedure, the next surgical option is often fixation of the osteochondral lesion. The general principles of lesion fixation are to attempt to restore the articular surface, enhance the blood supply of the osseous inter-

Historically, after lesions were debrided and bone grafted, they were pinned in place with Kirschner wires; after, the lesion had been debrided and bone grafting had been applied [54]. However, this technique has largely been abandoned due to K-wire bending and inability to hold and provide an adequate compressive force to the lesion. K-wires were replaced by the use of rigid metal screw fixation, either with variable pitch or cannulated partially threaded screws. Most recently, bioabsorbable implants designed as screws or pins have become popularized for fixation. Fixation is again particularly important given the poor results seen with detached frag-

Variable pitch headless screws were initially described for use in scaphoid fixation, but indications spread to include fixation of OCD lesions [56–58]. The goal of fixation with these screws is to achieve compression encouraging bony union of the subchondral fractures. The main advantage of variable pitch headless screws (Herbert screws) lies in their ability to provide strong compression and be sunk completely under the articular surface to prevent protrusion. The rigid fixation also allows early joint motion due to anatomic restoration of the joint surface [59]. The majority of patients undergoing this technique report good to excellent results without major complications [60–62]. The use of cannulated screws has also been described

ment removal, especially in weight-bearing areas of the femoral condyles [49, 51, 55].

tional posterolateral medial condyle [45–47].

and cartilage that is damaged in an OCD lesion.

face, and initiate early range of motion postoperatively [8].

**10. Debridement**

128 Cartilage Repair and Regeneration

**11. Lesion fixation**

Microfracture is a marrow stimulation technique that was developed and implemented in the early 1980s to allow for cartilage repair. The goal of the procedure is to create microfractures in the subchondral bone perpendicular to the surface to create a surface rough enough to hold the generated marrow clot. The pluripotent cells of the clot proliferate and differentiate into cells with morphological features similar to chondrocytes. These cells then produce a cartilaginous repair tissue to fill the chondral defect [75]. The fibrocartilage which matures though is often predominately type 1 collagen, a structurally different entity from hyaline cartilage [76].

Indications for microfracture include smaller partial and full-thickness cartilage defects in patients with acceptable knee alignment. The greatest improvement occurs with the treatment of acute lesions less than 4 cm in size in patients under 35 years old [77]. Younger patients have better results with microfracture as it is crucial to have adequate height of cartilage on the lesion rim to hold the clot in place, which is difficult in degenerative lesions where the cartilage is thinner [75].

Early results of microfracture are positive with clear improvement in knee function noted throughout the literature at 2 years, particularly in smaller lesions. Despite good midterm results published by the developer of the technique, the longevity and durability of microfracture have been questioned [78–80]. When compared to other cartilage procedures like OAT and ACI, the results are mixed, although no study showed superior results for microfracture [81–83]. Microfracture has been found to have a significantly higher failure rate and need for reoperation than OAT or ACI with larger lesions (>4.5 cm<sup>2</sup> ) and at greater than 5 years postoperatively [84]. An even smaller size threshold (<2 cm<sup>2</sup> ) has been shown for microfracture to be successful in the demanding athletic population [81, 85].

## **13. Autograft transplantation**

In the cases of failed fixation, lesion fragmentation, or chronically detached lesions, more advanced chondral procedures, like osteochondral autograft transplantation (OAT), are required. OAT was developed and then popularized in the 1990s [86, 87]. The procedure entails the harvesting of a cylindrical graft of healthy cartilage and subchondral bone from a less stressed area of the distal femur and implementing into an area of chondral defect. The graft is matched to the surface area of the defect and seated to restore a smooth cartilage surface in the joint [88]. A single plug of cartilage may be transferred or an alternative procedure termed mosaicplasty can be performed where multiple smaller plugs are implemented.

banks based on size, which is usually measured off an AP radiograph of the knee. The affected condyle is used for sizing and a match is sought based on the overall condyle size, with an acceptable match noted to be within ±2 mm. While it is preferred to have patient size, side, and condyle-specific matching, depending on the location of the lesion, it has been shown that plugs may be successfully transplanted to the other compartment (medial to lateral) or even to the other side (left vs. right). Once harvested, OCAs should be properly stored and implanted within 28 days for maintained chondrocyte viability and subsequent clinical ben-

Osteochondritis Dissecans of the Knee http://dx.doi.org/10.5772/intechopen.70275 131

OCA is effective as a majority of patients are satisfied with their treatment and are able to return to sport or recreational activity [109]. The success of OCA is highest when a single articular surface is replaced, the surrounding ligaments and menisci are intact, and the alignment is normal [110]. Osteoarthritis or the presence of disease on both articular surfaces is a contraindication to OCA [111]. The number of previous ipsilateral knee surgical procedures, elevated BMI, age >30 years old, and medial femoral graft location have been found to be independent factors predictive of reoperation and failure after allograft transplantation [101, 112]. Overall, there is a 1 in 3 chance of undergoing an additional operation, with vast majority being arthroscopic debridement, within the first 5 years following OCA. Despite this high rate of requiring a second surgery, OCA remains an attractive option due to allograft having the ability to treat larger defects, the lack of donor site morbidity, reduced surgical time, and the

Autologous chondrocyte implantation is a two-stage procedure indicated for full thickness cartilage or OCD lesions of the knee. The initial procedure involves arthroscopic evaluation and cartilage harvesting. After 2 weeks of culturing, the harvested chondrocytes are then implanted and sealed into the cartilage defect in an attempt to recreate a hyaline cartilage interface. ACI is indicated for full thickness cartilage or osteochondral lesions of the

The treatment of OCD lesions with ACI has been associated with clinical improvements, including reduced pain and improved function, in both adolescents and adults at midterm follow-up [114–117]. As with other cartilage repair techniques, younger patients with more

A drawback to ACI is the requirement of two separate procedures. However, most patients undergoing ACI have already failed numerous other options and are willing to undergo the extra surgery for a chance at salvage. Most complications of ACI seem to be related to the periosteal flap, including overgrowth, delamination, and arthrofibrosis. Majority of failures occur with the first 2 years after surgery [121]. Despite these limitations, ACI remains a cartilage

salvage option, particularly in those who have failed other surgical modalities.

with minimal cartilage damage on the opposing articular

ability to customize the graft to the recipient's defect site.

**15. Autologous chondrocyte implantation**

knee ranging from 2 to 16 cm<sup>2</sup>

localized lesions tend to do better [118–120].

surface [113].

efit [103–108].

Osteochondral autograft transplantation is currently recommended as a viable option for osteochondral lesions measuring 1–4 cm<sup>2</sup> in a load-bearing area [89]. OAT offers the opportunity to repair cartilaginous defects by restoring hyaline cartilage anatomy [90]. Graft plugs should be taken from nonweight-bearing areas to avoid being arthrogenic [91]. OAT provides an immediate functional surface that allows a relatively quick rehabilitation and return to play, but a mismatch of cartilage thickness between the two sites can lead to abnormal stresses and poor function [92, 93].

Mosaicplasty has been shown to give reliably good short-term results [94–97]. In longer term studies evaluating patients who underwent mosaicplasty, there is a significant decrease in level of physical activity noted, particularly in patients whose activity level prior to surgery was high. This reduction in activity level is often due to apprehension and a desire to preserve the joint [91]. Older age, female sex, and more extensive initial lesions have been shown to be factors leading to poor prognoses after mosaicplasty [98]. Limb malalignment has also been shown to affect outcomes if not corrected, and thus concomitant osteotomy is recommended in these cases [99].

The primary concern with autografting comes from possible donor site morbidity. Cadaveric studies have shown load across donor sites during range of motion, but multiple studies have shown minimal to no complications associated with donor sites at midterm follow-up [81, 95, 97, 100]. Athletes report nearly double the rate of donor site pain compared to less active patients, indicating that vigorous exercise potentially increases donor site pain [99].

## **14. Allograft transplantation**

Osteochondral allograft transplantation (OCA) involves the transfer of size-matched allograft cartilage and subchondral bone into large osteochondral defects of the knee [30]. OCA is primarily used in the management of large osteochondral defects and as a salvage option for those who have previously failed other cartilage repair techniques. Fresh osteochondral allograft transplantation is theoretically an attractive option because it can restore both the osseous and the chondral components caused by the OCD lesion [101].

Allograft tissue is harvested within 24 hours of donor death, ideally from a donor aged 15–40 years with grossly healthy articular cartilage [102]. Allografts are often matched by tissue banks based on size, which is usually measured off an AP radiograph of the knee. The affected condyle is used for sizing and a match is sought based on the overall condyle size, with an acceptable match noted to be within ±2 mm. While it is preferred to have patient size, side, and condyle-specific matching, depending on the location of the lesion, it has been shown that plugs may be successfully transplanted to the other compartment (medial to lateral) or even to the other side (left vs. right). Once harvested, OCAs should be properly stored and implanted within 28 days for maintained chondrocyte viability and subsequent clinical benefit [103–108].

OCA is effective as a majority of patients are satisfied with their treatment and are able to return to sport or recreational activity [109]. The success of OCA is highest when a single articular surface is replaced, the surrounding ligaments and menisci are intact, and the alignment is normal [110]. Osteoarthritis or the presence of disease on both articular surfaces is a contraindication to OCA [111]. The number of previous ipsilateral knee surgical procedures, elevated BMI, age >30 years old, and medial femoral graft location have been found to be independent factors predictive of reoperation and failure after allograft transplantation [101, 112].

Overall, there is a 1 in 3 chance of undergoing an additional operation, with vast majority being arthroscopic debridement, within the first 5 years following OCA. Despite this high rate of requiring a second surgery, OCA remains an attractive option due to allograft having the ability to treat larger defects, the lack of donor site morbidity, reduced surgical time, and the ability to customize the graft to the recipient's defect site.

## **15. Autologous chondrocyte implantation**

**13. Autograft transplantation**

130 Cartilage Repair and Regeneration

osteochondral lesions measuring 1–4 cm<sup>2</sup>

and poor function [92, 93].

**14. Allograft transplantation**

In the cases of failed fixation, lesion fragmentation, or chronically detached lesions, more advanced chondral procedures, like osteochondral autograft transplantation (OAT), are required. OAT was developed and then popularized in the 1990s [86, 87]. The procedure entails the harvesting of a cylindrical graft of healthy cartilage and subchondral bone from a less stressed area of the distal femur and implementing into an area of chondral defect. The graft is matched to the surface area of the defect and seated to restore a smooth cartilage surface in the joint [88]. A single plug of cartilage may be transferred or an alternative procedure termed mosaicplasty can be performed where multiple smaller plugs are implemented.

Osteochondral autograft transplantation is currently recommended as a viable option for

tunity to repair cartilaginous defects by restoring hyaline cartilage anatomy [90]. Graft plugs should be taken from nonweight-bearing areas to avoid being arthrogenic [91]. OAT provides an immediate functional surface that allows a relatively quick rehabilitation and return to play, but a mismatch of cartilage thickness between the two sites can lead to abnormal stresses

Mosaicplasty has been shown to give reliably good short-term results [94–97]. In longer term studies evaluating patients who underwent mosaicplasty, there is a significant decrease in level of physical activity noted, particularly in patients whose activity level prior to surgery was high. This reduction in activity level is often due to apprehension and a desire to preserve the joint [91]. Older age, female sex, and more extensive initial lesions have been shown to be factors leading to poor prognoses after mosaicplasty [98]. Limb malalignment has also been shown to affect outcomes if not corrected, and thus concomitant osteotomy is recommended in these cases [99]. The primary concern with autografting comes from possible donor site morbidity. Cadaveric studies have shown load across donor sites during range of motion, but multiple studies have shown minimal to no complications associated with donor sites at midterm follow-up [81, 95, 97, 100]. Athletes report nearly double the rate of donor site pain compared to less active

patients, indicating that vigorous exercise potentially increases donor site pain [99].

osseous and the chondral components caused by the OCD lesion [101].

Osteochondral allograft transplantation (OCA) involves the transfer of size-matched allograft cartilage and subchondral bone into large osteochondral defects of the knee [30]. OCA is primarily used in the management of large osteochondral defects and as a salvage option for those who have previously failed other cartilage repair techniques. Fresh osteochondral allograft transplantation is theoretically an attractive option because it can restore both the

Allograft tissue is harvested within 24 hours of donor death, ideally from a donor aged 15–40 years with grossly healthy articular cartilage [102]. Allografts are often matched by tissue

in a load-bearing area [89]. OAT offers the oppor-

Autologous chondrocyte implantation is a two-stage procedure indicated for full thickness cartilage or OCD lesions of the knee. The initial procedure involves arthroscopic evaluation and cartilage harvesting. After 2 weeks of culturing, the harvested chondrocytes are then implanted and sealed into the cartilage defect in an attempt to recreate a hyaline cartilage interface. ACI is indicated for full thickness cartilage or osteochondral lesions of the knee ranging from 2 to 16 cm<sup>2</sup> with minimal cartilage damage on the opposing articular surface [113].

The treatment of OCD lesions with ACI has been associated with clinical improvements, including reduced pain and improved function, in both adolescents and adults at midterm follow-up [114–117]. As with other cartilage repair techniques, younger patients with more localized lesions tend to do better [118–120].

A drawback to ACI is the requirement of two separate procedures. However, most patients undergoing ACI have already failed numerous other options and are willing to undergo the extra surgery for a chance at salvage. Most complications of ACI seem to be related to the periosteal flap, including overgrowth, delamination, and arthrofibrosis. Majority of failures occur with the first 2 years after surgery [121]. Despite these limitations, ACI remains a cartilage salvage option, particularly in those who have failed other surgical modalities.

## **16. Future research**

Despite over 100 years of research, there is still much to be learned regarding osteochondritis dissecans. In 2011, the American Academy of Orthopedic Surgeons released Clinical Practice guidelines regarding OCD of the knee [122]. These guidelines found limited evidence for all aspects of the treatment of knee OCD. To provide better insight and advance the understanding of this condition, multicenter study research groups have been formed. These groups are undertaking clinical trials attempting to answer many of the unsolved issues relating to knee OCD [123].

[3] Campbell CJ, Ranawat CS. Osteochondritis dissecans: The question of etiology. Journal

Osteochondritis Dissecans of the Knee http://dx.doi.org/10.5772/intechopen.70275 133

[4] Linden B, Telhag H. Osteochondritis dissecans: A histologic and autoradiographic study

[5] Portigliatti Barbos M, Brach del Prever E, Borroni L, Salvadori L, Battiston B. Osteochondritis dissecans of the femoral condyles. A histological study with pre-operative fluorescent bone labelling and microradiography. Italian Journal of Orthopaedics

[6] Uozumi H, Sugita T, Aizawa T, Takahashi A, Ohnuma M, Itoi E. Histologic findings and possible causes of osteochondritis dissecans of the knee. American Journal of Sports

[7] Edmonds EW, Shea KG. Osteochondritis dissecans: Editorial comment. Clinical

[8] Cahill BR. Osteochondritis dissecans of the knee: Treatment of juvenile and adult forms. Journal of the American Academy of Orthopaedic Surgeons. 1995;**3**(4):237-247

[9] Smillie IS. Osteochondritis Dissecans Loose Bodies in Joints. London: E. & S. Livingstone

[10] Kocher MS, Tucker R, Ganley TJ, Flynn JM. Management of osteochondritis dissecans of the knee: Current concepts review. American Journal of Sports Medicine.

[11] Heyworth BE, Kocher MS. Osteochondritis dissecans of the knee. JBJS Reviews.

[12] Edmonds EW, Polousky J. A review of knowledge in osteochondritis dissecans: 123 years of minimal evolution from König to the ROCK study group. Clinical Orthopaedics

[13] Hefti F, Beguiristain J, Krauspe R, et al. Osteochondritis dissecans: A multicenter study of the European pediatric orthopedic society. Journal of Pediatric Orthopaedics B.

[14] Cepero S, Ullot R, Sastre S. Osteochondritis of the femoral condyles in children and adolescents: Our experience over the last 28 years. Journal of Pediatric Orthopaedics B.

[15] Bradley J, Dandy DJ. Osteochondritis dissecans and other lesions of the femoral con-

[16] Aroen A, Loken S, Heir S, et al. Articular cartilage lesions in 993 consecutive knee

[17] Widuchowski W, Widuchowski J, Trzaska T. Articular cartilage defects: Study of 25,124

dyles. Journal of Bone and Joint Surgery. British. 1989;**71**(3):518-522

arthroscopies. American Journal of Sports Medicine. 2004;**32**(1):211-215

of Trauma and Acute Care Surgery. 1966;**6**(2):201-221

Orthopaedics and Related Research. 2013;**471**(4):1105

and Related Research®. 2013;**471**(4):1118-1126

knee arthroscopies. The Knee. 2007;**14**(3):177-182

and Traumatology. 1985;**11**(2):207-213

Medicine. 2009;**37**(10):2003-2008

Ltd.; 1960

2015;**3**(7):e1

1999;**8**(4):231-245

2005;**14**(1):24-29

2006;**34**(7):1181-1191

in man. Acta Orthopaedica Scandinavica. 1977;**48**(6):682-686

## **17. Conclusion**

Osteochondritis dissecans of the knee remains a poorly understood and difficult problem-facing patients and orthopedic surgeons today. Affecting both articular cartilage and subchondral bone, OCD is a progressive condition leading to knee pain, mechanical symptoms, and ultimately osteoarthritis if left untreated. OCD recognized in patients with open distal femoral physes is termed juvenile OCD and has a better prognosis, particularly with nonoperative management. Adult OCD is found in patients after skeletal maturity and almost always requires surgical intervention. The stability and size of the lesion is critical in determining the appropriate surgical modality. Reparative procedures such as drilling, microfracture, and lesion stabilization have shown good early results for smaller lesions, but larger and more chronic lesions often require regenerative chondral techniques like osteochondral autograft, allograft, or acellular chondrocyte implantation. Further research is underway comparing the different techniques to determine the gold standard for each size and type of lesion. The interest and understanding of knee OCD has progressed considerably in the past 20 years, but still more prospective research studies are needed to improve the assessment and treatment of this complex condition.

## **Author details**

Anthony C. Egger and Paul Saluan\*

\*Address all correspondence to: saluanp@ccf.org

Department of Orthopaedics, The Cleveland Clinic Foundation, Cleveland, OH, United States

## **References**


[3] Campbell CJ, Ranawat CS. Osteochondritis dissecans: The question of etiology. Journal of Trauma and Acute Care Surgery. 1966;**6**(2):201-221

**16. Future research**

132 Cartilage Repair and Regeneration

**17. Conclusion**

**Author details**

**References**

Anthony C. Egger and Paul Saluan\*

\*Address all correspondence to: saluanp@ccf.org

Research®. 2013;**471**(4):1107-1115

and Related Research®. 2013;**471**(4):1127-1136

Despite over 100 years of research, there is still much to be learned regarding osteochondritis dissecans. In 2011, the American Academy of Orthopedic Surgeons released Clinical Practice guidelines regarding OCD of the knee [122]. These guidelines found limited evidence for all aspects of the treatment of knee OCD. To provide better insight and advance the understanding of this condition, multicenter study research groups have been formed. These groups are undertaking clinical trials attempting to answer many of the unsolved issues relating to knee OCD [123].

Osteochondritis dissecans of the knee remains a poorly understood and difficult problem-facing patients and orthopedic surgeons today. Affecting both articular cartilage and subchondral bone, OCD is a progressive condition leading to knee pain, mechanical symptoms, and ultimately osteoarthritis if left untreated. OCD recognized in patients with open distal femoral physes is termed juvenile OCD and has a better prognosis, particularly with nonoperative management. Adult OCD is found in patients after skeletal maturity and almost always requires surgical intervention. The stability and size of the lesion is critical in determining the appropriate surgical modality. Reparative procedures such as drilling, microfracture, and lesion stabilization have shown good early results for smaller lesions, but larger and more chronic lesions often require regenerative chondral techniques like osteochondral autograft, allograft, or acellular chondrocyte implantation. Further research is underway comparing the different techniques to determine the gold standard for each size and type of lesion. The interest and understanding of knee OCD has progressed considerably in the past 20 years, but still more prospective research studies are needed to improve the assessment and treatment of this complex condition.

Department of Orthopaedics, The Cleveland Clinic Foundation, Cleveland, OH, United States

[1] König F. The classic: On loose bodies in the joint. Clinical Orthopaedics and Related

[2] Shea KG, Jacobs JC, Carey JL, Anderson AF, Oxford JT. Osteochondritis dissecans knee histology studies have variable findings and theories of etiology. Clinical Orthopaedics


[18] Hjelle K, Solheim E, Strand T, Muri R, Brittberg M. Articular cartilage defects in 1,000 knee arthroscopies. Arthroscopy: The Journal of Arthroscopic & Related Surgery. 2002;**18**(7):730-734

[34] Nelson DW, DiPaola J, Colville M, Schmidgall J. Osteochondritis dissecans of the talus and knee: Prospective comparison of MR and arthroscopic classifications. Journal of

Osteochondritis Dissecans of the Knee http://dx.doi.org/10.5772/intechopen.70275 135

[35] Jacobs JC, Archibald-Seiffer N, Grimm NL, Carey JL, Shea KG. A review of arthroscopic classification systems for osteochondritis dissecans of the knee. Orthopedic Clinics of

[36] Brittberg M, Winalski CS. Evaluation of cartilage injuries and repair. Journal of Bone and

[37] Dipaola JD, Nelson DW, Colville MR. Characterizing osteochondral lesions by magnetic resonance imaging. Arthroscopy: The Journal of Arthroscopic & Related Surgery.

[38] Carey JL, Wall EJ, Grimm NL, et al. Novel arthroscopic classification of osteochondritis dissecans of the knee: A multicenter reliability study. American Journal of Sports

[39] Paletta GA Jr., Bednarz PA, Stanitski CL, Sandman GA, Stanitski DF, Kottamasu S. The prognostic value of quantitative bone scan in knee osteochondritis dissecans. A prelimi-

[40] Carey JL, Grimm NL. Treatment algorithm for osteochondritis dissecans of the knee.

[41] DellaMaggiora R, Vaishnav S, Vangsness CT. Osteochondritis dissecans of the adult

[42] McNickle AG, Provencher MT, Cole BJ. Overview of existing cartilage repair technol-

[43] Mesgarzadeh M, Sapega AA, Bonakdarpour A, et al. Osteochondritis dissecans: Analysis of mechanical stability with radiography, scintigraphy, and MR imaging. Radiology.

[44] Gunton MJ, Carey JL, Shaw CR, Murnaghan ML. Drilling juvenile osteochondritis dissecans: Retro-or transarticular? Clinical Orthopaedics and Related Research®.

[45] Boughanem J, Riaz R, Patel RM, Sarwark JF. Functional and radiographic outcomes of juvenile osteochondritis dissecans of the knee treated with extra-articular retrograde

[46] Kocher MS, Micheli LJ, Yaniv M, Zurakowski D, Ames A, Adrignolo AA. Functional and radiographic outcome of juvenile osteochondritis dissecans of the knee treated with transarticular arthroscopic drilling. American Journal of Sports Medicine. 2001;**29**(5):562-566

[47] Louisia S, Beaufils P, Katabi M, Robert H. Transchondral drilling for osteochondritis dissecans of the medial condyle of the knee. Knee Surgery, Sports Traumatology,

nary experience. American Journal of Sports Medicine. 1998;**26**(1):7-14

knee. Operative Techniques in Sports Medicine. 2008;**16**(2):65-69

ogy. Sports Medicine and Arthroscopy Review. 2008;**16**(4):196-201

drilling. American Journal of Sports Medicine. 2011;**39**(10):2212-2217

Computer Assisted Tomography. 1990;**14**(5):804-808

North America. 2015;**46**(1):133-139

Medicine. 2016;**44**(7):1694-1698

1991;**7**(1):101-104

1987;**165**(3):775-780

2013;**471**(4):1144-1151

Arthroscopy. 2003;**11**(1):33-39

Joint Surgery. America. 2003;**85-A**(2):58-69

Clinics in Sports Medicine. 2014;**33**(2):375-382


[34] Nelson DW, DiPaola J, Colville M, Schmidgall J. Osteochondritis dissecans of the talus and knee: Prospective comparison of MR and arthroscopic classifications. Journal of Computer Assisted Tomography. 1990;**14**(5):804-808

[18] Hjelle K, Solheim E, Strand T, Muri R, Brittberg M. Articular cartilage defects in 1,000 knee arthroscopies. Arthroscopy: The Journal of Arthroscopic & Related Surgery.

[19] Kessler JI, Nikizad H, Shea KG, Jacobs Jr JC, Bebchuk JD, Weiss JM. The demographics and epidemiology of osteochondritis dissecans of the knee in children and adolescents.

[20] Yonetani Y, Matsuo T, Nakamura N, et al. Fixation of detached osteochondritis dissecans lesions with bioabsorbable pins: Clinical and histologic evaluation. Arthroscopy: The

[21] Schenck RC Jr., Goodnight JM. Osteochondritis dissecans. Journal of Bone and Joint

[22] Enneking WF. Clinical Musculoskeletal Pathology. University of Florida Press/J. Hillis

[23] Koch S, Kampen W, Laprell H. Cartilage and bone morphology in osteochondritis dis-

[24] Reddy AS, Frederick RW. Evaluation of the intraosseous and extraosseous blood supply to the distal femoral condyles. American Journal of Sports Medicine. 1998;**26**(3):415-419

[25] Rogers WM, Gladstone H. Vascular foramina and arterial supply of the distal end of the

[26] Wall E, Von Stein D. Juvenile osteochondritis dissecans. Orthopedic Clinics of North

[27] Gornitzky AL, Mistovich RJ, Atuahuene B, Storey EP, Ganley TJ. Osteochondritis dissecans lesions in family members: Does a positive family history impact phenotypic potency? Clinical Orthopaedics and Related Research®. June 2017:**475**(6);1573-1580 [28] Hughston JC, Hergenroeder PT, Courtenay BG. Osteochondritis dissecans of the femoral condyles. Journal of Bone and Joint Surgery. America. 1984;**66**(9):1340-1348

[29] Wilson J.A diagnostic sign in osteochondritis dissecans of the knee. JBJS. 1967;**49**(3):477-480 [30] Sherman SL, Garrity J, Bauer K, Cook J, Stannard J, Bugbee W. Fresh osteochondral allograft transplantation for the knee: Current concepts. Journal of the American

[31] Zbojniewicz AM, Laor T. Imaging of osteochondritis dissecans. Clinics in Sports

[32] O'Connor MA, Palaniappan M, Khan N, Bruce CE. Osteochondritis dissecans of the knee in children. A comparison of MRI and arthroscopic findings. Journal of Bone and Joint

[33] Chen C, Liu Y, Chou P, Hsieh C, Wang C. MR grading system of osteochondritis dissecans lesions: Comparison with arthroscopy. European Journal of Radiology.

secans. Knee Surgery, Sports Traumatology, Arthroscopy. 1997;**5**(1):42-45

femur. Journal of Bone and Joint Surgery. America. 1950;**32 A**(4):867-874

American Journal of Sports Medicine. 2014;**42**(2):320-326

Miller Health Science Center; Gainseville, Florida. 1990

Academy of Orthopaedic Surgeons. 2014;**22**(2):121-133

Surgery. American. 1996;**78**(3):439-456

America. 2003;**34**(3):341-353

Medicine. 2014;**33**(2):221-250

2013;**82**(3):518-525

Surgery. British. 2002;**84**(2):258-262

Journal of Arthroscopic & Related Surgery. 2010;**26**(6):782-789

2002;**18**(7):730-734

134 Cartilage Repair and Regeneration


[48] Denoncourt PM, Patel D, Dimakopoulos P. Arthroscopy update #1. treatment of osteochondrosis dissecans of the knee by arthroscopic curettage, follow-up study. Orthopedic Reviews. 1986;**15**(10):652-657

[62] Makino A, Muscolo DL, Puigdevall M, Costa-Paz M, Ayerza M. Arthroscopic fixation of osteochondritis dissecans of the knee: Clinical, magnetic resonance imaging, and arthroscopic follow-up. American Journal of Sports Medicine. 2005;**33**(10):1499-1504

Osteochondritis Dissecans of the Knee http://dx.doi.org/10.5772/intechopen.70275 137

[63] Cugat R, Garcia M, Cusco X, et al. Osteochondritis dissecans: A historical review and its treatment with cannulated screws. Arthroscopy: The Journal of Arthroscopic & Related

[64] Johnson LL, Uitvlugt G, Austin MD, Detrisac DA, Johnson C. Osteochondritis dissecans of the knee: Arthroscopic compression screw fixation. Arthroscopy: The Journal of

[65] Barrett I, King AH, Riester S, et al. Internal fixation of unstable osteochondritis dissecans in the skeletally mature knee with metal screws. Cartilage. 2016;**7**(2):157-162

[66] Tabaddor RR, Banffy MB, Andersen JS, et al. Fixation of juvenile osteochondritis dissecans lesions of the knee using poly 96L/4D-lactide copolymer bioabsorbable implants.

[67] Camathias C, Gögüs U, Hirschmann MT, et al. Implant failure after biodegradable screw fixation in osteochondritis dissecans of the knee in skeletally immature patients.

[68] Wouters DB, van Horn JR, Bos RR. The use of biodegradables in the treatment of osteochondritis dissecans of the knee: Fiction or future? Acta Orthopaedica Belgica.

[69] Kocher MS, Czarnecki JJ, Andersen JS, Micheli LJ. Internal fixation of juvenile osteochondritis dissecans lesions of the knee. American Journal of Sports Medicine.

[70] Friederichs MG, Greis PE, Burks RT. Pitfalls associated with fixation of osteochondritis dissecans fragments using bioabsorbable screws. Arthroscopy: The Journal of

[71] Scioscia TN, Giffin JR, Allen CR, Harner CD. Potential complication of bioabsorbable screw fixation for osteochondritis dissecans of the knee. Arthroscopy: The Journal of

[72] Fridén T, Rydholm U. Severe aseptic synovitis of the knee after biodegradable internal

[73] Barfod G, Svendsen RN. Synovitis of the knee after intraarticular fracture fixation with biofix®: Report of two cases. Acta Orthopaedica Scandinavica. 1992;**63**(6):680-681

[74] Yellin JL, Gans I, Carey JL, Shea KG, Ganley TJ. The surgical management of osteochondritis dissecans of the knee in the skeletally immature: A survey of the pediatric orthopaedic society of North America (POSNA) membership. Journal of Pediatric

fixation: A case report. Acta Orthopaedica Scandinavica. 1992;**63**(1):94-97

Arthroscopy: The Journal of Arthroscopic & Related Surgery. 2015;**31**(3):410-415

Surgery. 1993;**9**(6):675-684

2003;**69**(2):175-181

2007;**35**(5):712-718

Orthopaedics. 2015

Arthroscopic & Related Surgery. 1990;**6**(3):179-189

Journal of Pediatric Orthopaedics. 2010;**30**(1):14-20

Arthroscopic & Related Surgery. 2001;**17**(5):542-545

Arthroscopic & Related Surgery. 2001;**17**(2):1-5


[62] Makino A, Muscolo DL, Puigdevall M, Costa-Paz M, Ayerza M. Arthroscopic fixation of osteochondritis dissecans of the knee: Clinical, magnetic resonance imaging, and arthroscopic follow-up. American Journal of Sports Medicine. 2005;**33**(10):1499-1504

[48] Denoncourt PM, Patel D, Dimakopoulos P. Arthroscopy update #1. treatment of osteochondrosis dissecans of the knee by arthroscopic curettage, follow-up study. Orthopedic

[49] Aglietti P, Ciardullo A, Giron F, Ponteggia F. Results of arthroscopic excision of the fragment in the treatment of osteochondritis dissecans of the knee. Arthroscopy: The Journal

[50] Michael J, Wurth A, Eysel P, König D. Long-term results after operative treatment of osteochondritis dissecans of the knee joint—30 year results. International Orthopaedics.

[51] Anderson AF, Pagnani MJ. Osteochondritis dissecans of the femoral condyles. Longterm results of excision of the fragment. American Journal of Sports Medicine. 1997;**25**(6):

[52] Wright RW, McLean M, Matava MJ, Shively RA. Osteochondritis dissecans of the knee: Long-term results of excision of the fragment. Clinical Orthopaedics and Related

[53] Murray J, Chitnavis J, Dixon P, et al. Osteochondritis dissecans of the knee; long-term clinical outcome following arthroscopic debridement. The Knee. 2007;**14**(2):94-98 [54] Anderson AF, Lipscomb AB, Coulam C. Antegrade curettement, bone grafting and pinning of osteochondritis dissecans in the skeletally mature knee. American Journal of

[55] Sanders TL, Pareek A, Obey MR, et al. High rate of osteoarthritis after osteochondritis dissecans fragment excision compared with surgical restoration at a mean 16-year

[56] Herbert TJ, Fisher WE. Management of the fractured scaphoid using a new bone screw.

[57] Wombwell JH, Nunley JA. Compressive fixation of osteochondritis dissecans fragments

[58] Thomson NL. Osteochondritis dissecans and osteochondral fragments managed by Herbert compression screw fixation. Clinical Orthopaedics and Related Research®.

[59] Kouzelis A, Plessas S, Papadopoulos AX, Gliatis I, Lambiris E. Herbert screw fixation and reverse guided drillings, for treatment of types III and IV osteochondritis dissecans.

[60] Zuniga JR, Sagastibelza J, Blasco JL, Grande MM. Arthroscopic use of the Herbert screw in osteochondritis dissecans of the knee. Arthroscopy: The Journal of Arthroscopic &

[61] Mackie IG, Pemberton DJ, Maheson M. Arthroscopic use of the Herbert screw in osteochondritis dissecans. Journal of Bone and Joint Surgery. British. 1990;**72**(6):1076

follow-up. American Journal of Sports Medicine. 2017;**45**(8):1799-1805

with Herbert screws. Journal of Orthopaedic Trauma. 1987;**1**(1):74-77

Knee Surgery, Sports Traumatology, Arthroscopy. 2006;**14**(1):70-75

Journal of Bone and Joint Surgery. British. 1984;**66**(1):114-123

Reviews. 1986;**15**(10):652-657

2008;**32**(2):217-221

136 Cartilage Repair and Regeneration

Research®. 2004;**424**:239-243

Sports Medicine. 1990;**18**(3):254-261

Related Surgery. 1993;**9**(6):668-670

830-834

1987;**224**:71-78

of Arthroscopic & Related Surgery. 2001;**17**(7):741-746


[75] Steadman JR, Rodkey WG, Rodrigo JJ. Microfracture: Surgical technique and rehabilitation to treat chondral defects. Clinical Orthopaedics and Related Research®. 2001;**391**:S362-S369

[87] Hangody L, Fules P. Autologous osteochondral mosaicplasty for the treatment of fullthickness defects of weight-bearing joints: Ten years of experimental and clinical experi-

Osteochondritis Dissecans of the Knee http://dx.doi.org/10.5772/intechopen.70275 139

[88] Richter DL, Tanksley JA, Miller MD. Osteochondral autograft transplantation: A review of the surgical technique and outcomes. Sports Medicine and Arthroscopy Review.

