**1. Introduction**

#### **1.1. Fracture Incidences**

Bone injuries are frequent occurrences in daily life. Considering Germany as an example for a country with a health system guaranteeing treatment for fracture patients at a high standard, fractures of the extremities ranged between 560,000 and 640,000 cases per year over the past 10 years, with around 150,000 fractures of the femur and tibia, respectively (**Figure 1**). The statistical federal ministry recorded 802,662 fractures in Germany in the year 2014 (Statistisches Bundesamt, Wiesbaden, 2016-01-11). These numbers can be split up even further by age, where 38% of the patients with fractures of the extremities were older than 75 years, 33% between the age of 50 and 75 years, 16% between 25 and 50 years, and only 13% were younger than 25 years (**Figure 2A, B**).

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**Figure 1.** Fracture incidence in Germany (Gesundheitsberichterstattung des Bundes, 2016-01-11)—fractures of hand, arm, shoulder, leg and foot—incidence for 2004–2014.

Even in an environment with a good healthcare system and the normally very good healing potential of bone, 10–20% of all fracture patients still experience a delayed or nonunion after osseous injury [1–3] (**Figure 2C**). To overcome these delays in healing or reduce the nonhealing ratio, further research to gain understanding on the causes of healing delay or lack of healing is essential to enable new treatment strategies that support bone regeneration even under compromised conditions. With respect to the development of our population, the research into fracture treatment strategies becomes even more important as demography predicts an aging of the population. In Europe, it is Germany with the highest percentage of people over 65 years of age, and this percentage is rising (**Figure 2A**). In 1990, about 15% of the Germans were older than 65 years, and in 2011, this percentage had grown to 21% of people being over 65 years old (Statistisches Bundesamt, Eurostat 2011). This is important because the fracture incidence is higher in elderly people (**Figure 2B**). The demographic projection of the UN World Popu‐ lation Projections for the years up to 2025 foresees an increase of over 50-year-old people of 20%, which equals 219 million people in 2025. Further stratifying this by age groups, the highest growth of 32% is expected for people aged 80 years or older. Consequently, the fracture incidence in elderly will increase by 28% of the 4.5 million fractures estimated for 2025. With this high number of fracture patients with an advanced age, it is eminent to consider agerelated alterations that might influence the capacity of osseous tissue to regenerate normally. With increasing age, it is the immune system that undergoes major transformation influencing bone regeneration considerably. To provide adequate treatment options, it is essential to unravel the interactions of the immune and skeletal system.

**Figure 2.** (A) Age distribution in Germany 2014 and (B) fracture incidence according to designated age groups. (C) Un‐ satisfactory healing results in fracture patients in corresponding age groups are shown, this includes malalignment, delayed healing and pseudarthrosis (nonunion) (M84 classification) (based on Statistisches Bundesamt, Wiesbaden 2016).

#### **1.2. Primary and secondary healing**

**Figure 1.** Fracture incidence in Germany (Gesundheitsberichterstattung des Bundes, 2016-01-11)—fractures of hand,

Even in an environment with a good healthcare system and the normally very good healing potential of bone, 10–20% of all fracture patients still experience a delayed or nonunion after osseous injury [1–3] (**Figure 2C**). To overcome these delays in healing or reduce the nonhealing ratio, further research to gain understanding on the causes of healing delay or lack of healing is essential to enable new treatment strategies that support bone regeneration even under compromised conditions. With respect to the development of our population, the research into fracture treatment strategies becomes even more important as demography predicts an aging of the population. In Europe, it is Germany with the highest percentage of people over 65 years of age, and this percentage is rising (**Figure 2A**). In 1990, about 15% of the Germans were older than 65 years, and in 2011, this percentage had grown to 21% of people being over 65 years

arm, shoulder, leg and foot—incidence for 2004–2014.

170 Advanced Techniques in Bone Regeneration

Bone is a remarkable organ because it is capable of regeneration and complete restoration of the osseous integrity both in form and function. Bone repair and fracture healing are unique because they recapitulate many of the ontological events that occur during the embryological development of the skeleton [4, 5]. To reach the "restitutio ad integrum," bone provides two mechanisms of scarless healing and regeneration: primary and secondary bone healing. Primary bone healing is only possible when the bone fragments are realigned anatomically, and the fracture zone is held under compression by an adequate fixation without a gap between the bony ends (**Figure 3A**). Stable fixation and no relative movement are required when basic multicellular units consisting of cutting cones with osteoclasts and following bone-forming osteoblasts cross the fracture line to directly rebuild bone and thus re-establishing the osseous integrity at the fracture side [6, 7]. During this process, the new bone is directly organized as osteons and oriented along the dominant mechanical loading direction [8, 9]. Primary bone healing was for a long time considered as the best possible healing process and thus was the aim when fractured bone was clinically treated [10].

**Figure 3.** X-ray images from fracture patients: (A) fracture treated with an open reposition and internal fixation (ORIP) procedure with correct anatomical reconstruction of the fracture ends without fracture gap consistency—the bone will heal without callus formation through primary bone healing. (B) Comminuted fracture treated with an internal nail. Several gaps between the fractured bone ends remain and healing takes place by secondary bone healing as the callus visible in the image B2 taken 3 months after treatment clearly shows.

