Section 1 Rotator Cuff Pathology

#### **Chapter 1**

## Review of Ortho-Biologics in Rotator Cuff Repair

*Andrew Konopitski and Ajith Malige*

#### **Abstract**

Rotator cuff repair is one of the most commonly performed surgeries in orthopedics, yet rates of postoperative failure and retear remain relatively high. Poor biology and limited healing potential at the cuff insertion are frequently cited as potential confounders to otherwise technically successful surgeries. Over the past several years, ortho-biologics have been developed in an attempt to augment rotator cuff repairs. The following review will briefly cover normal biomechanics and histology of the rotator cuff and how this is altered in cuff tears, provide an in-depth summary of the available literature on various ortho-biologic agents, outline the limitations of each agent and give an idea on the future of ortho-biologics in rotator cuff.

**Keywords:** rotator cuff repair, biologics, stem cells, growth factors, platelet rich plasma

#### **1. Introduction**

Rotator cuff disease is among the most common causes of shoulder pain and dysfunction in adults. The overall incidence ranges from 87 to 198 cases per 100,000 person-years, with the prevalence only increasing with age [1]. Rotator cuff (RTC) pathology is present in as few as 10% of symptomatic patients under the age of 20 years, but this rate increases precipitously to 63% in patients over 50 years of age [2]. While technology and techniques used in rotator cuff repair (RCR) have evolved, outcomes have generally plateaued. Rates of repair failure continue to range from 20 to 60% and usually occur within the first 15 months of surgery [3]. Furthermore, rotator cuff re-tear has been associated with significant decreases in patient reported outcomes and function [3, 4].

Several factors have been postulated to contribute to the relatively high failure rate of RCR, mostly due to either patient specific versus factors involving surgical technique. Patient related risk factors can be modifiable (smoking, compliance to post-operative protocol, strict blood sugar control) or non-modifiable (RCT size, chronicity, patient age, etc.) [5]. In an effort to improve success after RCR as well as patient outcomes, surgeons have explored the addition of biologic augmentation aimed at addressing each of these obstacles to tendon healing. The goals of this review are as follows:


#### **2. Biomechanics and histology of the native and diseased rotator cuff**

#### **2.1 Biomechanics**

The rotator cuff is a confluence of both static and dynamic stabilizers that work together to maintain the instantaneous center of rotation of the humeral head within the glenoid fossa throughout the arc of shoulder motion [6]. The static stabilizers include four glenohumeral ligaments, the coracohumeral ligament (CHL) and the glenoid labrum. The glenohumeral ligaments are discrete capsuloligamentous bands which become variably tensioned depending on arm position and serve as checkreins to excessive humeral head translation at the extremes of motion [7, 8]. The CHL works in conjunction with the superior glenohumeral ligament (SGHL) to resist inferior humeral head translation with the arm adducted, and the labrum serves not only to deepen the relatively shallow glenoid fossa but also to contribute to the overall negative pressure within the glenohumeral joint [8].

While static stabilizers are instrumental in maintaining normal shoulder biomechanics, they are far less frequently injured than the dynamic stabilizers which fall victim to degenerative changes of age, chronic overuse and acute trauma. The four rotator cuff muscles are the supraspinatus, infraspinatus, teres minor and subscapularis. The supraspinatus originates in the supraspinatus fossa of the scapula and inserts along the superior aspect of the greater tuberosity. Its primary function is to work in conjunction with the deltoid to initiate shoulder abduction and to counteract superior migration of the humeral head [6]. The infraspinatus and teres minor both insert along the posterior aspect of the greater tuberosity and function primarily as external rotators of the shoulder as well as resistors to posterior translation, though the infraspinatus does contribute somewhat to abduction and resistance to superior translation as well [6, 8]. Lastly, the subscapularis originates in the subscapular fossa and inserts broadly along the lesser tuberosity, medial to the bicipital groove where it becomes confluent with the transverse humeral ligament. The subscapularis is a strong internal rotator of the humerus, resists anterior and inferior translation, and provides stability to the biceps tendon [8]. Disruption of any one of these dynamic stabilizers can result in the loss of the physiologic force coupling between the humeral head and the glenoid leading to pain, weakness, reduced active range of motion and eventual degenerative changes.

#### **2.2 Histology**

Understanding the histology of the rotator cuff is imperative in order to contextualize the use of biologic adjuncts to improve healing responses. Near their insertion points on the greater tuberosity, the tendons of the supraspinatus and infraspinatus become confluent into one conjoined tendon. The microscopic cross-sectional anatomy of the conjoined tendon has been described as being 5 distinct layers.

#### *Review of Ortho-Biologics in Rotator Cuff Repair DOI: http://dx.doi.org/10.5772/intechopen.102284*

Layer 1 is the most superficial layer composed of fibers from the CHL and is rich in blood supply. Layer 2 is composed of large bundles of parallel tendon fibers with arterioles from layer 1 intermixed. Layer 3 has small diameter tendinous bundles which are loosely packed and have a sparse blood supply. Layer 4 is primarily loose connective tissue with collagen bundles, and Layer 5 is continuous with the joint capsule and inserts on the humerus as Sharpey fibers [9]. More simply, the cuff can be thought of as having a bursal side superficially and an articular side abutting the joint capsule. The bursal side has more tensile strength and better vascularity than the joint side, yet it is prone to degenerative tears frequently resulting from impingement whereas joint sided tears often result from acute trauma [10].

The blood supply to the rotator cuff plays an important role in both injury and healing potential. Codman in 1934 first described a "critical zone" of the supraspinatus tendon roughly 1 cm proximal to its insertion on the greater tuberosity which exhibited poor blood supply. A cadaveric study by Determe et al. in 1996 confirmed the presence of this hypovascular zone, and Levy et al. later showed that the presence of this hypovascular zone is exacerbated in impingement [11, 12]. It has therefore been postulated that the critical zone plays a significant role in the development of degenerative rotator cuff tears and may also provide a suboptimal environment for tendon healing after attempted repair.

The tendon-bone interface, known as the enthesis, is the region of the RTC most prone to tears and can be separated into four distinct zones: tendon, nonmineralized fibrocartilage, mineralized fibrocartilage, and bone [13–16]. Healing of rotator cuff tears (RCT) progresses through three overlapping stages. Stage 1 (0–7 days) is characterized as the inflammatory phase. In this stage, damaged tissues release various cytokines which recruit inflammatory cells such as neutrophils, monocytes and fibroblasts. These inflammatory cells release further cytokines, clear cellular debris and promote early angiogenesis. Stage 2 is the repair phase (5–21 days) in which a pro-fibrotic environment causes scar formation primarily composed of type III collagen. Stage 3 is the remodeling phase which can last for up to 8 weeks where type III collagen is steadily converted into type I [17]. Unfortunately, even after complete remodeling, the resulting healed scar at the enthesis fails to reach the same biomechanical strength as the native tendon insertion [13]. This is compounded by the frequent formation of gaps within the repaired tendon which have been shown through post-operative ultrasonographic and MRI studies [18–20]. The aim of ortho-biologic augmentation in RCR is to create an environment which minimizes the amount of type III collagen scar formation and instead

#### **3. Osteoinductive growth factors**

The introduction of osteogenic growth factors in RCR is one of the earliest uses of biologic augmentation aimed at improving the healing response. Studies have shown that healing of a repaired cuff tendon to bone is dependent on bony ingrowth. In vitro studies were able to demonstrate improved attachment strength of tendon within bone tunnels with the addition of bone morphogenic proteins (BMPs) [20]. Through immunohistological staining, Würgler-Hauri et al. isolated eight different osteoinductive growth factors (bFGF, BMP-12, BMP-13, BMP-14, COMP, CTGF, PDGF-B, and TGF-β1) which were temporally expressed throughout the 16 week arc of healing [21]. Following this, Rodeo et al. in 2007 were the first to introduce an exogenous osteogenic bone protein extract in vivo in a sheep model. A bovine derived extract

contained a mixture of BMP-2, BMP-7, transforming growth factor-β-1-3 (TGF-β1, TGF-β3) and fibroblast growth factor (FGF) which was impregnated into a type I collagen sponge and placed over the repair site. This study demonstrated greater formation of new bone, fibrocartilage, and soft tissue, with a concomitant increase in tendon attachment strength, but less stiffness than repairs treated with the type I collagen sponge carrier alone [20]. An important caveat to this study is that MRI evaluation of the repairs showed consistent gap formation at the repair sites.

#### **3.1 Bone morphogenic proteins**

BMPs are part of the TGF-β family and have been identified as growth factors important for new bone formation [22]. In vitro studies of BMP-2 and 7 have demonstrated dose dependent increases in type I collagen production, expression and cellular activity [22, 23]. Further in vitro study of BMP-7 has shown that it can induce differentiation of mesenchymal stem cells into chondrocytes which promotes the regeneration of interfacial cartilage and improves the quality of tendon healing [24]. In both rabbit and rat models, BMP-2 and 7 have demonstrated the ability to enhance new bone formation and tensile strength in repaired tendon insertions [24–26]. Unfortunately, no studies have been published on the use of BMP-2 or 7 in human RCR.

BMP-12 and 13 are thought to be important regulators of fibrocartilage, neotendon, and ligament formation [27]. There are limited in vitro studies of BMP-12 and 13 in the literature, but several in vivo studies have been published. Seeherman et al. in 2008 used human recombinant BMP-12 (rhBMP-12) on a collagen sponge carrier in the sheep model which resulted in higher tensile strength and faster healing times compared to untreated controls [28]. In the rat model, Lamplot et al. administered recombinant adenoviral vectors which caused the upregulation of BMP-13 and found increased biomechanical strength in the healing tendons after 2 weeks [29]. There is one randomized, multicenter study in humans which implanted an absorbable collagen sponge treated with BMP-12. This study did demonstrate safety of BMP-12, but did not evaluate whether there were any clinical, biomechanical or structural improvements with BMP-12 treatment [30].

