distraction osteogenesis: origins and evolution

DISTRACTION OSTEOGENESIS: ORIGINS AND EVOLUTION Mikhail L. Samchukov Alexander M. Cherkashin Jason B. Cope Distraction osteogenesis is a biologic process of new bone formation between bone segments that are gradually separated by incremental traction. This process begins when a distraction force is applied to the healing callus that joins the divided bone segments and continues as long as the tissue is stretched. Importantly, a distraction force applied to bone also creates tension in the surrounding soft tissues, initiating a sequence of adaptive changes termed distraction histogenesis. HISTORICAL REVIEW The evolution of distraction osteogenesis involves a history of the development and improvement of skeletal traction, bone segment fixation, and osteotomy techniques (Paterson, 1990; Murray and Fitch, 1996; Wiedemann, 1996). Principles of mechanical manipulation of bone fragments have been practiced in medicine since ancient time. Hippocrates, more than 2,000 years ago, described the placement of traction forces on broken bones. He used an external apparatus (Fig. 1) consisting of two rings of Egyptian leather that were connected by four slightly bent rods made from the Corne] tree. The tension applied to the bone segments was controlled by the amount of bending of the rods (Peltier, 1990). The first occurrence of continuous traction for bone fractures can be traced to the work of Guy de Chauliac in the fourteenth century (Peltier, 1968). He applied traction with a pulley system that consisted of a weight attached to the leg by a cord (Fig. 2). The weight was suspended over a pulley to create tension. J.R. Barton, in 1826, is credited with being the first to perform a surgical division of bone, or osteotomy. Through a short lateral incision with a small saw, Barton divided the ankylosed femur at the level of the lesser trochanter (Fig. 3) to produce a pseudoarthrosis (Barton, 1827). In 1880, Macewen designed a new instrument for bone division, which he called an osteotome (Peltier, 1993). He was the first to perform a subcutaneous osteotomy. At this time, however, antibiotics and

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Distraction Osteogenesis: Origins and Evolution

Figure 1. Fracture reduction technique and external fixation device of Hippocrates.

aseptic surgical techniques had not been developed, and the risk of infection was tremendous. Therefore, considerable time passed before the osteotomy was accepted as a routine procedure. The history of external skeletal fixation dates from the middle of the nineteenth century when Joseph Malgaigne constructed an apparatus (Fig. 4) for external fixation of displaced transverse patellar fractures (Malgaigne, 1847). His simple external frame consisted of two double hooks, which were inserted through the skin into the patellar fragments and connected by a screw. Tightening the screw drew the fragments into apposition, creating compression at the fracture level. This was the 2

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Figure 2. Guy de Chauliac's pulley system for the application of continuous traction to treat femoral fractures.

first device attached directly to bone, thereby allowing direct transmission of a mechanical force to the skeleton. Since then, considerable evolution of external skeletal fixation has occurred. At the turn of the twentieth century, Alessandro Codivilla first performed limb lengthening using external skeletal traction after an oblique osteotomy of the femur (Codivilla, 1905). His device (Fig. 5) utilized a traditional plaster cast that was placed on the leg and cut in half at the level of the osteotomy. The proximal part of the cast was fastened to a stationary external frame, and the distal part of the cast was connected to a pin inserted through the calcaneus. The elongation was achieved by skeletal traction applied to the transcalcaneal pin and repeated as often as necessary to achieve the desired result. Later, several surgeons modernized Codivilla's "continuous extension" proce3


Figure 3. John Barton's corrective osteotomy technique for the treatment of hip ank:ylosis.

dure by modifying either the osteotomy technique, distraction protocol, or the device for bone fixation. In 1908, based on his experimental studies in dogs, Paul Magnuson recognized the biologic potential of periosteum and endosteum. To maximize the amount of bone surface for limb lengthening, he proposed a longitudinal division of the periosteum followed by a Z-shaped osteotomy accomplished by connecting pre-drilled holes (Magnuson, 1913 ). Omberdanne further suggested that limb lengthening procedures be performed slowly and gradually (Omberdanne, 1913). 4

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Figure 4. Joseph Malgaigne's external skeletal clamp with double hooks for compressive fixation of displaced patellar fractures .

Figure 5. Alessandro Codivilla's device for limb lengthening by "continuous extension."