[89] Versier G, Dubrana F. Treatment of knee cartilage defect in 2010. Orthopaedics &

[90] Baltzer A, Ostapczuk M, Terheiden H, Merk H. Good short-to medium-term results after osteochondral autograft transplantation (OAT) in middle-aged patients with focal, nontraumatic osteochondral lesions of the knee. Orthopaedics & Traumatology: Surgery &

[91] Cognault J, Seurat O, Chaussard C, Ionescu S, Saragaglia D. Return to sports after autogenous osteochondral mosaicplasty of the femoral condyles: 25 cases at a mean follow-up of 9 years. Orthopaedics & Traumatology: Surgery & Research. 2015;**101**(3):313-317 [92] Pareek A, Reardon PJ, Maak TG, Levy BA, Stuart MJ, Krych AJ. Long-term outcomes after osteochondral autograft transfer: A systematic review at mean follow-up of 10.2 years. Arthroscopy: The Journal of Arthroscopic & Related Surgery. 2016;**32**(6):1174-1184

[93] Thaunat M, Couchon S, Lunn J, Charrois O, Fallet L, Beaufils P. Cartilage thickness matching of selected donor and recipient sites for osteochondral autografting of the medial femoral condyle. Knee Surgery, Sports Traumatology, Arthroscopy. 2007;**15**(4):381-386 [94] Hangody L, Kish G, Kárpáti Z, Udvarhelyi I, Szigeti I, Bély M. Mosaicplasty for the treatment of articular cartilage defects: Application in clinical practice. Orthopedics.

[95] Marcacci M, Kon E, Zaffagnini S, et al. Multiple osteochondral arthroscopic grafting (mosaicplasty) for cartilage defects of the knee: Prospective study results at 2-year follow-up. Arthroscopy: The Journal of Arthroscopic & Related Surgery. 2005;**21**(4):462-470

[96] Berlet GC, Mascia A, Miniaci A. Treatment of unstable osteochondritis dissecans lesions of the knee using autogenous osteochondral grafts (mosaicplasty). Arthroscopy: The

[97] Miniaci A, Tytherleigh-Strong G. Fixation of unstable osteochondritis dissecans lesions of the knee using arthroscopic autogenous osteochondral grafting (mosaicplasty).

[99] Hangody L, Dobos J, Balo E, Panics G, Hangody LR, Berkes I. Clinical experiences with autologous osteochondral mosaicplasty in an athletic population: A 17-year prospective

multicenter study. American Journal of Sports Medicine. 2010;**38**(6):1125-1133

Arthroscopy: The Journal of Arthroscopic & Related Surgery. 2007;**23**(8):845-851 [98] Solheim E, Hegna J, Øyen J, Austgulen OK, Harlem T, Strand T. Osteochondral autografting (mosaicplasty) in articular cartilage defects in the knee: Results at 5 to 9 years.

Journal of Arthroscopic & Related Surgery. 1999;**15**(3):312-316

ence. Journal of Bone and Joint Surgery. America. 2003;**85-A**(2):25-32

Traumatology: Surgery & Research. 2011;**97**(8):S140-S153

2016;**24**(2):74-78

1998;**21**(7):751-756

The Knee. 2010;**17**(1):84-87

Research. 2016;**102**(7):879-884


[87] Hangody L, Fules P. Autologous osteochondral mosaicplasty for the treatment of fullthickness defects of weight-bearing joints: Ten years of experimental and clinical experience. Journal of Bone and Joint Surgery. America. 2003;**85-A**(2):25-32

[75] Steadman JR, Rodkey WG, Rodrigo JJ. Microfracture: Surgical technique and rehabilitation to treat chondral defects. Clinical Orthopaedics and Related Research®.

[76] Frisbie DD, Oxford JT, Southwood L, et al. Early events in cartilage repair after subchondral bone microfracture. Clinical Orthopaedics and Related Research®. 2003;**407**:215-227

[77] Steadman JR, Rodkey WG, Singleton SB, Briggs KK. Microfracture technique for fullthickness chondral defects: Technique and clinical results. Operative Techniques in

[78] Steadman JR, Briggs KK, Rodrigo JJ, Kocher MS, Gill TJ, Rodkey WG. Outcomes of microfracture for traumatic chondral defects of the knee: Average 11-year follow-up.

[79] Goyal D, Keyhani S, Lee EH, Hui JHP. Evidence-based status of microfracture technique: A systematic review of level I and II studies. Arthroscopy: The Journal of Arthroscopic &

[80] Mithoefer K, McAdams T, Williams RJ, Kreuz PC, Mandelbaum BR. Clinical efficacy of the microfracture technique for articular cartilage repair in the knee: An evidence-based

[81] Gudas R, Kalesinskas RJ, Kimtys V, et al. A prospective randomized clinical study of mosaic osteochondral autologous transplantation versus microfracture for the treatment of osteochondral defects in the knee joint in young athletes. Arthroscopy: The Journal of

[82] Gudas R, Gudaitė A, Pocius A, et al. Ten-year follow-up of a prospective, randomized clinical study of mosaic osteochondral autologous transplantation versus microfracture for the treatment of osteochondral defects in the knee joint of athletes. American Journal

[83] Ulstein S, Årøen A, Røtterud JH, Løken S, Engebretsen L, Heir S. Microfracture technique versus osteochondral autologous transplantation mosaicplasty in patients with articular chondral lesions of the knee: A prospective randomized trial with long-term follow-up. Knee Surgery, Sports Traumatology, Arthroscopy. 2014;**22**(6):1207-1215

[84] Devitt BM, Bell SW, Webster KE, Feller JA, Whitehead TS. Surgical treatments of cartilage defects of the knee: Systematic review of randomised controlled trials. The Knee.

[85] Mithoefer K, Williams RJ 3rd, Warren RF, Wickiewicz TL, Marx RG. High-impact athletics after knee articular cartilage repair: A prospective evaluation of the microfracture

[86] Matsusue Y, Yamamuro T, Hama H. Arthroscopic multiple osteochondral transplantation to the chondral defect in the knee associated with anterior cruciate ligament disruption. Arthroscopy: The Journal of Arthroscopic & Related Surgery. 1993;**9**(3):318-321

technique. American Journal of Sports Medicine. 2006;**34**(9):1413-1418

systematic analysis. American Journal of Sports Medicine. 2009;**37**(10):2053-2063

Arthroscopy: The Journal of Arthroscopic & Related Surgery. 2003;**19**(5):477-484

2001;**391**:S362-S369

138 Cartilage Repair and Regeneration

Orthopaedics. 1997;**7**(4):300-304

Related Surgery. 2013;**29**(9):1579-1588

Arthroscopic & Related Surgery. 2005;**21**(9):1066-1075

of Sports Medicine. 2012;**40**(11):2499-2508

2017;**3**:508-517


[100] Kish G, Módis L, Hangody L. Osteochondral mosaicplasty for the treatment of focal chondral and osteochondral lesions of the knee and talus in the athlete: Rationale, indications, techniques, and results. Clinics in Sports Medicine. 1999;**18**(1):45-66

[113] Peterson L. Technique of autologous chondrocyte transplantation. Techniques in Knee

Osteochondritis Dissecans of the Knee http://dx.doi.org/10.5772/intechopen.70275 141

[114] Mithöfer K, Minas T, Peterson L, Yeon H, Micheli LJ. Functional outcome of knee articular cartilage repair in adolescent athletes. American Journal of Sports Medicine.

[115] Cole BJ, DeBerardino T, Brewster R, et al. Outcomes of autologous chondrocyte implantation in study of the treatment of articular repair (STAR) patients with osteochondritis

[116] Peterson L, Brittberg M, Kiviranta I, Åkerlund EL, Lindahl A. Autologous chondrocyte transplantation biomechanics and long-term durability. American Journal of Sports

[117] Peterson L, Minas T, Brittberg M, Lindahl A. Treatment of osteochondritis dissecans of the knee with autologous chondrocyte transplantation. Journal of Bone and Joint

[118] Behery OA, Harris JD, Karnes JM, Siston RA, Flanigan DC. Factors influencing the outcome of autologous chondrocyte implantation: A systematic review. Journal of Knee

[119] Harris JD, Siston RA, Pan X, Flanigan DC. Autologous chondrocyte implantation: A systematic review. Journal of Bone and Joint Surgery. America. 2010;**92**(12):2220-2233

[120] Krishnan SP, Skinner JA, Bartlett W, et al. Who is the ideal candidate for autologous chondrocyte implantation? Journal of Bone and Joint Surgery. British. 2006;**88**(1):61-64

[121] Polousky JD, Albright J. Salvage techniques in osteochondritis dissecans. Clinics in

[122] Chambers HG, Shea KG, Carey JL.AAOS clinical practice guideline: Diagnosis and treatment of osteochondritis dissecans. Journal of the American Academy of Orthopaedic

[123] Nepple JJ, Milewski MD, Shea KG. Research in osteochondritis dissecans of the knee:

2016 update. The Journal of Knee Surgery. 2016;**29**(07):533-538

dissecans. American Journal of Sports Medicine. 2012;**40**(9):2015-2022

Surgery. 2002;**1**(1):2-12

2005;**33**(8):1147-1153

Medicine. 2002;**30**(1):2-12

Surgery. 2013;**26**(03):203-212

Sports Medicine. 2014;**33**(2):321-333

Surgeons. 2011;**19**(5):307-309

Surgery. America. 2003;**85**(suppl 2):17-24


[113] Peterson L. Technique of autologous chondrocyte transplantation. Techniques in Knee Surgery. 2002;**1**(1):2-12

[100] Kish G, Módis L, Hangody L. Osteochondral mosaicplasty for the treatment of focal chondral and osteochondral lesions of the knee and talus in the athlete: Rationale, indi-

[101] Sadr KN, Pulido PA, McCauley JC, Bugbee WD. Osteochondral allograft transplantation in patients with osteochondritis dissecans of the knee. American Journal of Sports

[102] Gortz S, Bugbee WD. Allografts in articular cartilage repair. Journal of Bone and Joint

[103] Pallante AL, Bae WC, Chen AC, Gortz S, Bugbee WD, Sah RL. Chondrocyte viability is higher after prolonged storage at 37 degrees C than at 4 degrees C for osteochondral

[104] Garrity JT, Stoker AM, Sims HJ, Cook JL. Improved osteochondral allograft preservation using serum-free media at body temperature. American Journal of Sports Medicine.

[105] LaPrade RF, Botker J, Herzog M, Agel J. Refrigerated osteoarticular allografts to treat articular cartilage defects of the femoral condyles. A prospective outcomes study.

[106] Williams RJ 3rd, Dreese JC, Chen CT. Chondrocyte survival and material properties of hypothermically stored cartilage: An evaluation of tissue used for osteochondral allograft transplantation. American Journal of Sports Medicine. 2004;**32**(1):132-139 [107] Ball ST, Amiel D, Williams SK, et al. The effects of storage on fresh human osteochondral allografts. Clinical Orthopaedics and Related Research®. 2004;**418**:246-252

[108] Pallante AL, Chen AC, Ball ST, et al. The in vivo performance of osteochondral allografts in the goat is diminished with extended storage and decreased cartilage cellularity.

[109] Nielsen ES, McCauley JC, Pulido PA, Bugbee WD. Return to sport and recreational activity after osteochondral allograft transplantation in the knee. American Journal of

[110] Emmerson BC, Gortz S, Jamali AA, Chung C, Amiel D, Bugbee WD. Fresh osteochondral allografting in the treatment of osteochondritis dissecans of the femoral condyle.

[111] Garrett JC. Fresh osteochondral allografts for treatment of articular defects in osteochondritis dissecans of the lateral femoral condyle in adults. Clinical Orthopaedics and

[112] Frank RM, Lee S, Levy D, et al. Osteochondral allograft transplantation of the knee: Analysis of failures at 5 years. American Journal of Sports Medicine. Mar 2016;**45**(4):

grafts. American Journal of Sports Medicine. 2009;**37**(1):24S-32S

Journal of Bone and Joint Surgery. America. 2009;**91**(4):805-811

American Journal of Sports Medicine. 2012;**40**(8):1814-1823

American Journal of Sports Medicine. 2007;**35**(6):907-914

Sports Medicine. 2017:**45**(7):1608-1614

Related Research®. 1994;**303**:33-37

864-874

cations, techniques, and results. Clinics in Sports Medicine. 1999;**18**(1):45-66

Medicine. 2016;**44**(11):2870-2875

140 Cartilage Repair and Regeneration

2012;**40**(11):2542-2548

Surgery. America. 2006;**88**(6):1374-1384


**Chapter 8**

**Provisional chapter**

**Autologous Chondrocyte Implantation: Scaffold-Based**

Autologous chondrocyte implantation is a surgical technique utilized for repair of articular cartilage defects. The originally described technique for autologous chondrocyte implantation involves applying a liquid suspension of the cultured chondrocytes to a cartilage defect and sealing the defect with a periosteum or collagen patch. Scaffolds for housing chondrocytes were introduced to allow for increased ease of delivery and application, to avoid leakage of chondrocytes out of the defect, and to allow for an implant that more closely mimics the non-uniform tissue architecture of healthy articular cartilage. In this chapter we describe the design, clinical outcomes, and commercial availability of various scaffolds reported in the clinical literature for autologous chondrocyte implantation. **Keywords:** scaffold, MACI, MACT, autologous chondrocyte implantation, 3rd generation

**Autologous Chondrocyte Implantation: Scaffold-Based** 

DOI: 10.5772/intechopen.70276

© 2016 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution,

© 2018 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

and reproduction in any medium, provided the original work is properly cited.

Autologous chondrocyte implantation (ACI) is a two-stage articular cartilage repair technique for treatment of articular cartilage defects. Originally described by Brittberg et al. [1], it involves an initial surgery to harvest chondrocytes from a non-weight bearing portion of the distal femur, typically the intercondylar notch or medial or lateral margin of the trochlea. The cartilage extracellular matrix is then enzymatically digested within the laboratory to isolate the chondrocytes. The harvested chondrocytes are then cultured in a laboratory. In the second stage, a liquid suspension of chondrocytes is applied to the cartilage defect and is sealed in place with a soft tissue membrane cover [1]. Originally periosteum was utilized as the cover, though a collagen membrane was later introduced to minimize periosteal donor site morbidity and risk of periosteal

**Solutions**

**Solutions**

Nicholas A. Early

**Abstract**

ACI

**1. Introduction**

Nicholas A. Early

David C. Flanigan, Joshua S. Everhart and

David C. Flanigan, Joshua S. Everhart and

Additional information is available at the end of the chapter

Additional information is available at the end of the chapter

http://dx.doi.org/10.5772/intechopen.70276

**Provisional chapter**

## **Autologous Chondrocyte Implantation: Scaffold-Based Solutions Solutions**

**Autologous Chondrocyte Implantation: Scaffold-Based** 

DOI: 10.5772/intechopen.70276

David C. Flanigan, Joshua S. Everhart and Nicholas A. Early Nicholas A. Early Additional information is available at the end of the chapter

David C. Flanigan, Joshua S. Everhart and

Additional information is available at the end of the chapter

http://dx.doi.org/10.5772/intechopen.70276

#### **Abstract**

Autologous chondrocyte implantation is a surgical technique utilized for repair of articular cartilage defects. The originally described technique for autologous chondrocyte implantation involves applying a liquid suspension of the cultured chondrocytes to a cartilage defect and sealing the defect with a periosteum or collagen patch. Scaffolds for housing chondrocytes were introduced to allow for increased ease of delivery and application, to avoid leakage of chondrocytes out of the defect, and to allow for an implant that more closely mimics the non-uniform tissue architecture of healthy articular cartilage. In this chapter we describe the design, clinical outcomes, and commercial availability of various scaffolds reported in the clinical literature for autologous chondrocyte implantation.

**Keywords:** scaffold, MACI, MACT, autologous chondrocyte implantation, 3rd generation ACI

## **1. Introduction**

Autologous chondrocyte implantation (ACI) is a two-stage articular cartilage repair technique for treatment of articular cartilage defects. Originally described by Brittberg et al. [1], it involves an initial surgery to harvest chondrocytes from a non-weight bearing portion of the distal femur, typically the intercondylar notch or medial or lateral margin of the trochlea. The cartilage extracellular matrix is then enzymatically digested within the laboratory to isolate the chondrocytes. The harvested chondrocytes are then cultured in a laboratory. In the second stage, a liquid suspension of chondrocytes is applied to the cartilage defect and is sealed in place with a soft tissue membrane cover [1]. Originally periosteum was utilized as the cover, though a collagen membrane was later introduced to minimize periosteal donor site morbidity and risk of periosteal

© 2016 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. © 2018 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

patch hypertrophy [2]. Disadvantages of ACI with periosteum or collagen membrane covers with the use of a liquid cultured chondrocyte suspension include a high degree of technical difficulty, potential for leakage of chondrocytes, and non-uniform distribution of chondrocytes.

**2. Scaffolds utilized for autologous chondrocyte implantation**

As of December 2016, matrix-assisted chondrocyte implantation (MACI; Vericel, Cambridge, MA) is currently the only FDA approved MACT technique for use in the United States. In this technique, chondrocytes are cultured ex-vivo in a monolayer and then seeded on one side of a porcine collagen I/III membrane (**Table 2**). At the second stage operation (reimplantation), the side seeded with chondrocytes (the roughened side) is placed against the subchondral bone surface and the graft is secured with fibrin glue [8]. The implantation may be performed arthroscopically or with a mini-arthrotomy, and recent work demonstrates MACI grafts may be safely applied with use of carbon dioxide insufflation arthroscopy [9]. Regardless of technique, gentle handling of the graft is recommended, as excessive or forceful handling of the graft causes a significant decrease in viable chondrocytes [10]. A histologic study of 56 MACI patients up to 6 months after surgery demonstrated that chondrocytes appeared well-integrated and maintained chondrocyte phenotype [11]. Hyalinelike cartilage production began as early as 21 days after implantation, and there was 75% hyaline-like cartilage regeneration at 6 months [11]. Another histologic study of 33 secondlook biopsies at median 15 months after surgery found a median ICRS histological grade of 57 which did not correlate with an arthroscopic ICRS grade of normal in 30% of cases and

Several comparative studies have been performed with MACI, all of which demonstrated encouraging results (**Table 3**). However, it should be noted that use of MACI in clinical

SUMMIT trial, reported by Saris et al. [14]. In this randomized trial, 144 patients with high grade femoral condylar defects were randomized to MACI or microfracture and followed for

fracture) [14]. At final follow-up there was significantly better improvement in KOOS symptom scores with MACI, lower failure rates, yet no difference in repair quality as assessed by histology or MRI versus microfracture [14]. A randomized controlled trial was performed by Bartlett et al. with comparison of ACI-C (ACI with collagen cover) and MACI for treatment

**Manufacturer Structure Expansion Availability**

Porcinederived collagen I/III bilayer

) [13]. Approval by the FDA was based primarily on results of the

Cells are expanded in monolayer then seeded onto porous side of collagen membrane

) than lesions treated in clinical trials

Autologous Chondrocyte Implantation: Scaffold-Based Solutions

http://dx.doi.org/10.5772/intechopen.70276

145

MACI vs. 4.7 cm<sup>2</sup>

FDA approved for use in the USA. Available in Europe and Australia

micro-

**2.1. Porcine collagen I/III membranes**

nearly normal in 51% of cases [12].

MACI Vericel, Cambridge, MA (Formerly

FDA, U.S. Food and Drug Administration.

provided by Verigen Transplantation Service, Copenhagen, Denmark)

**Table 2.** MACT with porcine collagen I/III membrane scaffold.

(weighted mean 4.89 cm2

**Commercial name**

practice tends to be in larger defects (mean 5.64 cm2

2 years; mean defect size was equivalent between groups (4.9 cm<sup>2</sup>

*2.1.1. MACI*

Scaffolds for housing chondrocytes were introduced for increased ease of delivery and application, to avoid leakage of chondrocytes out of the defect, and to allow homogeneous distribution of chondrocytes within the defect [3]. Additionally, there is some evidence that chondrocytes grown in monolayer culture do not fully regain their original phenotype [3, 4], which has prompted research in culture directly within a scaffold and design of implants that more closely mimics the non-uniform tissue architecture of healthy articular cartilage [3]. Use of a 3-dimensional structure for chondrocyte culture has been shown to maintain the chondrocyte differentiated phenotype [5]. Use of a scaffold is termed 'matrix-assisted autologous chondrocyte transplantation,' or the MACT procedure, and has been employed in clinical practice in Europe since 1998. The MACT procedure involves implantation of a chondrocyte seeded biocompatible scaffold in the articular defect [2]. The implant is fixed in place with fibrin glue with no membrane cover and allows for implantation with use of a mini-arthrotomy or arthroscopic implantation. The field of scaffold-based ACI has greatly expanded in recent years, with more than a dozen implants developed (**Table 1**). A wide variety of natural and synthetic materials have been utilized in MACT scaffolds; though clinical outcomes studies are generally favorable regardless of scaffold design, the number or published studies and length of follow-up vary widely among implants.

In this chapter, the design rationale, commercial availability, and clinical results of various scaffolds for use in MACT will be described. Of note, all implants described in this chapter follow a two-step implantation protocol (initial cartilage harvest and culturing of chondrocytes followed by a delayed implantation several weeks later). The single-stage implantation techniques with published outcomes data are either no longer commercially available (the CAIS implant) [6], or have yet to be marketed [7].


**Table 1.** Summary of MACT scaffolds.

## **2. Scaffolds utilized for autologous chondrocyte implantation**

#### **2.1. Porcine collagen I/III membranes**

#### *2.1.1. MACI*

patch hypertrophy [2]. Disadvantages of ACI with periosteum or collagen membrane covers with the use of a liquid cultured chondrocyte suspension include a high degree of technical difficulty, potential for leakage of chondrocytes, and non-uniform distribution of chondrocytes.

Scaffolds for housing chondrocytes were introduced for increased ease of delivery and application, to avoid leakage of chondrocytes out of the defect, and to allow homogeneous distribution of chondrocytes within the defect [3]. Additionally, there is some evidence that chondrocytes grown in monolayer culture do not fully regain their original phenotype [3, 4], which has prompted research in culture directly within a scaffold and design of implants that more closely mimics the non-uniform tissue architecture of healthy articular cartilage [3]. Use of a 3-dimensional structure for chondrocyte culture has been shown to maintain the chondrocyte differentiated phenotype [5]. Use of a scaffold is termed 'matrix-assisted autologous chondrocyte transplantation,' or the MACT procedure, and has been employed in clinical practice in Europe since 1998. The MACT procedure involves implantation of a chondrocyte seeded biocompatible scaffold in the articular defect [2]. The implant is fixed in place with fibrin glue with no membrane cover and allows for implantation with use of a mini-arthrotomy or arthroscopic implantation. The field of scaffold-based ACI has greatly expanded in recent years, with more than a dozen implants developed (**Table 1**). A wide variety of natural and synthetic materials have been utilized in MACT scaffolds; though clinical outcomes studies are generally favorable regardless of scaffold design, the number or published studies and

In this chapter, the design rationale, commercial availability, and clinical results of various scaffolds for use in MACT will be described. Of note, all implants described in this chapter follow a two-step implantation protocol (initial cartilage harvest and culturing of chondrocytes followed by a delayed implantation several weeks later). The single-stage implantation techniques with published outcomes data are either no longer commercially available (the

**Scaffold content Commercial name Implantation steps**

Porcine collagen I/III membrane MACI Two-steps Three-dimensional collagen I based scaffold NeoCart Two-steps Three-dimensional collagen I based scaffold CaReS Two-steps Three-dimensional collagen I based scaffold Novocart 3D Two-steps Hyaluronic acid based scaffold Hyalograft C Two-steps Human fibrin and recombinant hyaluronic acid-based scaffold BioCart II Two-steps Fibrin based gel Chondron Two-steps Hydrogel of agarose and alginate Cartipatch Two-steps Atelocollagen gel Koken Atelocollagen Implant Two-steps Fibrin, polyglycolic/polylactic acid, polydioxanone BioSeed-C Two-steps

length of follow-up vary widely among implants.

144 Cartilage Repair and Regeneration

CAIS implant) [6], or have yet to be marketed [7].

**Table 1.** Summary of MACT scaffolds.

As of December 2016, matrix-assisted chondrocyte implantation (MACI; Vericel, Cambridge, MA) is currently the only FDA approved MACT technique for use in the United States. In this technique, chondrocytes are cultured ex-vivo in a monolayer and then seeded on one side of a porcine collagen I/III membrane (**Table 2**). At the second stage operation (reimplantation), the side seeded with chondrocytes (the roughened side) is placed against the subchondral bone surface and the graft is secured with fibrin glue [8]. The implantation may be performed arthroscopically or with a mini-arthrotomy, and recent work demonstrates MACI grafts may be safely applied with use of carbon dioxide insufflation arthroscopy [9]. Regardless of technique, gentle handling of the graft is recommended, as excessive or forceful handling of the graft causes a significant decrease in viable chondrocytes [10]. A histologic study of 56 MACI patients up to 6 months after surgery demonstrated that chondrocytes appeared well-integrated and maintained chondrocyte phenotype [11]. Hyalinelike cartilage production began as early as 21 days after implantation, and there was 75% hyaline-like cartilage regeneration at 6 months [11]. Another histologic study of 33 secondlook biopsies at median 15 months after surgery found a median ICRS histological grade of 57 which did not correlate with an arthroscopic ICRS grade of normal in 30% of cases and nearly normal in 51% of cases [12].

Several comparative studies have been performed with MACI, all of which demonstrated encouraging results (**Table 3**). However, it should be noted that use of MACI in clinical practice tends to be in larger defects (mean 5.64 cm2 ) than lesions treated in clinical trials (weighted mean 4.89 cm2 ) [13]. Approval by the FDA was based primarily on results of the SUMMIT trial, reported by Saris et al. [14]. In this randomized trial, 144 patients with high grade femoral condylar defects were randomized to MACI or microfracture and followed for 2 years; mean defect size was equivalent between groups (4.9 cm<sup>2</sup> MACI vs. 4.7 cm<sup>2</sup> microfracture) [14]. At final follow-up there was significantly better improvement in KOOS symptom scores with MACI, lower failure rates, yet no difference in repair quality as assessed by histology or MRI versus microfracture [14]. A randomized controlled trial was performed by Bartlett et al. with comparison of ACI-C (ACI with collagen cover) and MACI for treatment


**Table 2.** MACT with porcine collagen I/III membrane scaffold.


Several randomized trials of delayed versus accelerated weight-bearing after MACI have been performed (**Table 3**). A randomized trial of 6 week versus 8 week return to full weight bearing found no significant difference in failure rates or symptom improvement at 2 years (interim 12-month results reported in an earlier publication [19]); the study authors concluded accelerated weight bearing after MACI is safe [20]. Another trial of 6 week versus 10 week return to full weight bearing with 5 years follow-up after MACI similarly found no difference in symptom improvement between groups [21]. The authors note that MRI-based MOCART scores

Autologous Chondrocyte Implantation: Scaffold-Based Solutions

http://dx.doi.org/10.5772/intechopen.70276

147

Several case series have reported also reported good results with MACI (**Table 3**). The series with the longest follow-up is reported by Gille et al.; of 19 cases with mean 16 years follow-up, 21% underwent knee arthroplasty (4/19), with durable symptom improvement in the remaining 15 patients [22]. In another series of MACI patients, Basad et al. report durable improvements in activity and symptoms scores and a failure rate of 18.5% at 5 years with MACI [23]. Behrens et al. similarly report 8/11 patients rated their current knee function as 'much better or better' than their pre-operative function at 5 years follow-up [24]. A larger case series by Ebert et al. of 41 patients and 5 years follow up (35/41, 85% with 5 years follow-up) reported significant improvements in knee function, a 12% rate of graft hypertrophy at 5 years, and a graft failure rate of 3% at 5 years [25]. Durable results are seen with arthroscopic implantation of MACI scaffolds, as Ebert et al. report stable clinical improvement at 5 years follow-up and a failure rate of 6.4% [26]. Ventura et al. note improvement in Lysholm symptom scores at 2 years but no change in Tegner activity scores in a series of 53 patients; a high rates of subchondral abnormalities were noted on MRI at 1 year (70% of cases) which did not correlate

For the patellofemoral joint, Meyerkort et al. report durable improvement in symptoms at 5 years with MACI; clinical improvement did not correlate with MRI assessment of graft appearance at 5 years [28]. Gigante et al. published results of treatment of patellar defects with MACI and concomitant distal realignment; at 3 years, there was significant improvement

As a salvage operation in young patients with medial compartment osteoarthritis, Bauer et al. report significant clinical improvement at 5 years with combined high tibial osteotomy and MACI; however, they note declining results and high graft failure over time for this salvage operation [30]. Finally, outcomes for MACI and concomitant bone grafting for treatment of osteochondral lesions with use of a bilayer 'sandwich' technique have also been reported. Vijayan et al. report outcomes with use of two MACI membranes and impaction bone grafting of osteochondral lesions greater than 8 mm depth; at a mean 5.2 year's follow-up, 12/14

NeoCart (Histogenics Corporation, Waltham, Massachusetts) is an MACT implant that consists of a three-dimensional bovine collagen I scaffold (**Table 4**). Rather than being cultured

in symptoms in most patients and one clinical failure (7%) [29].

patients had good to excellent results with one graft failure [31].

**2.2. Three-dimensional collagen I based scaffolds**

decreased from years 2 to 5 but did not correlate with symptom scores [21].

with clinical symptoms [27].

*2.2.1. NeoCart*

**Table 3.** Outcomes of MACT with collagen I/III membrane scaffold (MACI) from level 1 prospective clinical studies.

of high grade chondral defects. Mean defect size was 6.0 cm<sup>2</sup> for the MACI group and 6.1 cm<sup>2</sup> for the ACI-C group [8]. At 1 year follow-up both groups demonstrated significant improvement in Cincinnati knee scores and similar re-operation rates (9% for both groups) [8]. Basad et al. performed a randomized study of MACI versus microfracture with 2 years follow-up on high grade defects 4–10 cm2 [15]. The MACI group in this study had greater improvements in symptom scores, activity scores, and ICRS surgeon grading of cartilage appearance at second look arthroscopy [15]. In a comparative imaging and clinical study of MACI versus osteochondral autograft transfer (OAT) by Salzmann et al., superior Lysholm symptoms scores were observed in the MACI group; patients in this study were matched for demographics, but MACI-treated lesions were >3 cm<sup>2</sup> and OAT-treated lesions were <3 cm<sup>2</sup> [16]. For treatment of chondromalacia patella, Macmull et al. noted a higher rate of good-excellent patient symptom scores with MACI (56.5%) than ACI-C (40%). Higher rates of clinical failure (poor patient-rated symptoms) were noted with lateral facet lesions, and the authors did not report distribution of lesions (medial facet, lateral facet, or multiple facets) by treatment group [17]. Finally, Akgun et al. report a small randomized trial of MACI versus autologous mesenchymal stem cells (also seeded onto a collagen scaffold) with 2 years follow-up [18]. The stem cell group had greater symptom improvement at 6 months but similar improvement at final follow-up; no clinical failures were noted in either group [18].

Several randomized trials of delayed versus accelerated weight-bearing after MACI have been performed (**Table 3**). A randomized trial of 6 week versus 8 week return to full weight bearing found no significant difference in failure rates or symptom improvement at 2 years (interim 12-month results reported in an earlier publication [19]); the study authors concluded accelerated weight bearing after MACI is safe [20]. Another trial of 6 week versus 10 week return to full weight bearing with 5 years follow-up after MACI similarly found no difference in symptom improvement between groups [21]. The authors note that MRI-based MOCART scores decreased from years 2 to 5 but did not correlate with symptom scores [21].

Several case series have reported also reported good results with MACI (**Table 3**). The series with the longest follow-up is reported by Gille et al.; of 19 cases with mean 16 years follow-up, 21% underwent knee arthroplasty (4/19), with durable symptom improvement in the remaining 15 patients [22]. In another series of MACI patients, Basad et al. report durable improvements in activity and symptoms scores and a failure rate of 18.5% at 5 years with MACI [23]. Behrens et al. similarly report 8/11 patients rated their current knee function as 'much better or better' than their pre-operative function at 5 years follow-up [24]. A larger case series by Ebert et al. of 41 patients and 5 years follow up (35/41, 85% with 5 years follow-up) reported significant improvements in knee function, a 12% rate of graft hypertrophy at 5 years, and a graft failure rate of 3% at 5 years [25]. Durable results are seen with arthroscopic implantation of MACI scaffolds, as Ebert et al. report stable clinical improvement at 5 years follow-up and a failure rate of 6.4% [26]. Ventura et al. note improvement in Lysholm symptom scores at 2 years but no change in Tegner activity scores in a series of 53 patients; a high rates of subchondral abnormalities were noted on MRI at 1 year (70% of cases) which did not correlate with clinical symptoms [27].

For the patellofemoral joint, Meyerkort et al. report durable improvement in symptoms at 5 years with MACI; clinical improvement did not correlate with MRI assessment of graft appearance at 5 years [28]. Gigante et al. published results of treatment of patellar defects with MACI and concomitant distal realignment; at 3 years, there was significant improvement in symptoms in most patients and one clinical failure (7%) [29].

As a salvage operation in young patients with medial compartment osteoarthritis, Bauer et al. report significant clinical improvement at 5 years with combined high tibial osteotomy and MACI; however, they note declining results and high graft failure over time for this salvage operation [30]. Finally, outcomes for MACI and concomitant bone grafting for treatment of osteochondral lesions with use of a bilayer 'sandwich' technique have also been reported. Vijayan et al. report outcomes with use of two MACI membranes and impaction bone grafting of osteochondral lesions greater than 8 mm depth; at a mean 5.2 year's follow-up, 12/14 patients had good to excellent results with one graft failure [31].

