Rockwood & Green’s Fractures in Adults
6th Edition

Chapter 9
Bone Grafting and Enhancement of Fracture Repair
Sanjeev Kakar
Eleftherios Tsiridis
Thomas A. Einhorn
Fracture healing is a well-orchestrated biological process resulting in optimal skeletal repair. Despite this, it is estimated that between 5% and 10% of the fractures occurring annually in the United States exhibit some degree of impaired healing (1). In many instances, the cause is unknown and may be related to inadequate reduction, instability (2), the systemic state of the patient (3,4) or the nature of the traumatic insult itself (5,6). In addition, there are certain areas within the appendicular skeleton that have a predilection to impaired healing due to aspects of the local biomechanical environment or anatomy of the blood supply. Examples include the subtrochanteric region of the femur where, until the introduction of locked intramedullary nailing, control of the mechanical environment was challenging, and the scaphoid where the repair process is influenced by the anatomy of arterial blood flow (7). Despite most fractures healing uneventfully, clinical scenarios arise in which enhancement

of fracture repair would be beneficial to ensure rapid restoration of skeletal function.
Each year, more than 2.2 million bone grafts are performed worldwide, with 450,000 being performed in the United States (8). The indications for grafting include the treatment of delayed unions, failed joint replacements, spinal and long bone arthro- deses, limb salvage reconstructions for malignant bone tumors and complex spine reconstructions for instability and deformity. Approximately 11% of bone grafts are performed in the craniofacial bones.
Autogenous bone graft is still considered the implant of choice for most applications as it naturally provides the basic components required to stimulate skeletal repair. These include osteoinductive growth factors, an osteoconductive extracellular matrix and osteogenic stem cells present in bone marrow elements. Osteoinduction refers to the process by which pluripotent mesenchymal stem cells are recruited from the surrounding host tissues and differentiate into bone forming osteoprogenitor cells. This is mediated by graft-derived growth factors such as bone morphogenetic proteins and other peptide signaling molecules (9,10). An osteoconductive material is one that acts as a scaffold, supporting ingrowth of capillaries, perivascular tissue and osteoprogenitor cells from the recipient bed. This occurs in an ordered sequence determined by the three dimensional structure of the graft, the local blood supply and the biomechanical forces exerted on the graft and surrounding tissues (10). Osteogenesis refers to the process of bone formation. In terms of bone grafting, an osteogenic material is one which contains living cells capable of differentiating into bone.
Despite the effectiveness of autogenous bone graft, several shortcomings exist including donor site morbidity, nerve or arterial injury, and infection rates of between 8% and 10% associated with graft harvesting (11,12,13,14). These limitations have prompted the use of an alternate graft material like allogeneic bone. However, despite its ready availability, the risk of disease transmission, diminished biologic and mechanical properties in comparison to autogenous bone, and increased cost have limited its use (15). For these reasons, development of effective bone graft substitutes and strategies for tissue engineering of bone have led to a new field of study for the future of fracture management.
Autologous Bone
Autologous bone graft (also known as autograft, autogenous graft) refers to bone harvested from and implanted into the same individual and includes cancellous bone, cortical bone (nonvascularized and vascularized grafts) and bone marrow. Although much has been written about its use in skeletal reconstruction, relatively little attention has been paid to its application in the healing of fresh fractures.[pa[xn[is1p]Bone graft incorporation follows a similar sequence of events to those which occur during fracture repair. Once implanted into the host, hematoma forms around the graft, releasing bioactive molecules such as growth factors and pro-inflammatory cytokines (16). Mediators such as interleukin-1 (IL-1), IL-6, and tumor necrosis factor-alpha (TNFα) are secreted and are chemotactic for hematopoietic cells including neutrophils, macrophages, and osteoclasts. These cells invade the graft, thereby initiating the resorptive phase of incorporation. Peptide signaling molecules such as platelet-derived growth factor (PDGF) and transforming browth factor-beta (TGF-β) facilitate the repair process by acting on mesenchymal cell recruitment and differentiation (17,18).
Once the inflammatory process subsides, formation of a callus occurs. A fibrovascular stroma develops in which host- derived blood vessels and osteogenic precursor cells migrate toward the graft. These pluripotential mesenchymal cells differentiate into osteoblasts and synthesize osteoid. At the same time, the graft undergoes partial necrosis and osteoclasts continue to remove dead bone with release of additional biochemical mediators of repair from its extracellular matrix. Osteoblasts and endosteal lining cells on the surface of the graft may survive the transplantation and contribute to the healing, although the magnitude of this response is not clearly understood. Most likely, the main contribution of the graft is as an osteoinductive and osteoconductive substrate. It provides the necessary physical and chemical properties to support the attachment, spreading, division, and differentiation of normal osteoblastic or osteoblast-like cells to form bone. The remodeling process marks the last stage of graft incorporation with woven bone slowly being transformed into mechanically robust lamellar bone through the coordinated activities of osteoblasts and osteoclasts.
In addition to the biologic events surrounding graft organization, several other local factors have been shown to have an effect on this process (19). The quality of the tissues at the host site, including their vascularity, is particularly important in influencing the rate and extent of graft union. An avascular bed or one that is deficient in endothelial or connective tissue cell precursors, will be less able to respond to the osteoinductive and osteoconductive signals emanating from the graft. This may occur in patients who have undergone previous radiation therapy or who are exposed to a therapeutic or nontherapeutic agent such as glucocorticoid or nicotine, which impairs cell function. Moreover, if mechanical instability exists at the implantation site, granulation and fibrous tissue will develop at the graft–host interface thereby preventing bony union (19).
Autologous Cancellous Bone Graft
The host response to cancellous bone grafts differs from that to cortical bone in terms of its rate and completeness of repair. Cancellous bone, with its large surface area covered by quiescent lining cells or active osteoblasts, has the potential to induce more new bone than cortical bone (20). Bone formation and resorption occur concomitantly. Osteoblasts secrete osteoid onto the surface of necrotic bone, while osteoclasts gradually