In 1921, Vittorio Putti , Codivilla's star pupil, designed the "Osteoton," a unilateral fixator for femoral lengthening (Putti, 1921). The apparatus (Fig. 6) consisted of two pins that were attached directly to the proximal and distal bone fragments and connected together by a

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Distraction Osteogenesis: Origins and Evolution telescoping tube. A special spring mechanism was used to control the forces of traction. Leroy Abbott used a U-shaped osteotomy (Fig. 7) in conjunction with pins attached to the frame on both sides of the limb. In his original paper, he suggested that leg lengthening begin 7 to 10 days after the osteotomy when the swelling had disappeared (Abbott, 1927). He also recommended limiting the total amount of limb lengthening to 5 cm, with a daily rate not more than 3 mm (Abbott and Saunders, 1939). During the 1930s, further modifications and considerable improvements in distraction osteogenesis procedures were developed. In 1932, Edward Haboush and Harry Finkelstein described a new osteotomy technique. They incised the periosteum away from the level of surgical bone separation, and new bone formed more rapidly within the intact periosteal sleeve (Haboush and Finkelstein, 1932). In 1938, David Bosworth was the first to use the term skeletal (bone) distraction in the literature. He suggested that neither the level nor the number of osteotomi es made a difference in the end result of lengthening (Bosworth, 1938). Distraction osteogenesis was quickly adopted by surgeons around the world as a technique for limb lengthening, and shortly thereafter, large clinical series of patients treated with this procedure were collected. Summaries soon appeared reporting success and complications during limb lengthening. The complications included bone-associated problems such as delayed healing, nonunions, deformities, and fractures after frame removal, and soft tissue-associated problems due to overstretching, including nerve palsy and joint contracture (Brockway and Fowler, 1942; Compere, 1936). These problems prevented widespread acceptance of distraction osteogenesis. Further improvements in osteotomy technique, distraction protocol, and appliance design were required. In 1932, Joseph Bitner first introduced the use of a circular external fixator with thin tensioned wires instead of thick pins (Volkov and Oganesyan, 1987). The thin tensioned wires were tolerated much better by the bone and soft tissue, thereby reducing the rate of complications; however, bone fixation by single wires was not stable enough for the multi-directional manipulation of bone segments often required during limb lengthening. In 1948, F.G. Allan presented his results of limb lengthening procedures. He performed a relatively non-traumatic osteotomy, breaking 6

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Figure 6. Vittorio Putti's "Osteoton"-a unilateral fixator capable of monitoring the traction force during femoral lengthening.

Figure 7. Leroy Abbot's osteotomy technique and bilateral external skeletal fixator for tibial lengthening.

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Figure 8. W.V. Anderson's subcutaneous osteotomy technique with predrilled holes and transverse osteoclasis.

the bone after making a partial division of the opposite cortex with a chisel (Allan, 1948). His frame secured the bone fragments with tensioned Kirschner wires in several planes, providing more stable fixation and producing controlled progressive distraction at a rate of 1.6 mm per day (Allan, 1951). In 1952, W. V. Anderson introduced a procedure that utilized a subcutaneous division of bone. His osteotomy technique (Fig. 8) included drilling holes into the cortical bone through a very small periosteal incision, followed by transverse closed osteoclasis, thereby preserving the surrounding soft tissues (Anderson, 1952; Coleman and Noonan, 1967). Bun'Ichiro Kawamura further modified the Anderson technique by dividing the bony cortex only after subcutaneous circumferential "tube-like" elevation of the periosteum through a small skin incision (Kawamura et al., 1968, 1981). 8

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Figure 9. G.A. Ilizarov's external fixator with cross tensioned wires secured to the rings.

A significant contribution in the development of distraction osteogenesis was made by the Russian surgeon Gavriil Ilizarov (Ilizarov and Sobelman, 1969; Ilizarov, 1988, 1989a,b, 1995). In 1951, he designed a new apparatus for bone fixation (Fig. 9). His device consisted of two metal rings joined together with three or four threaded rods. Each bone segment was secured to the rings by two thin tensioned wires inserted into the bone at a right angle to each other. This fixation technique has several distinct advantages over other methods : (1) stable, but not rigid fixation to provide axial micromotion of bone segments, yet allow weight bearing of the extremity with physiologic function , and (2) full control over the manipulation of bone segments regardless of their 9


Figure 10. G.A. Ilizarov's low energy subperiosteal corticotomy technique.