#### **2.2. Three-dimensional collagen I based scaffolds**

#### *2.2.1. NeoCart*

of high grade chondral defects. Mean defect size was 6.0 cm<sup>2</sup>

**Author Implant and sample size**

> WB; 18 MACIaccelerated WB

15 MACI-standard WB; 16 MACIaccelerate WB

mesenchymal stem

microfracture

microfracture

cell

1 Ebert et al. [20] 19 MACI-standard

1 Akgun et al. [18] 7 MACI; seven

1 Basad et al. [15] 40 MACI; 20

1 Saris et al. [14] 72 MACI; 72

1 Wondrasch et al. [21]

146 Cartilage Repair and Regeneration

follow-up; no clinical failures were noted in either group [18].

high grade defects 4–10 cm2

**Level of evidence**

but MACI-treated lesions were >3 cm<sup>2</sup>

for the ACI-C group [8]. At 1 year follow-up both groups demonstrated significant improvement in Cincinnati knee scores and similar re-operation rates (9% for both groups) [8]. Basad et al. performed a randomized study of MACI versus microfracture with 2 years follow-up on

**Table 3.** Outcomes of MACT with collagen I/III membrane scaffold (MACI) from level 1 prospective clinical studies.

symptom scores, activity scores, and ICRS surgeon grading of cartilage appearance at second look arthroscopy [15]. In a comparative imaging and clinical study of MACI versus osteochondral autograft transfer (OAT) by Salzmann et al., superior Lysholm symptoms scores were observed in the MACI group; patients in this study were matched for demographics,

ment of chondromalacia patella, Macmull et al. noted a higher rate of good-excellent patient symptom scores with MACI (56.5%) than ACI-C (40%). Higher rates of clinical failure (poor patient-rated symptoms) were noted with lateral facet lesions, and the authors did not report distribution of lesions (medial facet, lateral facet, or multiple facets) by treatment group [17]. Finally, Akgun et al. report a small randomized trial of MACI versus autologous mesenchymal stem cells (also seeded onto a collagen scaffold) with 2 years follow-up [18]. The stem cell group had greater symptom improvement at 6 months but similar improvement at final

[15]. The MACI group in this study had greater improvements in

**Mean follow-up Outcome**

2 years Randomized trial of standard 8 week

improvement.

5 years Randomized trial of 6 versus 10 week

symptom scores

2 years Small randomized trial of MACI versus

2 years At 24 months, greater improvements

2 years Greater improvement in KOOS scores,

return to weight bearing versus accelerated 6 week return to weight bearing. No difference in symptom

return to weight bearing. No difference in symptom improvement between groups. MOCART score decreased from years 2 to 5 which did not correlate with

stem cells (also seeded onto a collagen scaffold. Stem cell group had greater symptom improvement at 6 months but similar improvement at final follow-up.

seen with MACI in Tegner activity score, subjective symptoms scores and ICRS scores on 2nd look arthroscopy.

lower failure rate with MACI (12.5%) versus microfracture (31.9%). Similar MRI and histologic outcomes.

and OAT-treated lesions were <3 cm<sup>2</sup>

for the MACI group and 6.1 cm<sup>2</sup>

[16]. For treat-

NeoCart (Histogenics Corporation, Waltham, Massachusetts) is an MACT implant that consists of a three-dimensional bovine collagen I scaffold (**Table 4**). Rather than being cultured


clinical and MRI-based study with 5 years follow-up by Anderson et al. demonstrate that clinical improvement and graft appearance on MRI both evolve over the first 24 months after surgery [34]. Both clinical scores and MRI appearance appeared stable from 24 to 60 months

The Cartilage Regeneration System (CaReS, Ars Arthro, Esslingen, Germany) utilizes a ratderived collagen I gel rather than the bovine collagen matrix utilized by NeoCart (**Table 4**). The harvested chondrocytes are similarly seeded into the collagen gel and cultured in this 3-dimensional environment with the intention of preserving cartilage phenotype. In a small comparative study of CaReS (9 patients) versus MACI (11 patients) with 1 year follow-up, Flohe et al. demonstrate significant improvement in symptoms with no difference between groups (**Table 5**) [35]. A small comparative study of microfracture (n = 10) vs. CaReS (n = 17) for patellofemoral lesions found significant improvements in symptoms from baseline with no difference in outcomes between groups [36]. In a multicenter clinical trial, Schneider et al. report outcomes of 116 at mean 30.6 month follow-up from 9 different centers; mean defect

VAS and SF-36 scores and a patient satisfaction rate of 80%. A total of 8 revision arthroscopies were performed for pain with 2 cases of implant hypertrophy and 2 cases of early failure [37]. In an imaging based outcome study, Welsch et al. compared 3T MRI results at 2 years for Hyalograft C versus CaReS and found greater T2 relaxation times for CaReS despite similar

The Novocart 3D implant (B. Braun-Tetec, Reutlingen, Germany) is a collagen-chondroitin sulfate sponge (**Table 4**). After chondrocyte harvest, cells are initially cultured in a monolayer and

after which the scaffold is cultivated in serum for 2 days before shipment for re-implantation [39]. Niethammer et al. performed several MRI-based studies of graft maturation and graft filling with Novocart 3D. In a 3 years prospective MRI study, graft maturation as assessed by T2 mapping required at least 1 year [40]. In a 2 years prospective MRI study, incomplete graft filling as assessed by MRI was common (55.7%) at 2 years and did not correlate with clinical results; the authors noted that graft thickness appeared to increase throughout the 2 years follow-up period [41]. A 2 years follow-up MRI study showed a 25% graph hypertrophy rate in Novocart 3D patients (11/44 patients), with higher hypertrophy rates in cases of acute trau-

In a small non-randomized comparative study, Panagopoulos et al. report outcomes of Novocart 3D (n = 9) and ACI-P (periosteal cover) (n = 11) and mean 37.5 months follow-up (**Table 5**) [43]. No significant difference in Tegner, Lysholm, or IKDC scores was noted between groups. The patient population consisted of high demand athletes and soldiers, with low rates of return to pre-injury activity levels (6/19, 31.5%) [43]. In a comparative study of 40 pediatric (<20 years old) patients treated with Novocart 3D versus 40 matched adult historical controls who also

then seeded onto the collagen-chondroitin sulfate scaffold at a density of 0.5–3.0 × 10<sup>6</sup>

[37]. At final follow-up there was significant improvement in IKDC,

Autologous Chondrocyte Implantation: Scaffold-Based Solutions

http://dx.doi.org/10.5772/intechopen.70276

149

cells/cm2

,

follow-up [34].

size in the trial was 5.4 cm2

*2.2.3. Novocart 3D*

clinical outcomes between groups [38].

matic defects or osteochondritis dissecans [42].

*2.2.2. CaReS*

**Table 4.** MACT with three-dimensional collagen 1 scaffold.

in a monolayer, the scaffold is seeded initially with chondrocytes which then proliferate in a custom bioreactor [32]. The bioreactor is designed to incubate the scaffold in a low-oxygen tension environment with varying pressure to mimic the native intra-articular environment with the goal of preserving the chondrocyte phenotype [33]. At the time of implantation, the graft is fixed to the defect with a proprietary adhesive (CT3 bioadhesive, Histogenics). A randomized phase II trial by Crawford et al. of distal femoral lesions treated with NeoCart versus microfracture demonstrated superior improvement in IKDC and KOOS scores at 24 months with NeoCart and no difference in adverse events between groups (**Table 5**) [33]. A small case series (8 patients) with 2 years follow-up demonstrated significant symptom improvement from baseline and no cases of graft hypertrophy or arthrofibrosis (**Table 5**) [32]. Defect fill was noted to be moderate (33–66%) in 1/8 cases and poor (<33%) in 1/8 cases. A longitudinal


**Table 5.** MACT clinical outcome studies with three-dimensional collagen 1 scaffold.

clinical and MRI-based study with 5 years follow-up by Anderson et al. demonstrate that clinical improvement and graft appearance on MRI both evolve over the first 24 months after surgery [34]. Both clinical scores and MRI appearance appeared stable from 24 to 60 months follow-up [34].

#### *2.2.2. CaReS*

The Cartilage Regeneration System (CaReS, Ars Arthro, Esslingen, Germany) utilizes a ratderived collagen I gel rather than the bovine collagen matrix utilized by NeoCart (**Table 4**). The harvested chondrocytes are similarly seeded into the collagen gel and cultured in this 3-dimensional environment with the intention of preserving cartilage phenotype. In a small comparative study of CaReS (9 patients) versus MACI (11 patients) with 1 year follow-up, Flohe et al. demonstrate significant improvement in symptoms with no difference between groups (**Table 5**) [35]. A small comparative study of microfracture (n = 10) vs. CaReS (n = 17) for patellofemoral lesions found significant improvements in symptoms from baseline with no difference in outcomes between groups [36]. In a multicenter clinical trial, Schneider et al. report outcomes of 116 at mean 30.6 month follow-up from 9 different centers; mean defect size in the trial was 5.4 cm2 [37]. At final follow-up there was significant improvement in IKDC, VAS and SF-36 scores and a patient satisfaction rate of 80%. A total of 8 revision arthroscopies were performed for pain with 2 cases of implant hypertrophy and 2 cases of early failure [37]. In an imaging based outcome study, Welsch et al. compared 3T MRI results at 2 years for Hyalograft C versus CaReS and found greater T2 relaxation times for CaReS despite similar clinical outcomes between groups [38].

#### *2.2.3. Novocart 3D*

in a monolayer, the scaffold is seeded initially with chondrocytes which then proliferate in a custom bioreactor [32]. The bioreactor is designed to incubate the scaffold in a low-oxygen tension environment with varying pressure to mimic the native intra-articular environment with the goal of preserving the chondrocyte phenotype [33]. At the time of implantation, the graft is fixed to the defect with a proprietary adhesive (CT3 bioadhesive, Histogenics). A randomized phase II trial by Crawford et al. of distal femoral lesions treated with NeoCart versus microfracture demonstrated superior improvement in IKDC and KOOS scores at 24 months with NeoCart and no difference in adverse events between groups (**Table 5**) [33]. A small case series (8 patients) with 2 years follow-up demonstrated significant symptom improvement from baseline and no cases of graft hypertrophy or arthrofibrosis (**Table 5**) [32]. Defect fill was noted to be moderate (33–66%) in 1/8 cases and poor (<33%) in 1/8 cases. A longitudinal

FDA, U.S. Food and Drug Administration; SFDA, State Food and Drug Administration of China; 3D, three-dimensional.

**Manufacturer Structure Expansion Availability**

Cells are expanded directly on 3D scaffold via a custom bioreactor

Cells are mixed with collagen which forms a gel and cultured for 2 weeks

Initial monolayer culture followed by seeding onto scaffold; re-implantation 3–4 weeks after harvest

Ongoing phase III clinical trials; not yet approved by

SFDA certified; not yet approved by the FDA

Available in Europe, ongoing phase III clinical

the FDA

trials.

Bovine collagen type

Rat collagen type I

I matrix

matrix

Collagenchondroitin sulfate

scaffold

**Mean follow-up** **Outcome**

groups.

2 years Randomized trial of distal femoral lesions.

1 year No difference in clinical outcomes between

3 years Comparative trial for patellofemoral defects.

2 years with NeoCart.

Greater IKDC and KOOS improvement at

No difference in groups between IKDC, SF-36, or Cincinnati knee scores at 3 years follow-up.

**Level of evidence**

**Commercial name**

148 Cartilage Repair and Regeneration

NeoCart Histogenics Corporation,

CaReS Arthro Kinetics (Ars

Novocart 3D B. Braun-Tetec,

Waltham, Massachusetts

Arthro, Esslingen, Germany)

Reutlingen, Germany

**Table 4.** MACT with three-dimensional collagen 1 scaffold.

**Author Implant and** 

1 Crawford et al. [33] 21 NeoCart; 9

3 Flohe et al. [35] 9 CaReS; 11

3 Petri et al. [36] 17CaReS; 10

**sample size**

microfracture

microfracture

**Table 5.** MACT clinical outcome studies with three-dimensional collagen 1 scaffold.

MACI

The Novocart 3D implant (B. Braun-Tetec, Reutlingen, Germany) is a collagen-chondroitin sulfate sponge (**Table 4**). After chondrocyte harvest, cells are initially cultured in a monolayer and then seeded onto the collagen-chondroitin sulfate scaffold at a density of 0.5–3.0 × 10<sup>6</sup> cells/cm2 , after which the scaffold is cultivated in serum for 2 days before shipment for re-implantation [39]. Niethammer et al. performed several MRI-based studies of graft maturation and graft filling with Novocart 3D. In a 3 years prospective MRI study, graft maturation as assessed by T2 mapping required at least 1 year [40]. In a 2 years prospective MRI study, incomplete graft filling as assessed by MRI was common (55.7%) at 2 years and did not correlate with clinical results; the authors noted that graft thickness appeared to increase throughout the 2 years follow-up period [41]. A 2 years follow-up MRI study showed a 25% graph hypertrophy rate in Novocart 3D patients (11/44 patients), with higher hypertrophy rates in cases of acute traumatic defects or osteochondritis dissecans [42].

In a small non-randomized comparative study, Panagopoulos et al. report outcomes of Novocart 3D (n = 9) and ACI-P (periosteal cover) (n = 11) and mean 37.5 months follow-up (**Table 5**) [43]. No significant difference in Tegner, Lysholm, or IKDC scores was noted between groups. The patient population consisted of high demand athletes and soldiers, with low rates of return to pre-injury activity levels (6/19, 31.5%) [43]. In a comparative study of 40 pediatric (<20 years old) patients treated with Novocart 3D versus 40 matched adult historical controls who also underwent Novocart for similar size/location lesions, both groups had significant improvement in VAS and IKDC scores at 36 months, but the pediatric group had greater improvement than the adult group at final follow-up [44]. A case series of 23 patients with 2 years follow-up by Zak et al. report improvement in symptoms scores as well as activity scores versus baseline with use of Novocart 3D [39]. At final follow-up, hypertrophy was noted via MRI in 16% and incomplete filling (>50%) in 20% of patients [39]. A large case series by Angele et al. of 433 patients with mean 6.9 months follow-up (max 2.5 years) found an 8.5% re-operation rate, a 6% graft failure rate in patients with >12 months follow-up [45]. Finally, in a case series with 2 years follow-up, Niethammer noted that clinical outcomes at 2 years were worse for patients who returned to sport/physical activities at earlier than 12 months after surgery [46].

## **2.3. Hyaluronic acid or fibrin based scaffolds**

#### *2.3.1. Hyalograft C*

The Hyalograft C scaffold is based on the benzylic ester of hyaluronic acid (HYAFF 11; Fidia Advanced Biopolymers Laboratories, Padova, Italy) (**Table 6**). The resulting scaffold is a meshwork of 20 micrometer diameter fibers. The cells are cultured directly on the scaffold with resulting collagen II and aggrecan production [5]. The implant is naturally adhesive and does not require an additional adhesive at time of implantation. Clinical outcomes of Hyalograft C were encouraging, with superior results in comparison to microfracture [47] and comparable results to MACI [48] or traditional ACI with a periosteum cover (**Table 7**) [49]. However, production of this implant has been discontinued by the manufacturer in favor of further development of a single-stage delivery system (no published clinical outcomes data available for the single-stage system).

*2.3.2. BioCart II*

3 Ferruzzi et al. [49]

**Level of evidence** **Author Implant and sample size**

MACI

ACI-P

microfracture

50 Hyalograft C; 48

**Table 7.** MACT clinical outcome studies with hyaluronic acid or fibrin-based scaffolds.

2 Kon et al. [47] 21 Hyalograft C; 20

3 Kon et al. [48] 22 Hyalograft C; 39

lage surgeries [51].

*2.3.3. Chondron*

An implant called BioCart II (Histogenics Corporation, Waltham, MA formerly supplied by ProChon Biotech prior to merger with Histogenics) is comprised of a scaffold of recombinant hyaluronan with fibrin to form a sponge (**Table 6**). Cells are initially cultured in human serum with recombinant fibroblast growth factor 2 variant (FGF2v1) and then seeded onto the scaffold prior to implantation with a mini-open approach. A small 1 year outcome study by Nehrer et al. of 8 patients demonstrated significant improvement in IKDC and Lysholm scores; 3 patients had a transient effusion post-operatively and there were no clinical failures (**Table 7**) [50]. A case series by Eshed et al. of patients who underwent MRI evaluation at mean 17.3 months after surgery (range 6–48 months) found continued maturation of cartilage with time (>1 year versus <1 year) and higher IKDC scores in patients with >12 months follow-up and without a history of prior carti-

**Mean follow-up** **Outcome**

durable.

(mini-open)

7.5 years Return to sport was a median 8 months for

5 years All patients 40 years or older, treated with mini-

seen in both treatment groups.

2–5 years Similar IKDC improvement at 2+ years. Greater

microfracture, 12.5 months for Hyalograft C. Symptom improvement with microfracture deteriorated with time whereas Hyalograft C was

Autologous Chondrocyte Implantation: Scaffold-Based Solutions

http://dx.doi.org/10.5772/intechopen.70276

151

open MACI or arthroscopic Hyalograft C. Overall failure rate 20%, similar symptom improvement

symptom improvement in first 12 months in Hyalograft C (arthroscopic) group versus ACI-P

The Chondron scaffold is a fibrin-based gel (Sewon Cellontech Co. Ltd., Seoul, Korea) (**Table 6**). Chondrocytes are first cultured separately in a specialized serum (CRM kit, Sewon Cellontech, Korea). At the time of surgery the serum and cultured chondrocytes are mixed 1:1 with fibrin and injected directly onto the defect. In addition to typical preparation of the defect for ACI, several holes are drilled into the subchondral bone to improve adherence [52]. Choi et al. report a multicenter study of 98 patients with mean 24 month follow-up treated with Chondron (**Table 7**) [52]. Symptom improvement increased with time, with greater improvement noted with >25 months follow-up versus <25 months. Complication rates were low with one early repeat operation (1%) and two cases of symptomatic catching (2%) [52]. Similar findings were reported in a series by Kim et al., with no graft-related complications among 30 patients at 24 months follow up; a second look arthroscopy at 12 months showed nearly normal cartilage


AIFA, Italian Medicines Agency; FDA, U.S. Food and Drug Administration.

**Table 6.** Hyaluronic acid or fibrin-based scaffolds.


**Table 7.** MACT clinical outcome studies with hyaluronic acid or fibrin-based scaffolds.

#### *2.3.2. BioCart II*

underwent Novocart for similar size/location lesions, both groups had significant improvement in VAS and IKDC scores at 36 months, but the pediatric group had greater improvement than the adult group at final follow-up [44]. A case series of 23 patients with 2 years follow-up by Zak et al. report improvement in symptoms scores as well as activity scores versus baseline with use of Novocart 3D [39]. At final follow-up, hypertrophy was noted via MRI in 16% and incomplete filling (>50%) in 20% of patients [39]. A large case series by Angele et al. of 433 patients with mean 6.9 months follow-up (max 2.5 years) found an 8.5% re-operation rate, a 6% graft failure rate in patients with >12 months follow-up [45]. Finally, in a case series with 2 years follow-up, Niethammer noted that clinical outcomes at 2 years were worse for patients

who returned to sport/physical activities at earlier than 12 months after surgery [46].

**Commercial name Manufacturer Structure Expansion Availability**

Benzylic ester of hyaluronic acid (HYAFF) combined with expanded patient cells

Human fibrin and recombinant hyaluronic acidbased scaffold

Cells seeded and cultured directly on scaffold

Cells cultured in human serum and growth factor FGF2v1, then seeded onto scaffold

in serum; at time of surgery, suspension is mixed 1:1 with fibrin

Fibrin based gel Cells cultured

No longer commercially available; production discontinued

the FDA

Available in Italy, Greece, and Israel; ongoing clinical trials in the United States; not yet approved by

Available in Korea

The Hyalograft C scaffold is based on the benzylic ester of hyaluronic acid (HYAFF 11; Fidia Advanced Biopolymers Laboratories, Padova, Italy) (**Table 6**). The resulting scaffold is a meshwork of 20 micrometer diameter fibers. The cells are cultured directly on the scaffold with resulting collagen II and aggrecan production [5]. The implant is naturally adhesive and does not require an additional adhesive at time of implantation. Clinical outcomes of Hyalograft C were encouraging, with superior results in comparison to microfracture [47] and comparable results to MACI [48] or traditional ACI with a periosteum cover (**Table 7**) [49]. However, production of this implant has been discontinued by the manufacturer in favor of further development of a single-stage delivery system (no published clinical outcomes data

**2.3. Hyaluronic acid or fibrin based scaffolds**

available for the single-stage system).

Hyalograft C Anika Therapeutics (Fidia

Italy)

BioCart II Histogenics Corporation,

Chondron Sewon Cellontech, Seoul, Korea

**Table 6.** Hyaluronic acid or fibrin-based scaffolds.

Advanced Biopolymers Laboratories, Padova,

Waltham, MA (merger with former supplier, ProChon Biotech)

AIFA, Italian Medicines Agency; FDA, U.S. Food and Drug Administration.

*2.3.1. Hyalograft C*

150 Cartilage Repair and Regeneration

An implant called BioCart II (Histogenics Corporation, Waltham, MA formerly supplied by ProChon Biotech prior to merger with Histogenics) is comprised of a scaffold of recombinant hyaluronan with fibrin to form a sponge (**Table 6**). Cells are initially cultured in human serum with recombinant fibroblast growth factor 2 variant (FGF2v1) and then seeded onto the scaffold prior to implantation with a mini-open approach. A small 1 year outcome study by Nehrer et al. of 8 patients demonstrated significant improvement in IKDC and Lysholm scores; 3 patients had a transient effusion post-operatively and there were no clinical failures (**Table 7**) [50]. A case series by Eshed et al. of patients who underwent MRI evaluation at mean 17.3 months after surgery (range 6–48 months) found continued maturation of cartilage with time (>1 year versus <1 year) and higher IKDC scores in patients with >12 months follow-up and without a history of prior cartilage surgeries [51].

#### *2.3.3. Chondron*

The Chondron scaffold is a fibrin-based gel (Sewon Cellontech Co. Ltd., Seoul, Korea) (**Table 6**). Chondrocytes are first cultured separately in a specialized serum (CRM kit, Sewon Cellontech, Korea). At the time of surgery the serum and cultured chondrocytes are mixed 1:1 with fibrin and injected directly onto the defect. In addition to typical preparation of the defect for ACI, several holes are drilled into the subchondral bone to improve adherence [52]. Choi et al. report a multicenter study of 98 patients with mean 24 month follow-up treated with Chondron (**Table 7**) [52]. Symptom improvement increased with time, with greater improvement noted with >25 months follow-up versus <25 months. Complication rates were low with one early repeat operation (1%) and two cases of symptomatic catching (2%) [52]. Similar findings were reported in a series by Kim et al., with no graft-related complications among 30 patients at 24 months follow up; a second look arthroscopy at 12 months showed nearly normal cartilage in 8/10 patients [53]. A small series by Konst et al. of 9 patients with osteochondral defects (mean depth 0.9 cm) treated with autologous bone grafting as well as Chondron showed satisfactory short term results at 12 months; there was one treatment failure which was converted to a unicompartmental knee arthroplasty [54].

**2.5. Atelocollagen gel**

Koken Atelocollagen Implant

**Level of evidence**

*2.5.1. Koken Atelocollagen Implant*

but no correlation between T2 values and outcomes [58].

Koken, Tokyo, Japan

**Author Implant and** 

**sample size**

Atelocollagen Implant

Atelocollagen Implant

**Table 11.** MACT clinical outcome studies with alginate-based scaffolds.

**Table 10.** Atelocollagen based scaffold.

4 Tohyama et al. [57] 27 Koken

4 Tadenuma et al. [58] 11 Koken

The MACT technique with use of the Koken Atelocollagen Implant (Koken, Tokyo, Japan) is similar to the ACI-P (periosteum cover) technique, but chondrocytes are suspended in atelocollagen gel rather than a liquid to obtain uniform distribution of chondrocytes within the defect and theoretically reduce risk of leakage (**Table 10**). In this technique, after initial isolation of chondrocytes from cartilage biopsy, the chondrocyte suspension is mixed 1:4 with a 3% bovine atelocollagen solution (Koken, Tokyo, Japan) [57]. Chondrocytes are expanded in this mixture for 28 days; the final product (the Koken Atelocollagen Implant) is an opaque implant with a jelly-like consistency. The Koken Atelocollagen Implant is implanted with a mini-arthrotomy and requires a periosteum cover to contain the atelocollagen-based scaffold within the defect [57]. A multicenter trial in Japan reported by Tohyama et al. reports use of the Koken Atelocollagen Implant and periosteum cover in 27 patients (**Table 11**) [57]. Overall there was a significant improvement in Lysholm scores at final 2 years follow-up. On second look arthroscopy, 24% of repair sites were ICRS grade normal and 48% were nearly normal. There was one case of graft hypertrophy, two cases of graft detachment, and two cases of abnormal or severely normal ICRS grade on second look arthroscopy [57]. Recently, Tadenuma et al. report clinical and imaging outcomes of 8 patients (11 knees) at mean 5.9 years after surgery [58]. The authors note significant improvement in Lysholm scores over baseline with one clinical failure (9%) and one traumatic repeat injury 7 years after surgery (9%). The authors report a correlation between T1 values of the repair site on MRI and clinical outcomes

**Commercial name Manufacturer Structure Expansion Availability**

**Mean follow-up**

Chondrocyte suspension is initially mixed 1:4 with 3% atelocollagen solution. The mixture is cultured for 4 weeks and thickens to a jelly-like consistency over that time.

Autologous Chondrocyte Implantation: Scaffold-Based Solutions

http://dx.doi.org/10.5772/intechopen.70276

153

2 years Multicenter study. Symptom scores (Lysholm)

second look arthroscopy (8%, 2/25).

5.9 years Improved Lysholm scores at final follow-up with

improved at 2 years from baseline. Two cases of graft detachment (7.4%). Two remaining cases were graded abnormal or severely abnormal on

one clinical failure (9%). T1 scores on MRI at final follow-up correlated with clinical scores but T2

**Outcome**

scores did not.

Available in Japan

Atelocollagen gel (3% type 1 bovine collagen gel)

#### **2.4. Alginate based scaffolds**

## *2.4.1. Cartipatch*

Cartipatch (TBF Tissue Engineering, Mions, France) is a MACT implant with a scaffold composed of agarose and alginate (**Table 8**). Chondrocytes are first cultured in a monolayer and then mixed with a hydrogel of agarose and alginate. The hydrogel can be manipulated at 37°C and will solidify around 25°C, allowing formation of complex/irregular shapes with the scaffold. A multicenter randomized trial with 2 years follow-up was recently published by Clave et al. (**Table 9**) [55]. In this study, 30 patients were randomized to Cartipatch and 25 to mosaicplasty; all patients had isolated high grade femoral condylar defects 2.5–7.5 cm<sup>2</sup> in size. At 2 years, there was significantly greater improvement in IKDC scores with mosaicplasty than Cartipatch, though both groups had significant improvement over baseline. A total of 12 adverse events were reported for the Cartipatch groups and six in the mosaicplasty group [55]. An earlier case series by Selmi et al. reported 2 years outcomes of 17 patients treated with Cartipatch with a mean defect size of 3 cm<sup>2</sup> [56]. All patients had significant symptom improvement with no clinical failures; second look biopsies in 13 patients had mostly hyalinelike cartilage in 62% of cases (8/13) [56].


FDA, U.S. Food and Drug Administration.

**Table 8.** Alginate hydrogel.


**Table 9.** MACT clinical outcome studies with alginate-based scaffolds.

#### **2.5. Atelocollagen gel**

in 8/10 patients [53]. A small series by Konst et al. of 9 patients with osteochondral defects (mean depth 0.9 cm) treated with autologous bone grafting as well as Chondron showed satisfactory short term results at 12 months; there was one treatment failure which was converted

Cartipatch (TBF Tissue Engineering, Mions, France) is a MACT implant with a scaffold composed of agarose and alginate (**Table 8**). Chondrocytes are first cultured in a monolayer and then mixed with a hydrogel of agarose and alginate. The hydrogel can be manipulated at 37°C and will solidify around 25°C, allowing formation of complex/irregular shapes with the scaffold. A multicenter randomized trial with 2 years follow-up was recently published by Clave et al. (**Table 9**) [55]. In this study, 30 patients were randomized to Cartipatch and 25 to

mosaicplasty; all patients had isolated high grade femoral condylar defects 2.5–7.5 cm<sup>2</sup>

At 2 years, there was significantly greater improvement in IKDC scores with mosaicplasty than Cartipatch, though both groups had significant improvement over baseline. A total of 12 adverse events were reported for the Cartipatch groups and six in the mosaicplasty group [55]. An earlier case series by Selmi et al. reported 2 years outcomes of 17 patients treated

improvement with no clinical failures; second look biopsies in 13 patients had mostly hyaline-

**Manufacturer Structure Expansion Availability**

Alginate-agarose hydrogel combined with autologous cells

> **Mean follow-up**

4 Selmi et al. [56] 17 Cartipatch 2 years Multicenter study. Significant symptom

in size.

[56]. All patients had significant symptom

Ongoing phase III clinical trials; not yet approved by the FDA

Two-step procedure; reduces cell leakage and implantation

2 years Both groups showed improvement in IKDC scores over baseline though mosaicplasty had greater symptom improvement than Cartipatch at 2 years

.

improvement in all patients, no clinical failures. Second look biopsies showed mostly hyaline-like

for femoral lesions 2.5–7.5 cm2

cartilage in 8/13 patients (62%).

time

**Outcome**

to a unicompartmental knee arthroplasty [54].

with Cartipatch with a mean defect size of 3 cm<sup>2</sup>

like cartilage in 62% of cases (8/13) [56].

(TBF) Tissue Engineering,

**Author Implant and** 

1 Clave et al. [55] 30 Cartipatch; 25

**sample size**

mosaicplasty

**Table 9.** MACT clinical outcome studies with alginate-based scaffolds.

Cartipatch Tissue Bank of France

Mions, France

FDA, U.S. Food and Drug Administration.

**Table 8.** Alginate hydrogel.

**2.4. Alginate based scaffolds**

152 Cartilage Repair and Regeneration

*2.4.1. Cartipatch*

**Commercial name**

**Level of evidence**

#### *2.5.1. Koken Atelocollagen Implant*

The MACT technique with use of the Koken Atelocollagen Implant (Koken, Tokyo, Japan) is similar to the ACI-P (periosteum cover) technique, but chondrocytes are suspended in atelocollagen gel rather than a liquid to obtain uniform distribution of chondrocytes within the defect and theoretically reduce risk of leakage (**Table 10**). In this technique, after initial isolation of chondrocytes from cartilage biopsy, the chondrocyte suspension is mixed 1:4 with a 3% bovine atelocollagen solution (Koken, Tokyo, Japan) [57]. Chondrocytes are expanded in this mixture for 28 days; the final product (the Koken Atelocollagen Implant) is an opaque implant with a jelly-like consistency. The Koken Atelocollagen Implant is implanted with a mini-arthrotomy and requires a periosteum cover to contain the atelocollagen-based scaffold within the defect [57]. A multicenter trial in Japan reported by Tohyama et al. reports use of the Koken Atelocollagen Implant and periosteum cover in 27 patients (**Table 11**) [57]. Overall there was a significant improvement in Lysholm scores at final 2 years follow-up. On second look arthroscopy, 24% of repair sites were ICRS grade normal and 48% were nearly normal. There was one case of graft hypertrophy, two cases of graft detachment, and two cases of abnormal or severely normal ICRS grade on second look arthroscopy [57]. Recently, Tadenuma et al. report clinical and imaging outcomes of 8 patients (11 knees) at mean 5.9 years after surgery [58]. The authors note significant improvement in Lysholm scores over baseline with one clinical failure (9%) and one traumatic repeat injury 7 years after surgery (9%). The authors report a correlation between T1 values of the repair site on MRI and clinical outcomes but no correlation between T2 values and outcomes [58].




**Table 11.** MACT clinical outcome studies with alginate-based scaffolds.

## **2.6. Polyglycolic/polylactic acid and polydioxanone based scaffold**

## *2.6.1. BioSeed-C*

The BioSeed-C (BioTissue Technologies GmbH, Freiburg, Germany) MACT scaffold is comprised polyglycolic/polylactic acid (polyglactin, vicryl), and polydioxanone (**Table 12**). Harvested chondrocytes are first expanded in serum and then seeded into the polymer scaffold with fixation by fibrin. The scaffold is available in a standard rectangular shape (2 cm × 3 cm × 0.2 cm thickness) can be implanted arthroscopically or with a mini-arthrotomy. The defect must be contoured to a rectangular shape (more than one scaffold can be used as needed for larger defects) and corners of the scaffold are secured with transosseous resorbable suture loops [59].

Several case series have also been reported for BioSeed-C (**Table 13**). Ossendorf et al. report a case series of 40 patients treated with BioSeed-C with 2 years follow-up; symptom scores were significantly improved at both 1 and 2 years after baseline [59]. Reoperations occurred in 12.5% of patients including synovectomy (n = 2), debridement (n = 1), total knee arthroplasty (n = 1), and graft removal (n = 1) [59]. The mid-term outcomes of the same patient cohort with 4-years follow-up were reported by Kreuz et al. [62]. The authors note a durable symptom improvement over 4 years and a high rate of graft filling (mostly or completely filled in 43/44 patients on MRI assessment) [62]. In the subgroup analysis of 19 patients in this cohort with baseline osteoarthritis and a high grade focal defect, Kreuz et al. noted symptom improvement at 6–12 months which remained stable at 4 years as well as two clinical failures that went

Autologous Chondrocyte Implantation: Scaffold-Based Solutions

http://dx.doi.org/10.5772/intechopen.70276

155

In conclusion, short and mid-term clinical outcomes studies of MACT therapies for cartilage defects of the knee have been encouraging. However, commercial availability of MACT procedures is highly variable with respect to geographic region. Recent approval was granted in December 2016 by the FDA for use of MACI in the United States. To date this is the only MACT therapy available in this region. Availability is greater for multiple MACT therapies in Europe, though European Medicine Agency marketing approval for MACI was recently

and Nicholas A. Early2

1 Sports Medicine, The Ohio State University Wexner Medical Center, Columbus, OH,

2 Department of Physical Medicine and Rehabilitation, Washington University, St. Louis, MO,

[1] Brittberg M, Lindahl A, Nilsson A, Ohlsson C, Isaksson O, Peterson L. Treatment of deep cartilage defects in the knee with autologous chondrocyte transplantation. The New

[2] Ruta DJ, Villarreal AD, Richardson DR. Orthopedic surgical options for joint cartilage repair and restoration. Physical Medicine and Rehabilitation Clinics of North America.

on to total knee arthroplasty (10.5%) [63].

David C. Flanigan1,2\*, Joshua S. Everhart<sup>1</sup>

\*Address all correspondence to: david.flanigan@osumc.edu

England Journal of Medicine. 1994;**331**:889-895

**3. Conclusions**

suspended in June 2016.

**Author details**

United States

United States

**References**

2016;**27**:1019-1042

In a comparative non-randomized study of ACI-P versus BioSeed-C with minimum 2 years follow up, Erggelet et al. report similar improvement in symptom scores (**Table 13**) [60]. The graft failure rate was similar between groups (3/42 ACI-P; 2/40 BioSeed-C), but reoperation rates were twice as high in the ACI-P group, primarily due to graft hypertrophy [60]. A smaller randomized study of ACI-P (n = 10) versus BioSeed-C (n = 9) with 2 years follow-up by Zeifang et al. found similar improvement in symptoms between groups (per IKDC score) at both 1 and 2 years [61]. In contrast to the findings reported by Erggelet et al. [60], re-operation rates were higher in the BioSeed C group (3/11 patients) versus ACI-P (1/10 patients) [61].