resorb the dead trabeculae. This process of creeping substitution (21) is characteristic of the late phase of autogenous cancellous bone grafting (Fig. 9-1). Therefore, although a cancellous graft does not provide much, if any, immediate structural support, it incorporates quickly and is completely replaced by host bone and marrow after 1 year (Table 9-1).
FIGURE 9-1 Low-power photomicrograph showing creeping substitution. Newly formed woven bone, containing osteoblasts with basophilic-staining nuclei, is laid down on dead lamellar bone identified by the presence of empty osteocytic lacunae (× 25; hematoxylin and eosin stain).
Cancellous bone graft is usually harvested in fragments from sites such as the iliac crest, distal radius, greater trochanter and proximal tibial and distal femoral metaphyses (22,23). It is an excellent choice for the treatment of conditions that do not require structural integrity from the graft (24,25,26).
Table 9-1. Properties of Types of Autologous Bone Grafts
Property Cancellous Nonvascularized Cortical Vascularized Cortical
Osteoconduction +++ + +
Osteoinduction ++a +/- +/-
Osteoprogenitor cells +++ - ++
Immediate strength - +++ +++
Strength at 6 mo ++ ++, +++ +++
Strength at 1 yr +++ +++ +++
aAlthough cancellous bone is widely believed to be osteoinductive, there is no evidence to critically demonstrate that inductive proteins and cytokines are active in autologous cancellous bone graft.
Reprinted with permission from Finkemeier CG. Bone grafting and bone graft substitutes. J Bone Joint Surg Am 2002;8:4:454–464.
Autologous Cortical Bone Graft
Cortical bone grafts are usually harvested from the ribs, fibula or shell of the ilium and can be transplanted with or without their vascular pedicle. They are mostly osteoconductive with little or no osteoinductive properties (Table 9-1). The thickness of the matrix of cortical bone limits the diffusion of nutrients to support the survival of any useful fraction of osteocytes after transplantation, thereby limiting its osteogenic properties (27).
Cortical autografts proceed through a similar sequence of incorporation as seen with cancellous grafts. However, because of the density of cortical bone, the rate of revascularization is substantially slower (28,29,30). This is more commonly seen with nonvascularized grafts where vascular penetration is primarily the result of peripheral osteoclastic resorption and vascular invasion of Volkmann and haversian canals (31).
Vascularized cortical grafts function relatively independently of the host bed (27) as they are implanted with their own functional blood supply. The three main sources for free vascularized bone grafts are the fibula, iliac crest, and rib. The fibula may be isolated on its peroneal vessels, the iliac crest graft uses the deep circumflex iliac artery and vein, while the rib uses the posterior intercostal artery and vein. Once the vessels are successfully anastomosed, greater than 90% of the osteocytes survive the transplantation procedure. Consequently, graft–host union occurs much more rapidly without substantial bone resorption and remodeling as is seen with nonvascularized grafts (32). This lack of resorption and revascularization results in the vascularized grafts providing superior strength during the first 6 weeks after implantation (27). As with cancellous bone, these grafts still require internal or external fixation to provide mechanical stability while they incorporate into the host bed.

Nonvascularized autologous cortical bone grafts can be used to treat segmental bone defects of up to 6 cm in length which require immediate structural support (26). There are no definitive reports regarding the use of nonvascularized grafts for defects of between 6 and 12 cm in length. For defects greater than 12 cm, vascularized grafts are recommended (33). The harvesting of these large grafts, however, is not without problems. Tang et al (34) examined donor site morbidity in 39 patients with avascular necrosis of the femoral head treated by curettage and transplantation of free ipsilateral fibular grafts. Subjective complaints were common and included weakness in 37% of cases. Twenty-nine percent of patients demonstrated weakness in great toe flexion with 43% experiencing difficulty with toe extension.
Autologous Bone Marrow
Bone marrow contains osteogenic precursor cells (35,36) and may become a prime material in the future for use in tissue engineering of bone (37). In the treatment of bony defects, Connolly and Shindell (38) first reported its clinical use in the management of tibial nonunions. Injecting freshly harvested bone marrow into the defects resulted in clinical and radiographic union by 6 months. Others have described similar successes (39,40). Garg and colleagues (40) percutaneously administered autogenous bone marrow to stimulate healing in 20 ununited long bone fractures. Patients were kept nonweight bearing for 6 weeks after surgery, after which they mobilized with protected weight bearing until union was reached. Seventeen out of 20 fractures demonstrated clinical and radiographic union by 5 months. These clinical reports provide encouraging data in support of the use of bone marrow in fracture treatment. However, randomized controlled trials have not been conducted and these will be required to demonstrate true clinical efficacy.
One of the major setbacks associated with bone marrow use is its limited number of osteoprogenitor stem cells. Muschler et al (41) noted that the mean prevalence of colony forming units expressing alkaline phosphatase (CFU-APs), a marker of osteoblast progenitors, is 55 per million nucleated cells. These values undergo a significant age-related decline for both men and women (p = 0.002). Muschler and co-workers (42) also noted that the volume of aspirate used for grafting procedures can also affect the number of CFU-APs. As the aspirate volume increases, so does the number of CFU-APs. Contamination of the sample by peripheral blood, however, also grows as the aspiration volume increases. The investigators noted that an increase in the aspiration volume from 1 to 4 mL causes approximately a 50% decrease in the final concentration of CFU-APs. On the basis of these data, the authors recommended that the volume of aspiration from any one site should not be greater than 2 mL. In addition, four 1 mL aspirates will provide almost twice the number of CFU-APs as would one 4 mL aspirate.
As the success of bone marrow grafting depends on the transfer of sufficient numbers of osteoprogenitor cells, investigators have tried to increase the concentrations of these cells. Takigami et al (43) described a technique involving the use of a cell retention system that selectively retains osteoblastic stem cells and progenitors within an implantable graft material. Bone marrow aspirates from the posterior superior iliac spine are taken in 2 mL aliquots and flowed through a customized allograft matrix using the selective cell retention processing system. The resulting graft–bone marrow composite can then be used as an adjunct to stimulate bone formation. In a series of four patients, the authors used this technique to treat tibial, clavicular, and femoral neck nonunions. Results demonstrated stimulation of bony repair thereby providing surgeons with an alternative to iliac crest autograft, which eliminates pain, blood loss and other surgical complications associated with autogenous bone graft harvesting. This was a limited case series and randomized controlled clinical studies are required to demonstrate selective cell retention technology’s efficacy on a larger basis.
Allogeneic Bone
The use of allograft bone accounts for approximately one third of bone grafts performed in the United States (44). It is an attractive alternate to autogenous bone as it avoids donor site morbidity and its relative abundance permits it to be tailored to fit the defect size. Despite its use in other areas of orthopaedics such as in spinal surgery (45) or in joint arthroplasty (46), considerably less is known about its use in the repair of fresh fractures or nonunions. This may be in part related to the risk of blood borne disease transmission (47) and suboptimal clinical results compared to autograft (48). These findings may be attributed to its storage and sterilization procedures such as freeze-drying or freezing that are used to lower disease transmission. Freeze-drying or lyophilization involves removal of water and vacuum packing of the tissue. Although this reduces the immunogenecity (49), Pelker et al (50) demonstrated that it also reduces the mechanical integrity of the graft, thereby reducing its load bearing properties. In addition, freeze-drying reduces the allograft osteoinductive potential by inducing the death of its osteogenic cells. Freezing allografts to temperatures of -60°C or below lowers their immunogenecity by diminishing the degradation of enzymes without altering the biomechanical properties.
Allogeneic bone is available in many preparations including morselized and cancellous chips, corticocancellous and cortical grafts, osteochondral segments, and demineralized bone matrix (26). In general, the processes involved in allograft incorporation are similar to those seen with nonvascularized autografts, except that they occur much more slowly and when large grafts are used, incorporation as opposed to resorption and replacement results (51). This is in part related to the lack of viable donor cells that contribute to healing and the immune response that occurs during the inflammatory process of allograft incorporation. This lack of biological activity results in limited revascularization, creeping substitution and remodeling of the graft (52,53). Studies have shown that this lack of vascularization may account for the high incidence of fractures seen with these