size, shape, or anatomic location. He later developed a low energy, percutaneous subperiosteal osteotomy technique, called a corticotomy (Fig. 10). Ilizarov divided two-thirds of the bony cortex with a narrow osteotome and completed the corticotomy by rotational osteoclasis, thereby causing minimal trauma to the periosteum and bone marrow. His lengthening protocol utilized a 5 to 7 day latency period followed by a distraction of 1 mm per day performed in 4 increments of 0.25 mm. Based on his clinical experience, Ilizarov discovered two biological principles of distraction osteogenesis that came to be known as the "Ilizarov effects" : (1) the tension-stress effect on the genesis and growth of tissues, and (2) the influence of blood supply and loading on the shape of bones and joints. The first Ilizarov biological principle suggests that gradual traction on living tissue creates stress that can stimulate and maintain regeneration and active growth. The second Ilizarov biological principle suggests that the shape and mass of bones and joints are dependent upon an interaction between mechanical loading and blood supply. 10

Samchukov et al. Ilizarov not only described these biological principles of distraction osteogenesis, he also characterized the parameters necessary for the successful application of these principles in clinical practice. His classic series of dog experiments were focused on the mechanisms of distraction osteogenesis and the optimal parameters for new bone formation (Frankel et al., 1988; Green, 1992; Shevtsov, 1997). The first set of experiments was designed to determine the effect of bone fragment fixation stability on the distraction regenerate. He found that stable circular external fixation generated direct intramembranous bone formation in the distraction gap. The second series attempted to determine the relative importance of the preservation of osteogenic tissues during osteotomy. His results demonstrated that periosteum, bone marrow, and the nutrient artery are equally important for new bone formation. The third group of experiments sought to investigate the effect of the direction of distraction on the orientation of newly formed tissues . Ilizarov discovered that the regenerate within the distraction gap always was formed along the axis of applied traction. In the next set of experiments, the influence of the rate and rhythm of distraction on the formation of the bone regenerate was studied. His results proved that more frequent rates of distraction led to more favorable regenerate formation and caused less soft tissue problems. The last study looked at the relationship between blood supply and mechanical loading and its influence upon the shape-forming process in bones and joints. He suggested that both the blood supply and mechanical loading have a significant influence on the shape and mass of the resulting bone. Therefore, in order to maintain function , the blood supply must be proportional to the mechanical load. Although the Ilizarov technique was adopted as the standard in Russia, his work remained largely unknown in other countries. At that time, the worldwide standard of orthopedic treatment for leg length discrepancies was the Wagner technique, which was first introduced in 1963. This method of limb lengthening required three sequential operations. The first involved an open mid-diaphyseal osteotomy, followed by the application of a monolateral external fixator with an acute 5 mm lengthening. Gradual distraction was initiated the day after surgery and continued at rate of 1.5 to 3.0 mm per day until the desired length was achieved. The external fixator then was replaced with an internal plate and an extensive cancellous bone graft placed across the distraction gap. Finally, the internal plate was removed after complete bone healing (Wagner, 1971, 1978). 11

Distraction Osteogenesis: Origins and Evolution Ilizarov began to gain worldwide recognition in the late 1980s after he successfully treated the famous Italian alpinist and explorer Carlo Mauri (Golyakhovsky, 1988 ; Bianchi Maiocchi, 1997) . For years Mauri had suffered with an infected non-union and foot deformity after unsuccessful treatment by the world's leading surgeons who finally suggested amputation. When Mauri returned to Italy from the Ilizarov clinic in Kurgan, Italian orthopedic surgeons were so impressed with the result of his treatment that they invited Ilizarov to present his data at the next orthopedic convention. In 1981, the Italians formed the Association for the Study and Application of the Methods of Ilizarov, known as ASAMI. From Italy, the Ilizarov method made its way to the United States via Dror Paley, Victor Frankel, and Stuart Green, who organized the first Ilizarov meeting in New York in 1988. A year later ASAMI North America was formed. Finally, in 1996, ASAMI International was created to foster the exchange of knowledge about different aspects of gradual distraction. BIOLOGICAL FOUNDATION OF OSTEODISTRACTION Distraction osteogenesis begins with the development of a reparative callus. The callus is placed under tension by stretching, which generates new bone. Distraction osteogenesis consists of three sequential periods: (1) latency, (2) distraction, and (3) consolidation. The latency period is the period from bone division to the onset of traction and represents the time allowed for callus formation. The distraction period is that time when gradual traction is applied and new bone, or distraction regenerate, is formed . The consolidation period allows maturation and corticalization of the regenerate after traction forces are discontinued.