CE, Conformité Européenne; FDA, U.S. Food and Drug Administration.

**Table 12.** Scaffolds with polyglycolic/polylactic acid and polydioxanone.


**Table 13.** MACT clinical outcome studies with polyglycolic/polylactic acid and polydioxanone based scaffold.

Several case series have also been reported for BioSeed-C (**Table 13**). Ossendorf et al. report a case series of 40 patients treated with BioSeed-C with 2 years follow-up; symptom scores were significantly improved at both 1 and 2 years after baseline [59]. Reoperations occurred in 12.5% of patients including synovectomy (n = 2), debridement (n = 1), total knee arthroplasty (n = 1), and graft removal (n = 1) [59]. The mid-term outcomes of the same patient cohort with 4-years follow-up were reported by Kreuz et al. [62]. The authors note a durable symptom improvement over 4 years and a high rate of graft filling (mostly or completely filled in 43/44 patients on MRI assessment) [62]. In the subgroup analysis of 19 patients in this cohort with baseline osteoarthritis and a high grade focal defect, Kreuz et al. noted symptom improvement at 6–12 months which remained stable at 4 years as well as two clinical failures that went on to total knee arthroplasty (10.5%) [63].

## **3. Conclusions**

**2.6. Polyglycolic/polylactic acid and polydioxanone based scaffold**

The BioSeed-C (BioTissue Technologies GmbH, Freiburg, Germany) MACT scaffold is comprised polyglycolic/polylactic acid (polyglactin, vicryl), and polydioxanone (**Table 12**). Harvested chondrocytes are first expanded in serum and then seeded into the polymer scaffold with fixation by fibrin. The scaffold is available in a standard rectangular shape (2 cm × 3 cm × 0.2 cm thickness) can be implanted arthroscopically or with a mini-arthrotomy. The defect must be contoured to a rectangular shape (more than one scaffold can be used as needed for larger defects) and corners of the scaffold are secured with transosseous resorb-

In a comparative non-randomized study of ACI-P versus BioSeed-C with minimum 2 years follow up, Erggelet et al. report similar improvement in symptom scores (**Table 13**) [60]. The graft failure rate was similar between groups (3/42 ACI-P; 2/40 BioSeed-C), but reoperation rates were twice as high in the ACI-P group, primarily due to graft hypertrophy [60]. A smaller randomized study of ACI-P (n = 10) versus BioSeed-C (n = 9) with 2 years follow-up by Zeifang et al. found similar improvement in symptoms between groups (per IKDC score) at both 1 and 2 years [61]. In contrast to the findings reported by Erggelet et al. [60], re-operation rates were higher in the BioSeed C group (3/11 patients) versus ACI-P

**Manufacturer Structure Expansion Availability**

Chondrocytes cultured in serum then subsequently seeded into scaffold.

2 years Similar IKDC symptom improvement in both

rate in BioSeed C group.

groups at 1 year and 2 years. Higher re-operation

Twice as many re-operations required for ACI-P versus BioSeed-C. Three graft failures in ACI-P group and two in BioSeed-C group. Equivalent improvement in symptom scores between

CE mark approval; not yet approved by the FDA.

Fibrin, polyglycolic/polylactic acid and polydioxanone-based material combined with culture-expanded autologous chondrocytes and suspended in fibrin.

> **Mean follow-up**

36 m ACI-P 24 m BioSeed-C

**Table 13.** MACT clinical outcome studies with polyglycolic/polylactic acid and polydioxanone based scaffold.

**Outcome**

groups.

*2.6.1. BioSeed-C*

154 Cartilage Repair and Regeneration

able suture loops [59].

(1/10 patients) [61].

BioSeed-C BioTissue AG (BioTissue

Technologies, GmbH, Freiburg, Germany)

CE, Conformité Européenne; FDA, U.S. Food and Drug Administration.

**Table 12.** Scaffolds with polyglycolic/polylactic acid and polydioxanone.

**sample size**

ACI-P

ACI-P

**Author Implant and** 

2 Zeifang et al. [61] 11 BioSeed-C; 9

3 Erggelet et al. [60] 40 BioSeed-C; 42

**Commercial name**

**Level of evidence** In conclusion, short and mid-term clinical outcomes studies of MACT therapies for cartilage defects of the knee have been encouraging. However, commercial availability of MACT procedures is highly variable with respect to geographic region. Recent approval was granted in December 2016 by the FDA for use of MACI in the United States. To date this is the only MACT therapy available in this region. Availability is greater for multiple MACT therapies in Europe, though European Medicine Agency marketing approval for MACI was recently suspended in June 2016.

## **Author details**

David C. Flanigan1,2\*, Joshua S. Everhart<sup>1</sup> and Nicholas A. Early2

\*Address all correspondence to: david.flanigan@osumc.edu

1 Sports Medicine, The Ohio State University Wexner Medical Center, Columbus, OH, United States

2 Department of Physical Medicine and Rehabilitation, Washington University, St. Louis, MO, United States

## **References**


[3] Kon E, Filardo G, Di Martino A, Marcacci M. ACI and MACI. The Journal of Knee Surgery. 2012;**25**:17-22

[16] Salzmann GM, Paul J, Bauer JS, et al. T2 assessment and clinical outcome following autologous matrix-assisted chondrocyte and osteochondral autograft transplantation.

Autologous Chondrocyte Implantation: Scaffold-Based Solutions

http://dx.doi.org/10.5772/intechopen.70276

157

[17] Macmull S, Jaiswal PK, Bentley G, Skinner JA, Carrington RW, Briggs TW. The role of autologous chondrocyte implantation in the treatment of symptomatic chondromalacia

[18] Akgun I, Unlu MC, Erdal OA, et al. Matrix-induced autologous mesenchymal stem cell implantation versus matrix-induced autologous chondrocyte implantation in the treatment of chondral defects of the knee: A 2-year randomized study. Archives of

[19] Edwards PK, Ackland TR, Ebert JR. Accelerated weightbearing rehabilitation after matrix-induced autologous chondrocyte implantation in the tibiofemoral joint: Early clinical and radiological outcomes. The American Journal of Sports Medicine.

[20] Ebert JR, Edwards PK, Fallon M, Ackland TR, Janes GC, Wood DJ. Two-year outcomes of a randomized trial investigating a 6-week return to full weightbearing after matrix-induced autologous chondrocyte implantation. The American Journal of Sports

[21] Wondrasch B, Risberg MA, Zak L, Marlovits S, Aldrian S. Effect of accelerated weightbearing after matrix-associated autologous chondrocyte implantation on the femoral condyle: A prospective, randomized controlled study presenting MRI-based and clinical outcomes after 5 years. The American Journal of Sports Medicine. 2015;**43**:146-153

[22] Gille J, Behrens P, Schulz AP, Oheim R, Kienast B. Matrix-associated autologous chondrocyte implantation: A clinical follow-up at 15 years. Cartilage. 2016;**7**:309-315

[23] Basad E, Wissing FR, Fehrenbach P, Rickert M, Steinmeyer J, Ishaque B. Matrix-induced autologous chondrocyte implantation (MACI) in the knee: Clinical outcomes and chal-

[24] Behrens P, Bitter T, Kurz B, Russlies M. Matrix-associated autologous chondrocyte transplantation/implantation (MACT/MACI)—5-year follow-up. The Knee. 2006;**13**:194-202

[25] Ebert JR, Robertson WB, Woodhouse J, et al. Clinical and magnetic resonance imagingbased outcomes to 5 years after matrix-induced autologous chondrocyte implantation to address articular cartilage defects in the knee. The American Journal of Sports Medicine.

[26] Ebert JR, Fallon M, Wood DJ, Janes GC. A prospective clinical and radiological evaluation at 5 years after arthroscopic matrix-induced autologous chondrocyte implantation.

[27] Ventura A, Memeo A, Borgo E, Terzaghi C, Legnani C, Albisetti W. Repair of osteochondral lesions in the knee by chondrocyte implantation using the MACI® technique. Knee

The American Journal of Sports Medicine. 2017;**45**:59-69

Surgery, Sports Traumatology, Arthroscopy. 2012;**20**:121-126

lenges. Knee Surgery, Sports Traumatology, Arthroscopy. 2015;**23**:3729-3735

Osteoarthritis and Cartilage. 2009;**17**:1576-1582

patellae. International Orthopaedics. 2012;**36**:1371-1377

Orthopaedic and Trauma Surgery. 2015;**135**:251-263

2013;**41**:2314-2324

2011;**39**:753-763

Medicine. 2017;**45**:838-848


[16] Salzmann GM, Paul J, Bauer JS, et al. T2 assessment and clinical outcome following autologous matrix-assisted chondrocyte and osteochondral autograft transplantation. Osteoarthritis and Cartilage. 2009;**17**:1576-1582

[3] Kon E, Filardo G, Di Martino A, Marcacci M. ACI and MACI. The Journal of Knee

[4] Kon E, Verdonk P, Condello V, et al. Matrix-assisted autologous chondrocyte transplantation for the repair of cartilage defects of the knee: Systematic clinical data review and study quality analysis. The American Journal of Sports Medicine. 2009;**37**(Suppl 1):

[5] Grigolo B, Lisignoli G, Piacentini A, et al. Evidence for redifferentiation of human chondrocytes grown on a hyaluronan-based biomaterial (HYAff 11): Molecular, immunohis-

[6] Cole BJ, Farr J, Winalski CS, et al. Outcomes after a single-stage procedure for cell-based cartilage repair: A prospective clinical safety trial with 2-year follow-up. The American

[7] Chiang H, Liao CJ, Hsieh CH, Shen CY, Huang YY, Jiang CC. Clinical feasibility of a novel biphasic osteochondral composite for matrix-associated autologous chondrocyte

[8] Bartlett W, Skinner JA, Gooding CR, et al. Autologous chondrocyte implantation versus matrix-induced autologous chondrocyte implantation for osteochondral defects of the knee: A prospective, randomised study. Journal of Bone and Joint Surgery. British

[9] Vascellari A, Rebuzzi E, Schiavetti S, Coletti N. Implantation of matrix-induced autologous chondrocyte (MACI®) grafts using carbon dioxide insufflation arthroscopy. Knee

[10] Hindle P, Hall AC, Biant LC. Viability of chondrocytes seeded onto a collagen I/III membrane for matrix-induced autologous chondrocyte implantation. Journal of Orthopaedic

[11] Zheng MH, Willers C, Kirilak L, et al. Matrix-induced autologous chondrocyte implantation (MACI): Biological and histological assessment. Tissue Engineering. 2007;**13**:737-746

[12] Enea D, Cecconi S, Busilacchi A, Manzotti S, Gesuita R, Gigante A. Matrix-induced autologous chondrocyte implantation (MACI) in the knee. Knee Surgery, Sports

[13] Foldager CB, Farr J, Gomoll AH. Patients scheduled for chondrocyte implantation treatment with MACI have larger defects than those enrolled in clinical trials. Cartilage.

[14] Saris D, Price A, Widuchowski W, et al. Matrix-applied characterized autologous cultured chondrocytes versus microfracture: Two-year follow-up of a prospective random-

[15] Basad E, Ishaque B, Bachmann G, Stürz H, Steinmeyer J. Matrix-induced autologous chondrocyte implantation versus microfracture in the treatment of cartilage defects of the knee: A 2-year randomised study. Knee Surgery, Sports Traumatology, Arthroscopy.

ized trial. The American Journal of Sports Medicine. 2014;**42**:1384-1394

tochemical and ultrastructural analysis. Biomaterials. 2002;**23**:1187-1195

Journal of Sports Medicine. 2011;**39**:1170-1179

Volume (London). 2005;**87**:640-645

Research. 2014;**32**:1495-1502

2016;**7**:140-148

2010;**18**:519-527

Traumatology, Arthroscopy. 2012;**20**:862-869

implantation. Osteoarthritis and Cartilage. 2013;**21**:589-598

Surgery, Sports Traumatology, Arthroscopy. 2014;**22**:219-225

Surgery. 2012;**25**:17-22

156S-166S

156 Cartilage Repair and Regeneration


[28] Meyerkort D, Ebert JR, Ackland TR, et al. Matrix-induced autologous chondrocyte implantation (MACI) for chondral defects in the patellofemoral joint. Knee Surgery, Sports Traumatology, Arthroscopy. 2014;**22**:2522-2530

[39] Zak L, Albrecht C, Wondrasch B, et al. Results 2 years after matrix-associated autologous chondrocyte transplantation using the Novocart 3D scaffold: An analysis of clinical and

Autologous Chondrocyte Implantation: Scaffold-Based Solutions

http://dx.doi.org/10.5772/intechopen.70276

159

[40] Niethammer TR, Safi E, Ficklscherer A, et al. Graft maturation of autologous chondrocyte implantation: Magnetic resonance investigation with T2 mapping. The American

[41] Niethammer TR, Pietschmann MF, Ficklscherer A, Gülecyüz MF, Hammerschmid F, Müller PE. Incomplete defect filling after third generation autologous chondrocyte

[42] Niethammer TR, Pietschmann MF, Horng A, et al. Graft hypertrophy of matrix-based autologous chondrocyte implantation: A two-year follow-up study of NOVOCART 3D implantation in the knee. Knee Surgery, Sports Traumatology, Arthroscopy.

[43] Panagopoulos A, van Niekerk L, Triantafillopoulos I. Autologous chondrocyte implantation for knee cartilage injuries: Moderate functional outcome and performance in

[44] Niethammer TR, Holzgruber M, Gülecyüz MF, Weber P, Pietschmann MF, Müller PE. Matrix based autologous chondrocyte implantation in children and adolescents: A match paired analysis in a follow-up over three years post-operation. International

[45] Angele P, Fritz J, Albrecht D, Koh J, Zellner J. Defect type, localization and marker gene expression determines early adverse events of matrix-associated autologous chondro-

[46] Niethammer TR, Müller PE, Safi E, et al. Early resumption of physical activities leads to inferior clinical outcomes after matrix-based autologous chondrocyte implantation in

[47] Kon E, Filardo G, Berruto M, et al. Articular cartilage treatment in high-level male soccer players: A prospective comparative study of arthroscopic second-generation autologous chondrocyte implantation versus microfracture. The American Journal of Sports

[48] Kon E, Filardo G, Condello V, et al. Second-generation autologous chondrocyte implantation: Results in patients older than 40 years. The American Journal of Sports Medicine.

[49] Ferruzzi A, Buda R, Faldini C, et al. Autologous chondrocyte implantation in the knee joint: Open compared with arthroscopic technique. Comparison at a minimum follow-up of five years. The Journal of Bone and Joint Surgery. American Volume. 2008;**90**(Suppl 4):

[50] Nehrer S, Chiari C, Domayer S, Barkay H, Yayon A. Results of chondrocyte implantation with a fibrin-hyaluronan matrix: A preliminary study. Clinical Orthopaedics and

the knee. Knee Surgery, Sports Traumatology, Arthroscopy. 2014;**22**:1345-1352

radiological data. The American Journal of Sports Medicine. 2014;**42**:1618-1627

Journal of Sports Medicine. 2014;**42**:2199-2204

2014;**22**:1329-1336

Orthopaedics. 2017;**41**:343-350

Medicine. 2011;**39**:2549-2557

Related Research. 2008;**466**:1849-1855

2011;**39**:1668-1675

90-101

cyte implantation. Injury. 2015;**46**(Suppl 4):S2-S9

implantation. Archives of Medical Science. 2016;**12**:785-792

patients with high-impact activities. Orthopedics. 2012;**35**:e6-14


[39] Zak L, Albrecht C, Wondrasch B, et al. Results 2 years after matrix-associated autologous chondrocyte transplantation using the Novocart 3D scaffold: An analysis of clinical and radiological data. The American Journal of Sports Medicine. 2014;**42**:1618-1627

[28] Meyerkort D, Ebert JR, Ackland TR, et al. Matrix-induced autologous chondrocyte implantation (MACI) for chondral defects in the patellofemoral joint. Knee Surgery,

[29] Gigante A, Enea D, Greco F, et al. Distal realignment and patellar autologous chondrocyte implantation: Mid-term results in a selected population. Knee Surgery, Sports

[30] Bauer S, Khan RJ, Ebert JR, et al. Knee joint preservation with combined neutralising high tibial osteotomy (HTO) and Matrix-induced Autologous Chondrocyte Implantation (MACI) in younger patients with medial knee osteoarthritis: A case series with prospec-

[31] Vijayan S, Bartlett W, Bentley G, et al. Autologous chondrocyte implantation for osteochondral lesions in the knee using a bilayer collagen membrane and bone graft: A two- to eight-year follow-up study. Journal of Bone and Joint Surgery. British Volume (London).

[32] Crawford DC, Heveran CM, Cannon WD, Foo LF, Potter HG. An autologous cartilage tissue implant NeoCart for treatment of grade III chondral injury to the distal femur: Prospective clinical safety trial at 2 years. The American Journal of Sports Medicine.

[33] Crawford DC, DeBerardino TM, Williams RJ. NeoCart, an autologous cartilage tissue implant, compared with microfracture for treatment of distal femoral cartilage lesions: An FDA phase-II prospective, randomized clinical trial after two years. The Journal of

[34] Anderson DE, Williams RJ, DeBerardino TM, et al. Magnetic resonance imaging characterization and clinical outcomes after NeoCart surgical therapy as a primary reparative treatment for knee cartilage injuries. The American Journal of Sports Medicine.

[35] Flohé S, Betsch M, Ruße K, Wild M, Windolf J, Schulz M. Comparison of two different matrix-based autologous chondrocyte transplantation systems: 1 year follow-up results.

[36] Petri M, Broese M, Simon A, et al. CaReS (MACT) versus microfracture in treating symptomatic patellofemoral cartilage defects: A retrospective matched-pair analysis. Journal

[37] Schneider U, Rackwitz L, Andereya S, et al. A prospective multicenter study on the outcome of type I collagen hydrogel-based autologous chondrocyte implantation (CaReS) for the repair of articular cartilage defects in the knee. The American Journal of Sports

[38] Welsch GH, Mamisch TC, Zak L, et al. Evaluation of cartilage repair tissue after matrixassociated autologous chondrocyte transplantation using a hyaluronic-based or a collagen-based scaffold with morphological MOCART scoring and biochemical T2 mapping:

Preliminary results. The American Journal of Sports Medicine. 2010;**38**:934-942

European Journal of Trauma and Emergency Surgery. 2011;**37**:397-403

Bone and Joint Surgery. American Volume. 2012;**94**:979-989

tive clinical and MRI follow-up over 5 years. The Knee. 2012;**19**:431-439

Sports Traumatology, Arthroscopy. 2014;**22**:2522-2530

Traumatology, Arthroscopy. 2009;**17**:2-10

2012;**94**:488-492

158 Cartilage Repair and Regeneration

2009;**37**:1334-1343

2017;**45**:875-883

of Orthopaedic Science. 2013;**18**:38-44

Medicine. 2011;**39**:2558-2565


[51] Eshed I, Trattnig S, Sharon M, et al. Assessment of cartilage repair after chondrocyte transplantation with a fibrin-hyaluronan matrix—Correlation of morphological MRI, biochemical T2 mapping and clinical outcome. European Journal of Radiology. 2012;**81**:1216-1223

[62] Kreuz PC, Müller S, Freymann U, et al. Repair of focal cartilage defects with scaffoldassisted autologous chondrocyte grafts: Clinical and biomechanical results 48 months after transplantation. The American Journal of Sports Medicine. 2011;**39**:1697-1705 [63] Kreuz PC, Müller S, Ossendorf C, Kaps C, Erggelet C. Treatment of focal degenerative cartilage defects with polymer-based autologous chondrocyte grafts: Four-year clinical

Autologous Chondrocyte Implantation: Scaffold-Based Solutions

http://dx.doi.org/10.5772/intechopen.70276

161

results. Arthritis Research & Therapy. 2009;**11**:R33


[62] Kreuz PC, Müller S, Freymann U, et al. Repair of focal cartilage defects with scaffoldassisted autologous chondrocyte grafts: Clinical and biomechanical results 48 months after transplantation. The American Journal of Sports Medicine. 2011;**39**:1697-1705

[51] Eshed I, Trattnig S, Sharon M, et al. Assessment of cartilage repair after chondrocyte transplantation with a fibrin-hyaluronan matrix—Correlation of morphological MRI, biochemical T2 mapping and clinical outcome. European Journal of Radiology.

[52] Choi NY, Kim BW, Yeo WJ, et al. Gel-type autologous chondrocyte (Chondron) implantation for treatment of articular cartilage defects of the knee. BMC Musculoskeletal

[53] Kim MK, Choi SW, Kim SR, Oh IS, Won MH. Autologous chondrocyte implantation in the knee using fibrin. Knee Surgery, Sports Traumatology, Arthroscopy. 2010;**18**:528-534

[54] Könst YE, Benink RJ, Veldstra R, van der Krieke TJ, Helder MN, van Royen BJ. Treatment of severe osteochondral defects of the knee by combined autologous bone grafting and autologous chondrocyte implantation using fibrin gel. Knee Surgery, Sports

[55] Clavé A, Potel JF, Servien E, Neyret P, Dubrana F, Stindel E. Third-generation autologous chondrocyte implantation versus mosaicplasty for knee cartilage injury: 2-year

[56] Selmi TA, Verdonk P, Chambat P, et al. Autologous chondrocyte implantation in a novel alginate-agarose hydrogel: Outcome at two years. Journal of Bone and Joint Surgery.

[57] Tohyama H, Yasuda K, Minami A, et al. Atelocollagen-associated autologous chondrocyte implantation for the repair of chondral defects of the knee: A prospective multi-

[58] Tadenuma T, Uchio Y, Kumahashi N, et al. Delayed gadolinium-enhanced MRI of cartilage and T2 mapping for evaluation of reparative cartilage-like tissue after autologous chondrocyte implantation associated with Atelocollagen-based scaffold in the knee.

[59] Ossendorf C, Kaps C, Kreuz PC, Burmester GR, Sittinger M, Erggelet C. Treatment of posttraumatic and focal osteoarthritic cartilage defects of the knee with autologous polymer-based three-dimensional chondrocyte grafts: 2-year clinical results. Arthritis

[60] Erggelet C, Kreuz PC, Mrosek EH, et al. Autologous chondrocyte implantation versus ACI using 3D-bioresorbable graft for the treatment of large full-thickness cartilage lesions of the knee. Archives of Orthopaedic and Trauma Surgery. 2010;**130**:957-964 [61] Zeifang F, Oberle D, Nierhoff C, Richter W, Moradi B, Schmitt H. Autologous chondrocyte implantation using the original periosteum-cover technique versus matrix-associated autologous chondrocyte implantation: A randomized clinical trial. The American

center clinical trial in Japan. Journal of Orthopaedic Science. 2009;**14**:579-588

randomized trial. Journal of Orthopaedic Research. 2016;**34**:658-665

2012;**81**:1216-1223

160 Cartilage Repair and Regeneration

Disorders. 2010;**11**:103

Traumatology, Arthroscopy. 2012;**20**:2263-2269

British Volume (London). 2008;**90**:597-604

Skeletal Radiology. 2016;**45**:1357-1363

Research & Therapy. 2007;**9**:R41

Journal of Sports Medicine. 2010;**38**:924-933

[63] Kreuz PC, Müller S, Ossendorf C, Kaps C, Erggelet C. Treatment of focal degenerative cartilage defects with polymer-based autologous chondrocyte grafts: Four-year clinical results. Arthritis Research & Therapy. 2009;**11**:R33

**Chapter 9**

**Provisional chapter**

**Management of Knee Cartilage Defects with the**

**Management of Knee Cartilage Defects with the** 

**Technique**

**Abstract**

**1. Introduction**

**Technique**

Michael E. Hantes and Apostolos H. Fyllos

Michael E. Hantes and Apostolos H. Fyllos

http://dx.doi.org/10.5772/intechopen.71776

Additional information is available at the end of the chapter

step arthroscopic procedure proposals is steadily increasing.

**Keywords:** matrix-induced chondrogenesis, cartilage, microfractures, AMIC

Despite its durable mechanical properties, hyaline cartilage has low intrinsic regenerative and reparative capacity since it lacks blood supply, nerves and lymphangion. Cartilage defects potentially lead to severe osteoarthritis and disability, and painful symptomatology during that process. None of the pharmacological or surgical cartilage degeneration management options have clearly shown the potential of restoring chondral surface, in order to avoid prosthetic replacement in the final stages of the disease. Numerous reparative techniques

Additional information is available at the end of the chapter

**Autologous Matrix-Induced Chondrogenesis (AMIC)**

The arthroscopic findings of knee articular cartilage lesions are reported to be as high as 60%, although only a fragment of these are considered to be symptomatic. Such lesions are believed to accelerate the onset of arthritis. Long-term results of the microfracture technique for chondral and osteochondral defects of the knee cartilage are not satisfactory. The autologous matrix induced chondrogenesis (AMIC) technique offers a promising alternative as an effective cartilage repair procedure in the knee resulting in stable clinical results and with a wide range of indications. An extensive literature review has been performed aiming at providing the rationale behind AMIC, to report clinical results of AMIC and to compare AMIC with other chondrogenesis techniques. Finally, we comment on the appropriate surgical technique and its indications, since the number of one-

**Autologous Matrix-Induced Chondrogenesis (AMIC)** 

© 2016 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

© 2018 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

DOI: 10.5772/intechopen.71776

#### **Management of Knee Cartilage Defects with the Autologous Matrix-Induced Chondrogenesis (AMIC) Technique Management of Knee Cartilage Defects with the Autologous Matrix-Induced Chondrogenesis (AMIC) Technique**

DOI: 10.5772/intechopen.71776

Michael E. Hantes and Apostolos H. Fyllos Michael E. Hantes and Apostolos H. Fyllos

Additional information is available at the end of the chapter Additional information is available at the end of the chapter

http://dx.doi.org/10.5772/intechopen.71776

#### **Abstract**

The arthroscopic findings of knee articular cartilage lesions are reported to be as high as 60%, although only a fragment of these are considered to be symptomatic. Such lesions are believed to accelerate the onset of arthritis. Long-term results of the microfracture technique for chondral and osteochondral defects of the knee cartilage are not satisfactory. The autologous matrix induced chondrogenesis (AMIC) technique offers a promising alternative as an effective cartilage repair procedure in the knee resulting in stable clinical results and with a wide range of indications. An extensive literature review has been performed aiming at providing the rationale behind AMIC, to report clinical results of AMIC and to compare AMIC with other chondrogenesis techniques. Finally, we comment on the appropriate surgical technique and its indications, since the number of onestep arthroscopic procedure proposals is steadily increasing.

**Keywords:** matrix-induced chondrogenesis, cartilage, microfractures, AMIC

## **1. Introduction**

Despite its durable mechanical properties, hyaline cartilage has low intrinsic regenerative and reparative capacity since it lacks blood supply, nerves and lymphangion. Cartilage defects potentially lead to severe osteoarthritis and disability, and painful symptomatology during that process. None of the pharmacological or surgical cartilage degeneration management options have clearly shown the potential of restoring chondral surface, in order to avoid prosthetic replacement in the final stages of the disease. Numerous reparative techniques

© 2016 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. © 2018 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

for resurfacing articular cartilage defects are currently under extensive clinical research, with promising results. These include cell-based and cell-free materials such as autologous and allogeneic cell-based approaches and multipotent stem-cell-based techniques [1].

age and presence of a meniscal tear for the odds of having a chondral lesion subsequent to having an ACL injury. Advanced patient's age and long time from initial ACL injury are predictive factors of the severity of chondral lesions, and time from initial ACL injury is significantly associated with the number of chondral lesions [8–10]. However, no reliable correlation between

Management of Knee Cartilage Defects with the Autologous Matrix-Induced Chondrogenesis…

http://dx.doi.org/10.5772/intechopen.71776

165

Appropriate imaging modality to reach diagnosis is cartilage-sensitive MRI, but definitive diagnosis and classification is set by arthroscopy. Cartilage is a soft, viscoelastic tissue with strong imaging and anisotropic mechanical properties. The MRI signal properties are dependent on the cellular composition of collagen, proteoglycan, and water, but also the MR pulse sequence utilized. Normal cartilage demonstrates "gray-scale stratification," with lower signal intensity closer to the tidemark and subchondral plate and higher signal intensity in the transitional zone, related largely to collagen orientation in the extracellular matrix. Loss of normal gray-scale stratification is an important clinical feature that may herald subsequent delamination of cartilage from the subchondral bone. The assessment and grading of chondral and osteochondral injuries by using MR imaging are straightforward when true morphologic alterations are present. In the setting of higher grade acute injury, the signal alteration in the articular cartilage is readily visible and frequently associated with altered signal intensity in the adjacent subchondral bone marrow and displaced cartilage. On the other hand, lowgrade chondral injury typically involves very little morphologic change. Traditional grading systems have classically used altered T2 signal within the cartilage to infer the presence of infrastructural damage. Recent developments in quantitative MR imaging provides direct evaluation of tissue biochemistry in the setting of injury. Several techniques are available to assess the integrity of cartilage glycosaminoglycan, including sodium MR imaging, delayed gadolinium-enhanced MR imaging of cartilage, and T1 ρ imaging. To assess collagen orienta-

Operative treatment for chondral and osteochondral knee defects generally is unavoidable at some point and is indicated when nonoperative symptomatic methods fail to relieve pain and mechanical symptoms. Treatment options include debridement, marrow stimulation, transplantation to fill the defect, cell-based therapy, and the use of growth factors or pharmacological agents. The choice of procedure is based primarily on the classification of the lesion and the activity demands of the patient. AMIC is a fairly new but very promising method for cartilage regeneration and was first described by Behrens and Benthien in 2011 [13]. It is a one-step and culture-free procedure, it has the potential for homogeneous distribution of chondrocytes and MSCs to enhance chondrogenesis, and it also has the ability to regenerate hyaline-like cartilage tissue. It has been proven that MSCs can be isolated from the matrix material [14]. The literature

defects in the high-demand (but also highly compliant) young patient [15]. Some authors have mentioned underlying rheumatic disease and total meniscectomy as contraindications, whereas "kissing" lesions are unanimously considered an absolute contraindication. Needless to say that

) full thickness

currently supports AMIC procedures for moderate to large (greater than 6 cm2

clinical symptoms and articular cartilage status has been established.

tion, quantitative T2 mapping is most often utilized [11, 12].

**3. Indications**

Microfracture technique, a low-cost, fully arthroscopic procedure, is still considered the gold standard approach for small cartilage lesions (less than 2 cm2 ), not without dispute. This technique enhances migration of mesenchymal stem cells (MSCs) from bone marrow bleeding to the site of a cartilage defect; however, it often results in the formation of fibrocartilage that is biochemically and biomechanically inferior to hyaline articular cartilage, not to mention scatter of the newly formed blood clot into the joint [2]. Its efficacy as a marrow stimulating technique is being questioned due to progressive decrease of the clinical benefit after 2 years, especially as far as large defects are concerned [3].

The autologous matrix induced chondrogenesis (AMIC) offers a promising alternative as an effective cartilage repair procedure in the knee resulting in stable clinical results. It is a onestep procedure that combines microfracture with the application of a biological scaffold acting as a collagen, cell-free matrix that covers the produced blood clot, permitting the containment and ingrowing of MSCs to differentiate into the chondrogenic lineage. The clot induces a repair that covers the cartilage defect with a combination of fibrous and hyaline-like cartilage. AMIC has the potential for homogeneous distribution of MSCs under the membrane that could enhance chondrogenesis and accelerate cartilage healing.

## **2. Incidence, symptomatology, diagnosis and classification of chondral lesions**

Chondral lesions are caused through degradation of joint cartilage, in response to metabolic, genetic, vascular or traumatic stimuli. Chondral defects have been macroscopically graded by the International Cartilage Repair Society (ICRS) in a systematic manner, a system with good inter- and intra-observer reliability [4]. Most commonly used classification systems are the ICRS system and the modified Outerbridge.

The real incidence of osteochondral lesions in humans is unknown, because a large proportion of them are asymptomatic or undiagnosed. The prevalence of single or multiple focal knee articular cartilage pathologies (excluding osteoarthritis and chondromalacia patellae) is reported as high as 30% in arthroscopies, the commonest sites being the medial femoral condyle and the patella [5, 6]. 60% of the lesions are considered to be as severe as grade 3 or worse according to the ICRS system, while 64% of all chondral lesions have a diameter of less than 1 cm [6, 7]. Medial meniscus tears (37%) and ACL ruptures (36%) are the most common concomitant injuries with articular cartilage injuries. The presence of other injuries further influences management of these lesions, such as ACL insufficiency, patellar instability and patellofemoral malalignment [8, 9].

Patients with articular cartilage injuries usually complain of arthritis-like symptoms, such as pain, effusion, and mechanical symptoms varying with location of the lesion. Patients' history is important, although only 60% of patients with a chondral defect diagnosis definitely correlate their symptoms with a specific traumatic incidence [6]. Clinicians should consider the patients' age and presence of a meniscal tear for the odds of having a chondral lesion subsequent to having an ACL injury. Advanced patient's age and long time from initial ACL injury are predictive factors of the severity of chondral lesions, and time from initial ACL injury is significantly associated with the number of chondral lesions [8–10]. However, no reliable correlation between clinical symptoms and articular cartilage status has been established.

Appropriate imaging modality to reach diagnosis is cartilage-sensitive MRI, but definitive diagnosis and classification is set by arthroscopy. Cartilage is a soft, viscoelastic tissue with strong imaging and anisotropic mechanical properties. The MRI signal properties are dependent on the cellular composition of collagen, proteoglycan, and water, but also the MR pulse sequence utilized. Normal cartilage demonstrates "gray-scale stratification," with lower signal intensity closer to the tidemark and subchondral plate and higher signal intensity in the transitional zone, related largely to collagen orientation in the extracellular matrix. Loss of normal gray-scale stratification is an important clinical feature that may herald subsequent delamination of cartilage from the subchondral bone. The assessment and grading of chondral and osteochondral injuries by using MR imaging are straightforward when true morphologic alterations are present. In the setting of higher grade acute injury, the signal alteration in the articular cartilage is readily visible and frequently associated with altered signal intensity in the adjacent subchondral bone marrow and displaced cartilage. On the other hand, lowgrade chondral injury typically involves very little morphologic change. Traditional grading systems have classically used altered T2 signal within the cartilage to infer the presence of infrastructural damage. Recent developments in quantitative MR imaging provides direct evaluation of tissue biochemistry in the setting of injury. Several techniques are available to assess the integrity of cartilage glycosaminoglycan, including sodium MR imaging, delayed gadolinium-enhanced MR imaging of cartilage, and T1 ρ imaging. To assess collagen orientation, quantitative T2 mapping is most often utilized [11, 12].