BMP-14 has been found at the tendon edges on the bursal side of torn rotator cuffs. In conjunction with BMP-13, it has been shown to increase the tensile strength of regenerated tendon [31]. As of yet, no human studies have evaluated the safety or efficacy of BMP-13 or 14 in isolation for RCR.

#### **3.2 Platelet derived growth factors**

Platelet derived growth factor (PDGF) includes a family of 5 soluble, dimeric glycoproteins (PDGF-AA, -BB, -CC, -DD, -EE) which are released from alpha granules in platelets. PDGF-BB has been shown to have mitogenic and chemotactic effects on tenocytes, fibroblasts and mesenchymal stems cells and is another important growth factor in tendon healing [32]. One notable point which has been demonstrated with PDGF research is the influence of timing of administration on tendon healing, as not all growth factors are present at equal concentrations throughout the healing process. The normal peak PDGF-BB concentration occurs between 7 and 14 days after surgical repair [31]. In a rat patellar-tendon defect model, there was an increased proliferative response when PDGF-BB was injected on day 3 after surgery, and addition of PDGF-BB on day 7 improved peak load and pyridinoline content after administration of the highest dosage of PDGF [33, 34].

*Review of Ortho-Biologics in Rotator Cuff Repair DOI: http://dx.doi.org/10.5772/intechopen.102284*

The primary modes of administration for PDGF-BB are by way of suture dipcoated with the growth factor or by being housed within a type I collagen scaffold. PDGF-BB dip-coated suture did show overall improved histological scores in sheep models, but there was no significant increase in ultimate load-to-failure after 6 weeks [32]. Studies measuring the effect of PDGF-BB impregnated collagen scaffolds in rat models have provided heterogeneous results and no study has been conducted in humans [35, 36].

#### **3.3 Transforming growth factor-β**

Transforming growth factor-β (TGF-β) is a ubiquitous growth factor which is present throughout all phases of tendon healing and is secreted by all cells participating in the healing response including platelets, lymphycytes, macrophages, endothelial cells and fibroblasts [37]. The three isoforms most closely linked to scar formation and tendon healing are TGF-β1, TGF-β2 and TGF-β3. Initial studies in TGF-β came from information gained through the study of healing fetal tissues. It was found that wound healing in fetal tissue is marked with decreased expression of TGF-β1 and β2 with increased expression of TGF-β3 [38]. These studies in fetal wound healing spawned a plethora of similar explorations of TGF-β as it relates to tendon healing in the rotator cuff. An early study performed by Kim et al. on rat supraspinatus models, neutralizing antibodies were used in conjunction with an osmotic pump to allow for the selective presence of each TGF-β isoform in isolation. They found that type III collagen production was increased in the context of TGF-β1, but were unable to show significant differences in mechanical properties with any of the isoforms [39]. At the same time, Manning et al. used a heparin/fibrin-based delivery system to affect a sustained concentration of TGF-β3 to the supraspinatus tendon of rats. They found significant improvements in tendon healing histologically as well as improved biomechanical strength [38]. Several years later, Yoon et al. again tested the sustained administration of TGF-β, but this time using the TGF-β1 isoform. This study found improved mechanical and histological properties of sustained TGF-β1 delivery on an alginate scaffold compared to a single TGF-β1 injection or suture repair alone in the rabbit models [40]. Most recently, Yoon et al. (2021) again tested a sustained release model of TGF-β1, but this time they developed a porous suture containing the growth factor and tested it on a rat model. They found similar improvements in the biomechanical and histological properties with the porous suture containing TGF-β1 compared to controls [41]. As of yet, no study has evaluated the safety or efficacy of isolated TGF-β biologics in human RCR.

#### **3.4 Basic fibroblast growth factor**

Early in vitro studies of basic fibroblast growth factor (bFGF) highlighted the importance of this growth factor in promoting the proliferation of mesenchymal stem cells as well as collagen production [42]. BFGF, specifically FGF-2, causes fibroblasts to produce collagenase and stimulates proliferation of capillary endothelial cells, both of which are necessary for angiogenesis. It also helps to initiate the formation of granulation tissue [34]. In one of the earliest studies investigating bFGF on rotator cuff tissue in mice, Ide et al. combined FGF-2 with a fibrin sealant which was then placed within the greater tuberosity decortication site. They compared the FGF-2 additive to fibrin sealant alone and found that the repair sites were histologically more mature and biomechanically stronger at 2 weeks, but these improvements were not

seen at 4 and 6 weeks [43]. Later, Lu et al. loaded bFGF onto a hydroxyapatite coated orthocord suture and found that the addition of bFGF increased tendon thickness, but did not show histological improvements [44].

With the advent of collagen scaffolds (discussed below), in vivo studies of bFGF have greatly expanded. In 2015, Peterson et al. used an FGF-2 impregnated scaffold in the repair of ovine supraspinatus tendons. At 8 weeks they found thicker tendon formation which mimicked native tendon structure, more new bone formation, less gap formation and improved biomechanical properties compared to controls [45]. Tokunaga et al. translated this information to the rabbit model and tested two different concentrations of FGF-2, 3 μg and 30 μg, in a gelatin hydrogel sheet which was inlayed into the greater tuberosity decortication site prior to tendon repair. At 12 weeks both treatment groups demonstrated improved histologic and biomechanical properties compared to controls [46]. Similar improvements in histologic scores and biomechanical strength have now been found with the addition of FGF-2 to chronic RTC tears as well as in the context of platelet-rich plasma (discussed below) [47, 48]. However, while in vivo evidence supporting the use of bFGF in tendon repair appears robust, there is no current evidence addressing the safety or efficacy of bFGF in human RCR.

#### **4. Platelet-rich plasma**

Platelet-rich plasma (PRP) has been extensively studied in its use as a stand-alone or adjunctive treatment option for rotator cuff tears, with its use projected to continue to increase in the coming years. This autologous agent is obtained from the patient and centrifuged down in a cost effective manner [49], resulting in a plasma layer that is highly concentrated in platelets (3–5 times higher than in normal blood) [50]. It is then most commonly delivered as an injectable concentration to the desired site. PRP can also be made [17] into a gel state that allows delivery to a specific area with prolonged function [51]. Ersen et al. studied the delivery method of PRP, finding that injectable PRP and absorption from a PRP sponge have similar effects on tendon-bone interface biomechanical properties [52].

There are four types of formulations described: platelet-rich fibrin matrices made from activating autogenous thrombin with the plasma, leukocyte-platelet-rich plasma made by retaining leukocytes while preparing the PRP concentration, platelet rich in growth factors, and an autologous conditioned plasma that is an Arthrex product (Naples, FL, United States) made from a centrifuged solution of autologous blood [53–55]. Regardless of type, PRPs have been theorized to be efficacious in tendon repair due to their myriad of growth factors and cytokines, including transforming growth factor beta (TGF-β), basic fibroblast growth factor (FGF), insulin-like growth factor (IGF-1), vascular endothelial growth factor (VEGF), and platelet rich derived growth factor (PDGF) [56–60].

Proponents of PRP argue that it is an easily harvestable autologous agent with a low-risk profile that offers the potential to deliver high concentrations of beneficial growth factors. Detractors note that the final PRP concentration can be highly variable based on patient biology and the preparation process [61]. When considering their benefit in RCR specifically, in vitro studies have theorized that PRP not only increases tenocyte matrix synthesis and cell proliferation but also can activate existing tenocyte progenitor cells that can aid in tendon regeneration and healing [62–64]. Hoppe et al. theorized that existing fibroblasts showed increased proliferation in

#### *Review of Ortho-Biologics in Rotator Cuff Repair DOI: http://dx.doi.org/10.5772/intechopen.102284*

the presence of PRP, citing PRP as a beneficial activator in the healing process [65]. Dolkart et al. used a rat model to demonstrate a higher load to failure, better stiffness, and improved histological characteristics in a PRP-augmented RCR [66].

Based on these theorized benefits, PRP has been explored as a stand-alone nonoperative treatment option for rotator cuff tears. Kesiburun et al. compared PRP injections to saline injections, finding that there was no difference in pain scores or functional outcomes between the two treatment options [67]. Shams et al. compared subacromial PRP injections to corticosteroid injections, finding that both groups had improved pain scores post-injection. They also found that patients who received PRP injections had more pain relief at 3 months postoperatively but similar pain improvement at 6 months compared to the corticosteroid injection group [68].

Studies exploring PRP as an adjunct during surgical rotator cuff repair are heterogeneous and hard to draw conclusions from due to the variety of patient biology, cuff tear patterns, tendon quality, and repair techniques. Studies have demonstrated the imaging-backed conclusion that PRP injections improve structural healing rates of the injured tendon with decreased failure rates [69]. This is important, especially in younger patients, since this can be associated with improved strength and overhead function. Hurley et al. in their review showed that PRP can reduce the rate of incomplete tendon healing in small to medium sized tears and medium to large sized tears [70]. A few studies have built off of these improvements in tendon healing and have noted improvements in patient satisfaction and pain scores after rotator cuff repairs utilizing PRP [71]. Multiple studies have noted lower re-tear rates after RCR utilizing PRP as well [69, 72, 73].