Latency Period The histologic sequence during the latency period is similar to that seen during fracture healing. Traditionally, fracture healing has been described as consisting of four stages or phases: (1) inflammation, (2) soft callus, (3) hard callus, and (4) remodeling (Brighton, 1997). The same sequence will be followed for histomorphological description of distraction regenerate formation. Stage of Inflammation. Following the surgical separation of a bone into two segments, a cascade of events takes place (Frost, 1989 ; Schenk and Hunziker, 1994a; Landry et al., 1996). Initially, as a result of vascular disruption and extravasation of blood from the damaged

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pf

df

A

B

Figure 11 . Inflammation stage of fracture healing. A. Radiograph of goat tibia 2 days after midshaft osteotomy and application of a circular external fixator on the proximal and distal bone fragments . B. Diagram of osteotomized proximal (pf) and distal (df) bone fragment with formed hematoma (h).

bone ends and the associated soft tissues, a hematoma forms between and around the bone segments (Fig. 11). The hematoma is converted to a clot, and bone necrosis occurs at the ends of the fracture segments. There is an ingrowth of vasoformative elements and capillaries for the restoration of blood supply, and a tremendous amount of cellular proliferation (McKibbin, 1978). Very quickly, the clot is replaced with granulation tissue consisting of inflammatory cells, fibroblasts , collagen, and invading capillaries (Hulth, 1989; Andrew et al., 1994). This stage of inflammation lasts from 1 to 3 days after which time callus formation begins. 13


B

A

Figure 12. Soft callus stage of fracture healing. A. Radiograph of goat tibia at the end of the 7 day latency period. B. Diagram of soft callus with subperiosteal and endosteal new bone formation (bf) and cartilage (er) replacing the granulation tissue (gt).

Stage of Soft Callus. During the soft callus stage (Fig. 12), which lasts approximately three weeks, granulation tissue is converted to fibrous tissue by fibroblasts. This period is marked by a great increase in vascularity and ingrowth of capillaries into the fracture callus. On the fifth day after fracture, a minicellular network of growing capillary loops is formed in the medullary canal of both proximal and distal segments in the areas adjacent to the fracture line (lrianov, 1996a,c). This time also is marked by an increase in cellularity (Postacchini et al., 1995). Less differentiated, free circulating osteogenic cells are located inside the terminals of the newly formed capillaries. During the soft callus stage, cartilage replaces the granulation tissue mainly toward the

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Inflam1nation 1

____...

Soft callus ',

~

0

""'+-'""' u

ro ;....

~

Hard callus

~

Remodeling

E--;

I

Figure 13. Transformation of fracture healing into distraction osteogenesis under the influence of a traction force .

periphery of the interfragmentary gap (Brighton, 1996). During normal fracture healing (Fig. 13), the fibrocartilaginous tissue of the soft callus is transformed by osteoblasts into a hard callus consisting of fiber bone. The cartilage calcifies as it is invaded by capillaries. Osteoblasts follow and lay down new bone on the calcified cartilage matrix. The hard callus stage lasts 3 to 4 months for many fractures and is followed by the stage of remodeling, when fiber bone is converted slowly to lamellar bone and the medullary canal is reconstituted.

Distraction Period During distraction osteogenesis, the normal process of fracture healing is interrupted by the application of gradual traction to the soft cal1us (Fig. 13). Through application of tensional stress to the interfragmentary tissues of the soft callus, a dynamic micro-environment is created. This environment encourages new tissue formation in a direction parallel to the vector of traction (Delloye et al. , 1990; White and Kenwright, 1991). 15