## **3. Indications**

for resurfacing articular cartilage defects are currently under extensive clinical research, with promising results. These include cell-based and cell-free materials such as autologous and

Microfracture technique, a low-cost, fully arthroscopic procedure, is still considered the gold

nique enhances migration of mesenchymal stem cells (MSCs) from bone marrow bleeding to the site of a cartilage defect; however, it often results in the formation of fibrocartilage that is biochemically and biomechanically inferior to hyaline articular cartilage, not to mention scatter of the newly formed blood clot into the joint [2]. Its efficacy as a marrow stimulating technique is being questioned due to progressive decrease of the clinical benefit after 2 years,

The autologous matrix induced chondrogenesis (AMIC) offers a promising alternative as an effective cartilage repair procedure in the knee resulting in stable clinical results. It is a onestep procedure that combines microfracture with the application of a biological scaffold acting as a collagen, cell-free matrix that covers the produced blood clot, permitting the containment and ingrowing of MSCs to differentiate into the chondrogenic lineage. The clot induces a repair that covers the cartilage defect with a combination of fibrous and hyaline-like cartilage. AMIC has the potential for homogeneous distribution of MSCs under the membrane that

**2. Incidence, symptomatology, diagnosis and classification of chondral** 

Chondral lesions are caused through degradation of joint cartilage, in response to metabolic, genetic, vascular or traumatic stimuli. Chondral defects have been macroscopically graded by the International Cartilage Repair Society (ICRS) in a systematic manner, a system with good inter- and intra-observer reliability [4]. Most commonly used classification systems are the

The real incidence of osteochondral lesions in humans is unknown, because a large proportion of them are asymptomatic or undiagnosed. The prevalence of single or multiple focal knee articular cartilage pathologies (excluding osteoarthritis and chondromalacia patellae) is reported as high as 30% in arthroscopies, the commonest sites being the medial femoral condyle and the patella [5, 6]. 60% of the lesions are considered to be as severe as grade 3 or worse according to the ICRS system, while 64% of all chondral lesions have a diameter of less than 1 cm [6, 7]. Medial meniscus tears (37%) and ACL ruptures (36%) are the most common concomitant injuries with articular cartilage injuries. The presence of other injuries further influences management of these lesions, such as ACL insufficiency, patellar instability and patellofemoral malalignment [8, 9]. Patients with articular cartilage injuries usually complain of arthritis-like symptoms, such as pain, effusion, and mechanical symptoms varying with location of the lesion. Patients' history is important, although only 60% of patients with a chondral defect diagnosis definitely correlate their symptoms with a specific traumatic incidence [6]. Clinicians should consider the patients'

), not without dispute. This tech-

allogeneic cell-based approaches and multipotent stem-cell-based techniques [1].

standard approach for small cartilage lesions (less than 2 cm2

could enhance chondrogenesis and accelerate cartilage healing.

especially as far as large defects are concerned [3].

164 Cartilage Repair and Regeneration

ICRS system and the modified Outerbridge.

**lesions**

Operative treatment for chondral and osteochondral knee defects generally is unavoidable at some point and is indicated when nonoperative symptomatic methods fail to relieve pain and mechanical symptoms. Treatment options include debridement, marrow stimulation, transplantation to fill the defect, cell-based therapy, and the use of growth factors or pharmacological agents. The choice of procedure is based primarily on the classification of the lesion and the activity demands of the patient. AMIC is a fairly new but very promising method for cartilage regeneration and was first described by Behrens and Benthien in 2011 [13]. It is a one-step and culture-free procedure, it has the potential for homogeneous distribution of chondrocytes and MSCs to enhance chondrogenesis, and it also has the ability to regenerate hyaline-like cartilage tissue. It has been proven that MSCs can be isolated from the matrix material [14]. The literature currently supports AMIC procedures for moderate to large (greater than 6 cm2 ) full thickness defects in the high-demand (but also highly compliant) young patient [15]. Some authors have mentioned underlying rheumatic disease and total meniscectomy as contraindications, whereas "kissing" lesions are unanimously considered an absolute contraindication. Needless to say that elderly patients (although the age limit is not yet determined) with advanced osteoarthritis and significant narrowing of the joint lines are more suitable for total knee arthroplasty than AMIC or similar to AMIC joint preserving interventions.

(such as platelet-rich plasma or leucocyte-platelet-concentrated membrane) of the original AMIC technique may improve cartilage repair outcome and optimize the operative approach [19]. The basic procedural rationale is chondral defect arthroscopic debridement and preparation of smooth surrounding boundaries, followed by subchondral microfrac-

Management of Knee Cartilage Defects with the Autologous Matrix-Induced Chondrogenesis…

http://dx.doi.org/10.5772/intechopen.71776

167

The patient is placed supine in an ordinary arthroscopy setup, under regional or general anesthesia, antibiotic prophylaxis and with tourniquet application to the thigh. The status of the joint, ligamentous structure integrity and the cartilage lesion are assessed by arthroscopy, including location, size, and depth according to the ICRS classification. Clear, smooth and stable borders of normal adjacent cartilage are defined, followed by removal of the calcified chondral layer with a burr or a curette. According to the original technique, a mini arthrotomy is performed at this stage and access to the subchondral bone is reached by nanofractures or microfractures or by microdrilling with appropriate instruments. The gaps between the holes should permit sufficient bridging to prevent subchondral fracture. Generally, nanofractures technique is preferred, with standardized drilled holes nine millimeters deep and one millimeter in diameter and standard needle angling [20–22]. All-arthroscopic techniques have been described as well [22–24]. The collagen matrix of choice is consequently trimmed to fill the size of the defect, usually by template or imprint. Undersize of the scaffold is recommended to avoid dislocation with movement. The matrix is then pressed and sutured or glued (allogenic or partially autologous fibrin glue) or with a combination of both stabilized on the defect, making sure that a smooth transition to normal cartilage has been ensured. There are usually two sides of the membrane; the rough side faces the subchondral bone and the smooth side faces the joint. The application of fibrin glue and the attachment of the membrane is best done in a dry environment in case of all-arthroscopic technique. The scaffold acts like a sponge that holds the blood clot within the defect and induces hemostasis while protecting the underlying tissue. This may be either performed arthroscopically or as an arthroscopically assisted mini-open technique. Before closure, multiple gentle movements of the joint are advised in order to confirm unhindered membrane placement. Irrigation of the joint is discouraged as this may almost certainly result in membrane dislocation and removal of the desired blood clot. The use of a drain deems unnecessary, not to

mention that suction could result in membrane dislodgement (**Figures 1**–**9**).

**Figure 1.** Mini arthotomy, identification and classification of the lesion.

ture technique and finally stable bilayer matrix fixation.

## **4. The basic science behind AMIC**

In vivo signaling molecules and biomechanical stimuli provides a much more appropriate environment for progenitor cells to differentiate than in vitro chondrogenesis. Fibrin, PDGF and other factors contained in a natural blood clot are highly chemoattractive for MSC. PDGF-BB, EGF and TGF-b are the most important potent mitogens. These factors also contained in the blood clot after subchondral microfracture induce the migration of MSC and have at the same time the potency to enhance their proliferation. Therefore, the migration and proliferation steps of MSC can take place simultaneously in vivo, excluding the need for in vitro culturing. Furthermore, cartilage differentiation initiates in contact with subchondral bone and earliest chondrogenesis is often seen in areas where active remodeling of the subchondral bone plate occurs and, thus, enhanced nutrition and a higher anabolic rate of the cells can take place. MSCs derived from microfractures have the same phenotypic plasticity as chondrogenic cells in the cartilage basal zone. One cm<sup>3</sup> of blood from a single microfracture hole has approximately 8000 CD34+ MSCs [16, 17].

Strength of integration of the neotissue depends on the age and metabolic activity of the tissue. The use of more immature cells has obvious benefits for integration, which argues in favor of MSC-based as opposed to chondrocyte-based repair strategies. Collagen and fibrinbased gels are subject to strong shrinking during chondrogenesis which points towards an increasing risk of partial defect filling and loss of a superclot after microfracturing during progress of chondrogenic differentiation. To be able to avoid this, a clinically applied solid collagen type I/III matrix as used in the AMIC technique appears to facilitate chondrogenesis of MSC. It has been proven that bone marrow cells can be guided directly to a cartilage defect by a collagenous matrix and MSCs can be isolated regularly from the matrix [14]. Inhibitory signals may come from the opposed cartilage surface and synovial fluid to dominate the surface area of fibrous repair tissue. The lowest cartilage layer is responsible for load transmission from cartilage into bone. Application of biomechanical loading during chondrogenesis of MSC stimulated cartilaginous matrix production in tissue engineering applications underlining the importance of mechanical signals for tissue guidance during repair [17].

## **5. Surgical technique**

The AMIC procedure can be performed with either a mini open approach, or a combination of arthroscopy and mini arthrotomy, or even as an all-arthroscopic technique. There are different types of scaffolds available: natural protein–based or carbohydrate-based scaffolds, and synthetic scaffolds. The 3 scaffolds that have been reported in the literature for AMIC are ChondroGide (Geistlich Biomaterials, Wolhausen, Switzerland), Hyalofast (Fidia Advanced Biopolymers, Padua, Italy), and Chondrotissue (BioTissue, Zurich, Switzerland) [18]. Modifications and enrichment of the scaffold with newer biomaterials (such as platelet-rich plasma or leucocyte-platelet-concentrated membrane) of the original AMIC technique may improve cartilage repair outcome and optimize the operative approach [19]. The basic procedural rationale is chondral defect arthroscopic debridement and preparation of smooth surrounding boundaries, followed by subchondral microfracture technique and finally stable bilayer matrix fixation.

elderly patients (although the age limit is not yet determined) with advanced osteoarthritis and significant narrowing of the joint lines are more suitable for total knee arthroplasty than AMIC

In vivo signaling molecules and biomechanical stimuli provides a much more appropriate environment for progenitor cells to differentiate than in vitro chondrogenesis. Fibrin, PDGF and other factors contained in a natural blood clot are highly chemoattractive for MSC. PDGF-BB, EGF and TGF-b are the most important potent mitogens. These factors also contained in the blood clot after subchondral microfracture induce the migration of MSC and have at the same time the potency to enhance their proliferation. Therefore, the migration and proliferation steps of MSC can take place simultaneously in vivo, excluding the need for in vitro culturing. Furthermore, cartilage differentiation initiates in contact with subchondral bone and earliest chondrogenesis is often seen in areas where active remodeling of the subchondral bone plate occurs and, thus, enhanced nutrition and a higher anabolic rate of the cells can take place. MSCs derived from microfractures have the same phenotypic plasticity as chondrogenic cells in the cartilage basal zone. One cm<sup>3</sup>

blood from a single microfracture hole has approximately 8000 CD34+ MSCs [16, 17].

ing the importance of mechanical signals for tissue guidance during repair [17].

The AMIC procedure can be performed with either a mini open approach, or a combination of arthroscopy and mini arthrotomy, or even as an all-arthroscopic technique. There are different types of scaffolds available: natural protein–based or carbohydrate-based scaffolds, and synthetic scaffolds. The 3 scaffolds that have been reported in the literature for AMIC are ChondroGide (Geistlich Biomaterials, Wolhausen, Switzerland), Hyalofast (Fidia Advanced Biopolymers, Padua, Italy), and Chondrotissue (BioTissue, Zurich, Switzerland) [18]. Modifications and enrichment of the scaffold with newer biomaterials

Strength of integration of the neotissue depends on the age and metabolic activity of the tissue. The use of more immature cells has obvious benefits for integration, which argues in favor of MSC-based as opposed to chondrocyte-based repair strategies. Collagen and fibrinbased gels are subject to strong shrinking during chondrogenesis which points towards an increasing risk of partial defect filling and loss of a superclot after microfracturing during progress of chondrogenic differentiation. To be able to avoid this, a clinically applied solid collagen type I/III matrix as used in the AMIC technique appears to facilitate chondrogenesis of MSC. It has been proven that bone marrow cells can be guided directly to a cartilage defect by a collagenous matrix and MSCs can be isolated regularly from the matrix [14]. Inhibitory signals may come from the opposed cartilage surface and synovial fluid to dominate the surface area of fibrous repair tissue. The lowest cartilage layer is responsible for load transmission from cartilage into bone. Application of biomechanical loading during chondrogenesis of MSC stimulated cartilaginous matrix production in tissue engineering applications underlin-

of

or similar to AMIC joint preserving interventions.

**4. The basic science behind AMIC**

166 Cartilage Repair and Regeneration

**5. Surgical technique**

The patient is placed supine in an ordinary arthroscopy setup, under regional or general anesthesia, antibiotic prophylaxis and with tourniquet application to the thigh. The status of the joint, ligamentous structure integrity and the cartilage lesion are assessed by arthroscopy, including location, size, and depth according to the ICRS classification. Clear, smooth and stable borders of normal adjacent cartilage are defined, followed by removal of the calcified chondral layer with a burr or a curette. According to the original technique, a mini arthrotomy is performed at this stage and access to the subchondral bone is reached by nanofractures or microfractures or by microdrilling with appropriate instruments. The gaps between the holes should permit sufficient bridging to prevent subchondral fracture. Generally, nanofractures technique is preferred, with standardized drilled holes nine millimeters deep and one millimeter in diameter and standard needle angling [20–22]. All-arthroscopic techniques have been described as well [22–24]. The collagen matrix of choice is consequently trimmed to fill the size of the defect, usually by template or imprint. Undersize of the scaffold is recommended to avoid dislocation with movement. The matrix is then pressed and sutured or glued (allogenic or partially autologous fibrin glue) or with a combination of both stabilized on the defect, making sure that a smooth transition to normal cartilage has been ensured. There are usually two sides of the membrane; the rough side faces the subchondral bone and the smooth side faces the joint. The application of fibrin glue and the attachment of the membrane is best done in a dry environment in case of all-arthroscopic technique. The scaffold acts like a sponge that holds the blood clot within the defect and induces hemostasis while protecting the underlying tissue. This may be either performed arthroscopically or as an arthroscopically assisted mini-open technique. Before closure, multiple gentle movements of the joint are advised in order to confirm unhindered membrane placement. Irrigation of the joint is discouraged as this may almost certainly result in membrane dislocation and removal of the desired blood clot. The use of a drain deems unnecessary, not to mention that suction could result in membrane dislodgement (**Figures 1**–**9**).

**Figure 1.** Mini arthotomy, identification and classification of the lesion.

**Figure 5.** After open scaffold placement in a large patellar defect.

**Figure 6.** After open membrane placement in medial femoral condyle osteochondral lesion.

Management of Knee Cartilage Defects with the Autologous Matrix-Induced Chondrogenesis…

http://dx.doi.org/10.5772/intechopen.71776

169

**Figure 7.** Arthroscopic curettage of osteochondral lesion to healthy bone depth.

**Figure 2.** Osteochondral lesion (ICRS grade 4) after open debridement and preparation of boundaries.

**Figure 3.** Performing nanofractures.

**Figure 4.** Imprint technique with aluminum foil.

Management of Knee Cartilage Defects with the Autologous Matrix-Induced Chondrogenesis… http://dx.doi.org/10.5772/intechopen.71776 169

**Figure 5.** After open scaffold placement in a large patellar defect.

**Figure 2.** Osteochondral lesion (ICRS grade 4) after open debridement and preparation of boundaries.

**Figure 3.** Performing nanofractures.

168 Cartilage Repair and Regeneration

**Figure 4.** Imprint technique with aluminum foil.

**Figure 6.** After open membrane placement in medial femoral condyle osteochondral lesion.

**Figure 7.** Arthroscopic curettage of osteochondral lesion to healthy bone depth.

6 months so limited weight bearing for a certain amount of time is important. However, remodeling of the chondral matrix may actually profit from early mobilization using a combination of compression and shear forces. Since there is sufficient bridging between the drilled holes and the holes are straight there should be no reason for a subchondral impression fracture. Earlier

Management of Knee Cartilage Defects with the Autologous Matrix-Induced Chondrogenesis…

http://dx.doi.org/10.5772/intechopen.71776

171

Range of motion is generally restricted for 6 weeks depending on site of the lesion. When the femoral condyles are involved, active and passive knee flexion up to 90° is permitted, whereas when the patella is involved knee flexion is restricted to 60° for the first month. Mobilization exercises including continuous passive motion, electrotherapy of leg muscles and proprioception training are an integral part of the rehabilitation program. Unrestricted weight-bearing and range of motion is permitted after 8 weeks. Contact sports are prohibited for at least a year [28–30]. No study has yet addressed the effect of rehabilitation on the quality of the repair.

Well-established rating systems have been used to summarize relevant outcome measures. The combination of the Lysholm score and the Visual Analog Score (VAS) have been recommended in the literature before. The Lysholm scoring system has demonstrated validity, reliability and responsiveness to cartilage pathology and treatment. The VAS has widely been used to monitor subjective satisfaction postoperatively [31, 32]. The Modified Cincinnati, the Modified ICRS scores and the knee injury and osteoarthritis outcome score (KOOS) have also been suggested. Structural repair can be assessed with MRI with a focus on the extent, signal intensity, and surface of the defect filling, integration to adjacent cartilage, and bone marrow lesion. Semiquantitative MRI scores of osteoarthritis established as BLOKS and WORMS can play the part. But it is magnetic resonance observation of cartilage repair tissue (MOCART) protocol that is more often used, with almost perfect interobserver reliability. The detection of subtle cartilage changes by MRI requires high resolution imaging, which is not provided by standard sequences. With the use of a surface coil placed over the knee compartment of interest, high resolution imaging with reasonable scan times is possible on routinely used 1 or 1.5 T MRI units by performing fast spin-echo imaging. The advantage of this imaging technique is that it can be used on every standard 1 or 1.5 T scanner. Nine variables are used to describe the morphology and signal intensity of the repair tissue compared to the adjacent native cartilage, according to the MOCART system. A statistically significant correlation between the clinical outcome (as measured by VAS and KOOS) and some of the radiological variables, including the filling of the defect, the structure of the repair tissue, changes in the subchondral bone and

Encouraging mid- to long-term results have been published that make the AMIC procedure seem promising for a wide range of indications. Gille et al. published their results after 2 years of follow-up of 57 patients who had undergone AMIC (and concomitant procedures in appro-

was III or higher, with mean patient age of 37 years. Mean Lysholm and VAS scores were

and classification grade in the Outerbridge system

weight-bearing has been suggested after nanofractures [25–27].

the signal intensities has been established [33] (**Figure 10**).

priate cases). Mean defect size was 3.4 cm2

**7. Results**

**Figure 8.** Arthroscopic microfracture technique.

**Figure 9.** Membrane attached after preparation of osteochondral defect under dry arthroscopy.

## **6. Rehabilitation**

Patient compliance is the key for success of this sensitive procedure, although consensus has not been reached. Most authors recommend foot sole contact for 6 weeks using crutches building up full weight bearing after 8 weeks. Partial weight bearing pertains to the possible risk of a compression fracture after microfracturing due to small and ill-defined bone bridges which might not bear enough weight. Articular remodeling and chondral maturation may take up to 6 months so limited weight bearing for a certain amount of time is important. However, remodeling of the chondral matrix may actually profit from early mobilization using a combination of compression and shear forces. Since there is sufficient bridging between the drilled holes and the holes are straight there should be no reason for a subchondral impression fracture. Earlier weight-bearing has been suggested after nanofractures [25–27].

Range of motion is generally restricted for 6 weeks depending on site of the lesion. When the femoral condyles are involved, active and passive knee flexion up to 90° is permitted, whereas when the patella is involved knee flexion is restricted to 60° for the first month. Mobilization exercises including continuous passive motion, electrotherapy of leg muscles and proprioception training are an integral part of the rehabilitation program. Unrestricted weight-bearing and range of motion is permitted after 8 weeks. Contact sports are prohibited for at least a year [28–30]. No study has yet addressed the effect of rehabilitation on the quality of the repair.

## **7. Results**

**6. Rehabilitation**

**Figure 8.** Arthroscopic microfracture technique.

170 Cartilage Repair and Regeneration

Patient compliance is the key for success of this sensitive procedure, although consensus has not been reached. Most authors recommend foot sole contact for 6 weeks using crutches building up full weight bearing after 8 weeks. Partial weight bearing pertains to the possible risk of a compression fracture after microfracturing due to small and ill-defined bone bridges which might not bear enough weight. Articular remodeling and chondral maturation may take up to

**Figure 9.** Membrane attached after preparation of osteochondral defect under dry arthroscopy.

Well-established rating systems have been used to summarize relevant outcome measures. The combination of the Lysholm score and the Visual Analog Score (VAS) have been recommended in the literature before. The Lysholm scoring system has demonstrated validity, reliability and responsiveness to cartilage pathology and treatment. The VAS has widely been used to monitor subjective satisfaction postoperatively [31, 32]. The Modified Cincinnati, the Modified ICRS scores and the knee injury and osteoarthritis outcome score (KOOS) have also been suggested.

Structural repair can be assessed with MRI with a focus on the extent, signal intensity, and surface of the defect filling, integration to adjacent cartilage, and bone marrow lesion. Semiquantitative MRI scores of osteoarthritis established as BLOKS and WORMS can play the part. But it is magnetic resonance observation of cartilage repair tissue (MOCART) protocol that is more often used, with almost perfect interobserver reliability. The detection of subtle cartilage changes by MRI requires high resolution imaging, which is not provided by standard sequences. With the use of a surface coil placed over the knee compartment of interest, high resolution imaging with reasonable scan times is possible on routinely used 1 or 1.5 T MRI units by performing fast spin-echo imaging. The advantage of this imaging technique is that it can be used on every standard 1 or 1.5 T scanner. Nine variables are used to describe the morphology and signal intensity of the repair tissue compared to the adjacent native cartilage, according to the MOCART system. A statistically significant correlation between the clinical outcome (as measured by VAS and KOOS) and some of the radiological variables, including the filling of the defect, the structure of the repair tissue, changes in the subchondral bone and the signal intensities has been established [33] (**Figure 10**).

Encouraging mid- to long-term results have been published that make the AMIC procedure seem promising for a wide range of indications. Gille et al. published their results after 2 years of follow-up of 57 patients who had undergone AMIC (and concomitant procedures in appropriate cases). Mean defect size was 3.4 cm2 and classification grade in the Outerbridge system was III or higher, with mean patient age of 37 years. Mean Lysholm and VAS scores were

for full-thickness defects larger than 2 cm2

clinical outcomes in all cases [30].

**8. Conclusion**

**Author details**

Michael E. Hantes<sup>1</sup>

dependent on patient compliance.

\* and Apostolos H. Fyllos1,2

\*Address all correspondence to: hantesmi@otenet.gr

, annual clinical reviews and an MRI was performed

http://dx.doi.org/10.5772/intechopen.71776

173

at 1 and 7 years postoperatively. All patients showed maintenance of good clinical and functional results 7 years after the procedure, although imaging findings did not support good

Management of Knee Cartilage Defects with the Autologous Matrix-Induced Chondrogenesis…

Two recent meta-analyses pointed out that conclusive evidence to determine whether morphological MRI is reliable in predicting clinical outcome after cartilage repair is lacking. These reports also stated that no MRI classification has been shown to correlate with clinical outcomes after different types of cartilage repair, although AMIC was not among the procedures included in the studies [35, 36]. Since the interpretation of cartilage structure from morphological MRI data is still debated and does not correlate with clinical scores, clinical and functional results should be considered as the most important outcomes, and so far, AMIC shows great clinical benefit for the patient. Finally, it should be outlined that no randomized controlled studies have been published comparing AMIC results with other cartilage repair procedures (apart from microfractures), such as autologous chondrocyte implantation (ACI) or matrix-induced chondrocyte implantation (MACI), in order to draw definite conclusions. The obvious advantage is the fact that it is a one-step procedure, faster, simpler and at a lower cost compared to ACI/MACI, since no cell culture and/or reoperation is needed. Standardization of the AMIC technique is also an issue due to different micro- or nanofracturing technique and open vs. arthroscopic procedures.

To sum up, AMIC is a one-step cartilage repair technique performed either by arthroscopy or by mini arthrotomy in the stable and well aligned knee. It shows great promise with good functional mid- and long-term results, and has a very low rate and range of complications and failures. The procedure seems to augment the healing potential thanks to homogeneous distribution of MSCs that enhances chondrogenesis, and also shows ability to regenerate hyaline-like cartilage tissue on MRI. Prospective long-term randomized trials are needed to compare the results of the AMIC procedure with other cartilage repair techniques, as well as to ensure maintenance of good clinical outcomes in the long run. A systematic and prolonged rehabilitation program is essential and outcome is absolutely

1 Department of Orthopedics, Faculty of Medicine, University of Thessaly, Larisa, Greece

2 Department of Anatomy, Faculty of Medicine, University of Thessaly, Larisa, Greece

**Figure 10.** MRI of patient pre- and 19 months post-op, with good filling of the chondral defect in the medial femoral condyle and good integration of the neotissue.

significantly improved in all age groups at 2 years post-op. Defect size (range 0–12 cm2 ) had no impact on the clinical outcome and no adverse effects or procedural failures were reported [34]. Furthermore, another prospective randomized control trial of 47 patients with mean age 37 years and mean defect size 3.6 cm2 , directly compared results after microfracturing alone with results after AMIC. After improvement for the first 2 years in all sub-groups, a progressive and significant score degradation was observed in the microfracture group, while all functional parameters remained stable for at least 5 years in the AMIC group. At two and 5 years, MRI defect filling was more complete in the AMIC groups (at least 60% of the patients had a defect filling of more than 2/3). No serious treatment-related adverse events were reported. Biopsies were obtained at 2 years in two patients, both belonging to the AMIC group. Both showed the presence of a fibrocartilaginous matrix, without evidence of residual membrane material, and in one case cell cluster formation was observed in the deep zone of the repair tissue. Hyaline cartilage specific markers were identified, as Safranin-O, collagen-type I and II and a glycosaminoglycan. Both repair tissues were characterized as mostly fibrocartilaginous [28]. In a retrospective review of results in 40 knees with a mean follow-up of 28.8 months, AMIC alone and in combination with unloading osteotomy or patella realignment significantly improved symptomatic knees with isolated osteochondral and chondral lesions. A relatively important complication rose, knee stiffness in the subgroup with patella defects, and manipulation under anesthesia was necessary. However, subgroups varied considerably in lesion site and size, the patient population was small and radiological results according to the MOCART system were inconsistent and therefore unreliable [29]. Finally, in a prospective trial of 21 patients treated for full-thickness defects larger than 2 cm2 , annual clinical reviews and an MRI was performed at 1 and 7 years postoperatively. All patients showed maintenance of good clinical and functional results 7 years after the procedure, although imaging findings did not support good clinical outcomes in all cases [30].

Two recent meta-analyses pointed out that conclusive evidence to determine whether morphological MRI is reliable in predicting clinical outcome after cartilage repair is lacking. These reports also stated that no MRI classification has been shown to correlate with clinical outcomes after different types of cartilage repair, although AMIC was not among the procedures included in the studies [35, 36]. Since the interpretation of cartilage structure from morphological MRI data is still debated and does not correlate with clinical scores, clinical and functional results should be considered as the most important outcomes, and so far, AMIC shows great clinical benefit for the patient. Finally, it should be outlined that no randomized controlled studies have been published comparing AMIC results with other cartilage repair procedures (apart from microfractures), such as autologous chondrocyte implantation (ACI) or matrix-induced chondrocyte implantation (MACI), in order to draw definite conclusions. The obvious advantage is the fact that it is a one-step procedure, faster, simpler and at a lower cost compared to ACI/MACI, since no cell culture and/or reoperation is needed. Standardization of the AMIC technique is also an issue due to different micro- or nanofracturing technique and open vs. arthroscopic procedures.

## **8. Conclusion**

) had

significantly improved in all age groups at 2 years post-op. Defect size (range 0–12 cm2

37 years and mean defect size 3.6 cm2

condyle and good integration of the neotissue.

172 Cartilage Repair and Regeneration

no impact on the clinical outcome and no adverse effects or procedural failures were reported [34]. Furthermore, another prospective randomized control trial of 47 patients with mean age

**Figure 10.** MRI of patient pre- and 19 months post-op, with good filling of the chondral defect in the medial femoral

with results after AMIC. After improvement for the first 2 years in all sub-groups, a progressive and significant score degradation was observed in the microfracture group, while all functional parameters remained stable for at least 5 years in the AMIC group. At two and 5 years, MRI defect filling was more complete in the AMIC groups (at least 60% of the patients had a defect filling of more than 2/3). No serious treatment-related adverse events were reported. Biopsies were obtained at 2 years in two patients, both belonging to the AMIC group. Both showed the presence of a fibrocartilaginous matrix, without evidence of residual membrane material, and in one case cell cluster formation was observed in the deep zone of the repair tissue. Hyaline cartilage specific markers were identified, as Safranin-O, collagen-type I and II and a glycosaminoglycan. Both repair tissues were characterized as mostly fibrocartilaginous [28]. In a retrospective review of results in 40 knees with a mean follow-up of 28.8 months, AMIC alone and in combination with unloading osteotomy or patella realignment significantly improved symptomatic knees with isolated osteochondral and chondral lesions. A relatively important complication rose, knee stiffness in the subgroup with patella defects, and manipulation under anesthesia was necessary. However, subgroups varied considerably in lesion site and size, the patient population was small and radiological results according to the MOCART system were inconsistent and therefore unreliable [29]. Finally, in a prospective trial of 21 patients treated

, directly compared results after microfracturing alone

To sum up, AMIC is a one-step cartilage repair technique performed either by arthroscopy or by mini arthrotomy in the stable and well aligned knee. It shows great promise with good functional mid- and long-term results, and has a very low rate and range of complications and failures. The procedure seems to augment the healing potential thanks to homogeneous distribution of MSCs that enhances chondrogenesis, and also shows ability to regenerate hyaline-like cartilage tissue on MRI. Prospective long-term randomized trials are needed to compare the results of the AMIC procedure with other cartilage repair techniques, as well as to ensure maintenance of good clinical outcomes in the long run. A systematic and prolonged rehabilitation program is essential and outcome is absolutely dependent on patient compliance.

## **Author details**

Michael E. Hantes<sup>1</sup> \* and Apostolos H. Fyllos1,2


## **References**

[1] Makris EA, Gomoll AH, Malizos KN, Hu JC, Athanasiou KA. Repair and tissue engineering techniques for articular cartilage. Nature Reviews Rheumatology. 2015 Jan;**11**(1): 21-34

[13] Benthien JP, Behrens P. The treatment of chondral and osteochondral defects of the knee with autologous matrix-induced chondrogenesis (AMIC): Method description and recent developments. Knee Surgery, Sports Traumatology, Arthroscopy. 2011 Aug;**19**(8):1316-1319

Management of Knee Cartilage Defects with the Autologous Matrix-Induced Chondrogenesis…

http://dx.doi.org/10.5772/intechopen.71776

175

[14] Kramer J, Böhrnsen F, Lindner U, Behrens P, Schlenke P, Rohwedel J.In vivo matrix-guided human mesenchymal stem cells. Cellular and Molecular Life Sciences. 2006 Mar;**63**(5):

[15] Zhang C, Cai YZ, Lin XJ. One-step cartilage repair technique as a next generation of cell therapy for cartilage defects: Biological characteristics, preclinical application, surgical

[16] Tallheden T, Dennis JE, Lennon DP, Sjögren-Jansson E, Caplan AI, Lindahl A. Phenotypic plasticity of human articular chondrocytes. The Journal of Bone and Joint Surgery.

[17] Richter W. Mesenchymal stem cells and cartilage in situ regeneration. Journal of Internal

[18] Lee YH, Suzer F, Thermann H. Autologous matrix-induced chondrogenesis in the knee:

[19] D'Antimo C, Biggi F, Borean A, Di Fabio S, Pirola I. Combining a novel leucocyte-plateletconcentrated membrane and an injectable collagen scaffold in a single-step AMIC procedure to treat chondral lesions of the knee: A preliminary retrospective study. European

[20] Steadman JR, Rodkey WG, Rodrigo JJ. Microfracture: Surgical technique and rehabilitation to treat chondral defects. Clinical Orthopaedics and Related Research. 2001 Oct;(391

[21] Chen H, Sun J, Hoemann C, Lascau-Coman V, Ouyang W, Trankhanh N, et al. Drilling and microfracture lead to different bone structure and necrosis during bone-marrow stimulation for cartilage repair. Journal of Orthopaedic Research. 2009 Nov;**27**(11):1432-1438

[22] Benthien JP, Behrens P. Nanofractured autologous matrix induced chondrogenesis (NAMIC©)—Further development of collagen membrane aided chondrogenesis combined with subchondral needling: A technical note. The Knee. 2015 Oct;**22**(5):411-415

[23] Piontek T, Ciemniewska-Gorzela K, Szulc A, Naczk J, Słomczykowski M. All-arthroscopic AMIC procedure for repair of cartilage defects of the knee. Knee Surgery, Sports

[24] Sadlik B, Wiewiorski M. Implantation of a collagen matrix for an AMIC repair during dry arthroscopy. Knee Surgery, Sports Traumatology, Arthroscopy. 2015 Aug;**23**(8):2349-2352

[25] Benthien JP, Behrens P. Reviewing subchondral cartilage surgery: Considerations for standardized and outcome predictable cartilage remodelling. International Orthopaedics.

Traumatology, Arthroscopy. 2012 May;**20**(5):922-925

Journal of Orthopaedic Surgery and Traumatology. 2016 Jul;**27**(5):673-681

techniques, and clinical developments. Arthroscopy. 2016 Jul;**32**(7):1444-1450

American Volume. 2003;**85-A**(Suppl 2):93-100

Medicine. 2009 Oct;**266**(4):390-405

Suppl):S362-S369

2013 Nov;**37**(11):2139-2145

A review. Cartilage. 2014 Jul;**5**(3):145-153

616-626


[13] Benthien JP, Behrens P. The treatment of chondral and osteochondral defects of the knee with autologous matrix-induced chondrogenesis (AMIC): Method description and recent developments. Knee Surgery, Sports Traumatology, Arthroscopy. 2011 Aug;**19**(8):1316-1319

**References**

174 Cartilage Repair and Regeneration

21-34

[1] Makris EA, Gomoll AH, Malizos KN, Hu JC, Athanasiou KA. Repair and tissue engineering techniques for articular cartilage. Nature Reviews Rheumatology. 2015 Jan;**11**(1):

[2] Kreuz PC, Steinwachs MR, Erggelet C, Krause SJ, Konrad G, Uhl M, et al. Results after microfracture of full-thickness chondral defects in different compartments in the knee.