However, for the most part these improvements in tendon healing have not resulted in sustained clinical improvements, as most studies detail a lack of differences long-term in patients who undergo rotator cuff repair with PRP using an adjunct versus those who undergo a repair in isolation [74–76]. Charousset et al. found no difference in outcomes, both functional and radiographic, or re-tear rates between repairs completed utilizing leukocyte-rich PRP and those without [77]. Rodeo et al. in their randomized controlled trial reported no difference in tendon healing or functional improvement after RCR utilizing platelet rich PRP versus repairs without an adjunct. Interestingly, they did report that using this PRP came with a 5.8 higher likelihood of tendon-bone healing failure at 12 weeks compared to repairs without this adjunct [78]. Ruiz-Moneo et al. reported similar improvements in functional outcomes, patient satisfaction, and tendon healing after RCR utilizing PRP versus repair without it [79]. These similarities between groups remained in studies that looked at 10-year outcomes after RCR utilizing PRP versus RCR alone [80].

#### **5. Stem cells**

The use of stem cells to enhance tendon healing responses is a fairly new and quickly evolving field. It has become evident that tendon healing is a complex process that involves the overlapping of a multitude of growth factors and cell types. Targeting pluripotent stem cells to RCR sites can theoretically prompt the cells to differentiate into the tenocyte lineage, thus allowing for the production of all the required growth factors and machinery to create a more robust repair that mimics the native tendon. The following sections will focus on different sources for stem cells and will summarize the evidence available for each in the context of RCR.

#### **5.1 Bone marrow-derived mesenchymal stem cells**

Mesenchymal stem cells are pluripotent cells which can differentiate into any tissue of mesenchymal embryologic origin including muscle, fat, bone and tendon. This, along with the relative ease with which the cells can be obtained via bone marrow aspirate, make bone marrow-derived mesenchymal stem cells (BMSC) attractive candidates for biologic augmentation in RCR.

In vivo studies of BMSCs have been flooding the literature over the last 10–15 years and have utilized several different animal models as well as delivery methods. A summary of the literature can be found in **Table 1**. Overall, in vivo data supporting the use of BMSC in isolation or in combination with other factors such as PRP or demineralized bone matrix is strong. It has been shown repeatedly that histology of repaired tendon in the context of BMSC tends to closely align with native tendon structure and biomechanical strength has been shown to improve in concert with this data [83–87].

#### **5.2 Adipose-derived stem cells**

Adipose-derived stem cells (ADSC) have been a more recent focus of investigation than BMSCs, but have similarly strong in vivo data supporting their use. ADSCs share a similar advantage to BMSCs in that they are fairly easily harvested and have significant pluripotent cell potential [98]. The most commonly cited method for purification of ADSCs is the protocol outlined by Zuk et al. in a series of eight steps: obtain adipose tissue by liposuction, wash raw lipoaspirate, enzymatically digest lipoaspirate, centrifugal separation, lyse contaminating red blood cells, filter, incubate, and final wash to remove residual red blood cells [98, 99].

A summary of the available evidence for the use of ADSCs is found in **Table 1**, but only three of these studies were based on human trials. Kim et al. in 2017 injected ADSC along with a fibrin glue at the conclusion of surgical repair. At one year, the patients treated with ADSC and fibrin glue did have a significantly lower retear rate, though this did not translate into improved pain or functional scores compared to control [100]. The following year Jo et al. published two studies in which they injected ADSCs directly into partial RCTs. In the first of the two studies, patients were given either a low, mid or high concentration of ADSC in order to establish safety and tolerability. After this, a second study was conducted where all patients received the high concentration injection. In both studies, patients exhibited improved pain and functional scores as well as near complete RCT healing on repeat MRI evaluation at 2 years [101, 102]. While the number of patients included in this study was relatively small, the results show promise for future applications.

#### **5.3 Umbilical cord blood-derived mesenchymal stem cells**

Of the various tissues containing mesenchymal stem cells, human umbilical cord blood-derived MSCs (UCB-MSC) have theoretical benefits over other tissue derivatives including: (1) the ability to home in on injured tissue, (2) low immunogenicity, (3) multidirectional differentiation, (4) extensive secretion profiles, (5) ability to be produced commercially in large quantities with homogenous quality and (6) allogenic UCB-MSCs are not prone to degenerative impairments of age seen with autologous MSCs [95].

*Review of Ortho-Biologics in Rotator Cuff Repair DOI: http://dx.doi.org/10.5772/intechopen.102284*


*BMSC—bone marrow-derived stem cells, RCT—rotator cuff tear, PGA—polyglycolic acid, PRP—platelet rich plasma, ADSC—Adipose-derived stem cells, BMP2—bone morphogenic protein 2, TGF-β3—transforming growth factor beta 3, UCB-MSC—umbilical cord blood-derived mesenchymal stem cell, PDRN—polydeoxyribonucleotudes.*

#### **Table 1.**

*Summary of studies conducted using mesenchymal stem cell derivatives.*

Thus far, all published data on UCB-MSCs has been conducted on animal models that undergo a simulated RCT followed by the later injection of UCB-MSCs under ultrasound guidance with no attempt at underlying repair. A summary of the

available data can be found in **Table 1**. While all studies have shown the ability to produce at least partial thickness healing with a high concentration of type I collagen, further investigation is needed to determine the utility of UCB-MSCs in the context of RCR. It should also be noted that all the available literature regarding UCB-MSC has been published solely out of Catholic University of Daegu School of Medicine in South Korea.

#### **5.4 Subacromial bursa-derived cells**

Perhaps the most recent tissue type to be harvested for stem cells is subacromial bursa tissue. The potential for subacromial bursal tissue to supply mesenchymal stem cells was first described in a protocol outlined by Lhee et al. where human tissue was obtained, treated with a collagenase to isolate cells, then serially cultured. The resulting cell lines were then subject to immunohistochemical staining to confirm their mesenchymal potential [103]. This process was later refined by Morikawa et al. in an effort to identify an effective, nonenzymatic method for maximizing the yield of subacromial bursa-derived nucleated cells (SBDC). They found that a mechanical chopping method of tissue processing led to similar yields of SBDC which could easily be implanted during surgery [104]. Morikawa et al. also conducted an in vitro study in an effort to compare SBDC to BMSC (discussed above) and found that SBDC possessed significantly increased differentiation ability and gene expression over time compared to BMSC [105]. This data has been further substantiated by the work of Meunch et al. and Landry et al. [106, 107].

Thus far, no in vivo or human trials investigating SBDCs have been published. Freislederer et al. did publish a technique in which subacromial bursal tissue from the lateral subdeltoid region is used to overlay the RCR and sutured in place, but no long-term results from this technique have been reported [108].

#### **6. Scaffolding devices**

Biomaterials that are used as a scaffold during rotator cuff repair should fulfill the following four criteria: (1) they should withstand the stresses placed at the bone-tendon interface by mimicking the biomechanical properties of native tissue (2) the physical structure should closely mimic fibrocartilage 3.) the material should both be biodegradable and lack side effects during degradation 4.) the biomaterial should be capable of being used in multiple settings and have multiple functions [22]. Furthermore, pore diameter, especially in porous scaffolds, is important to consider, as smaller pores are inefficient and larger pores can compromise the scaffold's mechanical properties [109].

Biological, or natural, scaffolds have been formed from human, equine, porcine, and bovine sources. All the non-collagen components are processed out while the collagen 1-predominant structure is kept in order to maintain its biomechanical properties [110]. Other scaffolds designed from natural polymers include silk, fibrin, and polysaccharide based augments [111]. Silk scaffolds in particular have been greatly explored due to its biodegradable and biocompatible properties. They have been theorized to both be reliable augments as well as a scaffold for stem cell delivery to the repair site [112, 113].

Synthetic scaffolds trade out the ability to have better biomechanical properties compared to natural scaffolds for limited biocompatibility when used *in vivo*.

#### *Review of Ortho-Biologics in Rotator Cuff Repair DOI: http://dx.doi.org/10.5772/intechopen.102284*

These scaffolds are theoretically more versatile in their tailoring and utilization as rotator cuff repair augments as well, representing a possibly reproducible source that can deliver growth factors and stimulate tendon healing with low immunogenicity. However, the lack of biomechanical or clinical superiority of these scaffolds compared to natural scaffolds has stifled much enthusiasm towards exploring these structures in rotator cuff repairs [111, 114, 115].

Extracellular matrices have been recently developed as a scaffold patch to support both cell attachment and matrix formation, aiding in tendon healing after rotator cuff repair [116]. These patches have been theorized to help augment repairs either by acting as a load-sharing device that reduces strain across the repair site or by acting as a scaffold to support cell attachment, matrix synthesis, and new tissue formation [117]. Data on the efficacy of this augment is limited but promising. Bokor et al. utilized a collagen patch augmentation and found new tissue formation in all patients by 3 months after repair and a nearly normal-looking rotator cuff tendon by 12 months [118].

Nanomaterial scaffolds are a more recently developed and utilized polymer that have had promising results. They have a high surface area to volume ratio and can be easily altered for their intended use. They have had promising *in vitro*, animal, and clinical studies showing the potential to be used regularly to improve results due to their ability to be a platform for nanotopography-mediated cell response, the incorporation of stem cells, and the housing and delivery of active growth factors [119–123]. Based on the structure and biomolecular basis of these scaffolds, they have been shown to aid in cell proliferation [124], osteogenic differentiation [125], osteogenesis [126], and improving the biomechanical strength [127] of the healing tendon.

Hydrogel scaffolds have also been explored as useful, biocompatible scaffolds. Hydrogels are gelatinous viscoelastic structures that can be utilized in various forms while augmenting rotator cuff repairs. They have been loaded with exogenous biomolecules, including platelet-derived growth factor [35] and bone morphogenic protein (BMP) [26], as well as delivered directly *in vivo* in combination with progenitor cells and BMP and allowed to polymerize [128]. Both utilizations yielded a bone-tendon interface that showed greater collagen fiber orientation, improved biomechanical properties, and higher ultimate failure loads.