grafts, which has been reported to occur in between 16% and 50% of grafts (54,55).
Histologically, mononuclear cells invade the graft and surround newly developing blood vessels. These become occluded leading to rapid necrosis of the graft. Necrotic graft bone remains in the host tissue much longer compared to autografts and may be seen for many years after implantation depending upon the size of the graft and its anatomic location (10,30). Osteoinduction and osteoconduction are markedly delayed with osteogenesis occurring 4 to 6 weeks after implantation.
The biological nature of the recipient host bed is a critical factor in facilitating allograft incorporation. A well-vascularized bed aids in the incorporation of the allograft through a combination of revascularization, osteoconduction, and remodeling (56).
Cortical allografts are harvested from a number of sites including the pelvis, ribs, and fibula. They are available as whole bone segments for limb salvage procedures or may be cut longitudinally to yield struts that can be used to fill bone defects or reconstitute cortical bone after periprosthetic fractures (57). In addition to conferring mechanical stability, they may enhance fracture healing and increase bone stock. Their modulus of elasticity is similar to that of host bone resulting in less stress shielding than with other more rigid forms of internal fixation.
The relative inertness of cortical allografts limits their potential to achieve graft–host union. To improve this, autograft harvested from the iliac crest can be placed at the allograft–host bone interface. The autograft provides osteogenic cells and osteoinductive proteins. This technique was described by Wang and Weng (58) in the treatment of distal femoral nonunions. Thirteen patients with femoral nonunions were treated with open reduction and internal fixation with deep-frozen cortical allograft struts. Seven unicortical, five bicortical and one tricortical allografts, with an average length of 10 cm, were used. Autogenous bone grafts were inserted into the defect between the allograft and host femur. All nonunions united at an average of 5 months with an improvement in knee function.
Demineralized Bone Matrix
Demineralized bone matrix (DBM) is produced by acid extraction of allograft bone (59). It contains type I collagen, noncollagenous proteins and osteoinductive growth factors but provides little structural support (60). The bioavailability of the growth factors contained in DBM results in its greater osteoinductive potential than conventional allografts (47). These properties can be affected by different storage, processing, and sterilization procedures. Donor to donor variability in DBM’s osteoinductive capacity exists, resulting in the American Association of Tissue Banks and the Food and Drug Administration (FDA) requiring that each batch of DBM be obtained from a single human donor (61).
Implantation of DBM is followed by hematoma formation and an inflammatory process characterized by polymorphonuclear cell migration into the implant within 18 hours. Mesenchymal cells differentiate into cartilage-producing chondrocytes by day 5. The cartilage becomes mineralized and is then invaded by new blood vessels by 10 to 12 days. The accompanying perivascular cells differentiate into osteoblasts leading to new bone formation. Remodeling then occurs with all implanted DBM being eventually resorbed and replaced by host bone (10).
Tiedeman et al (62) reported a case series on the use of DBM in conjunction with bone marrow in the treatment of 48 patients with bony disorders such as comminuted fractures with associated bone loss. Of these 48 patients, 39 were available to follow up and review. Thirty of 39 patients demonstrated bony union. Patients with fracture nonunion represented the most recalcitrant group clinically, with union being achieved in only 61% of these cases. Because no control patients were included in the study, the efficacy of the DBM/bone-marrow composite could not be determined.
Numerous DBM formulations exist based upon refinements of the manufacturing techniques. They are available as a freeze-dried powder, granules, gel, putty, or strips. All have osteoinductive effects in animal studies but no randomized controlled trials have been performed in patients. However, because these materials were originally developed as reprocessed human tissues, clearance for marketing was achieved without the need for randomized controlled trials comparing their efficacy to autologous bone. For this reason, it is unclear how well any of these products perform as bone graft substitutes. Because currently marketed formulations of these products include carrier substances such as glycerol, the FDA now plans to regulate DBM products as class II medical devices. Currently marketed DBM products will most likely be reclassified using the 510K pathway requiring demonstration of substantial equivalence to a predicate device but still not requiring demonstration of efficacy comparable to that achieved with autologous bone graft.

An ideal bone graft substitute should provide three elements: scaffolding for osteoconduction, growth factors for osteoinduction, and progenitor cells for osteogenesis (63). The currently available materials including calcium phosphate ceramics, calcium sulfate, bioactive glass, biodegradable polymers (64), recombinant human BMPs (OP-1 and BMP-2), and autologous bone marrow cells, each fulfill only one of these criteria. However, there is great interest in improving these materials as the availability of an effective bone graft substitute would solve some of the current limitations associated with the use of autologous bone.
Calcium Phosphate Ceramics
Calcium phosphate ceramics are osteoconductive materials produced by a sintering process in which mineral salts are heated to over 1000°C. Sintering reduces the amount of carbonated apatite, an unstable and weakly soluble form of hydroxyapatite. An ideal osteoconductive scaffold should have the appropriate three-dimensional structure to allow for osteointegration and invasion by cells and blood vessels. It should also be biocompatible and biodegradable with biomechanical properties similar to those of the surrounding bone. Many of the ceramics used as bone grafts enable osteoconduction to occur (65,66). Despite this, their brittleness and poor tensile strength limit their use as bone graft materials.
The first clinical use of calcium phosphate ceramics for the repair of bony defects was reported by Albee in 1920 (67). Since then, several animal studies have reported favorable results. Despite these early experiments, it was not until the 1970s that calcium phosphates, and in particular hydroxyapatite (HA), were synthesized, characterized and used clinically (68,69,70).
From a functional perspective, calcium phosphate ceramics can be divided into slow and rapid resorbing ceramics (47). Hydroxyapatite is a slow resorbing compound derived from marine coral (71). A simple hydrothermal treatment process converts it into the more mechanically stable hydroxyapatite form with pore diameters of between 200 and 500 μm, a structure very similar to human trabecular bone (Fig. 9-2).
Interpore (Interpore International, Irvine, CA) is a corraline hydroxyapatite and was the first calcium-phosphate–based bone graft substitute approved by the FDA (Fig. 9-2B). Bucholz et al (73) investigated its use to treat tibial plateau fractures. Forty patients with metaphyseal defects needing operative reduction were randomized into a control group treated with autogenous bone graft or a group treated with Interpore hydroxyapatite. Indications for surgery included valgus instability of the knee secondary to a lateral tibial plateau fracture, varus instability due to a medial plateau injury, articular incongruency of 10 mm or greater, and translation of the major condylar fragment of more than 5 mm. After insertion of the graft, cortical fracture fragments were reduced and a standard AO interfragmentary screw and plate fixation device was used to stabilize the reduction. After an average of 15.4 months for the autograft and 34.5 months for the Interpore-treated groups, radiological and functional knee joint assessments revealed no differences between the two groups. No evidence of ceramic resorption was found in the radiographic follow-up 3 years following implantation, highlighting the potential use of HA as a bone filler.
Tricalcium Phosphate
Tricalcium phosphate (TCP) is a fast resorbing ceramic that undergoes partial conversion to HA once implanted into the body. The HA is resorbed more slowly and will remain in place for years.
Reports have demonstrated the efficacy of TCP as a bone graft substitute. McAndrew et al (70) investigated the suitability of TCP to treat bony defects in a case series of 43 patients with 33 fractures and 13 nonunions. Patients were followed for an average of 1 year. Healing was demonstrated in 90% of the fracture patients and 85% of those with nonunions. Radiographic analysis showed complete resorption of TCP between 6 and 24 months after implantation.
Calcium Phosphate/Collagen Composites
Collagen is the most abundant protein in the extracellular matrix of bone and promotes mineral deposition by providing