[3] Mithoefer K, McAdams T, Williams RJ, Kreuz PC, Mandelbaum BR. Clinical efficacy of the microfracture technique for articular cartilage repair in the knee: An evidence-based systematic analysis. The American Journal of Sports Medicine. 2009 Oct;**37**(10):2053-2063

[4] Dwyer T, Martin CR, Kendra R, Sermer C, Chahal J, Ogilvie-Harris D, et al. Reliability and validity of the arthroscopic international cartilage repair society classification system: Correlation with histological assessment of depth. Arthroscopy. 2017 Jun;**33**(6):1219-1224

[5] Widuchowski W, Widuchowski J, Trzaska T. Articular cartilage defects: Study of 25,124

[6] Hjelle K, Solheim E, Strand T, Muri R, Brittberg M. Articular cartilage defects in 1,000

[7] Tandogan RN, Taser O, Kayaalp A, Taşkiran E, Pinar H, Alparslan B, et al. Analysis of meniscal and chondral lesions accompanying anterior cruciate ligament tears: Relationship with age, time from injury, and level of sport. Knee Surgery, Sports Traumatology,

[8] Logerstedt DS, Snyder-Mackler L, Ritter RC, Axe MJ. Knee pain and mobility impairments: Meniscal and articular cartilage lesions. The Journal of Orthopaedic and Sports

[9] Michalitsis S, Vlychou M, Malizos KN, Thriskos P, Hantes ME. Meniscal and articular cartilage lesions in the anterior cruciate ligament-deficient knee: Correlation between time from injury and knee scores. Knee Surgery, Sports Traumatology, Arthroscopy. 2015

[10] Flanigan DC, Harris JD, Trinh TQ, Siston RA, Brophy RH. Prevalence of chondral defects in athletes' knees: A systematic review. Medicine and Science in Sports and Exercise.

[11] Pathria MN, Chung CB, Resnick DL. Acute and stress-related injuries of bone and cartilage: Pertinent anatomy, basic biomechanics, and imaging perspective. Radiology. 2016

[12] Potter HG, Koff MF. MR imaging tools to assess cartilage and joint structures. HSS

Osteoarthritis and Cartilage. 2006 Nov;**14**(11):1119-1125

knee arthroscopies. The Knee. 2007 Jun;**14**(3):177-182

Arthroscopy. 2004 Jul;**12**(4):262-270

Jan;**23**(1):232-239

Jul;**280**(1):21-38

2010 Oct;**42**(10):1795-1801

Journal. 2012 Feb;**8**(1):29-32

Physical Therapy. 2010 Jun;**40**(6):A1-A35

knee arthroscopies. Arthroscopy. 2002 Sep;**18**(7):730-734


[26] Wang N, Grad S, Stoddart MJ, Niemeyer P, Reising K, Schmal H, et al. Particulate cartilage under bioreactor-induced compression and shear. International Orthopaedics. 2014 May;**38**(5):1105-1111

**Chapter 10**

**Provisional chapter**

**MRI Mapping for Cartilage Repair Follow-up**

**MRI Mapping for Cartilage Repair Follow-up**

DOI: 10.5772/intechopen.70372

Patients, who benefit from cartilage repair surgery, need a non-invasive and high-quality imaging modality to assess the structure and the biochemical property of the repair tissue. Magnetic resonance imaging (MRI), which provides better tissue contrast and high spatial resolution, is currently the best imaging technique available for the assessment of articular cartilage pathologies. In addition to MR morphology sequences, that allow cartilage lesions detection as well as repair tissue evaluation from the articular surface of the joint to the bone-cartilage interface, MRI mapping techniques help to assess the technical success of the procedure of cartilage repair and the state of cartilage healing, as well the identification of possible complications after cartilage repair surgery. MRI mapping techniques such as T1, T2 and T2\* mapping help to assess the biochemical property of the repair tissue using delayed gadolinium-enhanced MRI of cartilage (dGEMRIC) to assess the proteoglycan content and T2/T1rho (T1ρ) mapping to assess the collagen content and the fiber matrix arrangement. This chapter gives an overview about the MRI mapping techniques used for Cartilage Repair Tissue

**Keywords:** MRI, cartilage repair, T2 mapping, dGEMRIC, follow-up, T1rho, T2\* mapping

Many techniques are used to evaluate the knee articular cartilage however non-invasive conventional magnetic resonance imaging (MRI) is the method of choice for the evaluation of knee articular cartilage [1]. Imaging of articular cartilage needs MRI sequence which is able to characterize morphological alterations of cartilage as well as adjacent tissue and to measure with high accuracy the cartilage thickness [2]. Conventional MRI sequences allow the detection of degenerative cartilage lesions and the changes due to therapy response, e.g., after

> © 2016 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution,

© 2018 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

and reproduction in any medium, provided the original work is properly cited.

Additional information is available at the end of the chapter

Additional information is available at the end of the chapter

http://dx.doi.org/10.5772/intechopen.70372

Mars Mokhtar

**Abstract**

Follow-up.

**1. Introduction**

cartilage repair procedures.

Mars Mokhtar


**Provisional chapter**

## **MRI Mapping for Cartilage Repair Follow-up**

**MRI Mapping for Cartilage Repair Follow-up**

DOI: 10.5772/intechopen.70372

## Mars Mokhtar Mars Mokhtar Additional information is available at the end of the chapter

[26] Wang N, Grad S, Stoddart MJ, Niemeyer P, Reising K, Schmal H, et al. Particulate cartilage under bioreactor-induced compression and shear. International Orthopaedics. 2014

[27] Schaetti O, Grad S, Goldhahn J, Salzmann G, Li Z, Alini M, et al. A combination of shear and dynamic compression leads to mechanically induced chondrogenesis of human mes-

[28] Volz M, Schaumburger J, Frick H, Grifka J, Anders S. A randomized controlled trial demonstrating sustained benefit of Autologous Matrix-Induced Chondrogenesis over

[29] Kusano T, Jakob RP, Gautier E, Magnussen RA, Hoogewoud H, Jacobi M. Treatment of isolated chondral and osteochondral defects in the knee by autologous matrix-induced chondrogenesis (AMIC). Knee Surgery, Sports Traumatology, Arthroscopy. 2012 Oct;

[30] Schiavone Panni A, Del Regno C, Mazzitelli G, D'Apolito R, Corona K, Vasso M. Good clinical results with autologous matrix-induced chondrogenesis (Amic) technique in large knee chondral defects. Knee Surgery, Sports Traumatology, Arthroscopy. 2017 Mar

[31] Flandry F, Hunt JP, Terry GC, Hughston JC. Analysis of subjective knee complaints using visual analog scales. The American Journal of Sports Medicine. 1991 Mar-Apr;**19**(2):

[32] Fuchs S, Friedrich M. Possible influence of knee scores. Der Unfallchirurg. 2000 Jan;**103**(1):

[33] Marlovits S, Singer P, Zeller P, Mandl I, Haller J, Trattnig S. Magnetic resonance observation of cartilage repair tissue (MOCART) for the evaluation of autologous chondrocyte transplantation: Determination of interobserver variability and correlation to clinical

[34] Gille J, Behrens P, Volpi P, de Girolamo L, Reiss E, Zoch W, et al. Outcome of Autologous Matrix Induced Chondrogenesis (AMIC) in cartilage knee surgery: Data of the AMIC

[35] de Windt TS, Welsch GH, Brittberg M, Vonk LA, Marlovits S, Trattnig S, Saris DB. Is magnetic resonance imaging reliable in predicting clinical outcome after articular cartilage repair of the knee? A systematic review and meta-analysis. The American Journal

[36] Blackman AJ, Smith MV, Flanigan DC, Matava MJ, Wright RW, Brophy RH. Correlation between magnetic resonance imaging and clinical outcomes after cartilage repair surgery in the knee: A systematic review and meta-analysis. The American Journal of Sports

outcome after 2 years. European Journal of Radiology. 2006 Jan;**57**(1):16-23

Registry. Archives of Orthopaedic and Trauma Surgery. 2013 Jan;**133**(1):87-93

of Sports Medicine. 2013 Jul;**41**(7):1695-1702

Medicine. 2013 Jun;**41**(6):1426-1434

microfracture at five years. International Orthopaedics. 2017 Apr;**41**(4):797-804

enchymal stem cells. European Cells & Materials. 2011 Oct 11;**22**:214-225

May;**38**(5):1105-1111

176 Cartilage Repair and Regeneration

**20**(10):2109-2115

112-118

44-50

21. [Epub ahead of print]

Additional information is available at the end of the chapter

http://dx.doi.org/10.5772/intechopen.70372

#### **Abstract**

Patients, who benefit from cartilage repair surgery, need a non-invasive and high-quality imaging modality to assess the structure and the biochemical property of the repair tissue. Magnetic resonance imaging (MRI), which provides better tissue contrast and high spatial resolution, is currently the best imaging technique available for the assessment of articular cartilage pathologies. In addition to MR morphology sequences, that allow cartilage lesions detection as well as repair tissue evaluation from the articular surface of the joint to the bone-cartilage interface, MRI mapping techniques help to assess the technical success of the procedure of cartilage repair and the state of cartilage healing, as well the identification of possible complications after cartilage repair surgery. MRI mapping techniques such as T1, T2 and T2\* mapping help to assess the biochemical property of the repair tissue using delayed gadolinium-enhanced MRI of cartilage (dGEMRIC) to assess the proteoglycan content and T2/T1rho (T1ρ) mapping to assess the collagen content and the fiber matrix arrangement. This chapter gives an overview about the MRI mapping techniques used for Cartilage Repair Tissue Follow-up.

**Keywords:** MRI, cartilage repair, T2 mapping, dGEMRIC, follow-up, T1rho, T2\* mapping

## **1. Introduction**

Many techniques are used to evaluate the knee articular cartilage however non-invasive conventional magnetic resonance imaging (MRI) is the method of choice for the evaluation of knee articular cartilage [1]. Imaging of articular cartilage needs MRI sequence which is able to characterize morphological alterations of cartilage as well as adjacent tissue and to measure with high accuracy the cartilage thickness [2]. Conventional MRI sequences allow the detection of degenerative cartilage lesions and the changes due to therapy response, e.g., after cartilage repair procedures.

© 2016 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. © 2018 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

In addition to the evaluation of cartilage morphology which is possible by MRI conventional 2D or 3D sequences, there is a need to visualize the biochemical components of the cartilage especially after cartilage repair surgery. MRI has been demonstrated to be sensitive to the variation of local water content [3], the loss of collagen content [4] and the organization of the collagen fiber [5] in the extracellular matrix. MRI parameters such as T1, T2 and T2\* can serve as marker of biochemical properties of the knee articular cartilage. The most used mapping techniques are T2 and delayed gadolinium-enhanced MRI of cartilage (dGEMRIC). *T*2 mapping was reported to provide information about collagen matrix concentration and organization, whereas dGEMRIC is sensitive to proteoglycan content [6].

techniques require a non-invasive postoperative technique to monitor the cartilage repair tissue over time to detect complications or deviation of the normal maturation process. The normal appearance of cartilage repair tissues varies according to the applied surgical technique

MRI Mapping for Cartilage Repair Follow-up http://dx.doi.org/10.5772/intechopen.70372 179

Many parameters should be assessed in MR imaging examinations after cartilage repair procedure. Magnetic resonance observation of cartilage repair (MOCART) proposes the assessment of the following MR imaging parameters: the degree of defect repair and defect filling, integration to border zone, quality of repair tissue surface, structure of repair tissue, signal intensity of repair tissue, status of subchondral lamina, integrity of subchondral bone the

This scoring system was validated in a 2-year longitudinal study of patients with matrix assisted chondrocyte implantation and correlated well with clinical scores. The evaluated parameters are the degree of defect filling, structure of repair tissue, change in subchondral bone, and signal intensity of repair tissue [15]. In another study of patients who underwent either microfracture or ACI, the following MR imaging parameters were evaluated: signal intensity relative to native cartilage; morphology with respect to native cartilage; delamination; nature of the interface with the adjacent surface; degree of defect filling; integrity of

After microfracture and osteochondral autograft transplant sites, MRI can evaluate the degree of defect filling, the extent of integration of repair tissue with adjacent tissues, the presence or absence of proud subchondral bone formation, the characteristics of the graft substance and surface, and the appearance of the underlying bone [7]. After ACI, visualization of the biochemical properties of cartilage becomes more important, since repair tissue shows a gradual

In case of articular cartilage repair, first we need to fill the defect area with a tissue that has the same mechanical properties as normal articular cartilage; second we need to promote successful integration between the repair tissue and the native articular cartilage [19]. The parameters which determine the mechanical properties of knee articular cartilage are the content, the arrangement and the interaction between the main components such as the collagen matrix, proteoglycans (PGs), and interstitial water [20]. PGs have been shown to be the primary parameter which determines the compressive properties of cartilage and collagen was

Follow-up MR imaging studies should be performed at 3–6 postoperative months to assess the volume and the integration of repair tissue and after 1 year to evaluate the maturation of the graft and identification of any complications [22]. The ability to evaluate the organization of the collagen matrix in repair tissue over time is important, as failure within the collagenous

and the timing of postoperative follow-up.

maturation over time [17, 18].

**3.2. Cartilage repair surgery follow-up timing**

reported to responsible for the tensile property [21].

fiber network is considered as failure of cartilage repair procedure [6].

**3.1. Cartilage repair surgery follow-up parameters**

presence of complications (adhesions and effusion) [13, 14].

cartilage on the opposite articular surface and bony hypertrophy [16].

## **2. Cartilage repair surgery techniques**

It is very important to know the different repair procedures and the behavior of the repair tissue in MR imaging at various postoperative intervals to evaluate the success of the surgery or to check for any complications [7]. Different methods have been used to stimulate the formation of a new articular cartilage such as microfracture, autologous chondrocyte implantation (ACI) and Osteochondral Allograft.

## **2.1. Microfracture**

This procedure, introduced by Steadman et al., consists of removing all unstable and damaged articular cartilage till the subchondral bone plate, then making multiple small holes in it. This leads to bleeding, clot formation, as well as the introduction of marrow derived stem cells to the site [8]. The microfracture technique is generally used to repair small- to mid-sized cartilage defects in osteoarthritis (OA). It was reported that cartilage tends to deteriorate within a few years [9–11].

## **2.2. Autologous chondrocyte implantation (ACI)**

This technique was first performed by Peterson et al. in Gothenburg in 1987. First, cartilage is harvested from a patient using arthroscopy. Second, it is grown in tissue culture medium. Then, it is reimplanted within the patient's cartilage defect beneath a periosteal patch to produce new cartilage repair tissue [12].

## **2.3. Osteochondral allograft**

Osteochondral allografting involves the replacement of damaged articular cartilage with mature hyaline one from a suitable donor.

## **3. Cartilage repair surgery follow-up**

The ideal cartilage repair tissue should, over time, develop a collagen network with a similar organization and concentration of normal hyaline cartilage [6]. Cartilage repair surgery techniques require a non-invasive postoperative technique to monitor the cartilage repair tissue over time to detect complications or deviation of the normal maturation process. The normal appearance of cartilage repair tissues varies according to the applied surgical technique and the timing of postoperative follow-up.

## **3.1. Cartilage repair surgery follow-up parameters**

In addition to the evaluation of cartilage morphology which is possible by MRI conventional 2D or 3D sequences, there is a need to visualize the biochemical components of the cartilage especially after cartilage repair surgery. MRI has been demonstrated to be sensitive to the variation of local water content [3], the loss of collagen content [4] and the organization of the collagen fiber [5] in the extracellular matrix. MRI parameters such as T1, T2 and T2\* can serve as marker of biochemical properties of the knee articular cartilage. The most used mapping techniques are T2 and delayed gadolinium-enhanced MRI of cartilage (dGEMRIC). *T*2 mapping was reported to provide information about collagen matrix concentration and organiza-

It is very important to know the different repair procedures and the behavior of the repair tissue in MR imaging at various postoperative intervals to evaluate the success of the surgery or to check for any complications [7]. Different methods have been used to stimulate the formation of a new articular cartilage such as microfracture, autologous chondrocyte implantation

This procedure, introduced by Steadman et al., consists of removing all unstable and damaged articular cartilage till the subchondral bone plate, then making multiple small holes in it. This leads to bleeding, clot formation, as well as the introduction of marrow derived stem cells to the site [8]. The microfracture technique is generally used to repair small- to mid-sized cartilage defects in osteoarthritis (OA). It was reported that cartilage tends to deteriorate

This technique was first performed by Peterson et al. in Gothenburg in 1987. First, cartilage is harvested from a patient using arthroscopy. Second, it is grown in tissue culture medium. Then, it is reimplanted within the patient's cartilage defect beneath a periosteal patch to pro-

Osteochondral allografting involves the replacement of damaged articular cartilage with

The ideal cartilage repair tissue should, over time, develop a collagen network with a similar organization and concentration of normal hyaline cartilage [6]. Cartilage repair surgery

tion, whereas dGEMRIC is sensitive to proteoglycan content [6].

**2. Cartilage repair surgery techniques**

**2.2. Autologous chondrocyte implantation (ACI)**

duce new cartilage repair tissue [12].

mature hyaline one from a suitable donor.

**3. Cartilage repair surgery follow-up**

**2.3. Osteochondral allograft**

(ACI) and Osteochondral Allograft.

**2.1. Microfracture**

178 Cartilage Repair and Regeneration

within a few years [9–11].

Many parameters should be assessed in MR imaging examinations after cartilage repair procedure. Magnetic resonance observation of cartilage repair (MOCART) proposes the assessment of the following MR imaging parameters: the degree of defect repair and defect filling, integration to border zone, quality of repair tissue surface, structure of repair tissue, signal intensity of repair tissue, status of subchondral lamina, integrity of subchondral bone the presence of complications (adhesions and effusion) [13, 14].

This scoring system was validated in a 2-year longitudinal study of patients with matrix assisted chondrocyte implantation and correlated well with clinical scores. The evaluated parameters are the degree of defect filling, structure of repair tissue, change in subchondral bone, and signal intensity of repair tissue [15]. In another study of patients who underwent either microfracture or ACI, the following MR imaging parameters were evaluated: signal intensity relative to native cartilage; morphology with respect to native cartilage; delamination; nature of the interface with the adjacent surface; degree of defect filling; integrity of cartilage on the opposite articular surface and bony hypertrophy [16].

After microfracture and osteochondral autograft transplant sites, MRI can evaluate the degree of defect filling, the extent of integration of repair tissue with adjacent tissues, the presence or absence of proud subchondral bone formation, the characteristics of the graft substance and surface, and the appearance of the underlying bone [7]. After ACI, visualization of the biochemical properties of cartilage becomes more important, since repair tissue shows a gradual maturation over time [17, 18].

## **3.2. Cartilage repair surgery follow-up timing**

In case of articular cartilage repair, first we need to fill the defect area with a tissue that has the same mechanical properties as normal articular cartilage; second we need to promote successful integration between the repair tissue and the native articular cartilage [19]. The parameters which determine the mechanical properties of knee articular cartilage are the content, the arrangement and the interaction between the main components such as the collagen matrix, proteoglycans (PGs), and interstitial water [20]. PGs have been shown to be the primary parameter which determines the compressive properties of cartilage and collagen was reported to responsible for the tensile property [21].

Follow-up MR imaging studies should be performed at 3–6 postoperative months to assess the volume and the integration of repair tissue and after 1 year to evaluate the maturation of the graft and identification of any complications [22]. The ability to evaluate the organization of the collagen matrix in repair tissue over time is important, as failure within the collagenous fiber network is considered as failure of cartilage repair procedure [6].

## **4. Magnetic resonance imaging (MRI)**

The MRI principle can be explained by the fact that atomic nuclei of fluids in a magnetic field can be flipped off their preferred orientation parallel to a magnetic field when exposed to an electromagnetic radio frequency field (RF field). When the RF field is switched off, the atomic nuclei return to their original state and release the absorbed energy as electromagnetic radiation. During excitation, we send radio frequency energy to the hydrogen protons inside the body. Those protons will absorb this energy as a heat. When we stop excitation, the relaxation process starts and the energy introduced during excitation is transferred to the surrounding protons.

**5.1. T1 mapping calculation**

**5.2. T1 mapping clinical applications**

To calculate T1 mapping we can use either spin echo or gradient echo sequence. With the 2D spin echo sequence, there are two methods to calculate T1 maps either based on the phase inversion or saturation of the longitudinal magnetization. In each case, at least two data sets with different parameters are needed. In case of spin echo, we need to acquire the same sequences twice with the same parameters but different repetition time (TR) and in case of inversion recovery sequence, we use the same sequence but with different inversion time (TI). The acquisition time required for the T1 mapping using spin echo technique is relatively long and often limited to a small number of slices. 3D gradient echo sequences are better alternative solution which provide high signal to noise ratio (SNR) and thin slices in relatively less acquisition time. 3D spoiled fast gradient echo (3D FLASH) sequence with two different exci-

MRI Mapping for Cartilage Repair Follow-up http://dx.doi.org/10.5772/intechopen.70372 181

The measurements of T1ρ can be used to visualize interactions between the water molecules in restricted movement and local macromolecular environment. The extracellular matrix of the articular cartilage provides a limited movement environment of water molecules. The modifications of the extracellular matrix, such as loss PG, may be reflected by the change of the T1ρ values. In one study, the normalized T1ρ rate was strongly correlated with alterations in fixed charge density (FCD) due to depletion of PG which was confirmed by histology [23].

A dGEMRIC involves intravenous administration of negatively charged contrast agent (Gd-DTPA2−). After injection of Gd-DTPA2, the contrast agent penetrates the cartilage through both the articular surface and the subchondral bone [24]. Since the contrast agent has negative charge, it will interact with FCD which is directly related to the GAG concentration. The distribution of Gd-DTPA2− is inversely proportional to glycosaminoglycan (GAG) content of the tissue of interest. T1 relaxation times are inversely proportional to the concentration of Gd-DTPA2−. The Gd-DTPA2− will shorten the T1 of tissues in this case the cartilage, therefore T1 can be used as a specific marker of GAG concentration. Healthy cartilage, which contains an abundance of GAG, will show a low Gd-DTPA2− concentration, whereas GAG-depleted degraded cartilage will show a high Gd-DTPA2− concentration which will result in lower T1

It was recommended to inject a bolus of Gd-DTPA2− with a quantity of 0.2 mmol contrast agent per kilogram body weight (double dose). After injection, we ask the patient to do some exercises of the knee, for example, walking up and down stairs for about 20 minutes. Ninety minutes after IV injection, we acquire the postcontrast MRI study. This delay time of 90 minutes

tation flip angles of was used to assess the T1 relaxation times [23, 24].

**6. Delayed gadolinium-enhanced MRI of cartilage (dGEMRIC)**

values compared with healthy cartilage [25] (**Figure 1**).

**6.1. Exam preparation**

There are two types of relaxation. First, the T1 (longitudinal Relaxation) whereby there is energy transfer from the spins to the environment and the T2 (transverse Relaxation) where there is dephasing of spins. The contrast in MRI depends on many parameters mainly patient parameters, sequence type and sequences parameters. The patient related parameters are T1, T2 and proton density. By varying parameters such as repetition time (TR) and echo time (TE), we can obtain weighted sequence like T1, T2 and proton density weighted sequences.

#### **4.1. T1 relaxation**

The T1 relaxation curve which describes the relaxation speeds for any given tissue follows an exponential law. The constant T1 is defined as the time required for the longitudinal component of M0 to return to 63% of its initial value. The difference in relaxation times gives the T1 contrast. The T1 value depends on the mass and the size of the molecules constituting the tissue. It depends strongly on B0 and is a function of the micro-viscosity of the medium. For liquid, the values of T1 are greater than the second and for the most structured tissues, the T1 values are of the order of a few 100 ms.

#### **4.2. T2 relaxation**

During the T2 relaxation process, each tissue loses transverse coherence (magnetization) via an exponential decay process. T2 is defined as the time after which the transverse magnetization is decayed to 37% of its starting amplitude. T2 is a tissue specific parameter and is weakly dependent on the magnetic field B0 because it happens on a perpendicular plane to B0. In solids, which possess a rigid atomic network, T2 is extremely short, whereas in liquids where the decay of the transverse magnetization takes place slowly, T2 is longer and that is why pure water will appear as hyper signal on a T2-weighted sequence.

## **5. T1 mapping**

The contrasts in MRI morphology sequences depend on the difference of signal intensities between tissues at the time of echo measurement. To display the T1, T2 and T2\* values of each tissue, we need to calculate parametric maps. In those maps, the pixel intensities in the image provide quantitative values of the studied relaxation time.

#### **5.1. T1 mapping calculation**

**4. Magnetic resonance imaging (MRI)**

**4.1. T1 relaxation**

180 Cartilage Repair and Regeneration

**4.2. T2 relaxation**

**5. T1 mapping**

values are of the order of a few 100 ms.

The MRI principle can be explained by the fact that atomic nuclei of fluids in a magnetic field can be flipped off their preferred orientation parallel to a magnetic field when exposed to an electromagnetic radio frequency field (RF field). When the RF field is switched off, the atomic nuclei return to their original state and release the absorbed energy as electromagnetic radiation. During excitation, we send radio frequency energy to the hydrogen protons inside the body. Those protons will absorb this energy as a heat. When we stop excitation, the relaxation process starts and the energy introduced during excitation is transferred to the surrounding protons.

There are two types of relaxation. First, the T1 (longitudinal Relaxation) whereby there is energy transfer from the spins to the environment and the T2 (transverse Relaxation) where there is dephasing of spins. The contrast in MRI depends on many parameters mainly patient parameters, sequence type and sequences parameters. The patient related parameters are T1, T2 and proton density. By varying parameters such as repetition time (TR) and echo time (TE), we can obtain weighted sequence like T1, T2 and proton density weighted sequences.

The T1 relaxation curve which describes the relaxation speeds for any given tissue follows an exponential law. The constant T1 is defined as the time required for the longitudinal component of M0 to return to 63% of its initial value. The difference in relaxation times gives the T1 contrast. The T1 value depends on the mass and the size of the molecules constituting the tissue. It depends strongly on B0 and is a function of the micro-viscosity of the medium. For liquid, the values of T1 are greater than the second and for the most structured tissues, the T1

During the T2 relaxation process, each tissue loses transverse coherence (magnetization) via an exponential decay process. T2 is defined as the time after which the transverse magnetization is decayed to 37% of its starting amplitude. T2 is a tissue specific parameter and is weakly dependent on the magnetic field B0 because it happens on a perpendicular plane to B0. In solids, which possess a rigid atomic network, T2 is extremely short, whereas in liquids where the decay of the transverse magnetization takes place slowly, T2 is longer and that is why

The contrasts in MRI morphology sequences depend on the difference of signal intensities between tissues at the time of echo measurement. To display the T1, T2 and T2\* values of each tissue, we need to calculate parametric maps. In those maps, the pixel intensities in the image

pure water will appear as hyper signal on a T2-weighted sequence.

provide quantitative values of the studied relaxation time.

To calculate T1 mapping we can use either spin echo or gradient echo sequence. With the 2D spin echo sequence, there are two methods to calculate T1 maps either based on the phase inversion or saturation of the longitudinal magnetization. In each case, at least two data sets with different parameters are needed. In case of spin echo, we need to acquire the same sequences twice with the same parameters but different repetition time (TR) and in case of inversion recovery sequence, we use the same sequence but with different inversion time (TI). The acquisition time required for the T1 mapping using spin echo technique is relatively long and often limited to a small number of slices. 3D gradient echo sequences are better alternative solution which provide high signal to noise ratio (SNR) and thin slices in relatively less acquisition time. 3D spoiled fast gradient echo (3D FLASH) sequence with two different excitation flip angles of was used to assess the T1 relaxation times [23, 24].

## **5.2. T1 mapping clinical applications**

The measurements of T1ρ can be used to visualize interactions between the water molecules in restricted movement and local macromolecular environment. The extracellular matrix of the articular cartilage provides a limited movement environment of water molecules. The modifications of the extracellular matrix, such as loss PG, may be reflected by the change of the T1ρ values. In one study, the normalized T1ρ rate was strongly correlated with alterations in fixed charge density (FCD) due to depletion of PG which was confirmed by histology [23].

## **6. Delayed gadolinium-enhanced MRI of cartilage (dGEMRIC)**

A dGEMRIC involves intravenous administration of negatively charged contrast agent (Gd-DTPA2−). After injection of Gd-DTPA2, the contrast agent penetrates the cartilage through both the articular surface and the subchondral bone [24]. Since the contrast agent has negative charge, it will interact with FCD which is directly related to the GAG concentration. The distribution of Gd-DTPA2− is inversely proportional to glycosaminoglycan (GAG) content of the tissue of interest. T1 relaxation times are inversely proportional to the concentration of Gd-DTPA2−. The Gd-DTPA2− will shorten the T1 of tissues in this case the cartilage, therefore T1 can be used as a specific marker of GAG concentration. Healthy cartilage, which contains an abundance of GAG, will show a low Gd-DTPA2− concentration, whereas GAG-depleted degraded cartilage will show a high Gd-DTPA2− concentration which will result in lower T1 values compared with healthy cartilage [25] (**Figure 1**).

#### **6.1. Exam preparation**

It was recommended to inject a bolus of Gd-DTPA2− with a quantity of 0.2 mmol contrast agent per kilogram body weight (double dose). After injection, we ask the patient to do some exercises of the knee, for example, walking up and down stairs for about 20 minutes. Ninety minutes after IV injection, we acquire the postcontrast MRI study. This delay time of 90 minutes allows the contrast agent to fully diffuse into the cartilage. However, since cartilage thickness is variable within the knee and between patients, the delay time to reach equilibrium has to be adjusted [26]. Moreover, after different cartilage repair surgeries, the timing to reach the equilibrium, and the exercise period are difficult to be defined and standardized [21].

**6.2. Exam protocol**

surements when possible [21].

make statistics low significant [27].

stimulation repair techniques [21].

Another study also confirmed this correlation *in vivo* [30].

**6.4. Acquisition sequence**

**6.3. Spatial resolution**

To calculate proteoglycan content and fixed charge density (FCD) using dGEMRIC, it is required to acquire both precontrast and postcontrast T1 mapping for articular cartilage in addition to a known Gd-DTPA concentration [24]. It has been suggested that native articular cartilage has a relatively constant unenhanced T1 value. So, no need to acquire precontrast images to estimate FCD [26]. However, some authors have shown differences between the precontrast T1 values of ACI repair tissue and articular cartilage [27]. So, it is recommended for the study of cartilage repair tissues to acquire both precontrast and postcontrast T1 mea-

MRI Mapping for Cartilage Repair Follow-up http://dx.doi.org/10.5772/intechopen.70372 183

When evaluating cartilage repair tissue using dGEMRIC, we have to know that before contrast injection, repair tissue may show different T1 values compared to normal cartilage. In this case, the postcontrast T1 mapping may not correlate directly with GAG content. So, the solution will be to correlate the difference between precontrast and postcontrast imaging, so called "delta relaxation rate," ΔR1 = 1/T1 precontrast − 1/T1(Gd), which correlates well. Watanabe et al. demonstrated that on study done on 7 patients that the relative ΔR1 or "ΔR1 index" (Δ relaxation rate of repair tissue divided by the Δ relaxation rate of normal hyaline cartilage) correlates with the GAG concentration in ACI repair tissue, using such reference the gas chromatography which is accepted to be the gold standard for the measurement of GAG content in biopsy samples. The limitation of this study was the low number of patients which

Native articular cartilage and postoperative cartilage repair tissue are relatively thin structures which require very high-resolution images for an accurate assessment. In plane spatial resolution is characterized by the pixel size in both frequency and phase encoding direction. The pixel size is defined as the ratio of the field of view (FOV) over the matrix in both frequency and phase encoding direction whereas the through Plane resolution is characterized by the slice thickness. For accurate assessment of the articular cartilage, it was recommended to use slice thickness less or equal to 2 mm and a pixel size less than 0.3 mm [28] or better less than 0.2 mm [21]. Those recommendations need enough signal to noise ratio (SNR) which can be obtained at higher magnetic field (1.5 T and higher) [21]. This high resolution is recommended to assess fissures which can be developed at the area of peripheral integration as well as the development of proud subchondral bone formation which can be seen after marrow

In a previous study done on phantom, Trattnig et al. used a 3-D variable flip angle dGEMRIC technique to obtain information related to the long-term development and maturation of grafts in patients after matrix-induced ACI (MACI) surgery. There was a good correlation between variable flip angle technique and standard inversion recovery technique for T1 mapping [29].

**Figure 1.** MRI evaluation of cartilage regeneration 3 years after transplantation. (A) Preoperative MRI showing cartilage defect at the medial femoral condyle; (B) at 3 years posttransplantation, they observed cartilage regeneration at the defect site; (C) two ROI's were drawn to calculate the change in relaxation rate (ΔR1) in regenerated cartilage and in native cartilage; (D) map by delayed gadolinium-enhanced MRI (dGMRI) of the cartilage shows high glycosaminoglycan (GAG) in the regenerated cartilage. Higher T1 values (arrow 1) reflected an increase of relative GAG content, whereas lower T1 values (arrow 2) are associated with decreased GAG content [25].

## **6.2. Exam protocol**

allows the contrast agent to fully diffuse into the cartilage. However, since cartilage thickness is variable within the knee and between patients, the delay time to reach equilibrium has to be adjusted [26]. Moreover, after different cartilage repair surgeries, the timing to reach the

**Figure 1.** MRI evaluation of cartilage regeneration 3 years after transplantation. (A) Preoperative MRI showing cartilage defect at the medial femoral condyle; (B) at 3 years posttransplantation, they observed cartilage regeneration at the defect site; (C) two ROI's were drawn to calculate the change in relaxation rate (ΔR1) in regenerated cartilage and in native cartilage; (D) map by delayed gadolinium-enhanced MRI (dGMRI) of the cartilage shows high glycosaminoglycan (GAG) in the regenerated cartilage. Higher T1 values (arrow 1) reflected an increase of relative GAG content, whereas

lower T1 values (arrow 2) are associated with decreased GAG content [25].

equilibrium, and the exercise period are difficult to be defined and standardized [21].

182 Cartilage Repair and Regeneration

To calculate proteoglycan content and fixed charge density (FCD) using dGEMRIC, it is required to acquire both precontrast and postcontrast T1 mapping for articular cartilage in addition to a known Gd-DTPA concentration [24]. It has been suggested that native articular cartilage has a relatively constant unenhanced T1 value. So, no need to acquire precontrast images to estimate FCD [26]. However, some authors have shown differences between the precontrast T1 values of ACI repair tissue and articular cartilage [27]. So, it is recommended for the study of cartilage repair tissues to acquire both precontrast and postcontrast T1 measurements when possible [21].