#### **7. Vesicular phospholipid gels**

Vesicular phospholipid gels (VPGs) are lecithin and aqueous buffer solutions that allow for the non-toxic and safe prolonged release of growth factors to a specific location. These products are easy to produce and easy to deliver to a desired location with minimal systemic effects. This product can theoretically house and deliver any product that can help improve tendon healing [129, 130]. Buchmann et al. showed that VPGs filled with granulocyte colony-stimulating factor improved load-to-failure ratio and improved collagen I/III ratios when combined with rotator cuff repairs compared with repairs done without VPGs [129].

#### **8. Matrix metalloproteinase inhibitors**

Matrix metalloproteinases (MMPs) are a group of enzymes belonging to a family of 24 zinc-dependent endopeptidases that exist as inactive proenzymes and become

activated after proteolysis secondary to physiologic or pathologic conditions. Once active, they break down extracellular matrix components and have been found in high concentrations with acute RCTs, especially MMP-13 [22, 131, 132]. It has therefore been hypothesized that inhibiting local MMP activity in RCR will lead to a more robust healing response. Bedi et al. conducted a rat based study in which three treatment groups were given 130 mg/kg oral doxycycline, a known MMP synthesis inhibitor, at different time frames. Group 1 was treated in the immediate postoperative period, group 2 was given oral doxycycline starting 5 days postop, and group 3 began doxycycline treatment 14 days postoperatively. Groups 1 and 2 exhibited improved histologic healing and load to failure, while group 3 demonstrated no such benefit [133]. The same group of researchers conducted a follow-up study in a rat model in which alpha-2-macroglobuline (A2M) was locally applied to the RCR intraoperatively. While the repair sites did show improved histologic collagen organization, they failed to demonstrate biomechanical improvements [134].

Studies looking at the effects of MMP inhibition in RCR are limited in both scope and number, but preliminary in vivo studies have provided promise for future investigation.

#### **9. Future directions**

The most recent research has veered away from utilizing exogenous agents and towards utilizing intrinsic progenitor cells, or the "stem cell niche." It is theorized that while most of these cells are quiescent at baseline, they are stimulated during tissue injury and repair, and this property can be utilized during RCR. This includes sources such as previscular mesenchymal stem cells [135], subacromial bursa [136], and umbilical cord blood [95] among others. Furthermore, continued work is necessary to try to maximize the localization of stem cell treatments and avoid any systemic effects, side effects, or possible cellular mutations that can adversely affect the patient [22]. Finally, most adjuncts have been studied in isolation. The combination of one or more of the already discussed adjuncts could help achieve results that are more efficacious than any adjunct used in isolation.

Outside of the utilization of indogenous agents, gene therapy and gene editing has also been hypothesized as a possible target in helping to improve the biologic activity of progenitor cell lineages. The exosomes of mesenchymal stem cells have recently been extracted and studied as a possible adjunct. It is hypothesized that M2 macrophage-derived exosomes contain proteins and RNA that can stimulate tendon healing without triggering an immune rejection response; however, further research is necessary to truly know if they have a beneficial role in tendon healing and whether any benefit will translate to improved clinical outcomes [137, 138]. The use of augmented sutures and anchors should also continue to be explored [139]. The study of biomaterials that re-create the bone-tendon interface and can augment tendon repair have also been of interest recently and should continue to be explored [140]. Finally, nanotechnology has only been recently explored as a possible adjunct in aiding RCR success and can continue to be a topic of exploration [141].

#### **Conflict of interest**

The authors declare no conflict of interest.

*Review of Ortho-Biologics in Rotator Cuff Repair DOI: http://dx.doi.org/10.5772/intechopen.102284*

#### **Author details**

Andrew Konopitski\* and Ajith Malige St. Luke's University Health Network, Bethlehem, United States

\*Address all correspondence to: andrew.konopitski@gmail.com

© 2022 The Author(s). Licensee IntechOpen. 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.

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#### **Chapter 2**

## Single-Row Rotator Cuff Repair

*Amhaz Escanlar S., Jorge Mora A. and Pino Miguez J.*

#### **Abstract**

Rotator cuff tears are a common cause of pain and disability among adults. Partial tears are usually treated conservatively. Complete tears might be treated conservatively in some cases; however, surgical repair is often performed in selected cases and situations where conservative treatment fails to restore function and pain relief. In addition, some patients with acute tears might be good candidates for acute surgical repair, as will be studied in this chapter. A plethora of techniques is available to repair rotator cuff tears. Among these, the surgeon faces the dilemma to choose the best treatment for the patient. Open techniques were the gold standard in the 1990s. However, the advent of arthroscopy has led the shoulder and sports surgeon community towards these. Arthroscopic rotator cuff repair has become the gold standard nowadays despite the lack of proper evidence to support this change. Furthermore, simple single-row repairs had been discarded favouring double-row techniques, yet new evidence supports the use of the former due to similar results, simplicity and cost-effectiveness. This chapter examines current evidence to help the surgeon decide between open and minimally invasive techniques and select suitable repair configurations.

**Keywords:** rotator, cuff, single-row, transosseous, double-row, mini-open, arthroscopy

#### **1. Introduction**

Rotator cuff tears are commonly seen in the orthopedic surgeon clinic, even more in the shoulder and elbow subspecialized professional practice. Different muscles form the rotator cuff: subscapularis, supraspinatus, infraspinatus, teres minor, and some authors also include the teres major due to its role as an internal rotator. The primary role of the rotator cuff is to stabilize the humeral head regarding the glenoid to allow the deltoid to perform the elevation of the arm. In addition, the rotator cuff externally rotates the glenohumeral joint (infraspinatus and teres minor) and contributes to internal rotation (subscapularis, assisted by the pectoralis major, teres major and latissimus dorsi) [1].

Patients with rotator cuff tears mainly complain of pain during daily living activities but also at night, when the pain can likewise interfere with proper resting. Moreover, a significant tear may impair function, limiting the active range of motion and can be the culprit of premature glenohumeral arthritis. Loss of external rotation, sometimes isolated, may appear in the onset of a posterior rotator cuff tear [1, 2].

Rotator cuff tears are expected after 60 years old. They correspond with the Neer type 3 stage and can be identified in about 20–30% of the patients in this age group. Beyond 80 years old, the ratio of patients suffering from cuff tears rises to more than 60%. However, the symptoms do not correlate with the presence of tears or even the size or retraction. Most patients do not seek advice from an orthopedic surgeon and do not demand a surgical intervention. More than half of the patients where a tear is identified will also suffer from a tear in their contralateral shoulder, especially in those older than 60 years [2–7].

#### **1.1 Risk factors**

Several risk factors have been identified concerning cuff tears. Age, as it was aforementioned, is the most significant. However, others such as smoking, hypercholesterolemia, diabetes, hypo or hyperthyroidism, trauma, scapular dyskinesia and kyphosis also play a critical role in the development and progression of cuff tears [7–15].

#### **1.2 Classification**

A plethora of classifications for rotator cuff tears has been described since the pathology became more interesting for the orthopedic community.

Neer described the evolution of rotator cuff disease in three stages. First, in individuals younger than 40 years, one can observe oedema and hemorrhage in the rotator cuff. In a second stage, the disease evolves in individuals between 40 and 60 years old, and fibrotic and tendinosis phenomena might be observed. Finally, in a third stage, usually, in patients older than 60 years, a tendon rupture is observed. Probably a fourth stage would involve rotator cuff arthropathy, with cephalad migration of the humeral head and degenerative osteoarthritis at the level of the glenoid as well as in the humeral head [15, 16].

Some authors have advocated for a classification based on tear size. Cofield in 1982 described four types of tears: small (<1 cm) medium (1–3 cm) large (3–5 cm) massive (>5 cm) [17].

Bateman also described a four-group classification based on the size: Grade 1 (<1 cm after debridement), Grade 2 (1–3 cm, after debridement), Grade 3 (<5 cm) and Grade 4 (global tear with no cuff left) [18].

Harryman described a classification based on the number of injured tendons. It is commonly accepted in Europe that a complete tear of two or more tendons should be considered massive, and concerns about reparability should arise [19].

Ellman and Gartsman introduced in 1993 a classification differentiating partialthickness and full-thickness tears. Partial tears were classified in grade 1 (<3 mm deep, <25% thickness), grade 2 (3–6 mm, <50%) and grade 3 (>6 mm, >50%). The partial tear classification system is accepted worldwide as it helps in treatment selection, as discussed in the next section. These authors also proposed a full-thickness classification based on tear-shaped, which has been judged useful and is currently used worldwide. Five groups were described: crescent shape, L shape, Reverse L, trapezoidal shape and massive tears [20, 21].

Concerning partial tears, Snyder clarified that a distinction between articular and bursal tears is mandatory as the criteria for surgery are different.

Fox and Romeo described a specific classification for subscapularis tears in 2003. Four types were proposed: Type 1, partial thickness; Type 2, complete tear of the

#### *Single-Row Rotator Cuff Repair DOI: http://dx.doi.org/10.5772/intechopen.101911*

upper 25%; Type 3, a complete tear of the upper 50%; Type 4, complete rupture of the subscapularis tendon [22].

Other authors prefer to classify tears about the retraction, as it can help the surgeon assess reparability before the operation. Patte described in 1990 three groups: Stage 1, where the tendon stump is adjacent to its insertion; Stage 2, with a tendon stump at the level of the humeral head; Stage 3, where the tendon is at the glenoid level or even more medial.