binding sites for matrix proteins. Types I and III collagen have been combined with HA, TCP, and autologous bone marrow to form a graft material devoid of structural support but able to function as an effective bone graft substitute or bone graft expander to augment fracture healing. This was demonstrated by Chapman et al (74) who conducted a multicenter prospective, randomized controlled study comparing autogenous bone graft and a composite of bovine collagen, calcium phosphate and autogenous bone marrow (Collagraft, Zimmer, Inc., Warsaw, IN) in the treatment of acute long bone fractures. Two hundred and forty-nine fractures were grafted and followed for a minmum of 2 years. The authors observed no significant differences between the two treatment groups in terms of union rates, functional outcomes and impairments of activities of daily living. The prevalence of complications was similar in the two groups except for higher infection rates in patients receiving autogenous bone grafts. Antibodies to the bovine collagen developed in 12% of patients in the Collagraft-treated group but no specific allergic problems were identified. Similar results using this material have been reported by others (75).
FIGURE 9-2 A. High power photograph of cancellous bone demonstrating its interporous structure. (Reprinted with permission from Lee CA, Einhorn TA. The bone organ system. Form and function. In: Marcus R, Feldman D, Kelsey J, eds. Osteoporosis, 2nd ed, vol 1. New York: Academic Press, 2001:3–20.) B. High power photograph of Interpore, a coralline hydroxyapatite. Note the structural characteristics similar to normal trabecular bone.
Calcium Sulphate
Calcium sulphate or plaster of paris was first used as a bone filler in the early 1900s (76). It acts as an osteoconductive material which completely resorbs as newly formed bone remodels and restores anatomic features and structural properties.
Moed et al (77) investigated its ability as a bone graft substitute in a prospective nonrandomized clinical study for the treatment of acetabular fractures with intra-articular comminution, marginal impaction, or both. Thirty-one patients (32 fractures) were treated with calcium sulphate pellets. Radiographic analysis demonstrated that the majority of fractures healed successfully with most of the pellets being replaced by bone.
Two groups of investigators reported the use of calcium sulfate as a material which augments or extends the use of autologous bone graft. In a prospective nonrandomized multicenter study, Kelly et al (78) treated 109 patients with bone defects with calcium sulphate pellets alone or mixed with bone marrow aspirate, demineralized bone, or autograft. After 6 months, radiographic results for all patients showed that 99% of the pellets were resorbed and 88% of the defects were filled with trabeculated bone. Borrelli et al (79) treated 26 patients with persistent long bone nonunions or osseous defects after an open fracture, with a mixture of autogenous iliac crest bone graft and medical grade calcium sulphate. Twenty-two patients achieved healing after primary surgery, while a further two demonstrated union after a second procedure. Persistent nonunions were seen in two patients. Despite these encouraging reports, there have been no randomized, controlled trials to study the efficacy of calcium sulfate in the treatment of skeletal injuries.
Calcium Phosphate Cements
Calcium phosphate cements (CPC) can be used to fill bony defects in conjunction with the treatment of acute fractures. This involves the combination of inorganic calcium and phosphate to form an injectable paste which can be delivered into the fracture site. Under physiological conditions, the material begins to harden within minutes, forming a mineral known as dahllite. By 12 hours, dahllite formation is nearly complete, providing the cement with an ultimate compressive strength of 55 MPA. Studies in animals have shown that it is remodeled in vivo and, in some cases, is completely resorbed and replaced by host bone (80).
Sanchez-Sotelo et al (81) conducted a prospective, randomized controlled study examining the use of a commercially available calcium phosphate paste, Norian SRS (Norian Corporation, Cupertino, CA), in the treatment of distal radius fractures. One

hundred and ten patients, who were between 50 and 85 years of age, and who had sustained either an AO type A3 or C2 distal radius fracture were enrolled. Patients were prospectively randomized to receive either closed reduction with a short arm cast for 6 weeks or closed reduction and stabilization with Norian SRS for 2 weeks. They were followed for a 12-month period and assessed by radiography, range of motion, and grip strength. The results showed improved functional and radiographic outcomes in the patients treated with Norian SRS. In a subsequent randomized, controlled study, Cassidy et al (82) compared the use of Norian SRS and closed reduction versus closed reduction and application of a cast or external fixator in 323 patients with intra- or extra-articular fractures of the distal radius. Significant clinical differences were seen at 6 to 8 weeks postoperatively, with better grip strength, wrist and digit range of motion, hand function, and less swelling in the patients treated with Norian SRS. By 1 year, these differences had normalized.
In light of the promising results seen with distal radius fractures, Norian SRS has been used to treat other bony injuries. Schildhauer et al (83) reported its use in the treatment of complex calcaneal fractures. Thirty-six joint depression fractures were treated with Norian SRS after standard open reduction and internal fixation. Patients were allowed to weight bear fully as early as 3 weeks postoperatively. Results demonstrated no statistical difference in clinical outcome scores in patients who bore full weight before or after 6 weeks postoperatively suggesting that this cement may permit early full weight bearing after treatment of this fracture.
Lobenhoffer and co-workers (84) used Norian SRS in the treatment of 26 tibial plateau fractures (OTA types B2, B3, and C3) followed for a mean period of 19.7 months. Successive radiographs were taken and clinical parameters were measured using Lysholm and Tegner knee scores. Twenty-two fractures healed without any displacement or complications (two cases required early wound revision secondary to sterile drainage and two cases developed partial loss of fracture reduction between 4 and 8 weeks postoperatively requiring revision surgery). The high mechanical strength of the cement allowed earlier weight bearing after a mean postoperative period of 4.5 weeks. Similar results supporting the use of Norian SRS for filling metaphyseal defects in the treatment of displaced tibial plateau fractures have been reported by others (85) (Fig. 9-3)
FIGURE 9-3 Radiograph demonstrating the use of Norian SRS for filling metaphyseal defects in the treatment of a displaced tibial plateau fracture. (Reprinted with permission from Bucholz RW, Carlton A, Holmes R. Interporous hydroxyapatite as a bone graft substitute in tibial plateau fractures. Clin Orthop Relat Res 1989;240:53–62.)
Growth factors are proteins secreted by cells and function as signaling molecules. They comprise a family of molecules that have autocrine, paracrine, or endocrine effects on appropriate target cells. In addition to promoting cell differentiation, they