Distraction Osteogenesis: Origins and Evolution Mechanical tension is one of the basic factors of morphogenesis during natural growth and development. This phenomenon was utilized by Ilizarov as a basis for his distraction osteogenesis techniques and was the foundation of the "Ilizarov effects" (Ilizarov, 1989a,b). Tensional stress generated in gradually stretched tissues stimulates changes at both the cellular and sub-cellular levels, that can be characterized as: (1) growth-stimulating effects, and (2) shape-forming effects (Kallio et al., 1994; Holbein et al., 1995; Mosheiff et al., 1996; Asonova, 1996). The growth-stimulating effects of tension activates all structural elements of the interfragmentary connective tissue. These effects include prolongation of angiogenesis with increased tissue oxygenation, and increased fibroblast proliferation with intensification of biosynthetic activity. The shape-forming effects of tension cause an altered phenotypic expression of the fibroblasts. These fibroblast-like cells are characterized by a hypertrophic appearance of their intermediate filaments. The shape-forming effects also polarize these "distraction" fibroblasts, orienting them and their secreted collagen parallel to the vector of distraction. As distraction begins, the fibrous tissue of the soft callus becomes oriented longitudinally along the axis of distraction (Fig. 14). The spindle-shaped fibroblast-like cells located between the collagen fibers also are oriented along the direction of distraction. These cells form collagen fibrils that are grouped into fibers at the distal and proximal ends of the interfragmentary tissues (Aronson et al., 1989, Aronson, 1994; Asonova, 1996). Between the third and seventh day of distraction, capillaries grow into the fibrous tissues, thereby extending the vascular network not only toward the center of the gap but also toward the medullary canal of both adjacent bone segments. The newly formed capillary loops are parallel to each other as well as to the axis of distraction (lrianov, 1996a,c). Very often, newly formed vessels in the distraction regenerate have a spiral pathway and numerous circular folds suggesting growth rates much higher than the rate of distraction, and 10 times faster than vessel growth during normal fracture healing. Capillary terminals actively invade the fibrous tissues, supplying them with less differentiated cells that differentiate into fibroblasts , chondroblasts, or osteoblasts (lrianov, 1996b). During the second week of distraction, primary osteons begin to form (Maffuli, 1996). The osteoid-producing osteoblasts (Fig. 15), lo16

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Figure 14. Photomicrograph demonstrating longitudinally oriented collagen fibers (cf) in the distraction gap. Hematoxylin and eosin stain, x400.

cated among the collagen fibers, lay down osteoid tissue on these collagen fibers and eventually become enveloped as bone spicules gradually enlarge through circumferential apposition of collagen and osteoid (Aronson et al., 1989). Osteogenesis is initiated at the existing bone walls and progresses toward the center of the distraction gap. By the end of the second week, the osteoid begins to mineralize (Schenk and Gachter, 1994b). At that time, the distraction regenerate has a specific zonal structure (Fig. 16). A poorly mineralized, radiolucent fibrous interzone is located in the middle of the distraction gap, where the influence of tensional stress is maximal (Yasui et al., 1993). Again, this zone consists of highly organized, longitudinally oriented, parallel bundles of collagen with spindle-shaped fibroblasts and undifferentiated mesenchymal cells located throughout the matrix. The interzone functions as the center of fibroblast proliferation and fibrous tissue formation. Daily distraction aligns collagen fibrils in parallel bundles that canalize the 17


Figure 15. Photomicrograph demonstrating formation of a primary osteon (po) by osteoblasts (ob) between longitudinally oriented collagen fibers (cf). Hematoxylin and eosin stain, x160.

ingrowing vessels and the accompanying perivascular cells into longitudinal compartments. The invading vessels arise from both the periosteal envelope and the medullary system at the bone ends. At the periphery of this fibrous interzone, there are two zones with longitudinally oriented, cylindrical primary osteons, which are covered by a layer of osteoblasts and grow toward each other (Schenk and Gachter, 1994b; Irianov, 1996b). Bone formation along the vector of tension is maintained by the growing apices of the primary osteons, which remain open during the distraction period. Therefore, these areas function as "growth zones" of the distraction regenerate, providing active osteogenesis throughout the period of elongation. The elongation of the regenerate depends on the growth of primary osteons, the length of which increases rapidly, especially during the earliest stages of distraction (Aronson et al. , 1990). 18

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B

A

Figure 16. Zonal structure of the regenerate during early stages of distraction. A. Radiograph of a goat tibia after 30 days of distraction. B. Diagram demon-

strating two zones of mineralization (mz) with longitudinally oriented primary osteons, divided by a fibrous radiolucent interzone (fz) with longitudinally oriented collagen bundles.