Patte also described a classification in the sagittal plane based on six segments: Segment 1, isolated subscapularis tear; Segment 2, isolated rotator interval tear; Segment 3, isolated supraspinatus tear; Segment 4, supraspinatus and upper onehalf of the infraspinatus; Segment 5, complete supraspinatus and infraspinatus; and Segment 6, complete cuff rupture [23].

Finally, some authors prefer a classification based on tissue quality and atrophy. Currently, the classification proposed by Goutallier in 1994 is the most accepted and used. The author described stage 0, corresponding with a normal muscle. Stage 1, some fatty streaks; Stage 2, less than 50% of fatty atrophy; Stage 3, more than 50% of fat; Stage 4, fatty atrophy greater than 50% [24].

#### **2. Treatment**

The orthopedic surgeon's community has failed, to the date, to clearly identify which patients would benefit from surgical repair as the primary treatment. Most patients accept an initial attempt of conservative treatment, which is successful in most cases. They undergo a surgical rotator cuff repair if the former fails to provide pain relief and function improvement. Although this strategy is accepted worldwide, it does not provide a definitive solution for the tear, which seldom heals on its own (about 10% of small tears heal, and 10% become smaller). Tear progression is always worrisome as it may lead to non-repairability, arthritis and chronic pain. As a matter of fact, more than 50% of patients with partial tears experience a progression, which is closely correlated with the size of the index tear, and more than half of those with a full-thickness tear will suffer from an increase in the size of the tear, which may be the culprit for an increase in pain and disability. Acute traumatic tears, either in a previously asymptomatic patient or in patients with a previous history of rotator cuff disease yet compensated, with a significant loss of function, are good candidates for surgical repair without unnecessary delays [25–27].

The objective of the orthopedic surgeon, once the surgery is indicated and agreed upon by the patient, is to achieve sound fixation of the cuff to humeral tuberosities. Thorough attention to avoid gap formation is also a must. If the tendon is well fixed close to the bone, healing tissue will develop [28].

Despite some studies that show few differences in pain relief concerning tendon healing or retear, many others have identified a well-healed cuff as the main factor for improved strength and range of motion [28].

#### **2.1 Open vs. arthroscopic**

Open rotator cuff repair has been the gold standard when treating cuff tears. However, some concerns about infection and faster recovery have led shoulder surgeons to investigate the use of minimally invasive and arthroscopic technique.

Neviaser et al. retrospectively reviewed a cohort of patients who underwent anterosuperior rotator cuff repair with subscapularis involvement and found no differences in the outcomes between both modalities [29].

Hasler et al. in a prospective, randomized and long-term outcome study comparing open and arthroscopic rotator cuff repair did not document any difference either clinical or radiological. In addition, they did not find any harmful consequence due to transdeltoid mini-open approach [30].

Nazari et al. studied the effects of arthroscopic and mini-open rotator cuff repairs concerning pain and range of motion and did not find significant differences at 3, 6 and 12 months between both techniques [31].

Bayle et al. studied not only clinical outcomes but rotator cuff integrity at 1-year follow-up and did not find differences in a prospective study [32].

Fink Barnes et al. studied patient satisfaction and rotator cuff integrity in a cohort and found better results concerning integrity in the open surgery group. However, no statistical differences were found between both at the end of the study [33].

To sum up, if cost or time is an issue, open rotator cuff surgery is preferred. However, if short-term results are crucial and the patient seeks a faster return to work or sport, the arthroscopic repair is the technique of choice. The patient needs to be advised that both techniques may lead to excellent results and that the community of orthopedic surgeons cannot recommend one over the other if the factors mentioned above are not taken into account.

#### **2.2 Repair techniques**

With the advent of open and mini-open techniques, some classic repair techniques were developed. Transosseous sutures were mainly implemented, where bone tunnels are created, and sutures are placed directly through them, allowing for cuff reinsertion, as depicted in **Figure 1**.

A single-row repair is performed by means of anchors, usually one or two, with sutures integrated into them that permit cuff repair, as depicted in **Figure 2**. Singlerow techniques are easier to perform arthroscopically, as well as in an open fashion.

Double-row repairs use one or two anchors in a medial row, suturing far from the tendon stump border area and a lateral row, again with one or two anchors, closer to

**Figure 1.** *a. and b. Transosseous repair, usually used in open surgery.*

**Figure 2.** *a. and b. classic single-row repair with two lateral anchors.*

the end of the ruptured tendon and the lateral border of the cuff footprint along the tuberosity, as it can be seen in **Figure 3**.

More recent are transosseous equivalent techniques, similar to double-row techniques yet requiring only a medial row and knotless implants laterally (without sutures passing through the tendon laterally but applying those from the medial row against the tendon)(see **Figures 4** and **5**) [28].

#### **2.3 Single vs. double row**

Single- and double-row techniques have been compared about their failure loads and gap formation. In an experimental study, Kim et al. and Ma et al. reported significant more load to failure and less gap formation in favor of double row. They also confirmed in vitro that the strain using a double row was a third of that of a single row. However, other studies, such as the one performed by Mazzoca et al., compared both without finding any difference. Finally, a meta-analysis by Hohmann et al. revealed a possible superiority in vitro regarding gap formation and load to failure yet not observed clinically in vivo. Therefore, a superiority of a technique versus the other has not been demonstrated, and the final decision belongs to the orthopedic surgeon

#### **Figure 3.**

*a. and b. classic double-row configurations. Two anchors medial and two anchors lateral to the footprint with mattress sutures.*

#### **Figure 4.**

*On the left, a classic double row with independent sutures and anchors. On the right, the medial row sutures have been passed through the cuff, very close to the musculotendinous junction.*

#### *Single-Row Rotator Cuff Repair DOI: http://dx.doi.org/10.5772/intechopen.101911*

who should analyze factors such as simplicity, skill, cost and time consumption when choosing the right technique for the patient [28, 34–36].

Deveci et al. and Maasse et al. reported that most studies comparing single- and double-row techniques were comparing different constructs and suture configurations, and thus the results obtained are not valid. Most studies used lateral single-row configurations either in vitro or in vivo, and very few a more medial single row avoiding unnecessary tension at the level of the repair (which is a must, especially in large and retracted tears) When a proper, more medial, single-row configuration was used, the results become similar. It is not fair to compare single-row configurations performed poorly and too lateral to modern double-row techniques, and despite that, clinically relevant results have failed to be obtained [37, 38].

#### **2.4 Transsosseous vs. single row**

Transosseous repairs are of everyday use during open rotator cuff repair. The use of bony tunnels avoids anchors, which is a significant advantage concerning cost and ease of revision surgery. The former is performed either by employing guides and Kirschner wires or bone needles in the osteoporotic bone. Ahmad et al. and Park et al.compared micromotion in vitro at the footprint interface and concluded that transosseous repair minimizes strain and, therefore, would be advantageous concerning tendon to bone healing. Apreleva et al., in another experimental study, demonstrated that footprint anatomy restoration was superior when using transosseous techniques [39–42].

On the contrary, other authors such as Randelly et al. in a clinical study concluded that single-row and transosseous hardware-free repairs led to the same results concerning pain, function and retear rate at 15 months. However, transosseous repairs might be more cost-effective because they avoid the use of anchors [43].

Same principles apply to partial repairs when comparing transtendon single-row techniques versus double-row suture bridges. Zafra et al. demonstrated that partial tears might be treated with similar results using both techniques [44].

#### **2.5 Transosseous vs. double row**

Traditional transosseous repair focuses on restoring cuff footprint and applying pressure on the enthesis (against tuberosity bone). On the contrary, the traditional double row focuses on suturing the tendon medial and lateral in the footprint. Waltrip et al. compared both and demonstrated that a higher stress concentration was found in the latter at the medial anchors and suturing areas, while the former had more significant stress at the tendon to bone interface level. Forces through the tendon to bone enthesis can be beneficial, and on the contrary, forces around the anchors may explain the high recurrence rate and pull-out observed in double-row repairs [28, 45].

#### **2.6 Transosseous equivalent vs. double row**

Transosseous equivalent techniques mimic the effect created by traditional transosseous techniques utilizing lateral knotless anchors, which insert the sutures used in the medial row into the lateral cortex of the tuberosity. Hence, this technique mimics the effect of the classic techniques as it adds pressure forces that apply the tendon stump against the bone.

Siskoksy et al., in a cadaveric study, compared load to failure and gap formation using transosseous equivalent and double-row techniques. They concluded that load to failure was higher when using a transosseous equivalent construct. However, gap formation was similar between both [46]. The same conclusion was obtained by Costic et al. in a similar study in cadavers where cyclic loading was applied on the footprint [47].

Park et al. demonstrated in vitro that the pressure exerted by a transosseous equivalent is significantly higher than that observed in double rows. Nevertheless, it remains difficult to know the right amount of pressure or the ischemic effect of an excessive force on the tendon stump [48].

#### **3. The art of the single-row technique**

Not all single-row techniques are created equal. Arthroscopic rotator cuff repair emerged in the 1990s, and logically single-row constructs were the first used by shoulder and sports medicine surgeons. Initially, a unique row formed by one or two anchors (placed in the centre of the footprint or lateral to it) was used.

Not all single-row techniques are created equal. Arthroscopic rotator cuff repair emerged in the 1990s, and logically single-row constructs were the first used by shoulder and sports medicine surgeons. Initially, a unique row formed by one or two anchors (placed in the centre of the footprint or lateral to it) was used. Despite initial promising outcomes, the retear rate was undoubtedly worrisome, which explains the subsequent interest in developing double rows or transosseous equivalent techniques.