have direct effects on cell adhesion, proliferation, and migration by modulating the synthesis of proteins, other growth factors and receptors (86).
Bone Morphogenetic Proteins
Since the discovery of the osteoinductive properties of BMP (87), attention has focused on the role of these proteins in embryological development and bone repair in the postnatal skeleton (86,88,89). BMPs are a group of noncollagenous glycoproteins that belong to the TGF-β superfamily. They are synthesized locally and predominantly exert their effects by autocrine and paracrine mechanisms. Fifteen different human BMPs have been identified and their genes cloned (90). For clinical applications, the most extensively studied among these are BMP-2 and BMP-7 (osteogenic protein 1, or OP-1).
The importance of BMPs in bone repair has been the subject of much investigation. Cho et al (88) characterized the temporal expression of BMPs during murine fracture healing, defining specific periods when individual BMPs may exert important roles in normal skeletal repair. BMP-2 showed maximal expression on day one after fracture, suggesting its role as an early response gene in the cascade of healing events. BMPs-3, 4, 7, and 8 exhibited a restricted period of expression from day 14 through day 21, when the resorption of calcified cartilage and osteoblastic recruitment were most active. BMPs-5 and 6 were constitutively expressed from day 3 to day 21.
To determine if BMPs are likely to play a key role during fracture healing in patients, Kloen et al (91) demonstrated the presence of BMPs and their various receptors in human fracture callus. Tissue was obtained from the fracture site of malunions in five patients undergoing revision fracture treatment. Immunohistochemical analysis was performed, and the results demonstrated consistent positive staining for all BMPs and receptors, with immunoreactivity most intense for BMPs-3 and 7. These findings demonstrate that components of the BMP signaling cascade are expressed in human fracture callus and suggest that modulation of the repair process may be possible.
Over the past 20 years, investigators have tested the use of purified or recombinant BMPs in the treatment of several musculoskeletal conditions. While these studies have reported encouraging results, only two randomized, controlled studies have been reported in the treatment of fractures.
In a large prospective, randomized, controlled, partially blinded, multicenter study, Friedlaender et al (92) assessed the efficacy of rhBMP-7 (OP-1) versus iliac crest bone graft in the treatment of 122 patients with 124 tibial nonunions. All nonunions were at least 9 months old and had shown no progress towards healing for the 3 months prior to patient enrollment. Patients were randomized to receive either standard treatment with reduction and fixation with an intramedullary nail and autologous bone graft, or reduction and fixation with an intramedullary nail and implantation of rhBMP-7 (OP-1) on a type I collagen carrier. Results showed that 9 months after surgery, 81% of the 63 patients treated with BMP-7 and 85% of 61 patients treated with autologous bone grafting had achieved clinical union. Radiographic assessments suggested healing in 75% and 84% of these patients, respectively. As these results showed equivalent efficacy between OP-1 and autogenous bone graft, the authors concluded that OP-1 was a safe and effective alternative to bone graft in the treatment of tibial nonunions (Fig. 9-4).
More recently, the BMP-2 Evaluation in Surgery for Tibial Trauma (BESTT) Study Group reported on a large prospective, randomized, controlled multicenter trial evaluating the effects of rhBMP-2 in the treatment of open tibial fractures (93). Four hundred and fifty patients with these injuries were randomized to receive either initial irrigation and debridement followed by treatment with intramedullary (IM) nail fixation alone or IM fixation plus an implant containing either 0.75 mg/kg or 1.5 mg/kg of rhBMP-2 at the time of definitive treatment. The implant was placed over the fracture site at the time of wound closure. After 1 year, there were fewer secondary interventions (returns to the operating room for additional treatment) in the group treated with 1.5 mg/kg rhBMP-2. In addition, those patients treated with 1.5 mg/kg rhBMP-2 had accelerated times to union, improved wound healing, and reduced infection rates (Fig. 9-5).
Despite these promising results, the outcomes in human studies are not as impressive as those seen in animals where greater bone formation and healing has been noted. Diefen- derfer et al (94) noted that one of the reasons may be a differential response of human bone marrow stromal cells to BMPs. Bone marrow cells isolated from patients undergoing hip replacement were cultured and grown to confluence with or without dexamethasone, and treated with BMPs. The results demonstrated no significant osteogenic response to BMPs-2, 4, or 7 as determined by alkaline phosphatase induction, unless cells were pretreated with dexamethasone. Moreover, even when cells were pretreated, the alkaline phosphatase response to BMPs was only about 50% of that measured in murine bone marrow cell cultures. The authors concluded that the ability of human bone marrow cells to respond to BMPs may differ substantially from that which exists in lower mammalian species.
Other Peptide Signaling Molecules
Several growth factors, as decribed below, stimulate the activity of chondroprogenitor and osteoprogenitor cells but do not induce cartilage or bone formation from undifferentiated cells. Current interest to understand the role of these molecules in the treatment of fractures is based on the observations that these molecules are expressed during normal fracture healing. Although each has been tested in experimental settings, these factors are not currently available for treatment of patients.
Transforming Growth Factor Beta
Transforming growth factor beta (TGF-β) influences a number of cell processes including the stimulation of mesenchymal stem

cell (MSC) growth and differentiation, enhancement of collagen and other extracellular matrix (ECM) protein synthesis. It also functions as a chemotactic factor for fibroblast and macrophage recruitment (95).
FIGURE 9-4 Sequential radiographs of a tibial nonunion treated with OP-1 immediately postoperatively, 9 months, and 24 months later. Note the bridging callus and subsequent tibial union. [Reprinted with permission from Friedlaender GE, Perry CR, Cole JD, et al. Osteogenic protein 1 (bone morphogenetic protein 7) in the treatment of tibial nonunions. J Bone Joint Surg Am 2001;83:S151–S158.]
Lind et al (96) tested two doses of TGF-β in rabbits in which tibial defects had undergone unilateral plate fixation. After 6 weeks of healing, mechanical testing showed improved bending stiffness only in the group treated with the low dose, and no improvement in the group treated with the high dose. Critchlow et al (97) performed a study of tibial defect healing in rabbits to test the hypothesis that the anabolic effects of TGF-β on bony repair are dependent on the mechanical stability at the fracture site. The results showed that under stable mechanical conditions, a low dose of TGF-β-2 had an insignificant effect on callus development, whereas the higher dose led to a larger callus.
FIGURE 9-5 Radiographs of a patient who had sustained an open fracture of the left tibia (Gustilo-Anderson type IIIB) and was treated with an unreamed intramedullary nail and a 1.50 mg/mL rhBMP-2 implant. The fracture was considered to be clinically healed by 20 weeks, and radiographically healed by 26 weeks. (Reprinted with permission from Govender S, Csimma C, Genant HK, et al. Recombinant human bone morphogenetic protein 2 for treatment of open tibial fractures. A prospective, controlled, randomized study of four hundred and fifty patients. J Bone Joint Surg Am 2002;84:2123–2134.)
From these studies, TGF-β appears to have some efficacy in