When evaluating cartilage repair tissue using dGEMRIC, we have to know that before contrast injection, repair tissue may show different T1 values compared to normal cartilage. In this case, the postcontrast T1 mapping may not correlate directly with GAG content. So, the solution will be to correlate the difference between precontrast and postcontrast imaging, so called "delta relaxation rate," ΔR1 = 1/T1 precontrast − 1/T1(Gd), which correlates well. Watanabe et al. demonstrated that on study done on 7 patients that the relative ΔR1 or "ΔR1 index" (Δ relaxation rate of repair tissue divided by the Δ relaxation rate of normal hyaline cartilage) correlates with the GAG concentration in ACI repair tissue, using such reference the gas chromatography which is accepted to be the gold standard for the measurement of GAG content in biopsy samples. The limitation of this study was the low number of patients which make statistics low significant [27].

#### **6.3. Spatial resolution**

Native articular cartilage and postoperative cartilage repair tissue are relatively thin structures which require very high-resolution images for an accurate assessment. In plane spatial resolution is characterized by the pixel size in both frequency and phase encoding direction. The pixel size is defined as the ratio of the field of view (FOV) over the matrix in both frequency and phase encoding direction whereas the through Plane resolution is characterized by the slice thickness. For accurate assessment of the articular cartilage, it was recommended to use slice thickness less or equal to 2 mm and a pixel size less than 0.3 mm [28] or better less than 0.2 mm [21]. Those recommendations need enough signal to noise ratio (SNR) which can be obtained at higher magnetic field (1.5 T and higher) [21]. This high resolution is recommended to assess fissures which can be developed at the area of peripheral integration as well as the development of proud subchondral bone formation which can be seen after marrow stimulation repair techniques [21].

#### **6.4. Acquisition sequence**

In a previous study done on phantom, Trattnig et al. used a 3-D variable flip angle dGEMRIC technique to obtain information related to the long-term development and maturation of grafts in patients after matrix-induced ACI (MACI) surgery. There was a good correlation between variable flip angle technique and standard inversion recovery technique for T1 mapping [29]. Another study also confirmed this correlation *in vivo* [30].

## **6.5. Clinical dGEMRIC studies on patients with cartilage repair**

dGEMRIC has been used to evaluate GAG content in repair tissue after different surgical cartilage repair techniques such as microfracture, ACI, and MACI. Two previous studies reported that MRI non-invasive dGEMRIC technique could be used to monitor the content of GAG after ACI procedure. They suggested that the GAG concentration in repair cartilage after 10 months (or longer) of ACI is comparable with the GAG concentration in the adjacent normal hyaline cartilage [31, 32].

relative ΔR1 was 3.39 for microfracture and 2.18 for MACI and the difference between the cartilage repair groups was statistically significant [35]. The histology and biochemistry analyze showed that the repair tissue formed by microfracture contained less PGs and an abnormal distribution of collagen compared with normal cartilage which may explain the poor mechanical properties often exhibited by repair tissue. The T1 mapping showed a significantly higher relative ΔR1 of the repair tissue after microfracture when compared after MACI, suggesting a

MRI Mapping for Cartilage Repair Follow-up http://dx.doi.org/10.5772/intechopen.70372 185

In one study, Fibrocartilage formed after microfracture, evaluated using dGEMRIC, demonstrated a greater difference between precontrast and postcontrast T1 relaxation time compared with repair tissue formed after MACI. As dGEMRIC reflects the glycosaminoglycan content, they deduced from the results that glycosaminoglycan content in fibrocartilage were

Another study conducted on nine patients (average age, 21.2 years) reported that relative ΔR1 index was 1.32 after 1 year post-ACI for focal chondral defects. In nine patients (average age, 43.2 years) postosteochondral allograft transplantation, relative ΔR1 index were 1.13 at the

During the relaxation process of MRI experiment and due to the variations of the local magnetic field, the individual magnetic moments gradually lose their phase coherence, which leads to a decrease of the net magnetization vector. This decrease of the signal is called spinspin relaxation and noted T2 relaxation. The calculation of T2 mapping is obtained usually with a spin echo sequence using different echo times (**Figure 2**). From the signals measured with different TE's, we draw the T2 decay curve where T2 correspond to the time spent by the transverse relaxation magnetization to reach 37% from its initial value. T2 maps are usually obtained by using a pixelwise, monoexponential, non-negative least-squares fit analysis

The T2 relaxation time is affected by the speed the spins lose phase coherence during relaxation. The presence of free water molecules in knee cartilage will slow the decay of the transverse magnetization which will make from the T2 mapping a common tool to measure the

T2 value is also affected mostly by collagen network structure of cartilage [19]. It depends on both water [16, 17] and collagen content [18]. The concentration of collagen and proteoglycans is responsible for the water movements in the extracellular matrix and the appearance of the cartilage in T2-weighted images. Quantitative T2 MR mapping of articular cartilage is a noninvasive imaging technique that has the potential to characterize hyaline articular cartilage and repair tissue. The T2 relaxation time has been significantly correlated with collagen orientation in cartilage repair models using either polarized light microscopy or Fourier transform infrared imaging spectroscopy [40–42] where as it showed a poor correlation with collagen

lower GAG content after microfracture [36, 37].

first year and 1.55 at the second year [38].

**7. T2 mapping**

(**Figure 3**).

water content in the cartilage [39].

content in several repair models [42, 43].

lower compared to other types of cartilage repair tissue [35].

Besides, another study based on MR examinations of 45 patients after cartilage repair surgery using precontrast and dGEMRIC postcontrast, T1 mapping technique revealed a high correlation between T1Gd and ΔR1 in all examinations with R values above −0.8 [33]. From the results, they could assume that both T1Gd and ΔR1 might be useful for evaluation of cartilage repair tissue. Since the T1(Gd) needs only one MRI scan instead of 2 in case of ΔR1, they preferred using T1(Gd) method in order to save time and costs. However, in case they need to compare GAG content of native cartilage and repair tissue within the same patient, the noncontrast T1 values of the native cartilage and repair tissue need to be similar otherwise the comparison may not be valid [21].

In a previous study, a dGEMRIC MRI of cartilage was used to evaluate the quality of the regenerated cartilage at 3 years posttransplantation. The precontrast T1 relaxation time was calculated to evaluate the change in GAG content in the repair-cartilage tissue. The T1 relaxation time was measured in the repair tissue area and the healthy native cartilage. Then, they calculated the relaxation rate R1 as 1/T1 (in 1/second). After, they calculated ΔR1 which represents the change in R1 as the difference of R1 between the precontrast and postcontrast. The ΔR1 represents the concentration of Gd-DTPA2−. They defined relative index of ΔR1 as the ratio of ΔR1 in regenerated cartilage divided by ΔR1 in native cartilage. In case of perfect regeneration, this ratio will be equal to 1. The MRI evaluation of five participants after 3 years revealed that the mean relative ΔR1 index was 1.44 which indicated high GAG content of the regenerated cartilage [25, 27].

Trattnig et al. reported that biopsy studies have shown that most of the changes in cartilage implants occur in the early postoperative period. So, in order to assess the maturation of cartilage implants over time, they subdivided patients in 2 groups early postoperative (3–13 months) and late postoperative (19–42 months) groups [29]. In the early postoperative group, the mean ΔR1 (in s−1) for repair tissue was 2.49 (±1.15) versus 1.04 (±0.56) at the intact control site and 1.90 (±0.97) versus with 0.81 (±0.47) in the late postoperative group. The difference in ΔR1 between repair tissue and normal hyaline cartilage in both groups was statistically significant (*P* < 0.007), whereas the difference in ΔR1 of repair tissue and normal hyaline cartilage between the groups was not statistically significant (*P* = 0.205). The mean relative ΔR1 was 2.40 in the early group compared to 2.35 in the late group. They explained this fact by the results of biopsies histological investigations which have shown that MACI may develop hyaline-like, mixed hyaline-fibrous, or fibrous tissue over time [17, 34].

A previous study was conducted on 10 patients treated with microfracture and 10 with MACI. The mean ΔR1 was 1.07 ± 0.34 for microfracture and 0.32 ± 0.20 at the control site, whereas it was 1.90 ± 0.49 for MACI compared to 0.87 ± 0.44 at the control site. Calculated relative ΔR1 was 3.39 for microfracture and 2.18 for MACI and the difference between the cartilage repair groups was statistically significant [35]. The histology and biochemistry analyze showed that the repair tissue formed by microfracture contained less PGs and an abnormal distribution of collagen compared with normal cartilage which may explain the poor mechanical properties often exhibited by repair tissue. The T1 mapping showed a significantly higher relative ΔR1 of the repair tissue after microfracture when compared after MACI, suggesting a lower GAG content after microfracture [36, 37].

In one study, Fibrocartilage formed after microfracture, evaluated using dGEMRIC, demonstrated a greater difference between precontrast and postcontrast T1 relaxation time compared with repair tissue formed after MACI. As dGEMRIC reflects the glycosaminoglycan content, they deduced from the results that glycosaminoglycan content in fibrocartilage were lower compared to other types of cartilage repair tissue [35].

Another study conducted on nine patients (average age, 21.2 years) reported that relative ΔR1 index was 1.32 after 1 year post-ACI for focal chondral defects. In nine patients (average age, 43.2 years) postosteochondral allograft transplantation, relative ΔR1 index were 1.13 at the first year and 1.55 at the second year [38].

## **7. T2 mapping**

**6.5. Clinical dGEMRIC studies on patients with cartilage repair**

normal hyaline cartilage [31, 32].

184 Cartilage Repair and Regeneration

comparison may not be valid [21].

regenerated cartilage [25, 27].

dGEMRIC has been used to evaluate GAG content in repair tissue after different surgical cartilage repair techniques such as microfracture, ACI, and MACI. Two previous studies reported that MRI non-invasive dGEMRIC technique could be used to monitor the content of GAG after ACI procedure. They suggested that the GAG concentration in repair cartilage after 10 months (or longer) of ACI is comparable with the GAG concentration in the adjacent

Besides, another study based on MR examinations of 45 patients after cartilage repair surgery using precontrast and dGEMRIC postcontrast, T1 mapping technique revealed a high correlation between T1Gd and ΔR1 in all examinations with R values above −0.8 [33]. From the results, they could assume that both T1Gd and ΔR1 might be useful for evaluation of cartilage repair tissue. Since the T1(Gd) needs only one MRI scan instead of 2 in case of ΔR1, they preferred using T1(Gd) method in order to save time and costs. However, in case they need to compare GAG content of native cartilage and repair tissue within the same patient, the noncontrast T1 values of the native cartilage and repair tissue need to be similar otherwise the

In a previous study, a dGEMRIC MRI of cartilage was used to evaluate the quality of the regenerated cartilage at 3 years posttransplantation. The precontrast T1 relaxation time was calculated to evaluate the change in GAG content in the repair-cartilage tissue. The T1 relaxation time was measured in the repair tissue area and the healthy native cartilage. Then, they calculated the relaxation rate R1 as 1/T1 (in 1/second). After, they calculated ΔR1 which represents the change in R1 as the difference of R1 between the precontrast and postcontrast. The ΔR1 represents the concentration of Gd-DTPA2−. They defined relative index of ΔR1 as the ratio of ΔR1 in regenerated cartilage divided by ΔR1 in native cartilage. In case of perfect regeneration, this ratio will be equal to 1. The MRI evaluation of five participants after 3 years revealed that the mean relative ΔR1 index was 1.44 which indicated high GAG content of the

Trattnig et al. reported that biopsy studies have shown that most of the changes in cartilage implants occur in the early postoperative period. So, in order to assess the maturation of cartilage implants over time, they subdivided patients in 2 groups early postoperative (3–13 months) and late postoperative (19–42 months) groups [29]. In the early postoperative group, the mean ΔR1 (in s−1) for repair tissue was 2.49 (±1.15) versus 1.04 (±0.56) at the intact control site and 1.90 (±0.97) versus with 0.81 (±0.47) in the late postoperative group. The difference in ΔR1 between repair tissue and normal hyaline cartilage in both groups was statistically significant (*P* < 0.007), whereas the difference in ΔR1 of repair tissue and normal hyaline cartilage between the groups was not statistically significant (*P* = 0.205). The mean relative ΔR1 was 2.40 in the early group compared to 2.35 in the late group. They explained this fact by the results of biopsies histological investigations which have shown that MACI may develop

A previous study was conducted on 10 patients treated with microfracture and 10 with MACI. The mean ΔR1 was 1.07 ± 0.34 for microfracture and 0.32 ± 0.20 at the control site, whereas it was 1.90 ± 0.49 for MACI compared to 0.87 ± 0.44 at the control site. Calculated

hyaline-like, mixed hyaline-fibrous, or fibrous tissue over time [17, 34].

During the relaxation process of MRI experiment and due to the variations of the local magnetic field, the individual magnetic moments gradually lose their phase coherence, which leads to a decrease of the net magnetization vector. This decrease of the signal is called spinspin relaxation and noted T2 relaxation. The calculation of T2 mapping is obtained usually with a spin echo sequence using different echo times (**Figure 2**). From the signals measured with different TE's, we draw the T2 decay curve where T2 correspond to the time spent by the transverse relaxation magnetization to reach 37% from its initial value. T2 maps are usually obtained by using a pixelwise, monoexponential, non-negative least-squares fit analysis (**Figure 3**).

The T2 relaxation time is affected by the speed the spins lose phase coherence during relaxation. The presence of free water molecules in knee cartilage will slow the decay of the transverse magnetization which will make from the T2 mapping a common tool to measure the water content in the cartilage [39].

T2 value is also affected mostly by collagen network structure of cartilage [19]. It depends on both water [16, 17] and collagen content [18]. The concentration of collagen and proteoglycans is responsible for the water movements in the extracellular matrix and the appearance of the cartilage in T2-weighted images. Quantitative T2 MR mapping of articular cartilage is a noninvasive imaging technique that has the potential to characterize hyaline articular cartilage and repair tissue. The T2 relaxation time has been significantly correlated with collagen orientation in cartilage repair models using either polarized light microscopy or Fourier transform infrared imaging spectroscopy [40–42] where as it showed a poor correlation with collagen content in several repair models [42, 43].

**7.2. T2 mapping sequences**

patient's movement.

*7.2.1. Spin echo single echo sequence (SESE)*

*7.2.2. Multiecho spin echo sequence (MESE)*

*7.2.3. Dual echo steady state sequence (DESS)*

first echo from the calculation.

the 2D sequence.

*7.2.4. Turbo gradient spin echo*

The common point between the sequences used for T2 mapping calculation is the acquisition of multiechoes to describe the T2 decay curve and to allow the calculation of T2 value. Among those sequences we found spin echo single echo sequence (SESE), multiecho spin echo sequence

MRI Mapping for Cartilage Repair Follow-up http://dx.doi.org/10.5772/intechopen.70372 187

The SESE Sequence uses two RF pulses, 90 and 180° pulses. The 90° pulse will tilt the longitudinal magnetization vector M0 to the measurement plane which is the transverse plane. The spins start dephasing. Then we apply the 180° pulse to rephase spins. At a certain time called echo time (TE) when the spins are totally rephased we measure the signal. Then we repeat the pulse sequence many times as much as the phase encoding matrix. The Time which separates two consecutive 90° pulses is called repetition time (TR). In this sequence, we measure a single echo in each repetition time (TR). To calculate the T2 relaxation time, we need to repeat the sequence many times in order to collect different TE's. The main advantage of this type of sequence is that it is not contaminated by the stimulated echo. Also, this sequence, by the use of 180° refocusing pulses is less sensitive to artifacts in case of postoperative imaging [21]. The disadvantages are that the exam duration will be longer adding to that the risk of

The MESE sequence uses the same preparation radio frequency (RF) pulses as the SESE. The difference is that in SESE sequence we measure only one echo in a TR where as in the MESE sequence, we can measure many echoes. The biggest advantage is that we measure all the TE's on one scan which will save time with less movement artifact. In addition, this sequence gives the possibility to measure the T2 using the inline calculation method. The only disadvantage is the presence of the stimulated echo which can be reduced by the elimination of the

T2 can be calculated using dual echo steady state sequence (DESS) which demonstrated to provide results as comparable with the standard multiecho spin echo T2 [2]. In both 2D fat suppressed turbo spin echo proton density and 3D DESS sequence, hyaline cartilage has intermediate signal and synovial fluid has high signal. 3D DESS has the advantage to use thinner slices which make this sequence to me sensitive to detect smaller cartilage defects better than

This sequence combines a gradient echo and a spin echo imaging. It generates additional gradient echo before and after each spin echo. The spin echo gives the T2 contrast and the gradient

(MESE), dual echo steady state sequence (DESS) and turbo gradient spin echo (TGSE).

**Figure 2.** Images acquired using multi echo spin echo (MESE) sequence with different TE's in the range of 12.5–75 ms.

**Figure 3.** T2 mapping image calculated using a MESE sequence. Arrow 2 indicates higher T2 whereas arrow 1 indicates lower T2 values.

## **7.1. Spatial variation of T2 values**

The T2 relaxation time is affected by the organization of the extracellular matrix of native articular cartilage [6]. In native hyaline cartilage, the T2 relaxation times is varying over depth when going from deepest layers to superficial layers with shorter T2 values in the deeper, radial zone, where the collagen is highly ordered and the collagen fiber matrix has a preferred orientation perpendicular to the cartilage surface, and longer values in the transitional zone because of less organization of the collagen where the collagen fiber matrix has an oblique orientation. The superficial zone may not be visualized on morphological imaging and quantitative T2 mapping because it is too thin [44].

When doing quantitative MR T2 mapping in the knee articular cartilage to compare different cartilage repair surgeries, we can either evaluate mean global T2 value throughout the thickness of the repair or a zonal assessment in the deep versus the superficial half of the repair tissue. Cartilage repair tissue with a lack of zonal organization of collagen would not be expected to demonstrate a similar of T2 values from the deep to superficial aspects of the tissue compared to normal cartilage. Alteration in this orderly transition in T2 values within cartilage has been shown to correlate to changes in water content and changes in collagen structure and organization associated with hyaline articular cartilage degradation [45].

## **7.2. T2 mapping sequences**

The common point between the sequences used for T2 mapping calculation is the acquisition of multiechoes to describe the T2 decay curve and to allow the calculation of T2 value. Among those sequences we found spin echo single echo sequence (SESE), multiecho spin echo sequence (MESE), dual echo steady state sequence (DESS) and turbo gradient spin echo (TGSE).

## *7.2.1. Spin echo single echo sequence (SESE)*

The SESE Sequence uses two RF pulses, 90 and 180° pulses. The 90° pulse will tilt the longitudinal magnetization vector M0 to the measurement plane which is the transverse plane. The spins start dephasing. Then we apply the 180° pulse to rephase spins. At a certain time called echo time (TE) when the spins are totally rephased we measure the signal. Then we repeat the pulse sequence many times as much as the phase encoding matrix. The Time which separates two consecutive 90° pulses is called repetition time (TR). In this sequence, we measure a single echo in each repetition time (TR). To calculate the T2 relaxation time, we need to repeat the sequence many times in order to collect different TE's. The main advantage of this type of sequence is that it is not contaminated by the stimulated echo. Also, this sequence, by the use of 180° refocusing pulses is less sensitive to artifacts in case of postoperative imaging [21]. The disadvantages are that the exam duration will be longer adding to that the risk of patient's movement.

## *7.2.2. Multiecho spin echo sequence (MESE)*

**7.1. Spatial variation of T2 values**

lower T2 values.

186 Cartilage Repair and Regeneration

degradation [45].

titative T2 mapping because it is too thin [44].

The T2 relaxation time is affected by the organization of the extracellular matrix of native articular cartilage [6]. In native hyaline cartilage, the T2 relaxation times is varying over depth when going from deepest layers to superficial layers with shorter T2 values in the deeper, radial zone, where the collagen is highly ordered and the collagen fiber matrix has a preferred orientation perpendicular to the cartilage surface, and longer values in the transitional zone because of less organization of the collagen where the collagen fiber matrix has an oblique orientation. The superficial zone may not be visualized on morphological imaging and quan-

**Figure 3.** T2 mapping image calculated using a MESE sequence. Arrow 2 indicates higher T2 whereas arrow 1 indicates

**Figure 2.** Images acquired using multi echo spin echo (MESE) sequence with different TE's in the range of 12.5–75 ms.

When doing quantitative MR T2 mapping in the knee articular cartilage to compare different cartilage repair surgeries, we can either evaluate mean global T2 value throughout the thickness of the repair or a zonal assessment in the deep versus the superficial half of the repair tissue. Cartilage repair tissue with a lack of zonal organization of collagen would not be expected to demonstrate a similar of T2 values from the deep to superficial aspects of the tissue compared to normal cartilage. Alteration in this orderly transition in T2 values within cartilage has been shown to correlate to changes in water content and changes in collagen structure and organization associated with hyaline articular cartilage The MESE sequence uses the same preparation radio frequency (RF) pulses as the SESE. The difference is that in SESE sequence we measure only one echo in a TR where as in the MESE sequence, we can measure many echoes. The biggest advantage is that we measure all the TE's on one scan which will save time with less movement artifact. In addition, this sequence gives the possibility to measure the T2 using the inline calculation method. The only disadvantage is the presence of the stimulated echo which can be reduced by the elimination of the first echo from the calculation.

#### *7.2.3. Dual echo steady state sequence (DESS)*

T2 can be calculated using dual echo steady state sequence (DESS) which demonstrated to provide results as comparable with the standard multiecho spin echo T2 [2]. In both 2D fat suppressed turbo spin echo proton density and 3D DESS sequence, hyaline cartilage has intermediate signal and synovial fluid has high signal. 3D DESS has the advantage to use thinner slices which make this sequence to me sensitive to detect smaller cartilage defects better than the 2D sequence.

#### *7.2.4. Turbo gradient spin echo*

This sequence combines a gradient echo and a spin echo imaging. It generates additional gradient echo before and after each spin echo. The spin echo gives the T2 contrast and the gradient echo determines the image resolution. The main advantage of the sequence is that it is fast and provides high resolution images. The TGSE sequence combines the TSE and echo-planar imaging method. It provides T2-weighted images. There are technical differences between TSE and TGSE sequences that could make the contrast and signal-to-noise ratio potentially different.

high-resolution imaging of cartilage within reasonable scan time [6]. To further decrease the scan time while maintaining high-resolution, most of the new systems used a dedicated multi-elements coil which enables the use of parallel acquisition techniques with high acceleration factor [21].

MRI Mapping for Cartilage Repair Follow-up http://dx.doi.org/10.5772/intechopen.70372 189

High-field MRI system also allows the use of 3-D acquisition sequences with the advantage of isotropic high resolution where dimensions are equal in all 3 axes (frequency, phase and slice) while maintaining high SNR and high contrast-to-noise ratios (CNR). This permits multiplanar reconstruction (MPR) in any plane with the same resolution. Biochemical imaging techniques, such as sodium MR imaging, which is limited by low signal-to-noise ratio at stan-

Care must be taken when performing T2 mapping and interpreting the results since T2 may

One of the disadvantages of T2 relaxation time mapping is its susceptibility to the magic angle effect, in which T2 values may be artificially elevated in certain regions according to the orientation of cartilage in relation to the main magnetic field [5]. The magic angle effect may complicate evaluation of curved articular surfaces, such as the femoral condyle [47], and should not be misinterpreted as degeneration. However, a recent report has found that OA may affect T2 values to a greater degree than the magic angle effect [48]. This finding may enable utilization of magic angle T2 mapping data with the understanding that only regions of interest from similar anatomic locations may be compared. However, the magic angle effect should not impact results tracking changes over time or between study populations as long as

Significant differences between cartilage T2 values were obtained at the beginning and at the end of the MRI examination resulting from the different states of unloading of the knee in the course of the MRI examination due to the supine position of the patient. Therefore, the time point of T2 acquisition has to be considered in the MRI protocol. Apprich et al. recommended

The following questions have to be answered in case of cartilage repair follow-up: (1) are there different *T*2 relaxation times between repair tissues and adjacent native cartilage? (2) Are these differences reduced over time? (3) Is there a difference between a global assessment

In a previous study conducted by Welsch et al., they calculated the mean and the zonal T2 values within the repair tissue and hyaline native cartilage on twenty patients who

dard clinical field strength can be used at ultra–high magnetic field [12].

depend on Bo, with shorter T2 values found at higher field strengths.

the subjects are positioned in the same manner in the magnet [49].

to measure T2 after unloading, i.e., at the end of the MRI examination [46].

**7.4. Clinical application of T2 mapping in cartilage repair surgery**

*7.3.6. Magic angle effect*

*7.3.7. Exam timing*

*7.3.8. Question to be answered*

and line profile assessment? [6].

#### **7.3. Technical aspects**

When optimizing a T2 mapping acquisition protocol, we need to take into account many technical considerations.

## *7.3.1. Repetition time (TR)*

To minimize the T1 contribution in the image contrast of T2 images, it is recommended to use longer TR value compared to the T1 value of the articular cartilage. A TR of 1500 ms or longer is preferred.

## *7.3.2. Echo time (TE)*

Due to the shorter value of the T2 relaxation time of the knee articular cartilage, short TE and short echo spacing (ES) in case of multiecho sequences are required to accurately characterize the T2 decay curve. Since the expected T2 values of articular cartilage are in the range between 20 and 70 ms, we recommend using many echoes for better curve fitting. The greater the number of data sets, that is the number of TE values, the greater the accuracy of the T2 measurements but without using a higher TE which is susceptible to greater noises and errors.

## *7.3.3. Stimulated echo*

It is important to know that multi-slice multiecho spin echo sequences (MS MESE) uses a sliceselective refocusing pulses. In case of bad calibration or inhomogeneities of the radio frequency pulse, slice-selective refocusing pulses do not result in rectangular slice profiles causing stimulated echo contributions to the measured signal. The T2 relaxation time based on multiecho sequence is subject of measurement errors because of the stimulated echo which may increase artificially the T2 value [46]. This error may be avoided by ignoring the first echo when using a multiecho sequence or by using single echo acquisitions instead of multiecho acquisition.

#### *7.3.4. Bandwidth (BW)*

To reduce the chemical shift artifact between water and fat in the cartilage, we advise to use a higher bandwidth of ~217 Hz/pixel corresponding to a chemical shift of 1 pixel on 1.5 T system and 0.5 pixel at 3 T.

## *7.3.5. Magnetic field*

MR morphology imaging of cartilage repair tissue has significantly improved in recent years by the use of high-field MR systems like 3 T, the use of higher gradient strengths and the dedicated coils. This improvement increased the signal to noise ratio (SNR) which allows high-resolution imaging of cartilage within reasonable scan time [6]. To further decrease the scan time while maintaining high-resolution, most of the new systems used a dedicated multi-elements coil which enables the use of parallel acquisition techniques with high acceleration factor [21].

High-field MRI system also allows the use of 3-D acquisition sequences with the advantage of isotropic high resolution where dimensions are equal in all 3 axes (frequency, phase and slice) while maintaining high SNR and high contrast-to-noise ratios (CNR). This permits multiplanar reconstruction (MPR) in any plane with the same resolution. Biochemical imaging techniques, such as sodium MR imaging, which is limited by low signal-to-noise ratio at standard clinical field strength can be used at ultra–high magnetic field [12].

Care must be taken when performing T2 mapping and interpreting the results since T2 may depend on Bo, with shorter T2 values found at higher field strengths.

## *7.3.6. Magic angle effect*

echo determines the image resolution. The main advantage of the sequence is that it is fast and provides high resolution images. The TGSE sequence combines the TSE and echo-planar imaging method. It provides T2-weighted images. There are technical differences between TSE and TGSE sequences that could make the contrast and signal-to-noise ratio potentially different.

When optimizing a T2 mapping acquisition protocol, we need to take into account many

To minimize the T1 contribution in the image contrast of T2 images, it is recommended to use longer TR value compared to the T1 value of the articular cartilage. A TR of 1500 ms or longer

Due to the shorter value of the T2 relaxation time of the knee articular cartilage, short TE and short echo spacing (ES) in case of multiecho sequences are required to accurately characterize the T2 decay curve. Since the expected T2 values of articular cartilage are in the range between 20 and 70 ms, we recommend using many echoes for better curve fitting. The greater the number of data sets, that is the number of TE values, the greater the accuracy of the T2 measurements but without using a higher TE which is susceptible to greater noises and errors.

It is important to know that multi-slice multiecho spin echo sequences (MS MESE) uses a sliceselective refocusing pulses. In case of bad calibration or inhomogeneities of the radio frequency pulse, slice-selective refocusing pulses do not result in rectangular slice profiles causing stimulated echo contributions to the measured signal. The T2 relaxation time based on multiecho sequence is subject of measurement errors because of the stimulated echo which may increase artificially the T2 value [46]. This error may be avoided by ignoring the first echo when using a multiecho sequence or by using single echo acquisitions instead of multiecho acquisition.

To reduce the chemical shift artifact between water and fat in the cartilage, we advise to use a higher bandwidth of ~217 Hz/pixel corresponding to a chemical shift of 1 pixel on 1.5 T

MR morphology imaging of cartilage repair tissue has significantly improved in recent years by the use of high-field MR systems like 3 T, the use of higher gradient strengths and the dedicated coils. This improvement increased the signal to noise ratio (SNR) which allows

**7.3. Technical aspects**

188 Cartilage Repair and Regeneration

technical considerations.

*7.3.1. Repetition time (TR)*

is preferred.

*7.3.2. Echo time (TE)*

*7.3.3. Stimulated echo*

*7.3.4. Bandwidth (BW)*

*7.3.5. Magnetic field*

system and 0.5 pixel at 3 T.

One of the disadvantages of T2 relaxation time mapping is its susceptibility to the magic angle effect, in which T2 values may be artificially elevated in certain regions according to the orientation of cartilage in relation to the main magnetic field [5]. The magic angle effect may complicate evaluation of curved articular surfaces, such as the femoral condyle [47], and should not be misinterpreted as degeneration. However, a recent report has found that OA may affect T2 values to a greater degree than the magic angle effect [48]. This finding may enable utilization of magic angle T2 mapping data with the understanding that only regions of interest from similar anatomic locations may be compared. However, the magic angle effect should not impact results tracking changes over time or between study populations as long as the subjects are positioned in the same manner in the magnet [49].

## *7.3.7. Exam timing*

Significant differences between cartilage T2 values were obtained at the beginning and at the end of the MRI examination resulting from the different states of unloading of the knee in the course of the MRI examination due to the supine position of the patient. Therefore, the time point of T2 acquisition has to be considered in the MRI protocol. Apprich et al. recommended to measure T2 after unloading, i.e., at the end of the MRI examination [46].

## *7.3.8. Question to be answered*

The following questions have to be answered in case of cartilage repair follow-up: (1) are there different *T*2 relaxation times between repair tissues and adjacent native cartilage? (2) Are these differences reduced over time? (3) Is there a difference between a global assessment and line profile assessment? [6].

## **7.4. Clinical application of T2 mapping in cartilage repair surgery**

In a previous study conducted by Welsch et al., they calculated the mean and the zonal T2 values within the repair tissue and hyaline native cartilage on twenty patients who underwent MFX or MACT (10 in each group) with minimum 2-year follow-up. They compared cartilage T2 values after microfracture therapy (MFX) and matrix-associated autologous chondrocyte transplantation (MACT) repair procedures. They reported that in normal native hyaline cartilage, T2 values showed similar values for all patients with a significant increase of T2 values from deep to superficial zones (*P* < 0.05). In cartilage repair areas after MFX, global mean T2 was significantly decreased (*P* < 0.05), whereas cartilage repair areas after MACT showed no decrease of mean T2 (*P* ≥ 0.05). For zonal variation, repair tissue after MFX showed no significant trend between different depths (*P* ≥ 0.05), in contrast to repair tissue after MACT which showed a significant increase of T2 values from deep to superficial zones (*P* < 0.05) [50] (**Figure 4**).

Two previous studies evaluated the status of reparative fibrocartilage induced by microfracture using T2 mapping. They reported that spatial variation of T2 values in fibrocartilage and native hyaline cartilage were not the same (hyaline cartilage is characterized by higher T2 values near the articular surface and lower T2 values near subchondral bone) [41, 50]. Also, the overall global T2 value for fibrocartilage repair tissue was lower compared to native hyaline cartilage [50].

MRI Mapping for Cartilage Repair Follow-up http://dx.doi.org/10.5772/intechopen.70372 191

MACI has been studied using T2 mapping. The results showed similar spatial variation in the T2 values of repair cartilage like seen in native hyaline cartilage (although the increase in

T2 mapping of patients after MACT surgery at different postoperative intervals Quantitative *T*2 mapping was performed in 15 patients after MACT surgery at different postoperative intervals. With respect to the postoperative time interval, patients were subdivided into two groups: group I, 3–13 months (6 patients); group II, 19–42 months (9 patients). In group I, the mean global *T*2 values in cartilage repair tissue was 65.8 ± 16.6 compared with 50.0 ± 7.0 for native cartilage; this difference was statistically significant (*P* = 0.013). In group II, the mean *T*2 values of repair tissue were 56.5 ± 12.0 compared with 57.7 ± 9.2 for native cartilage. These differences were not statistically significant (*P* = 0.784). Results showed significantly higher *T*2 values, in cartilage repair tissue, in the early stage (3–13 months) compared with native hyaline cartilage. Over time, there was a decrease in repair tissue *T*2 values which became similar to native healthy cartilage [6]. This finding is in agreement with a study by Kurkijarvi et al. [54] who, in 1.5 T, reported *T*2 values in the repair tissue and normal hyaline cartilage with 60 ± 10 ms and 50 ± 7 ms, respectively, in 10 patients 10–15 months after ACI surgery. Domayer et al. introduced a T2 index defined as the ratio of the mean global repair tissue T2 divided the mean global normal cartilage expressed as a percentage. They reported that this

In addition to the phase shift of the individual spins, there is also the additional phase shift caused by field inhomogeneities that increase the phase shift of the spins and thus accelerates

The physical difference between T2\* and T2 is that magnetic gradients, and not a 180° RF pulse, are used to rephase the spins at a user defined TE. T2\* and T2 values are related by the

Where γ is the gyromagnetic ratio of the observed nucleus and ΔB0 is the magnetic field inhomogeneity. If we assume that the applied static magnetic field B0 is uniform then γ ΔB0

T2 + γ ΔB0 (1)

<sup>T</sup> <sup>2</sup><sup>∗</sup> <sup>=</sup> \_\_\_<sup>1</sup>

the decay. The total relaxation time (T2\*) is a consequence of these terms.

mean T2 values from deep to superficial layers of cartilage is less pronounced) [41].

T2 index correlated with clinical measurements [55].

**8. T2\* mapping**

equation (Eq. (1)):

**8.1. T2\* mapping principle**

\_\_\_\_ <sup>1</sup>

In another study, Welsch et al. compared T2 mapping of 17 patients who underwent MACT over the patella versus 17 patients who underwent MACT in the medial femoral condyle. They reported an increase of T2 values over the condyle compared to the patella repair tissue. They conclude that differential maturation of the repair tissue depends on its environment [51].