Complex and more robust suture configurations (such as the Mason-Allen technique) are complicated to replicate arthroscopically.

Simple or mattress sutures, often used arthroscopically, may not be sufficient to hold a rotator cuff with poor-quality tissue to the bone long enough to allow for proper healing. These statements led to a quest to find a better technique by adding anchors and complexity to the repairs. However, it was not until later that some surgeons started to question if a well-performed single row would be sufficient. To do so, a more medial single row started to be used with the rationale behind it that less tension on the rotator cuff would result. This is very useful in the onset of chronic and massive tears where even after proper slide liberation, tendon retraction impedes proper footprint anatomical restoration, as depicted in **Figures 6**–**9** [49].

Several factors may contribute to the final healing of the rotator cuff tendons to the bone. Among them, mechanical factors such as gap formation, stiffness and strength of the repair, load to failure, repair tension have already been discussed in previous sections of this chapter. However, other factors such as tendon vascularity, footprint coverage and respecting the proper biology of tendon healing are sometimes forgotten [49].

Suture bridge techniques have demonstrated in vitro superior strength, stiffness, less gap formation and more load to failure. However, this comes at the cost of vascularity disruption, high tension at the muscle to tendon junction (which may lead to a tear at this level). Transosseous equivalent techniques enhance the resistance and stability of the repair at the tendon to bone interface; nevertheless, they neglect biology as they create an ischemic environment. As a matter of fact, in vivo studies have failed to demonstrate the superiority of transosseous rotator cuff repair over single-row repair [49, 50].

#### **Figure 6.**

*Classic single row is performed with anchors in a more central or even lateral position in the footprint. Modern single row uses anchors closer to the cartilage, in a more medial position in the footprint (red area).*

#### **Figure 8.**

*A modern single-row construct uses sutures that pass about 1 cm medial to the border of the tendon stump. Thus, reducing the tension and minimizing retear rates due to excessive tension or damage to the musculotendinous junction.*

In the context of a single-row repair, a more medial row may enhance biology as it adds less loading forces and respects vascularity. However, footprint non-anatomic restoration may arise as a concern. By medializing the anchors in the footprint (not medial to it), a part of the surface may stay uncovered by the tendon stump. Although the real significance of this has not been established, surgeons commonly think anatomic restoration would be superior to a 'leave it alone' strategy. To cope with this problem, creating bone marrow vents through microfracture instruments would promote the formation of a neotendon and fibrocartilage. The benefits of adding mesenchymal cells to the healing area would also increase the chances of the tendon to bone healing. Yamakado et al. concluded in a prospective randomized trial comparing suture bridge configurations and single-row (medially based) repairs that both techniques lead to the same clinical results. They found that incomplete healing was more common in single-row repairs, and on the other hand, medial cuff failure was more common in patients with bridge constructs. However, the differences were not significant from a statistical point of view [49].

Another argument favoring single-row techniques is that excessive medial sutures in the cuff may lead to a myotendinous junction tear. Despite some authors that studied the use of more medial sutures in vitro, advocating for more stability of the construct, it is accepted globally that this can be dangerous as it might come with a rupture at the level of the muscle, ending up with a tendon stump anchored to the tuberosity but without a healthy muscle able to apply traction on it. Therefore, leaving a security distance from the musculotendinous junction of 10 mm is the wiser choice [51, 52].

#### **Figure 9.**

*Final modern single-row construct. Sutures are passed through the tendon far from the musculotendinous junction and far from the border. Less footprint is covered by the cuff when using this technique; however, bone marrow vents, lateral to the footprint, may provide stem cells which will develop a neotendon.*

It has also been suggested that a single-row technique mimicking the Masson-Allen suture technique might increase the strength of the repair. Despite some studies confirming that these modifications of the original technique ('modified Mason Allen' or 'massive cuff suture configuration') might increase in vitro the stability of the repair (similar to the original Mason-Allen technique), they have failed to demonstrate a statistical difference or a real relevance clinically. In fact, rotator cuff repairs usually fail at the suture-tissue interface due to poor quality of the latter; therefore, the culprit might not be suture configuration. This the interest in keeping it as simple as possible [53–58].

#### **4. Conclusions**

Rotator cuff tear is a common etiology for pain, disability and loss of function that might be considered a burden for some health systems.

Conservative treatment may be adequate for a large number of patients; however, it is utterly crucial to identify patients who would benefit from an acute repair and not to neglect patients who still suffer and do not achieve a satisfactory result employing conservative methods.

The selection of the surgical technique for those patients who require a rotator cuff repair should be guided by the current evidence. It should favor methods that provide the best results for the patient while maintaining simplicity and cost-effectiveness at the proper levels. Therefore, a modern single-row technique with a more medial

anchor placement and bone marrow vents in the rotator footprint is probably the technique that balances all the factors mentioned before.

#### **Acknowledgements**

The authors would like to thank ASIS Medica for their support in the development of this study.

### **Conflict of interest**

The authors declare no conflict of interest.

### **Author details**

Amhaz Escanlar S.1 \*, Jorge Mora A.2 and Pino Miguez J.3

1 University Hospital Complex, Santiago de Compostela, Spain

2 Reconstructive Surgery, University Hospital Complex, Santiago de Compostela, Spain

3 Pediatric Orthopedics and Spine Surgery, University Hospital Complex, Santiago de Compostela, Spain

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

© 2022 The Author(s). Licensee IntechOpen. 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.

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#### *Single-Row Rotator Cuff Repair DOI: http://dx.doi.org/10.5772/intechopen.101911*

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[52] Barber FA. Editorial commentary: Musculotendinous junction mattress sutures are inefficient. Arthroscopy: The Journal of Arthroscopic and Related Surgery. 2017;**33**:251-253

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#### **Chapter 3**

## Frozen Shoulder: Symptoms, Causes, Diagnosis, and Treatment

*Simona Maria Carmignano*

#### **Abstract**

Frozen shoulder, or adhesive capsulitis, is a condition caused by impaired soft tissues and the articular capsule of the shoulder. Although the precise etiology remains unclear, recent evidence identifies elevated serum cytokine levels as part of the process. It is characterized by an insidious and progressive loss of active and passive mobility in the glenohumeral joint presumably due to capsular contracture. Several treatments are recognized and utilized to reduce pain and improve range-of-motion faster than the disease's natural history course. The chapter aims to spread knowledge about this often-misunderstood pathology and to highlight the role of the rehabilitative therapeutic approach.

**Keywords:** shoulder, rehabilitation, pain, physical therapy, complementary therapy, physiotherapy

#### **1. Introduction**

Frozen shoulder, or adhesive capsulitis, is a condition caused by impaired soft tissues and the articular capsule of the shoulder. Primary frozen shoulder is common, and it is characterized by debilitating conditions. The prevalence is between 2% and 5% that increasing to 10–38% in patients with diabetes and thyroid disease. The age of patients is commonly between 40 and 65 years old, and the incidence appears higher in females than males [1–3]. It may also occur after trauma or in association with other joint diseases, as acromioclavicular osteoarthritis, which is referred to as a secondary frozen shoulder [4].

#### **2. Frozen shoulder: clinical definition**

Codman defined frozen shoulder as a clinical condition that can hardly be defined, it is complicated to enclose it in a single pathological mechanism, and therefore, even less easy to define its treatment. Instead, the term "adhesive capsulitis" was introduced by Neviaser [5] to describe a tissue inflammation condition and subsequent fibrosis involving the articular capsule of the shoulder. In addition, the definition of "frozen" shoulder refers to pain and immobility correlation. Lack of function causes

the capsule to thicken, making it even more difficult to move. Therefore the functional expression of pathology defines the term "frozen."

Frozen shoulder is characterized by an insidious and progressive loss of active and passive mobility in the glenohumeral joint presumably due to capsular contracture.

Frozen shoulder can be classified as primary or secondary. Primary idiopathic frozen shoulder can be often associated with other diseases, such as diabetes mellitus, thyroid diseases, and Parkinson's disease. Secondary adhesive capsulitis can occur after trauma or immobilization. Frozen shoulder is estimated to affect 2–5% of the general population. A patient who experiments with this pathology can be significantly painful and disabling for some months. It most commonly affects those in their fourth to sixth decades of life and more often occurs in women than in men [6].

#### **3. Frozen shoulder: pathophysiology**

The pathophysiological mechanism underlying the pathology remains poorly understood. Scientific literature shows a correlation with elevated serum cytokine levels [7]. Although the precise pathophysiology remains unclear, recent evidence identifies elevated serum levels of cytokines as part of the process. Cytokines are polypeptide, non-antigen-specific mediators that act as communication signals between immune system cells and between them and different organs and tissues. Elevated cytokine levels appear predominantly involved in the cellular mechanisms of inflammation and fibrosis sustained in the primary and some secondary frozen shoulder. Bunker et al. [8] defined that a mild lesional event would trigger an inflammatory response that results in excessive production of fibroblasts, which release type I and type III collagen. Fibroblasts differentiate into myofibroblasts, causing the newly deposited type III collagen to contract. This would result in an imbalance between the inflammatory phase and the remodeling underlying the fibrosis.

Rodeo et al. [9] described pathological processes like inflammation and fibrosis: synovial hyperplasia determines a decrease of vascularity. This phenomenon leads to fibrosis in the sub-synovium and synovium of capsular tissue. This condition could be the expression of an immune response [10]. Other studies have shown that frozen shoulder is associated with a dense collagen matrix containing fibroblasts and myofibroblasts, suggestive of a fibrotic process [9, 11–13]. Furthermore, the component of the immune system that is activated is represented by B lymphocytes, mast cells, and macrophages. Several studies have suggested the immune response overlaps with inflammatory synovitis, leading to capsular fibrosis in the later stages [5, 14].