This zonal distribution of newly formed tissues in the distraction regenerate remains until the end of the distraction period. Finally, two additional zones of primary osteon remodeling become evident at the junction of the regenerate and the host bone segments (Fig. 17). Fixation Period After distraction ceases, the fibrous interzone gradually ossifies and one distinct zone of woven bone completely bridges the gap (Fig. 18). The distraction regenerate forms predominantly via intramembranous ossification (Fig. 19), and isolated islands of cartilage (Fig. 20) also may be observed in areas of the distraction regenerate (Windhager et

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B

Figure 17. Zonal structure of regenerate during the late stages of distraction. A. Radiograph of a goat tibia after 45 days of distraction. B. Diagram demon-

strating two additional zones of primary osteon remodeling (rz) located between the zones of mineralization (mz) and the host bone fragments. The fibrous radiolucent interzone (fz) with longitudinally oriented collagen bundles is still present in the middle of the distraction regnerate.

al., 1995). As the regenerate matures, the zone of primary osteons significantly decreases and later is resorbed completely (Fig. 21). In the ensuing months, the initially formed bony scaffold is reinforced by parallel-fibered and lamellar bone (Fig. 22). Both the cortical bone and marrow cavity are restored. The bone structure is normalized by Havesian remodeling that represents the last stage of cortical reconstruction (Tajana et al., 1998 ; Saleh et al., 1993). It takes a year or more before the structure of newly formed bony tissue is comparable to the preexisting bone (Schenk, 1994). 20

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A

B

Figure 18. Zonal structure of the regenerate during the fixation period. A. Radiograph of a goat tibia after 30 days of fixation. B. Diagram demonstrating two zones of primary osteon remodeling (rz) divided by the mineralization zone (mz) . The fibrous interzone gradually ossified and was replaced by woven bone.

lntramembranous Bone Distraction The dynamics of new bone formation during distraction of membranous bone is similar to that of long bones (Costantino et al., 1990; Karp et al., 1990; Karaharju-Suvanto et al., 1992; Karaharju et al., 1993 ; Bell et al., 1997). Radiographically, the first evidence of bone regenerate usually is observed at the end of the distraction period. The bone regenerate is oriented along the direction of distraction and divided into three parts: two areas with increased density adjacent to the residual bone segments and a central radiolucent zone. Histologically, 21


B

A

Figure 19. Predominant intramembranous ossification of the distraction regenerate. A. Primary osteon mineralization zone (mz) and two zones of remodeling (rz) of the goat tibia distraction regenerate. Hematoxylin and eosin stain, x2. B. Photomicrograph demonstrating intramembranous ossification of newly formed bony trabeculae oriented parallel to the distraction vector. Hematoxylin and eosin stain, xl60.

the gap between the distracted bone segments first is occupied by fibrous tissue. The collagen fibers connect both residual bone surfaces. As distraction proceeds, the fibrou s tissue becomes longitudinally oriented in the direction of distraction. Early bone formation advances along the fibrous tissues . This bone formation starts from the surfaces of the existing bones and progresses toward the fibrous interzone. The newly formed trabecular columns originate from both residual bony walls and progresses toward the center of the distraction regenerate. Bone formation and remodeling activity in this area is significantly higher than in adjacent preexisting bone. Although the distraction regenerate is formed predominantly via direct intramembranous bone formation, some focal regions of cartilage also are observed (Fig. 23). Eventually the distraction regenerate is remodeled to mature bone. 22

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Figure 20. Islands of cartilage in the distraction regenerate. A. Ossifying cartilaginous tissues (ct) and newly formed bony trabeculae (bt) in the central area of goat tibial distraction regenerate. Hematoxylin and eosin stain, x 160. B. Photomicrograph demonstrating mineralized matrix and chondrocytes in the areas of ossifying cartilage. Hematoxylin and eosin stain, x400.

DISTRACTION HISTOGENESIS As was mentioned previously, distraction forces applied to bone also create tension in the surrounding soft tissues, initiating a sequence of adaptive changes in these tissues termed distraction histogenesis. It should be emphasized that, under the influence of tensional stresses produced by gradual distraction, active histogenesis occurs in different tissues, including skin, fascia, muscle, tendon, cartilage, blood vessels, and peripheral nerves (Murray and Fitch, 1996; Diachkova, 1997; Aston et al., 1992; Stanitski, 1994; Nakamura et al., 1993; Harper et al., 1997; Makarov et al., 1996; Block et al., 1993). Although all of the surrounding soft tissues are subjected to excessive local stretching dur23


B

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Figure 21. Structure of the distraction regenerate at the end of the fixation period. A. Radiograph of goat tibia after 66 days of fixation. B. Diagram demonstrating only one zone of remodeling (rz) in the distraction regenerate. The zone of primary osteon mineralization is completely resorbed during maturation of the distraction regenerate.