augmenting fracture healing, however, the effects are highly dose-dependent and not especially robust. To our knowledge, there are no studies underway or planned to test the use of TGF-β in human fracture healing.
Fibroblast Growth Factor
Fibroblast growth factors (FGF) are a group of structurally related compounds that share between 30% to 50% sequence homology. Acidic FGF (aFGF, FGF1) and basic FGF (bFGF, FGF2) are the most well studied members of this family with bFGF considered to be the more potent. It stimulates angiogenesis, endothelial cell migration and is mitogenic for fibroblasts, chondrocytes, and osteoblasts (98,99).
During fracture repair, FGFs differ in their temporal and spatial expression (100). In the early stages, FGF1 and -2 are localized to the proliferating periosteum. This expression is then limited to osteoblasts during intramembranous bone formation and in the chondrocytes and osteoblasts during endochondral bone formation. In light of their active involvement during fracture repair, investigators have studied the potential therapeutic roles of FGF in bone formation. Nakamura and associates (101) studied these effects by injecting bFGF into mid-diaphyseal transverse tibial fractures in dogs. Controls were injected with carrier molecules. Results showed that bFGF enlarged the callus area at four weeks and increased the callus bone mineral content at 8 weeks. Subsequent to the reporting of these findings in animals, at least one biotechnology company initiated preliminary studies in humans in order to set the stage for a multicenter randomized, controlled trial in patients with closed tibia fractures. Those preliminary results have not been reported and the multicenter clinical trial has not been conducted. At this time, the status of the development of FGFs for enhancement of fracture healing in patients is unknown.
Platelet-derived Growth Factor
Platelet-derived growth factor (PDGF) is synthesized by numerous cell types including platelets, macrophages, and endothelial cells. It consists of two polypeptide chains that share 60% amino acid sequence homology (102). PDGFs possess strong mitogenic properties and stimulate the proliferation of osteoblasts (103,104). This is particularly important in fracture healing where they exhibit differential spatial and temporal expression (105). Nash et al (106) examined the efficacy of PDGF on bone formation using a rabbit tibial osteotomy model. Each osteotomy was injected with either collagen or collagen containing 80 μg of PDGF. Results showed an increase in callus formation and a more advanced stage of endosteal and periosteal osteo- genic differentiation in the PDGF-treated group compared to the controls. However, there was no improvement in the mechanical properties of the calluses in the group treated with PDGF. Despite these unimpressive results from a single study, there is still interest in the potential role of PDGF in the treatment of fractures and further studies are underway to test its efficacy in experimental models.
Prostaglandin Agonists
Prostaglandins (PG) comprise a group of unsaturated long chain fatty acids. They are synthesized from arachidonic acid by the cyclo-oxygenase enzymes and are known to have profound osteogenic effects when implanted into skeletal sites (107) or systemically infused (108).
In a study of rabbit tibial fractures, Dekel et al (109) demonstrated that PGE2 caused a dose-dependent stimulation of callus formation and an increase in total bone mineral content. Its effects were also shown to be greatest during the latter stages of fracture healing, suggesting that the primary effect may be to stimulate osteoblasts and osteoprogenitor cells as opposed to undifferentiated Mesenchymal stem cells.
One of the major limitations of PG use in humans is its side effects. These include diarrhea, lethargy, and flushing and are mitigated by the binding of PG to all four of its receptors (EP1, EP2, EP3, EP4). Li and co-workers (107) investigated the effects of CP-533,536, a newly discovered nonprostanoid PGE2 agonist, selective for the EP2 receptor on fracture repair. This receptor primarily regulates bone anabolic activity. Using models of both rat and canine fracture healing, CP-533,536 in a poly- (D, L-lactide-co-glycolide) matrix was delivered to fracture sites in a dose-dependent fashion. Each dose increased callus size, density, and strength compared to the controls. Histologically, extensive endochondral and intramembranous ossification was noted. These data suggest that an EP2-receptor agonist may have a therapeutic role to augment the fracture repair process. Clinical trials are currently underway to investigate this application.
Parathyroid Hormone
Parathyroid hormone is an important regulator of calcium and phosphate metabolism that acts by enhancing gastrointestinal calcium absorption, increasing calcium and phosphate reabsorption from the kidneys, and participating in the regulation of 1,25 dihydroxyvitamin D synthesis (110). Although the effects of PTH are usually associated with bone resorption, the response of osteoclasts to PTH is more likely mediated via osteoblastic

activity as receptors for PTH are found on osteoblast membranes (110). Investigators have shown that while continuous exposure to PTH leads to an increase in osteoclast numbers and activity, intermittent exposure stimulates osteoblasts and results in increased bone formation in rats and humans (111,112).
Clinical trials using PTH (1-34) have shown an increase in bone mass in osteoporotic men and an increase in bone mineral density and a reduction of vertebral and other osteoporotic related fractures in postmenopausal women (113,114). Neer et al (113) assessed the efficacy of PTH (1-34) for improving bone mineral density in a clinical trial involving 1673 postmenopausal women, with prior nontraumatic vertebral fractures. Results demonstrated that PTH increased bone mineral density and reduced the risk of fracture.
Based on this anabolic effect of PTH on the skeleton, several animal studies have been conducted examining PTH effects on the repair of bone. All have demonstrated an enhancement of fracture healing at high doses (115,116). Recently, Alkhiary et al (117) investigated the effect of recombinant PTH on fracture healing in 270 rats that underwent standard, closed femoral fractures and received doses of PTH that are similar to those shown to be effective in the treatment of osteoporosis in postmenopausal women. Using biomechanical tests, histomor- phometry and quantitative microcomputed tomography, results demonstrated that daily systemic administration of both a 5 μg/kg/day and 30 μg/kg/day dose enhanced fracture healing by increasing bone mineral density, bone mineral content, and total osseous tissue volume. These findings have supported the initiation of clinical trials to study the role of systemic administration of PTH (1-34) in fracture patients.
Growth Hormone and Insulin-like Growth Factor 1
Growth hormone (GH) and insulin-like growth factors (IGF) play an important role in skeletal development and remodeling. Growth hormone is currently used clinically to treat patients with short stature (118) as it stimulates endochondral ossification, periosteal bone formation, and linear growth. It mediates these effects through the IGF system including the ligands, receptors, IGF binding proteins (IGFBP), IGFBP proteases and activators, and inhibitors of IGFBP proteases (119).
Two IGFs have been identified, IGF-1 (somatomedin C) and IGF-2. Although IGF-2 is the most abundant growth factor in bone, IGF-1 has the greater potency for promoting growth and has been localized in healing fractures of humans (120,121). IGF-1 and IGF-2 promote bone matrix formation (type I collagen and noncollagenous matrix proteins) by fully differentiated osteoblasts (122) and stimulate the proliferation of osteoprogenitor cells once human marrow stromal cells differentiate towards the osteoblast lineage.
Several studies have reported moderate enhancement of skeletal repair using either GH (121,123) or IGF-1 (124). Most recently, Kolbeck et al (125) showed that GH significantly improves the mechanical properties of fracture callus in minipigs. Although it is still unclear if this effect is a direct result of GH or IGF, the potential role of GH as a systemic enhancer of skeletal repair is of great interest.
The mechanical environment has a direct impact on fracture healing. Direct mechanical perturbation as well as biophysical modalities such as electrical and ultrasound stimulation, have been shown to affect fracture healing. In order to enhance fracture repair by these mechanical measures it is necessary to develop a fundamental understanding of the ways in which the mechanical environment impacts cellular and molecular signaling.
Mechanical Stimulation
The fracture repair process can be modulated by mechanical forces. By controlling the weight bearing status of a limb, the resultant load at the fracture site will influence the stress environment. Sarmiento and associates (126) found that early weight bearing accelerates the fracture healing process. Standardized femoral fractures were produced in rats and stabilized by nonrigid intramedullary fixation. The animals were either allowed to bear weight at an early stage or were kept nonweight bearing by cast immobilization. Histological, radiological, and mechanical differences were present by the second week after fracture. These differences became progressively greater during the next three weeks. The authors attributed these findings to early mobilization facilitating the maturation of callus tissue produced by endochondral ossification.
The degree of stability at the fracture site has a direct impact on the repair process (127). Using a standardized, bilateral tibial canine osteotomy model, compression plating of the fracture was compared with the less stable external fixation performed on the opposite side. At 120 days after injury, bone formation