There are many etiopathological hypotheses, and all studies suggest that both inflammation and fibrosis of the joint capsule are regulated by cytokines, growth factors, MMPs, and immune cells. The results of the next studies will provide the control mechanisms of FS and identify new therapeutic targets to identify its treatment [14–16].

#### **4. Frozen shoulder: symptoms**

Patients typically demonstrate a characteristic history, clinical presentation, and recovery. Clinical syndromes include pain, a limited range of motion (ROM), and muscle weakness from disuse [17].

The pain has a typical course involving the entire shoulder up to the insertion of the deltoid muscle. The patient reports difficulty sleeping on the affected side and

difficulty in active movement. Clinical examination shows atrophy of the spinate, restriction on passive mobilization, with painful and limited elevation and external rotation.

Pain is localized in the shoulder (in the deltoid region), sometimes in the arm with functional limitation. In patients who have been in pain for a long time, may present medial to the scapula. This happens because incorrect movements of the scapulothoracic are established to compensate for the limitation of the glenohumeral joint [18].

Neviaser et al. [19] elaborated on the natural history of frozen shoulder and distinguished the following stages:


**Figure 1.** *Natural history of frozen shoulder.*

#### **5. Diagnosis**

#### **5.1 Clinical diagnosis**

Primary frozen shoulder is essentially a clinical diagnosis. Frozen shoulder is characterized by an insidious and progressive loss of active and passive mobility in the glenohumeral joint presumably due to capsular contracture. Patients typically demonstrate a characteristic history, clinical presentation, and recovery. Clinical syndromes include pain, a limited range of motion (ROM), and muscle weakness from disuse [20]. To carry out the clinical examination of the shoulder it is necessary to observe the neck and evaluate through a functional examination if the pain comes from the cervical spine. Subsequently, following the standard shoulder examination protocol, it is necessary to proceed with the inspection of the shoulder. Observe if there are scars, reduced Tropism of rotator cuff/deltoid, bone landmarks, and spinal and scapular alignment. People with frozen shoulders have a limited range of both active and passive motion. Next, proceed to palpation to rule out acromioclavicular-induced pain. Following this, proceed with an assessment of shoulder range of motion (ROM). There are four movements that are useful in the examination—flexion, abduction, internal rotation, and external rotation. Flexion , abduction and internal rotation are evaluated with active and passive mobilization, while external rotation is evaluated only with passive mobilization [21].

Shoulder pain appears slowly and radiates to the insertion of the deltoid. The patient reports inability to sleep on the affected side, limitation to active movement, and painful elevation of the shoulder. Progressively atrophy of the spinate appears.

Imaging studies are not necessary for the diagnosis of adhesive shoulder capsulitis but may be helpful to rule out other causes of a painful and stiff shoulder. Usually, resistance in the last degrees of movement is described, this sensation is defined as firm and "leathery." During the examination the pain is prevalent, the patient cannot get to the point where even the examiner would feel the resistance. Therefore it is most frequently described as a feeling of "empty" end [22].

#### **5.2 Evaluation scale**

It should be used to validate functional outcome measures, such as the disabilities of the arm, shoulder, and hand (DASH), the American Shoulder and Elbow Surgeons shoulder scale (ASES), or the Shoulder Pain and Disability Index (SPADI). The DASH questionnaire consists of 30 questions that inquire about symptoms and functions of the upper limbs.

**Table 1** describes the 30 items that are carried out with the application of the scale. DASH investigates the severity of pain, activity-related pain, tingling, weakness, and stiffness (five items), and the effect of the upper limb problem on social activities, work, sleep, and self-image (four items). These provide a single main score, the DASH function/symptoms (DASH-FS) score, which is basically a summation of the responses on a one-to-five scale, after transformation to a zero (no disability) to 100 (severe disability) scale [23].

The shoulder and elbow surgeons shoulder scale (ASES) is a physician assessment section that includes physical examination and documentation of a range of motion, strength, and instability, and demonstration of specific physical signs. No score is derived for this section of the instrument. The patient self-evaluation section has 11 items that can be used to generate a score. These are divided into two areas—pain (one item) and function (10 items) (**Table 2**).



#### **Table 1.**

*Disabilities of the arm, shoulder, and hand (DASH).*

The final score is tabulated by multiplying the pain score (maximum 10) by 5 (therefore total possible 50) and the cumulative activity score (maximum 30) by 5/3 (therefore, a total possible 50) for a total of 100 [24].

The Shoulder Pain and Disability Index (SPADI) is a self-administered questionnaire that consists of two dimensions, one for pain and the other for functional activities. The pain dimension consists of five questions regarding the severity of an individual's pain [25].

#### **5.3 Diagnostic imaging**

Radiographic examination is carried out to make the differential diagnosis and exclude other pathologies, for example, calcific tendinitis, rupture of the rotator cuff, arthritis of the glenohumeral, and acromioclavicular joint or a neoplastic process. In


#### **Table 2.**

*Shoulder and elbow surgeons shoulder scale (ASES).*

patients with frozen shoulder radiographic examination is normal, however, osteopenia of the humerus head may be an indirect sign [26].

Ultrasound is an essential tool for diagnosing shoulder disorders. However, the role of ultrasound in assessing and diagnosing adhesive capsulitis has not been fully studied. Sonography had high diagnostic accuracy for the diagnosis of adhesive capsulitis using a combination of parameters, such as coracohumeral ligament (CHL) thickness, rotator interval (RI) thickness, and hypervascularity, axillary recess (AR) thickness [27, 28].

Several studies have shown that the CHL is thickened and stiffened in adhesive capsulitis on ultrasound [29–31]. Other researches correlate AR thickening as a key diagnostic finding of adhesive capsulitis [32] and approximately the AR cutoff value for adhesive capsulitis diagnosis was 4 mm [28].

RI vascularity is a sign of adhesive capsulitis, but controversy remains in the literature about hypervascularity of the RI in adhesive capsulitis [33].

Magnetic resonance imaging (MRI) and magnetic resonance angiography (MRA) may reveal thickening of capsular and pericapsular tissues as well as a contracted glenohumeral joint space. Sliding movement of the supraspinatus tendon [34].

Arthrography is rarely indicated in the diagnosis of frozen shoulder syndrome. It is an invasive procedure that is painful and costly and does not necessarily provide diagnostic insight but it may be associated with a therapeutic articular injection of corticosteroids as a therapeutic intervention [35].

#### **6. Treatments**

The goal of the treatment of adhesive capsulitis is to restore the shoulder to a painless and functional joint [36, 37].

#### **6.1 Pharmacological treatment**

Initial treatment is aimed at reducing inflammation and pain. Analgesic and antiinflammatory drugs are used. Aspirin and paracetamol are the most used and with fewer side effects, the dosage is similar to that used in osteoarthritis. Among the nonsteroidal anti-inflammatory drugs (NSAIDs) the most commonly used are ibuprofen, which has the lowest incidence of side effects, naproxen, and diclofenac [38].

Corticosteroids (for which the generic term "steroids" is usually used) strongly suppress all stages of acute and chronic inflammation. In relation to frozen shoulders, they may be injected intra-articularly (directly into the joint) or taken orally. Intraarticular injections of corticosteroids are the most used method. Corticosteroid intraarticular injections demonstrate short-term (4–6 weeks) benefits. Literature reported a moderate effect of corticosteroid injections on pain, external rotation ROM, and disability at 6 weeks, and only small effects after 12 weeks [39, 40]. Corticosteroid injections have been shown to be as effective as exercise for treating frozen shoulder, particularly when provided in the early stages of the pathology. Blanchard et al. [41] suggested that corticosteroid injections have a greater effect when compared to physical therapy when utilized within the first 6 weeks of treatment, although these differences diminished over time.

The injection of sodium hyaluronate (defined as distension or hydrodilation therapy) into the glenohumeral joint for the treatment of adhesive capsulitis results in an improvement in pain and range of motion, similar to the effects of corticosteroid injection but with fewer side effects. Hyaluronic acid has anti-inflammatory properties and it is similar the synovial fluid that occurs naturally in the joints. It works by acting like a lubricant and shock absorber in the joints and helps the joints to work properly [42].

These lubricating effects of hyaluronate have led to use in orthopedic surgery as well, via prevention of adhesion formation after both wrist and finger flexor tendon repair [43]. Thus, extrapolation to the treatment of stiff shoulder and adhesive capsulitis has demonstrated success and improvements in range of motion, pain, and function.

#### *6.1.1 Physical therapy*

#### *6.1.1.1 Ultrasound*

A common clinical practice among physical therapists is the use of ultrasound prior to capsular and soft tissue stretching techniques based upon its thermal and mechanical effects. Ultrasound is used to manage several soft-tissue conditions, such as tendinitis, bursitis, and muscle spasm; reabsorb calcium deposits in soft tissue; and

reduce joint contractures, pain, and scar tissue. Used in conjunction with hot packs, muscle spasms and muscle guarding may be reduced [44]. The effect of ultrasound therapy at a frequency of 1 MHz, unlike the hot pack that produces surface heating, is a heating in the deeper tissues due to the increase in blood flow resulting in an analgesic muscle relaxant effect and wash out of pain mediators. Ultrasound therapy is used in association with the electric current that produces a modulation of muscle tone or further modulates pain. Robertson et al. [45] reported the usage of ultrasound therapy (UST) clinically in the rehabilitation of patients with frozen shoulders. Direct contact is the most common method that therapist applies ultrasound. It consists in the application of a transducer that is pressed gently into conductive gel and against the skin.