Secondary bone healing occurs whenever a gap persists between the fractured ends or when there is instability and thus interfragmentary movement (**Figure 3B**). This for example is the case if anatomical repositioning is not possible due to comminuted fractures or large bone defects. In secondary bone healing, a substitute tissue is formed to regain stability as fast as possible: an intermediate cartilage callus ensues. While intramembranous bone formation starts to consolidate the injured bone in the periosteal regions of the fracture gap, endochondral ossification processes start with the formation of cartilage islands in the gap between the fracture ends, forming an intermediate soft callus. Cartilage mineralization starts the woven bone formation process, which results in a hard callus. The final remodeling then restores the form of the continuous bone [11]. The intermediate cartilage step that provides a fast regaining of stability and reduces any interfragmentary movements often has a larger diameter than the original bone, especially if, as it would occur in nature, the bone remains untreated. It provides an increased polar moment of inertia against torsion and also withstands bending loads [12, 13]. While the large callus provides an evolutionary advantage to quickly regain mobility, it can be prevented in clinical settings by a stable fixation of the fractured bone [14].

#### **1.3. Fracture treatment**

the bony ends (**Figure 3A**). Stable fixation and no relative movement are required when basic multicellular units consisting of cutting cones with osteoclasts and following bone-forming osteoblasts cross the fracture line to directly rebuild bone and thus re-establishing the osseous integrity at the fracture side [6, 7]. During this process, the new bone is directly organized as osteons and oriented along the dominant mechanical loading direction [8, 9]. Primary bone healing was for a long time considered as the best possible healing process and thus was the

**Figure 3.** X-ray images from fracture patients: (A) fracture treated with an open reposition and internal fixation (ORIP) procedure with correct anatomical reconstruction of the fracture ends without fracture gap consistency—the bone will heal without callus formation through primary bone healing. (B) Comminuted fracture treated with an internal nail. Several gaps between the fractured bone ends remain and healing takes place by secondary bone healing as the callus

Secondary bone healing occurs whenever a gap persists between the fractured ends or when there is instability and thus interfragmentary movement (**Figure 3B**). This for example is the case if anatomical repositioning is not possible due to comminuted fractures or large bone defects. In secondary bone healing, a substitute tissue is formed to regain stability as fast as possible: an intermediate cartilage callus ensues. While intramembranous bone formation starts to consolidate the injured bone in the periosteal regions of the fracture gap, endochondral ossification processes start with the formation of cartilage islands in the gap between the fracture ends, forming an intermediate soft callus. Cartilage mineralization starts the woven bone formation process, which results in a hard callus. The final remodeling then restores the form of the continuous bone [11]. The intermediate cartilage step that provides a fast regaining of stability and reduces any interfragmentary movements often has a larger diameter than the original bone, especially if, as it would occur in nature, the bone remains untreated. It provides an increased polar moment of inertia against torsion and also withstands bending loads [12, 13]. While the large callus provides an evolutionary advantage to quickly regain mobility, it

can be prevented in clinical settings by a stable fixation of the fractured bone [14].

aim when fractured bone was clinically treated [10].

172 Advanced Techniques in Bone Regeneration

visible in the image B2 taken 3 months after treatment clearly shows.

In the wild, a fractured long bone often leads to death of the injured animal. However, it seems that the younger the animal is when the fracture occurs, the higher are the chances of survival [15]. If an animal survives a long bone fracture, the bones most likely heals with a severe misalignment. The potent remodeling capacity of the bones will however strive to restore the mechanically defined form of the bone, which is dictated by the surface strains the bone sense during physiological activities.

In our society, most fractures are treated in such an efficient way that only in rare cases bone fractures lead to death. Fracture treatment in the form of stabilizing the fractured bone goes back at least to 2400 years before Christ as excavated mummies from an Egyptian tomb proved. Prof. G. Elliott Smith discovered the splintered bones during the Hearst Egyptian expedition at Naga-ed-Der in 1903 on two mummies [16]. Both died shortly after the fracture because no healing signs were observed on the bones even though the Egyptians seemed to have reached some proficiency in fracture treatment as other relicts with healed fractures, found later on, could prove. In most cases, healed femoral fractures showed limb shortening or deformation, whereas forearm fractures healed well, demonstrating the challenge of reestablishing weight bearing capacity with the fracture treatment. An Arab surgeon, El Zahrawi (936–1013 AD) described in his treatise "The Surgery" a splinting technique, which was used for a long time, consisting of several layers of bandages combined with splints to provide stability for the fractured limb [17]—a fracture treatment also described by Hippocrates and Celsus [18] and one that is to an extend still valid today.

In the early 1770, first records on internal fracture fixation using ligatures or wire fixation are reported from France [19]. This was followed by the introduction of screws around 1850, again in France [20], and the development of plate fixation reported in 1886 by Hansmann [21] of Hamburg.

Robert Danis (1880–1962) furthered the development of the concept of internal fixation to permit functional rehabilitation. He stated that an osteosynthesis is not entirely successful until it provides immediate mobilization, complete restoration of the form of the bone, and enables primary bone healing without the formation of a callus. This thesis was published in "Danis R.: *Théorie et Pratique de l'Ostéosynthèse*, Paris, Masson, 1949". Between the 15th and 17th of March 1958, a number of orthopedics met in the Kantonsspital of Chur and based on the work of Danis they formulated a number of papers on osteosynthesis and thus the AO—Arbeitsge‐ meinschaft für Osteosynthesefragen—was founded. The AO has continued to improve the principles of fracture treatment since then and is still a renowned entity in the orthopedic community.

Even with these tremendous progresses in fracture treatment, there are still several open questions concerning the treatment regimen: mal-fixation with too stable or too unstable fixation [22–25], critical gap size [26, 27], a deficit in angiogenesis together with the formation of atrophic pseudarthrosis [28–31], and deficits in the control of the inflammatory cascades [32–34] are challenging clinical situations that still lead to unsatisfactory healing results for patients and surgeons as well.