was biomechanically less mature on the external fixator side. These tibiae had significantly less intracortical new-bone formation and more bone porosity when compared with the tibiae that had been treated with compression plates. Endosteal new-bone formation was greater on the plated side. Since the in vitro stiffness of the external fixator was less in all modes tested (compression, distraction, torsion, and anteroposterior bending) except lateral bending, the authors concluded that the rigidity of the fixation may be an important factor in early remodeling of a healing osteotomy.
Several investigators have attempted to modulate fracture healing by altering the mechanical strain environment. In a prospective, randomized clinical trial, Kenwright et al (128) compared the effects of controlled axial micromotion on tibial diaphyseal fracture healing in patients who were treated with external fixation and stratified according to fracture severity and extent of soft tissue injury. A specially designed pneumatic pump was attached to the unilateral frame of one group of patients and delivered a cyclical axial displacement of 1.0 mm at 0.5 Hz for 20 to 30 minutes a day. Fracture healing was assessed clinically, radiologically, and by measurement of the mechanical stiffness of the fracture. Both clinical and mechanical healing were enhanced in the group subjected to micromovement, compared to those treated with frames without micromotion. The differences in healing times were statistically significant and independently related to the treatment method. There was no difference in complication rates between treatment groups.
Distraction Osteogenesis
Limb lengthening was first described by Codivilla in 1905 (129) for the treatment of limb length discrepancies. It was not until the work of Ilizarov (130,131) 50 years later that the technique of distraction osteogenesis gained popularity as a method for enhancing bone regeneration.
Distraction osteogenesis generates new tissue through the application of tensile forces to developing callus via a controlled osteotomy (132,133). It is characterized by three separate stages: (a) the latency phase that immediately follows osteotomy; (b) the active or distraction phase which permits active separation of bony segments; and (c) the consolidation phase where active distraction has ended and healing of the callus begins (134,135,136). The period of time for each stage varies depending upon the anatomic site and the size of the osseous defect needing repair.
In order to delineate the molecular mechanisms by which distraction osteogenesis promotes new bone formation, Pacicca et al (137) studied the expression of angiogenic factors during this process. They demonstrated the expression of several of these molecules localizing to the leading edge of the distraction gap, where nascent osteogensis was occurring. Expression of these factors was greatest during the active phase of distraction.
Several investigators have utilized the technique of distraction osteogenesis to stimulate new bone formation in the clinical setting. Kocaoglu et al (138) treated 16 patients with hypertrophic nonunions with the Ilizarov distraction method. All patients had at least 1 cm shortening, three patients had a deformity in one plane, and the remainder had a deformity in two planes. All nonunions healed at an average follow-up of 38.1 months, with correction of all preoperative length inequalities and limb angulation to normal anatomic alignment (Fig. 9-6). Sen et al (139) reported on the efficacy of distraction in the management of patients with grade III open tibia fractures. Twenty-four patients who had open tibia fractures with bone (mean bone defect of 5 cm) and soft-tissue (mean 2.5 × 3.5 cm) loss and a Mangled Extremity Severe Score of 6 and below were selected and treated with compression-distraction osteogenesis using the Ilizarov-type circular external fixator. After an average of 30 months follow-up, bone assessment results were excellent in 21 and good in three patients. Functional assessment scores were excellent in 19, good in four, and fair in one patient. These findings demonstrate that distraction osteogenesis is a safe, reliable and successful method for the treatment of acute open tibia fractures with bone and soft-tissue loss.
Electrical Stimulation
Fukada and Yasuda (140) first reported the occurrence of piezoelectric potentials in mechanically loaded dry bone in 1957. Since then, many investigators have studied the influence of electrical stimulation on bone formation and growth. In 1971, Freidenberg et al (141) reported the healing of a nonunion after the use of direct current. Within 5 years, over 119 articles had been published highlighting the use of electrical stimulation on bone growth and repair (142).
Currently available devices for electrical stimulation can be categorized as one of three types: constant direct-current (DC) stimulation with the use of percutaneous or implanted electrodes (invasive), capacitive coupling (noninvasive), or time varying inductive coupling produced by a magnetic field (noninvasive). In DC stimulation, stainless steel cathodes are placed in the tissues and electrically induced osteogenesis exhibits a dose response curve in relation to the amount of current that is delivered. Currents below a certain threshold result in no bone formation while those above a certain level lead to cellular necrosis (143). With electromagnetic stimulation, an alternating current produced by externally applied coils leads to a time varying magnetic field that, in turn, induces a time varying electrical field in bone. In capacitative coupling, an electrical field is induced in bone by an external capacitor—that is, two charged metal plates are placed on either side of a limb and are attached to a voltage source (144).
In terms of its applicability to orthopaedics, electrical stimulation has primarily been used in the treatment of nonunions. Brighton and co-workers (144) reported on the treatment of 178 nonunions in 175 patients with DC. Solid bone union was seen in 84% of patients. Patients with a history of osteomyelitis had a healing rate of nearly 75%. The presence of previously