It is recommended that ultrasound be applied in a pulsed mode at low intensity (0.5–1.0 W/cm<sup>2</sup> ) during the acute phase of inflammation to minimize the risk of aggravating the condition and to accelerate recovery, and that continuous ultrasound at high enough intensity to increase tissue temperature be applied in combination with stretching to assist in the resolution of chronic phase, only if the problem is accompanied by soft tissue shortening [46–48]. In a guideline it is reported that therapeutic ultrasound (US) was effective in the treatment of calcific tendonitis of the shoulder, there was no evidence that it was beneficial for other forms of shoulder pain (e.g., capsulitis, bursitis, tendonitis) [49].

The use of ultrasound therapy is indicated as a treatment for the painful phase of adhesive capsulitis and is indicated in the literature alone or in therapy with other therapies (stretching, mobilization, transcutaneous electrotherapy, and laser therapy) with a type B degree of evidence (there is research-based evidence to support the recommendation) [50]. Other studies have shown efficacy not superior to other therapies [51].

#### *6.1.1.2 Transcutaneous electrical nerve stimulation (TENS)*

TENS consists of low-frequency electrical pulses (generated by a small, portable unit) transmitted to the tissues through electrodes on the skin. The pulses stimulate peripheral nerves in such a way as to suppress the perception of pain. TENS therapy determines analgesia by different mechanisms—by causing interactions between types of nerve fibers, resulting in a "block" on the transmission of pain signals to the brain; or by releasing hormones that block pain receptors in the central nervous system. The effects of transcutaneous electrical nerve stimulation (TENS) for the treatment of adhesive capsulitis seem to be superior in comparison to stretching exercise [52].

#### *6.1.1.3 Electromagnetic therapy*

Electromagnetic fields (EMFs) provide a noninvasive, safe, and easy method to treat pain with respect to musculoskeletal diseases. Magnetic field therapy was applied to promote bone healing, treat osteoarthritis and inflammatory diseases of the musculoskeletal system, alleviate pain, enhance healing of ulcers, and reduce spasticity [53, 54]. This mechanism could promote the resolution of pain by accelerating the removal of inflammatory substances. PEMF stimulates chondrocyte proliferation, differentiation, and extracellular matrix synthesis through the release of anabolic morphogens, such as bone morphogenetic proteins and anti-inflammatory cytokines [55].

Pulsed electromagnetic field (PEMF) therapy has been reported to produce antiinflammatory and bone-healing effects, but it is unclear whether—it is more or less effective than placebo, or whether other electrotherapy modalities are an effective adjunct to exercise for the treatment of frozen shoulder.

#### *6.1.1.4 Extracorporeal shock wave therapy (ESWT)*

ESWT has been recently receiving attention for the treatment of the frozen shoulder. Extracorporeal shock waves therapy (ESWT) represents a valid tool for a wide range of disorders, both in orthopedics and rehabilitative medicine (tendon pathologies, bone healing disturbances, vascular bone diseases), but also in dermatology and vulnology (wound healing disturbances, ulcers, painful scars), neurology (spastic hypertonia and related disturbances), some andrologic disturbances (induratio penis plastica and erectyle disfunctions), and cardiology (in relation to ischemic heart diseases) [56]. ESWT is a treatment method that applies extracorporeal shock waves to lesions to aid revascularization and stimulate or reactivate the healing of bones and connective tissues such as tendons, thereby relieving pain and improving functions. Data suggest that in the field of tendinopathies ESWT can be considered not only as a symptomatologic therapy but rather a real curative treatment, able to relieve pain and inflammation in the short-medium term but also to positively interfere with tendon structure in a regenerative way [57]. In doing this, it causes changes in cells' metabolism and the permeability of endothelial cell tissues, leading to pain relief and having positive effects on soft tissues [58]. A recent systematic review demonstrated the effectiveness and safety of ESWT for frozen shoulder; ESWT determines the reduction of pain intensity, and it improves shoulder function, quality of life without adverse events [59].

#### **6.2 Physiotherapy**

Several studies have examined the effect of joint mobilization in patients with adhesive capsulitis, and although there is evidence that it may be beneficial, there is little evidence to support superior efficacy over other interventions [60–62].

Joint mobilization procedures are primarily directed to the glenohumeral joint to reduce pain and increase motion and function in patients with adhesive capsulitis. Mobilization techniques improve the normal extensibility of the shoulder capsule and stretch the tightened soft tissues to induce beneficial effects. Mulligan's mobilizationwith-movement (MWM) treatment techniques, could be used. The most important points of the Mulligan Concept include the active participation of the patient and the elimination of pain during therapy [63]. A recent review of the literature analyzed 16 controlled clinical trial (CCT) or randomized controlled trial (RCT) studies that used MWMs demonstrating efficacy on pain and disability [64].

Also, stretching exercises appear to influence pain and improve ROM. The Harvard Special Health Report offers some stretching exercises that are effective in the treatment of adhesive capsulitis—pendulum stretch, towel stretch finger walk, cross-body reach, armpit stretch, starting to strengthen, outward rotation, inward rotation. These exercises can be performed with the physiotherapist or carried out as a home program [65].

No evidence exists to guide the optimal frequency, number of repetitions, or duration of stretching exercises. Stretching beyond painful limits may result in poorer outcomes. Therefore, stretching intensity that matches the given level of tissue irritability is indicated.

#### **6.3 Manual myofascial therapy**

Manual therapy may include myofascial work to release abnormal tension and restore mobility and function and identify fascial restrictions using motion testing and palpation.

In the myofascial treatment could be used simple techniques for muscle treatment and joint manipulations, such as:


#### **6.4 Minimally invasive treatments**

#### *6.4.1 Acupuncture*

Acupuncture can be used to treat the pain of the frozen shoulder. It involves inserting needles into the skin at sites that vary from case to case and also depend on the practitioners'school of thought. Traditional Chinese medicine regarded acupuncture as an effective measure in aborting the signs and symptoms of frozen shoulder and in preventing future recurrence.

In the treatment of frozen shoulder, as in many other diseases, one in long, 30 gauge, disposable, sterilized, filiform needles are usually used. The sides of the application are defined as local points and distal points [67].

An integration approach can be ear acupuncture in the treatment of the frozen shoulder. According to traditional Chinese medicine, the sensitive spots on the auricle are anatomically and pathologically related to the affected shoulder joint [68] (**Figure 2**).

#### *6.4.1.1 Kinesio taping (KT)*

Kinesio taping is a complementary therapy based on the application of an elastic membrane that allows relieving pain. The effect on pain is pain modulation through pain gate control theory. The epidermis is equipped with a series of nerve receptors that, if subjected to a series of external stimuli, communicate with the underlying muscles. As a result, depending on how they are placed, the tapes can inhibit a contracted muscle or facilitate lymphatic flow, decreasing pain and inflammation [69]. The application KT

**Figure 2.** *Ear acupuncture in the treatment of frozen shoulder.*

can produce local physiological changes that resulted in therapeutic effects, such as the relief of pain (pain gate mechanism, reducing muscle spasm) and improvement in ROM (tissue extensibility) [70, 71].

#### **6.5 Operative treatments**

#### *6.5.1 Arthroscopic capsular release and manipulation under anesthetic (MUA)*

Arthroscopic treatment is usually indicated in patients who do not respond to drug and/or rehabilitation therapy. Usually, during this procedure, a manipulation under anesthetic (MUA) is carried out as in this way, it is possible to reduce the potential damage by allowing it to be performed with less force. In addition to a general anesthetic, it is normal for a regional nerve block to be given. This causes postoperative numbness and enables the patient to get moving at the earliest possible stage. Intensive physiotherapy is regarded as essential to a good outcome.

#### **6.6 Postural educational program**

After a period of unconditioning typical of the acute phase of pain and contracture, it is necessary to learn again the correct body schema and achieve the complete recovery of postural control. It is possible through a progressive recovery of good motor control, thanks to the muscular selective reinforcement with the increasing development of strength in different patterns of movement, both the proprioceptive recovery. In the last rehabilitation phase it is necessary to restore the sensorimotor skills including proprioception static and dynamic balance either with aquatic rehabilitation therapy or through platform swing walkway, which is a common way to improve gait pattern through activation of sensory stimuli (visual, auditory, vestibular, and somatosensory) [72, 73].


#### **Table 3.** *Summary of therapeutic strategies.*

#### *6.6.1 Summary of therapeutic strategies*

See **Table 3**.

#### **7. Conclusion**

Often a rehabilitative success is defined by the return of normal motion rather than pain-free functional motion, but adhesive capsulitis is a challenging condition for both the physical therapist and patient. In fact, the healing process takes months to restore full mobility without pain, considering the presence of dense fibrotic tissue and the months of collagen remodeling required to recover soft tissue length. The rehabilitation of frozen shoulder is frequently prolonged despite multiple therapeutic methods because of the difficulty of acting on the degenerative process of the cartilage matrix and the progress of adhesive capsulitis. It is important to the diagnosis process and assessment to choose the best intervention or a combination of strategies for each patient. Although in scientific literature, a definition of the best rehabilitation approach is still needed, following an integrated, multifaceted, and combination of evidence-based approaches, therapeutic success can be achieved!

#### **Disclosure**

The author reports no conflicts of interest in this work.

#### **Author details**

Simona Maria Carmignano1,2

1 Department of Medicine, Surgery and Dentistry, "Salernitan Medical School", University of Salerno, Baronissi, Italy

2 C.T.R. Rehabilitation Therapeutic Center, Basilicata, Italy

\*Address all correspondence to: simona.carmignano@gmail.com

© 2022 The Author(s). Licensee IntechOpen. 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.

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Section 2