ing distraction, muscles and nerves are the primary limiting factors when distraction osteogenesis is applied in clinical practice. Limited information is available regarding the mechanism of soft tissue elongation. Although morphologically different tissues react in different ways, there are two primary mechanisms of adaptation to gradual stretching: (1) neohistogenesis and growth stimulation as a result of the tensional stresses, and (2) reversible reactive changes as result of overstretching, followed by degenerative changes with possible regeneration (Fig. 24). To illustrate the dynamics of distraction histogenesis, we will briefly describe the adaptive changes in muscle tissue in response to a 30% increase in length by gradual stretching. 24

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Figure 22. Remodeling and maturation of the distraction regenerate with formation of lamellar bone. Undecalcified section of goat tibia distraction regenerate. A. Photomicrograph demonstrating rapid deposition of bone by osteoblasts. ob-osteoblasts, os-osteoid, wb-newly formed woven bone. Sanderson's Rapid Bone Stain, x160. B. Photomicrograph demonstrating osteoclastic bone resorption. oc-osteoclasts. Sanderson's Rapid Bone Stain, x400.

Muscle Structure

Embryologically, muscle fibers develop from mesenchymal tissues. Each skeletal muscle cell or skeletal muscle fiber is about 50 µm in diameter and composed of a large number of myofibrils bound by a cell membrane, or sarcolemma (Fig. 25). Many fibers are arranged together to form a muscle (Johnson, 1997; Wheater et al., 1997). Individual muscle fibers are surrounded by endomysium that anchors the muscle fibers to each other and contains both capillaries and individual nerve axons. Clusters of muscle fibers are held together by fine sheets of fibrocollagenous support tissue (perimysium) to form muscle fascicles. Muscle is composed anatomically of many fascicles, which are surrounded by a thick layer of fibrocollagenous support tissue, or epimysium. Ultrastructurally, each muscle cell contains striated parallel longitudinal myofibrils, each about 1 mm in diameter. Myofibrils, in turn, are composed of many sarcomeres that are aligned across the cell from one fibril to another. Each sarcomere essentially is a regular array of thick and thin filaments (myosin and actin, respectively) anatomically located between two z-disks. 25


B

c Figure 23. Structure of intramembranous distraction regenerate 8 weeks after midline mandibular widening on Macaca mulatta monkeys. A. Coronal section through the middle of the symphyseal distraction regenerate and adjacent fragments . Newly formed bony trabeculae (bt) by intramembranous ossification and. ossifying cartilaginous tissues (ct) in the middle of the regenerate. Hematoxylin and eosin stain, x2. B. lntramembranous ossification of newly formed bony trabeculae (bt) oriented parallel to the distraction vector. Hematoxylin and eosin stain, x 160. C. Photomicrograph demonstrating mineralized matrix and chondrocytes in the ossifying cartilage. Hematoxylin and eosin stain, x160.

Distraction Myogenesis Microscopic changes during distraction of skeletal muscles are dependent upon the degree of lengthening. During the first 10% of lengthening, no pathological changes were observed in the muscle tissue. As was demonstrated by Dyachkova, lengthening up to 10% was accommodated by tighter packing of muscle fibers with a sliding effect between the fibers (Dyachkova et al., 1982, Diachkova, 1997). Ili-

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Distraction Histogenesis

Tension

Irritation 1

'

Neogenesis

Degeneration

1

r

Growth

Regeneration

Figure 24. Distraction histogenesis. Mechanisms of tissue adaptation to gradual stretching.

zarov, using electron microscopy, observed hypertrophy of the Golgi complex and enlargement of mitochondria as a result of the activation of a bio-energetic system and a protein-synthesizing cell apparatus (Ilizarov, 1992). Others have studied cellular replication by using bromodeoxyuridine (BrdU) as a marker (Schumacher et al., 1994; Day et al., 1997). These authors conclude that gradual traction promotes muscle growth via cell proliferation, as indicated by an increase in muscle weight and an increase in the number of proliferating cell nuclei. No pathological changes were found during the next 10-20% of lengthening. Increased myoneogenesis with active formation of new myofibrils was observed. Significantly more satellite cells also were found. Although the accommodation of muscle to lengthening was predominantly by cellular proliferation, the addition of new sarcomeres to existing muscle cells also was documented. As was demonstrated by Williams and Goldspink in 1971, normal muscle growth appears to 27