inserted metallic fixation devices did not affect the healing rate. When this study was expanded to include other centers, an additional 58 out of 89 nonunions achieved similar results. Review of the nonunions treated unsuccessfully with constant direct current suggested that inadequate electricity, the presence of a synovial pseudarthrosis or infection, and dislodgment of the electrodes were the causes of failure with this procedure. Complications of DC were minor and no deep infections resulting from this procedure in patients without previous osteomyelitis were noted. The authors concluded that given proper electrical parameters and proper cast immobilization, a rate of bone union comparable to that seen with bone-graft surgery was achieved.
FIGURE 9-6 Radiographs of a 23-year-old woman with a hypertrophic nonunion of the distal femur, with a history of a previous open reduction and internal fixation and a 13-month period of nonunion. A. Preoperative anteroposterior radiograph. B. Preoperative photograph demonstrating leg length discrepancy. C. Callus formation during distraction osteogenesis using an Ilizarov fixator. D. Postoperative anteroposterior radiograph 3 months after frame removal. E. Postoperative photographs showing correction of leg length discrepancy and knee flexion. (Reprinted with permission from Kocaoglu M, Eralp L, Sen C, et al. Management of stiff hypertrophic nonunions by distraction osteogenesis: a report of 16 cases. J Orthop Trauma 2003;17:543–548.)
Similar results were reported by Scott and King (145) in a prospective, double-blind trial using capacitive coupling in patients with established nonunions. In a population of 21 patients, 10 were actively managed and 11 were treated with a placebo unit. Results showed healing in 60% of the patients who had received electrical stimulation. None of the patients managed with the placebo unit demonstrated any bone formation.
Bassett et al (146) reported on the use of pulsed electromagnetic fields (PEMF) in the treatment of ununited tibial diaphyseal fractures. One hundred and twenty-five patients with 127 nonunions underwent long-leg plaster cast immobilization. Patients were treated with nonweight bearing ambulation and a total of 10 hours of PEMF stimulation daily. The authors reported an overall fracture healing rate of 87%, with success being independent of the age or sex, number of previous surgeries, presence of infection, or metal fixation (Fig. 9-7).
Despite the promising results seen in patients with nonunions, the application of this technology to the treatment of fresh fractures has not been clearly defined. Although some studies have shown that pulsed electromagnetic fields favorably influences fracture healing in experimental animals (143), other studies have failed to demonstrate this effect (147). At present, there is a paucity of published clinical studies showing that electrical stimulation enhances the healing of fresh fractures.
FIGURE 9-7 Sequential radiographs of a 42-year-old woman with tibial nonunion. Note gradual trabecular bone formation and restoration of a medullary cavity in the tibia in response to pulsed electromagnetic fields over a 16-month period. (Reprinted with kind permission from Bassett CAL, Mitchell SN, Gaston SR. Treatment of ununited tibial diaphyseal fractures with pulsing electromagnetic fields. J Bone Joint Surg Am 1981;63:511–523.)
An important question concerning the use of electrical stimulation for fractures is whether it is possible to accelerate repair when healing has been slow or when there is early evidence that a nonunion may be developing. Sharrard (148) conducted a double-blind, multicenter trial of the use of pulsed electromagnetic fields in patients who had developed delayed union of tibial fractures. Forty-five tibial fractures that had not united for more than 16 weeks but less than 32 weeks were treated with immobilization in a plaster cast which incorporated the coils of an electromagnetic stimulation unit. The unit was activated for 20 of these fractures and was not turned on for 25. Radiographs showed evidence of union of nine of the fractures that had had active electromagnetic stimulation and in only three of the fractures in the control group (p = 0.02).
Ultrasound Stimulation
Low-intensity pulsed ultrasound (LIPUS) has been shown to promote fracture repair and increase the mechanical strength of fracture callus in both animal (149,150) and clinical studies (151,152). In a prospective, randomized double-blind trial, Heckman et al (151) examined the use of US as an adjunct to conventional treatment with a cast in 67 patients with closed or open grade I tibial shaft fractures. Thirty-three fractures were treated with the active device and 34 with the placebo. Using clinical and radiographic criteria, the authors noted that there

was a statistically significant decrease in the time to union (86 ± 5.8 days in the US treatment group compared with 114 ± 10.4 days in the control group) and in the time to overall healing (96 ± 4.9 days in the US treatment group vs. 154 ± 13.7 days in the controls). There were no issues with patient compliance in the treatment group and no serious complications reported with its use.
In a subsequent multicenter, prospective, randomized double-blind study, Kristiansen and co-workers (152) evaluated the efficacy of LIPUS in the treatment of dorsally angulated distal radius fractures that had been treated with manipulation and a cast. Results demonstrated that time to union was significantly shorter for the fractures that were treated with US compared to the controls (61 ± 3 days compared to 98 ± 5 days). The authors further noted that treatment with US was associated with a significantly smaller loss of reduction (20 ± 6% vs. 43 ± 8%) as determined by the degree of volar angulation as well as with a significant decrease in the mean time until the loss of reduction ceased (12 ± 4 days compared to 25 ± 4 days).
In a study by Cook et al (153), the ability of low intensity US to accelerate the healing of tibial and distal radius fractures in smokers was evaluated. In this patient group, the usual healing time for tibial fractures were 175 ± 27 days and for distal radius fractures were 98 ± 30 days. The investigators were able to show a statistically significant reduction in healing times with the use of US with 103 ± 8.3 days reported in the tibial fracture group and 48 ± 5.1 days in the patients with distal radius fractures. Treatment with US also substantially reduced the incidence of delayed unions in tibias in smokers and nonsmokers. These results are important because they suggest that US can override some of the detrimental effects that smoking has upon fracture healing.
In contrast to the above findings, Emami et al (154) noted that ultrasound did not appear to have a stimulatory role on tibial fracture repair. In a prospective, randomized, double-blinded controlled study, patients with fresh tibial fractures who were treated with a reamed and statically locked intramedullary nail were divided into an ultrasound group and placebo group. They all used an ultrasound device 20 minutes daily for 75 days without knowing whether it was active or inactive. Standardized radiographs were taken every third week until healing and at 6 and 12 months. Results showed that low-intensity ultrasound treatment did not shorten the healing time.
Most fractures heal uneventfully with patients returning to their previous levels of functioning. Unfortunately, however, there is a certain number of cases where difficulties in fracture repair occur and for which alternatives are needed. With improved understanding of the intracellular and extracellular pathways involved in bone healing, our ability to successfully augment this repair process continuously evolves.
Through the advent of tissue engineering, the ability to repair or regenerate the musculoskeletal system is developing rapidly and expanding in its applications. To date, strategies have met with limited success within the clinical setting. With ongoing research to enhance the osteogenic potential of cell concentrates, develop better delivery systems and gene therapy applications for growth factors and osteoinductive substances, this technology will add to current treatment modalities and greatly enhance the management of musculoskeletal injuries and diseases in the future.
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