Welsch and colleagues reported in another study that T2 mapping can be used to distinguish between MACI performed using a collagen-based scaffold and a hyaluronan-based scaffold (higher T2 values in collagen-based scaffolds) [52].

Quantitative T2 mapping has been used to assess the interface between transplanted and native cartilage. A clinical study of patellar autologous osteochondral transplantation reported progressive T2 increase at the offset of the tidemark that occurred between the thicker native cartilage over the patella and the thinner cartilage over the autologous plug [53].

A study of T2 mapping performed in 53 sites reported a perfect agreement between organized T2 and histologic findings of hyaline cartilage and between disorganized T2 and histologic findings of fibrous reparative tissue (k = 1.0). Mean T2 values were 53.3, 58.6, and 54.9 ms at the deep, middle, and superficial cartilage, respectively, at reparative fibrous tissue, whereas T2 mean values were 40.7, 53.6, and 61.6 ms at hyaline cartilage. A significant increase of T2 values (from deep to superficial) was found in hyaline cartilage (*P* < 0.01). Fibrous tissue sites showed no significant change with depth (*P* > 0.59) [45].

**Figure 4.** Enlarged section of sagittal cartilage T2 map. ROI of cartilage repair (between two arrows) shows no zonal variation and low T2 values, whereas control cartilage shows visible zonal variation from deep to superficial areas, with higher T2 values in superficial area [50].

Two previous studies evaluated the status of reparative fibrocartilage induced by microfracture using T2 mapping. They reported that spatial variation of T2 values in fibrocartilage and native hyaline cartilage were not the same (hyaline cartilage is characterized by higher T2 values near the articular surface and lower T2 values near subchondral bone) [41, 50]. Also, the overall global T2 value for fibrocartilage repair tissue was lower compared to native hyaline cartilage [50].

MACI has been studied using T2 mapping. The results showed similar spatial variation in the T2 values of repair cartilage like seen in native hyaline cartilage (although the increase in mean T2 values from deep to superficial layers of cartilage is less pronounced) [41].

T2 mapping of patients after MACT surgery at different postoperative intervals Quantitative *T*2 mapping was performed in 15 patients after MACT surgery at different postoperative intervals. With respect to the postoperative time interval, patients were subdivided into two groups: group I, 3–13 months (6 patients); group II, 19–42 months (9 patients). In group I, the mean global *T*2 values in cartilage repair tissue was 65.8 ± 16.6 compared with 50.0 ± 7.0 for native cartilage; this difference was statistically significant (*P* = 0.013). In group II, the mean *T*2 values of repair tissue were 56.5 ± 12.0 compared with 57.7 ± 9.2 for native cartilage. These differences were not statistically significant (*P* = 0.784). Results showed significantly higher *T*2 values, in cartilage repair tissue, in the early stage (3–13 months) compared with native hyaline cartilage. Over time, there was a decrease in repair tissue *T*2 values which became similar to native healthy cartilage [6]. This finding is in agreement with a study by Kurkijarvi et al. [54] who, in 1.5 T, reported *T*2 values in the repair tissue and normal hyaline cartilage with 60 ± 10 ms and 50 ± 7 ms, respectively, in 10 patients 10–15 months after ACI surgery.

Domayer et al. introduced a T2 index defined as the ratio of the mean global repair tissue T2 divided the mean global normal cartilage expressed as a percentage. They reported that this T2 index correlated with clinical measurements [55].

## **8. T2\* mapping**

underwent MFX or MACT (10 in each group) with minimum 2-year follow-up. They compared cartilage T2 values after microfracture therapy (MFX) and matrix-associated autologous chondrocyte transplantation (MACT) repair procedures. They reported that in normal native hyaline cartilage, T2 values showed similar values for all patients with a significant increase of T2 values from deep to superficial zones (*P* < 0.05). In cartilage repair areas after MFX, global mean T2 was significantly decreased (*P* < 0.05), whereas cartilage repair areas after MACT showed no decrease of mean T2 (*P* ≥ 0.05). For zonal variation, repair tissue after MFX showed no significant trend between different depths (*P* ≥ 0.05), in contrast to repair tissue after MACT which showed a significant increase of T2 values from deep to superficial

In another study, Welsch et al. compared T2 mapping of 17 patients who underwent MACT over the patella versus 17 patients who underwent MACT in the medial femoral condyle. They reported an increase of T2 values over the condyle compared to the patella repair tissue. They conclude that differential maturation of the repair tissue depends on its envi-

Welsch and colleagues reported in another study that T2 mapping can be used to distinguish between MACI performed using a collagen-based scaffold and a hyaluronan-based scaffold

Quantitative T2 mapping has been used to assess the interface between transplanted and native cartilage. A clinical study of patellar autologous osteochondral transplantation reported progressive T2 increase at the offset of the tidemark that occurred between the thicker native

A study of T2 mapping performed in 53 sites reported a perfect agreement between organized T2 and histologic findings of hyaline cartilage and between disorganized T2 and histologic findings of fibrous reparative tissue (k = 1.0). Mean T2 values were 53.3, 58.6, and 54.9 ms at the deep, middle, and superficial cartilage, respectively, at reparative fibrous tissue, whereas T2 mean values were 40.7, 53.6, and 61.6 ms at hyaline cartilage. A significant increase of T2 values (from deep to superficial) was found in hyaline cartilage (*P* < 0.01). Fibrous tissue sites

**Figure 4.** Enlarged section of sagittal cartilage T2 map. ROI of cartilage repair (between two arrows) shows no zonal variation and low T2 values, whereas control cartilage shows visible zonal variation from deep to superficial areas, with

cartilage over the patella and the thinner cartilage over the autologous plug [53].

zones (*P* < 0.05) [50] (**Figure 4**).

190 Cartilage Repair and Regeneration

(higher T2 values in collagen-based scaffolds) [52].

showed no significant change with depth (*P* > 0.59) [45].

higher T2 values in superficial area [50].

ronment [51].

In addition to the phase shift of the individual spins, there is also the additional phase shift caused by field inhomogeneities that increase the phase shift of the spins and thus accelerates the decay. The total relaxation time (T2\*) is a consequence of these terms.

## **8.1. T2\* mapping principle**

The physical difference between T2\* and T2 is that magnetic gradients, and not a 180° RF pulse, are used to rephase the spins at a user defined TE. T2\* and T2 values are related by the equation (Eq. (1)):

$$\frac{1}{\text{T}\,2^\*} = \frac{1}{\text{T}\,2} + \gamma \,\Delta\text{B}\,0\tag{1}$$

Where γ is the gyromagnetic ratio of the observed nucleus and ΔB0 is the magnetic field inhomogeneity. If we assume that the applied static magnetic field B0 is uniform then γ ΔB0 is only influenced by local magnetic susceptibility fields. In the case of knee articular cartilage, this susceptibility will be present at the cartilage bone interface or within the cartilage microstructure.

T2\* mapping is similar to T2 mapping [56]: multiple echo images at a single slice location are generated, and a mono- or bi-exponential decay equation [57] (**Figure 5**) is used to fit the signal intensity to the corresponding echo time data. The difference between T2 and T2\* mapping is that T2 mapping is calculated using a spin echo sequence however T2\* mapping is obtained using a gradient echo sequence (**Figure 6**). T2\* mapping has the advantage of shorter scan time compared to T2 mapping. Also, with T2\*, we can acquire shorter TE compared to T2 which is very important for short T2 components. In addition, with T2\* mapping using 3D gradient echo sequence, we have the possibility of isotropic three-dimensional reconstruction, which seems to offer a potential alternative and reliable results in cartilage imaging [58].

#### **8.2. Clinical application of T2\* mapping in cartilage repair surgery**

Goetz H. and al performed MRI examinations on 30 patients after MACT at a follow-up period of 28.1 ± 18.8 months. T2\* values are given in milliseconds (ms). In healthy control cartilage, T2\* mean value of all patients was 30.9 ± 6.6 with a significant increase of T2\* values from deep (27.9 ± 7.2) to superficial (33.9 ± 6.9) cartilage aspects. The cartilage repair tissue after MACT showed a mean (full-thickness) T2\* value of 24.5 ± 8.1 with a significant increase

from deep (21.6 ± 7.3) to superficial (27.5 ± 9.4) (*P* < 0.001). When comparing T2\* values of the healthy control cartilage with those of the cartilage repair tissue, the mean T2\* values and the T2\* values in deep and superficial cartilages were significantly lower in the cartilage repair

**Figure 7.** Depiction of cartilage in a patient 6 months after MACT of the lateral femoral condyle. Morphological PD-TSE sequence (a), matched quantitative T2 (b), and T2\* (c) maps. Arrows mark the area of cartilage repair. ROIs, considering a possible zonal variation, provide information on the mean (full-thickness) as well as the deep and superficial aspect of control cartilage (left) and cartilage repair tissue (right, arrows). Zonal stratification is visible for both T2 and T2\* images in most parts of the cartilage. A possible "magic angle" effect is visible within the trochlea. Higher T2/T2\* values are

MRI Mapping for Cartilage Repair Follow-up http://dx.doi.org/10.5772/intechopen.70372 193

The comparison of the mean (full-thickness) T2\* values over different postoperative intervals revealed a stability of T2\* values over time with T2\* value of 31.4 ± 6.2 for the short-term interval, 31.0 ± 6.7 for the mid-term interval and 30.4 ± 7.0 for the long-term interval. However, the cartilage repair tissue showed significantly higher T2\* values at the short-term follow-up (31.0 ± 8.1) than at the mid-term follow-up (20.7 ± 6.1) (*P* < 0.001), and stable values between the mid-term and long-term (22.2 ± 6.0) follow-up (*P* = 0.232). The difference between the

The comparison of mean (full-thickness) T2\* values for healthy control cartilage and cartilage repair tissue at the different postoperative follow-up time points revealed comparable values at the short-term follow-up (0.793), significantly lower mean (full-thickness) T2\* values in cartilage repair tissue compared to healthy control cartilage for the mid-term (*P* < 0.001) and

Goetz H. Welsch and al reported that mean T2\* values (ms) were lower at 7 T (18.3 ± 4.9) compared with 3 T (22.2 ± 4.3). Regarding zonal variation, T2\* relaxation times (ms) were significantly lower at 7 T (deep: 15.5 ± 3.7; superficial: 21.0 ± 4.5) (*P* < 0.001) compared with 3 T

The validation of cartilage repair techniques needs short, medium and long term follow-up. The follow-up periods remain a problem for cartilage repair because of the slow progression of cartilage degeneration over time. Choosing the best technique that addresses the individual

short-term and long-term follow-up was also significant (*P* < 0.001) [59].

apparent in the cartilage repair tissue, compared with the adjacent cartilage [59].

long-term (*P* < 0.001) postoperative intervals [59].

(mean: deep: 17.6 ± 3.7; superficial: 26.9 ± 5.4) [60].

**9. Conclusion**

tissue (*P* < 0.001) [59] (**Figure 7**).

**Figure 5.** Images acquired using multiecho gradient echo (MEGE) sequence with different TE's in the range of 5.1–50 ms.

**Figure 6.** T2\* mapping image calculated using a MEGE sequence. Arrow 2 indicates higher T2\* whereas arrow 1 indicates lower T2\* values.

**Figure 7.** Depiction of cartilage in a patient 6 months after MACT of the lateral femoral condyle. Morphological PD-TSE sequence (a), matched quantitative T2 (b), and T2\* (c) maps. Arrows mark the area of cartilage repair. ROIs, considering a possible zonal variation, provide information on the mean (full-thickness) as well as the deep and superficial aspect of control cartilage (left) and cartilage repair tissue (right, arrows). Zonal stratification is visible for both T2 and T2\* images in most parts of the cartilage. A possible "magic angle" effect is visible within the trochlea. Higher T2/T2\* values are apparent in the cartilage repair tissue, compared with the adjacent cartilage [59].

from deep (21.6 ± 7.3) to superficial (27.5 ± 9.4) (*P* < 0.001). When comparing T2\* values of the healthy control cartilage with those of the cartilage repair tissue, the mean T2\* values and the T2\* values in deep and superficial cartilages were significantly lower in the cartilage repair tissue (*P* < 0.001) [59] (**Figure 7**).

The comparison of the mean (full-thickness) T2\* values over different postoperative intervals revealed a stability of T2\* values over time with T2\* value of 31.4 ± 6.2 for the short-term interval, 31.0 ± 6.7 for the mid-term interval and 30.4 ± 7.0 for the long-term interval. However, the cartilage repair tissue showed significantly higher T2\* values at the short-term follow-up (31.0 ± 8.1) than at the mid-term follow-up (20.7 ± 6.1) (*P* < 0.001), and stable values between the mid-term and long-term (22.2 ± 6.0) follow-up (*P* = 0.232). The difference between the short-term and long-term follow-up was also significant (*P* < 0.001) [59].

The comparison of mean (full-thickness) T2\* values for healthy control cartilage and cartilage repair tissue at the different postoperative follow-up time points revealed comparable values at the short-term follow-up (0.793), significantly lower mean (full-thickness) T2\* values in cartilage repair tissue compared to healthy control cartilage for the mid-term (*P* < 0.001) and long-term (*P* < 0.001) postoperative intervals [59].

Goetz H. Welsch and al reported that mean T2\* values (ms) were lower at 7 T (18.3 ± 4.9) compared with 3 T (22.2 ± 4.3). Regarding zonal variation, T2\* relaxation times (ms) were significantly lower at 7 T (deep: 15.5 ± 3.7; superficial: 21.0 ± 4.5) (*P* < 0.001) compared with 3 T (mean: deep: 17.6 ± 3.7; superficial: 26.9 ± 5.4) [60].

## **9. Conclusion**

is only influenced by local magnetic susceptibility fields. In the case of knee articular cartilage, this susceptibility will be present at the cartilage bone interface or within the cartilage

T2\* mapping is similar to T2 mapping [56]: multiple echo images at a single slice location are generated, and a mono- or bi-exponential decay equation [57] (**Figure 5**) is used to fit the signal intensity to the corresponding echo time data. The difference between T2 and T2\* mapping is that T2 mapping is calculated using a spin echo sequence however T2\* mapping is obtained using a gradient echo sequence (**Figure 6**). T2\* mapping has the advantage of shorter scan time compared to T2 mapping. Also, with T2\*, we can acquire shorter TE compared to T2 which is very important for short T2 components. In addition, with T2\* mapping using 3D gradient echo sequence, we have the possibility of isotropic three-dimensional reconstruction, which seems to offer a potential alternative and reliable results in cartilage imaging [58].

Goetz H. and al performed MRI examinations on 30 patients after MACT at a follow-up period of 28.1 ± 18.8 months. T2\* values are given in milliseconds (ms). In healthy control cartilage, T2\* mean value of all patients was 30.9 ± 6.6 with a significant increase of T2\* values from deep (27.9 ± 7.2) to superficial (33.9 ± 6.9) cartilage aspects. The cartilage repair tissue after MACT showed a mean (full-thickness) T2\* value of 24.5 ± 8.1 with a significant increase

**Figure 6.** T2\* mapping image calculated using a MEGE sequence. Arrow 2 indicates higher T2\* whereas arrow 1

**Figure 5.** Images acquired using multiecho gradient echo (MEGE) sequence with different TE's in the range of 5.1–50 ms.

**8.2. Clinical application of T2\* mapping in cartilage repair surgery**

microstructure.

192 Cartilage Repair and Regeneration

indicates lower T2\* values.

The validation of cartilage repair techniques needs short, medium and long term follow-up. The follow-up periods remain a problem for cartilage repair because of the slow progression of cartilage degeneration over time. Choosing the best technique that addresses the individual defect is a challenge for the orthopedic surgeon. T2 mapping could provide information about collagen matrix concentration and organization, whereas dGEMRIC is sensitive to proteoglycan content. T2\* mapping has the advantage of shorter scan time with the possibility to acquire shorter TE compared to T2 which is very important for shorter T2 components. The modifications of the extracellular matrix, such as loss PG, may be reflected by the change of the T1ρ values. Each MRI parameter can characterize certain features of the articular cartilage properties. All together may provide complementary information's about cartilage repair tissue properties.

[9] Goyal D, Keyhani S, Lee EH, Hui JHP. Evidence based status of microfracture technique:

MRI Mapping for Cartilage Repair Follow-up http://dx.doi.org/10.5772/intechopen.70372 195

[10] Mithoefer K, McAdams T, Williams RJ, Kreuz PC, Mandelbaum BR, et al. Clinical efficacy of the microfracture technique for articular cartilage repair in the knee: An evidencebased systematic analysis. The American Journal of Sports Medicine. 2009;**37**:2053-2063

[11] Lee JJ, Lee SJ, Lee TJ, Yoon TH, Choi CH. Results of microfracture in the osteoarthritic knee with focal full-thickness articular cartilage defects and concomitant medial menis-

[12] Chang G, Sherman O, Madelin G, Recht M, Regatte R. MR imaging assessment of articular cartilage repair procedures. Magnetic Resonance Imaging Clinics of North America.

[13] Choi YS, Potter HG, Chun TJ. MR imaging of cartilage repair in the knee and ankle.

[14] Marlovits S, Striessnig G, Resinger CT, Aldrian SM, Vecsei V, Imhof H, et al. Definition of pertinent parameters for the evaluation of articular cartilage repair tissue with highresolution magnetic resonance imaging. European Journal of Radiology. 2004;**52**:310-319

[15] Marlovits S, Singer P, Zeller P, Mandl I, Haller J, Trattnig S. Magnetic resonance observation of cartilage repair tissue (MOCART) for the evaluation of autologous chondrocyte transplantation: Interobserver variability and correlation to clinical outcome after 2

[16] Brown WE, Potter HG, Marx RG, Wickiewicz TL, Warren RF. Magnetic resonance imaging appearance of articular cartilage repair in the knee. Clinical Orthopaedics and

[17] Tins BJ, McCall IW, Takahashi T, Cassar-Pullicino V, Roberts S, Ashton B, et al. Autologous chondrocyte implantation in knee joint: MR imaging and histologic features

[18] Trattnig S, Ba-Ssalamah A, Pinker K, Plank C, Vecsei V, Marlovits S. Matrix-based autologous chondrocyte implantation for cartilage repair: Noninvasive monitoring by highresolution magnetic resonance imaging. Magnetic Resonance Imaging. 2005;**23**:779-787

[19] Redman SN, Oldfield SF, Archer CW. Current strategies for articular cartilage repair.

[20] Mow VC, Zhu W, Ratcliffe A. Structure and function of articular cartilage and meniscus. In: Mow VC, Hayes WE, editors. Basic Orthopaedic Biomechanics. New York: Raven

[21] Trattnig S, Winalski CS, Marlovits S, Jurvelin JS, Welsch GH, Potter HG. Magnetic resonance imaging of cartilage repair: A review. Cartilage. 2011;**2**:5 originally published

[22] Trattnig S, Millington SA, Szomolanyi P, Marlovits S. MR imaging of osteochondral grafts and autologous chondrocyte implantation. European Radiology. 2007;**17**(1):103-118

A systematic review of level I and II studies. Arthroscopy. 2013;**29**:1579-1588

cal tears. Knee Surgery & Related Research. 2013;**25**:71-76

Radiographics. 2008 Jul-Aug;**28**(4):1043-1059 Review

years. European Journal of Radiology. 2006;**57**:16-23

at 1-year follow-up. Radiology. 2005;**234**(2):501-508

European Cells and Materials. 2005;**9**:23-32

Press; 1991. p. 143-198

online 18 April 2010

Related Research. 2004;**422**:214-223

2011 May;**19**(2):323-337

## **Author details**

Mars Mokhtar

Address all correspondence to: mokhtar.mars-mms@topnet.tn

Biophysics and Medical Technologies Laboratory, Institut Supérieur des Technologies Médicales de Tunis, Université de Tunis El Manar, Tunis, Tunisia

## **References**


[9] Goyal D, Keyhani S, Lee EH, Hui JHP. Evidence based status of microfracture technique: A systematic review of level I and II studies. Arthroscopy. 2013;**29**:1579-1588

defect is a challenge for the orthopedic surgeon. T2 mapping could provide information about collagen matrix concentration and organization, whereas dGEMRIC is sensitive to proteoglycan content. T2\* mapping has the advantage of shorter scan time with the possibility to acquire shorter TE compared to T2 which is very important for shorter T2 components. The modifications of the extracellular matrix, such as loss PG, may be reflected by the change of the T1ρ values. Each MRI parameter can characterize certain features of the articular cartilage properties. All together may provide complementary information's about cartilage repair tissue properties.

Biophysics and Medical Technologies Laboratory, Institut Supérieur des Technologies Médicales

[1] Baum T, Joseph GB, Karampinos DC, Jungmann PM, Link TM, Bauer JS. Cartilage and meniscal T2 relaxation time as non-invasive biomarker for knee osteoarthritis and carti-

[2] Ahlawat S, Padua A, Huisman TAGM, Carrino JA. 3T MR Imaging of the Pediatric Cartilage Using 3D Dual Echo Steady State (DESS). MAGNETOM Flash | 2/2014 | www.

[3] Lusse S, Claassen H, Gehrke T, Hassenpflug J, Schunke M, Heller M, et al. Evaluation of water content by spatially resolved transverse relaxation times of human articular

[4] Nieminen MT, Toyras J, Rieppo J, Hakumaki JM, Silvennoinen J, Helminen HJ, et al. Quantitative MR microscopy of enzymatically degraded articular cartilage. Magnetic

[5] Xia Y. Magic-angle effect in magnetic resonance imaging of articular cartilage: A review.

[6] Trattnig S, Mamisch TC, Welsch GH, Glaser C, Szomolanyi P, Gebetsroither S, et al. Quantitative T2 mapping of matrix-associated autologous chondrocyte transplantation at 3 Tesla: An in vivo cross-sectional study. Investigative Radiology. June 2007;**42**(6):442-448 [7] Choi YS, Potter HG, Chun TJ. MR imaging of cartilage repair in the knee and ankle.

[8] Smith GD, Knutsen G, Richardson JB. A clinical review of cartilage repair techniques.

The Journal of Bone and Joint Surgery. April 2005;**87-B**(4):445-449

lage repair procedures. Osteoarthritis and Cartilage. 2013;**21**:1474-1484

cartilage. Magnetic Resonance Imaging. 2000;**18**(4):423-430

Address all correspondence to: mokhtar.mars-mms@topnet.tn

de Tunis, Université de Tunis El Manar, Tunis, Tunisia

siemens.com/magnetom-world, Germany

Resonance in Medicine. 2000;**43**:676-681

Investigative Radiology. 2000;**35**:602-621

RadioGraphics. 2008;**28**:1043-1059

**Author details**

194 Cartilage Repair and Regeneration

Mars Mokhtar

**References**


[23] Deoni SC, Rutt BK, Peters TM. Rapid combined T1 and T2 mapping using gradient recalled acquisition in the steady state. Magnetic Resonance in Medicine. 2003;**49**:515-526

[35] Trattnig S, Mamisch TC, Pinker K, Domayer S, Szomolanyi P, Marlovits S, et al. Differentiating normal hyaline cartilage from post-surgical repair tissue using fast gradient echo imaging in delayed gadolinium-enhanced MRI (dGEMRIC) at 3 Tesla.

MRI Mapping for Cartilage Repair Follow-up http://dx.doi.org/10.5772/intechopen.70372 197

[36] Minas T, Nehrer S. Current concepts in the treatment of articular cartilage defects.

[37] Ghivizzani SC, Oligino TJ, Robbins PD, Evans CH. Cartilage injury and repair. Physical Medicine and Rehabilitation Clinics of North America. 2000;**11**(2):289-307 vi

[38] Brown DS, Durkan MG, Foss EW, Szumowski J, Crawford DC. Temporal in vivo assessment of fresh osteochondral allograft transplants to the distal aspect of the femur by dGEMRIC (delayed gadolinium-enhanced MRI of cartilage) and zonal T2 mapping

MRI. The Journal of Bone and Joint Surgery. American Volume. 2014;**96**:564-572

position. Quantitative Imaging in Medicine and Surgery. 2013;**3**(3):162-174

American Journal of Sports Medicine. 2006;**34**(9):1464-1477

mapping. Tissue Eng Part C Methods. 2010 Jun;**16**(3):355-364

T. Journal of Magnetic Resonance Imaging. 2003;**17**:358-364

Journal of Roentgenology. 2001;**177**:665-669

and Cartilage. 2009;**17**(10):1341-1349

[39] Matzat SJ, van Tiel J, Gold GE, Oei EHG. Quantitative MRI techniques of cartilage com-

[40] Kelly BT, Potter HG, Deng XH, Pearle AD, Turner AS, Warren RF, et al. Meniscal allograft transplantation in the sheep knee: Evaluation of chondroprotective effects. The

[41] White LM, Sussman MS, Hurtig M, Probyn L, Tomlinson G, Kandel R. Cartilage T2 assessment: Differentiation of normal hyaline cartilage and reparative tissue after

[42] Kim M, Foo L, Lyman S, Ryaby JT, Grande DA, Potter HG, et al. Evaluation of early osteochondral defect repair in a rabbit model utilizing Fourier transform infrared imaging spectroscopy (FT-IRIS), magnetic resonance imaging (MRI) and quantitative T2

[43] Watanabe A, Boesch C, Anderson SE, Brehm W, Mainil Varlet P.Ability of dGEMRIC and T2 mapping to evaluate cartilage repair after microfracture: A goat study. Osteoarthritis

[44] Potter HG, Foo LF. Magnetic resonance imaging of articular cartilage: Trauma, degeneration, and repair. The American Journal of Sports Medicine. 2006;**34**(4):661-677 [45] White LM, Sussman MS, Hurtig M, Probyn L, Tomlinson G, Kandel R. Cartilage T2 assessment: Differentiation of normal hyaline cartilage and reparative tissue after arthroscopic

cartilage repair in equine subjects. Radiology. November 2006;**241**(2):407-414

[46] Maier CF, Tan SG, Hariharan H, Potter HG. T2 quantitation of articular cartilage at 1.5

[47] Mosher TJ, Smith H, Dardzinski BJ, Schmithorst VJ, Smith MB. MR imaging and T2 mapping of femoral cartilage: In vivo determination of the magic angle effect. American

arthroscopic cartilage repair in equine subjects. Radiology. 2006;**241**(2):407-414

European Radiology. 2008;**18**(6):1251-1259

Orthopedics. 1997;**20**(6):525-538


[35] Trattnig S, Mamisch TC, Pinker K, Domayer S, Szomolanyi P, Marlovits S, et al. Differentiating normal hyaline cartilage from post-surgical repair tissue using fast gradient echo imaging in delayed gadolinium-enhanced MRI (dGEMRIC) at 3 Tesla. European Radiology. 2008;**18**(6):1251-1259

[23] Deoni SC, Rutt BK, Peters TM. Rapid combined T1 and T2 mapping using gradient recalled acquisition in the steady state. Magnetic Resonance in Medicine. 2003;**49**:515-526

[24] Fram EK, Herfkens RJ, Johnson GA, Glover GH, Karis JP, Shimakawa A, et al. Rapid calculation of T1 using variable flip angle gradient refocused imaging. Magnetic Resonance

[25] Park Y-B, Ha C-W, Lee C-H, Yoon YC, Park Y-G. Cartilage regeneration in osteoarthritic patients by a composite of allogeneic umbilical cord blood-derived mesenchymal stem cells and hyaluronate hydrogel: Results from a clinical trial for safety and proof-of-concept with 7 years of extended follow-up. Stem Cells Translational Medicine. 2016;**5**:1-9

[26] Burstein D, Velyvis J, Scott KT, Stock KW, Kim YJ, Jaramillo D, et al. Protocol issues for delayed Gd(DTPA)(2-)-enhanced MRI: (dGEMRIC) for clinical evaluation of articular

[27] Watanabe A, Wada Y, Obata T, Ueda T, Tamura M, Ikehira H, et al. Delayed gadolinium-enhanced MR to determine glycosaminoglycan concentration in reparative cartilage after autologous chondrocyte implantation: Preliminary results. Radiology. 2006;

[28] Rubenstein JD, Li JG, Majumdar S, Henkelman RM. Image resolution and signal-to-noise ratio requirements for MR imaging of degenerative cartilage. AJR. American Journal of

[29] Trattnig S, Marlovits S, Gebetsroither S, Szomolanyi P, Welsch GH, Salomonowitz E, et al. Three-dimensional delayed gadolinium-enhanced MRI of cartilage (dGEMRIC) for in vivo evaluation of reparative cartilage after matrix-associated autologous chondrocyte transplantation at 3.0T: Preliminary results. Journal of Magnetic Resonance

[30] Mamisch TC, Dudda M, Hughes T, Burstein D, Kim YJ. Comparison of delayed gadolinium enhanced MRI of cartilage (dGEMRIC) using inversion recovery and fast T1 map-

[31] Kurkijarvi JE, Mattila L, Ojala RO, Vasara AI, Jurvelin JS, Kiviranta I, et al. Evaluation of cartilage repair in the distal femur after autologous chondrocyte transplantation using T-2 relaxation time and dGEMRIC. Osteoarthritis and Cartilage. 2007;**15**(4):372-378 [32] Gillis A, Bashir A, McKeon B, Scheller A, Gray ML, Burstein D. Magnetic resonance imaging of relative glycosaminoglycan distribution in patients with autologous chon-

[33] Trattnig S, Burstein D, Szomolanyi P, Pinker K, Welsch GH, Mamisch TC. T1(Gd) gives comparable information as delta T1 relaxation rate in dGEMRIC evaluation of cartilage

[34] Nehrer S, Minas T. Treatment of articular cartilage defects. Investigative Radiology.

ping sequences. Magnetic Resonance in Medicine. 2008;**60**(4):768-773

drocyte transplants. Investigative Radiology. 2001;**36**(12):743-748

repair tissue. Investigative Radiology. 2009;**44**(9):598-602

cartilage. Magnetic Resonance in Medicine. 2001;**45**(1):36-41

Imaging. 1987;**5**:201-208

196 Cartilage Repair and Regeneration

**239**(1):201-208

Roentgenology. 1997;**169**(4):1089-1096

Imaging. 2007;**26**(4):974-982

2000;**35**(10):639-646


[48] Wang L, Regatte RR. Investigation of regional influence of magic-angle effect on t2 in human articular cartilage with osteoarthritis at 3 T. Academic Radiology. 2015; **22**:87-92

[59] Welsch GH, Trattnig S, Hughes T, Quirbach S, Olk A, Blanke M, et al. T2 and T2\* mapping in patients after matrix-associated autologous chondrocyte transplantation: Initial results on clinical use with 3.0-Tesla MRI. European Radiology. 2010;**20**:1515-1523 [60] Welsch GH, Apprich S, Zbyn S, Mamisch TC, Mlynarik V, Scheffler K, et al. Biochemical (T2, T2\* and magnetisation transfer ratio) MRI of knee cartilage: Feasibility at ultra-high field (7T) compared with high field (3T) strength. European Radiology. 2011;**21**:1136-1143

MRI Mapping for Cartilage Repair Follow-up http://dx.doi.org/10.5772/intechopen.70372 199


[59] Welsch GH, Trattnig S, Hughes T, Quirbach S, Olk A, Blanke M, et al. T2 and T2\* mapping in patients after matrix-associated autologous chondrocyte transplantation: Initial results on clinical use with 3.0-Tesla MRI. European Radiology. 2010;**20**:1515-1523

[48] Wang L, Regatte RR. Investigation of regional influence of magic-angle effect on t2 in human articular cartilage with osteoarthritis at 3 T. Academic Radiology. 2015;

[49] Matzat SJ, McWalter EJ, Kogan F, Chen W, Gold GE. T2 relaxation time quantitation differs between pulse sequences in articular cartilage. Journal of Magnetic Resonance

[50] Welsch GH, Mamisch TC, Domayer SE, Dorotka R, Kutscha-Lissberg F, Marlovits S, et al. Cartilage T2 assessment at 3-T MR imaging: In vivo differentiation of normal hyaline cartilage from reparative tissue after two cartilage repair procedures—Initial experi-

[51] Welsch GH, Mamisch TC, Quirbach S, Zak L, Marlovits S, Trattnig S. Evaluation and comparison of cartilage repair tissue of the patella and medial femoral condyle by using morphological MRI and biochemical zonal T2 mapping. European Radiology.

[52] Welsch GH, Mamisch TC, Zak L, Blanke M, Olk A, Marlovits S, et al. Evaluation of cartilage repair tissue after matrix-associated autologous chondrocyte transplantation using a hyaluronic-based or a collagen-based scaffold with morphological MOCART scoring and biochemical T2 mapping: Preliminary results. The American Journal of Sports

[53] Nho SJ, Foo LF, Green DM, Shindle MK, Warren RF, Wickiewicz TL, et al. Magnetic resonance imaging and clinical evaluation of patellar resurfacing with press-fit osteochondral autograft plugs. The American Journal of Sports Medicine. 2008;**36**(6):1101-1109

[54] Kurkijärvi JE, Nissi M, Ojala RO, Vasara AI, Jurvelin JS, Kiviranta I, et al. In vivo T2 mapping and dGEMRIC of human articular cartilage repair after autologous chondrocyte transplantation. ISMRM 13th Scientific Meeting & Exhibition in Miami Beach, Florida,

[55] Domayer SE, Kutscha-Lissberg F, Welsch G, Dorotka R, Nehrer S, Gabler C, et al. T2 mapping in the knee after microfracture at 3.0 T: Correlation of global T2 values and clinical outcome. Preliminary results. Osteoarthritis and Cartilage. 2008;**16**(8):903-908

[56] Eagle S, Potter HG, Koff MF. Morphologic and quantitative magnetic resonance imaging of knee articular cartilage for the assessment of post-traumatic osteoarthritis. Journal of

[57] Bittersohl B, Miese FR, Hosalkar HS, Herten M, Antoch G, Krauspe R, et al. T2\* mapping of hip joint cartilage in various histological grades of degeneration. Osteoarthritis and

[58] Murphy BJ. Evaluation of grades 3 and 4 chondromalacia of the knee using T2\*-weighted 3D gradient-echo articular cartilage imaging. Skeletal Radiology. 2001;**30**:305-311

Orthopaedic Research. March 2017;**35**(3):412-423

**22**:87-92

198 Cartilage Repair and Regeneration

Imaging. 2015;**42**:105-113

2009;**19**(5):1253-1262

USA. 2005;**13**:481

Cartilage. 2012;**20**:653-660

Medicine. 2010;**38**(5):934-942

ence. Radiology. April 2008;**247**(1):154-161

[60] Welsch GH, Apprich S, Zbyn S, Mamisch TC, Mlynarik V, Scheffler K, et al. Biochemical (T2, T2\* and magnetisation transfer ratio) MRI of knee cartilage: Feasibility at ultra-high field (7T) compared with high field (3T) strength. European Radiology. 2011;**21**:1136-1143

**Section 3**

**Head and Neck**

**Section 3**