A

B

Figure 25. Structure of normal muscle. A. Goat anterior tibialis muscle. B. Photomicrograph demonstrating the structure of a muscle on cross section. ep-epimysium, pr-perimysium, ed-endomysium. Hematoxylin and eosin stain, xl60.

occur primarily in the ends of the muscle, at the musculotendous junction (Williams and Goldspink, 1971 ). In contrast, new muscle tissue production during gradual distraction was distributed along the entire length of the muscle (Yasui et al., 1991). During lengthening of greater than 20%, both the muscle and fascia tended to lengthen more in the region of the osteotomy than throughout the entire muscle. Histopathologic changes of muscle tissue also occurred in this area (Lee et al. , 1993). The following histologic changes

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Figure 26. Histomorphologic changes in goat anterior tibialis muscle fibers after 30% of limb lengthening. Hematoxylin and eosin stain, xl60. A. Degenerating muscle fibers with different levels of atrophy and muscle nuclei internalization. B. Severe endomysial and perimysial fibrosis. C. Severe muscle fiber degeneration with muscle tissue necrosis and replacement by fibrous and adipose tissues. D. Regenerating muscle fibers .

(Fig. 26) were observed in the anterior tibialis muscle during our experimental investigations with goats: (1) different levels of muscle fiber atrophy, sometimes up to three-fourths of the normal size, (2) internalization of muscle nuclei, (3) disruption of muscle fibers followed by endomyseal and perimyseal fibrosis, and (4) severe degenerative changes with muscle fiber necrosis followed by replacement with fibrous or adipose tissue. Regeneration of muscle fibers may occur if distraction is discontinued before the development of irreversi ble changes. The presence of relatively large nuclei with prominent nucleoli and basophilic cytoplasm provides some evidence of muscle regeneration. CONCLUSIONS Distraction osteogenesis is a unique biologic process of new bone formation under the influence of traction forces. Low energy bone di-

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Distraction Osteogenesis: Origins and Evolution vision with maximum preservation of osteogenic tissues, stable fixation of the bone segments , and adequate distraction protocols are mandatory for the successful application of di straction osteogenesis in clinical practice. New bone formation during distraction osteogenesis is similar to fracture healing until it is interrupted by traction forces. The application of incremental gradual traction to the soft callus aligns the developing interfragmentary tissues parallel to the axis of distraction. Tensional stress provides an environment that maintains the soft callus at the center of the distraction gap, while at the same time allowing the progression of routine fracture healing at the periphery of the regenerate. Therefore, distraction osteogenesis represents a continuum of individual stages that, due to tensile force application, occur simultaneously rather than sequentially during distraction, yet separately during fracture healing. The mechanism of new bone formation during distraction is similar for membranous and long bones. Distraction forces applied to a segmented bone generate tensional stresses in the surrounding soft tissues, stimulating cellular proliferation and growth. Gradual elongation greater than 20% of initial limb length may cause irreversible degenerative changes in the surrounding soft tissues. Although a detailed description of the histological aspects of distraction osteogenesis exists, the exact mechanisms regulating distraction bone formation are still unknown. REFERENCES Abbott LC. The operative lengthening of the tibia and fibula. J Bone Joint Surg 1927;9-A:l28-152. Abbott LC, Saunders JBCM. The operative lengthening of the tibia and fibula . A preliminary report on the future development of the principles and technique. Ann Surg 1939;110:961-991. Allan FG. Bone lengthening. J Bone Joint Surg 1948;30-B:490-505. Allan FG. Leg-lengthening. Br Med J 1951;1 :218-222. Anderson WV. Leg lengthening. J Bone Joint Surg 1952;34-B:150 Andrew JG, Andrew SM, Freemont AJ, Marsh DR. Inflammatory cells in normal human fracture healing. Acta Orthop Scand 1994;65(4):462-466. Aronson J, Harrison BH, Stewart CL, Harp JH . The histology of distraction osteogenesis using different external fixators. Clin Orthop 1989;24 l : 106- 116. Aronson J, Good B, Stewart C, Harrison B, Harp J. Preliminary studies of mineralization during distraction osteogenesis. Clin Orthop 1990;250: 43-49.

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From Distraction osteogenesis and tissue engineering. J.A. McNamara, Jr., C.A. Trotman (Eds.), Craniofacial Growth Series 34, Center for Human Growth & Development, The University of Michigan, Ann Arbor, 1998.