CH 22

C H A P T E R zzzzzzzzzzzzzzzzzzzzzzzzzzz
22
Enhancement of Skeletal Repair Enhancement of Skeletal Repair
zzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzz
Calin S. Moucha, M.D. Thomas A. Einhorn, M.D.
The process of skeletal repair is considered to be biologically optimal under most clinical conditions. However, of the 6.2 million fractures that occur annually in the United States, 5% to 10% go on to nonunion or delayed union.210 In many instances, the cause of impaired healing is unknown; however, surgical and nonsurgical interventions can interfere with healing and may cause delayed union or nonunion.26 Technical errors during surgery,53 systemic status of the patient,78, 156, 165, 226, 274 and the nature of the traumatic injury itself66, 189, 268 are just some of the many factors that may inuence fracture healing. Even when some or all of these risk factors are avoided, many fractures fail to heal.77 Moreover, specic parts of the skeleton are known to be at increased risk for impaired fracture healing. At these sites, there may be problems related to peculiarities of local blood supply or difculties in controlling the mechanical strain environment. Examples include the neck of the talus, the neck of the femur, and the carpal scaphoid.32 Therefore, although most fractures heal uneventfully, clinical scenarios exist in which enhancement of fracture healing would be of benet to ensure rapid restoration of skeletal function. This chapter reviews some of the methods that have been shown to stimulate skeletal repair.
treatments such as rigid internal xation, external xation, or intramedullary xation. To develop new methods for the stimulation of fracture healing by mechanical means, it is necessary to gain a fundamental understanding of the ways by which mechanical forces are transduced into cellular and molecular signals. Methods for enhancing fracture repair using biophysical techniques include electrical or electromagnetic stimulation of nonunions and ultrasound stimulation of fresh fractures. Each of these techniques has shown substantial efcacy in well-controlled clinical trials and, as we discuss in this chapter, there is abundant cellular and molecular knowledge that exists on which to base hypothetical explanations for the observed effects in fractures. Treatment of a nonunion, however, may differ from that of a fresh fracture, and the successful use of a biophysical modality in one setting may not transfer to another.
Mechanical Enhancement
The quality and the quantity of the callus formed by a healing fracture can be greatly inuenced by the operative or nonoperative method used to treat it. Generally, motion at the site of a fracture causes callus formation.204 The callus functions to decrease the initial interfragmentary motion sufciently enough to produce an environment suitable for fracture union. This goal is attained by improving the structure of the fracture site (by increasing cross-sectional area) and by recruiting cells that are necessary for bony regeneration. If the motion becomes excessive, however, a hypertrophic nonunion may result. As early as the 19th century, physicians disagreed as to the implications of weight bearing on a healing bone. Nicholas Andre (16591742) and Just LucasChampionniere (18431913) believed that early controlled activity promoted healing of tissues, whereas John Hunter (17281793), John Hilton (18071878), and Hugh Owen Thomas (18341878) did not.31 In 1892, Julius Wolff280 suggested that the structure of bone adapts
639
PHYSICAL METHODS OF ENHANCEMENT
zzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzz A fractures mechanical environment can play an important role in its healing. For example, unstable xation causes excessive interfragmentary movement and may retard the repair process. On the other hand, controlled micromotion or controlled, rhythmic distraction of a fracture site can enhance fracture healing.109, 128, 142, 175 Knowledge of how strategic alteration of the mechanical environment of a fracture inuences its healing is based on results obtained from clinical studies using different operative
Copyright 2003 Elsevier Science (USA). All rights reserved.
640
SECTION I General Principles
to changes in its stress environment. This concept has come to be known as Wolffs law. Several investigators have attempted to delineate the molecular and cellular mechanisms that govern the ability of bone to respond to loading.* The conclusion drawn from these studies is that tissue loading inuences cell shape, gene expression, protein synthesis, and proliferation of several cell types found in the fracture callus. Controlling the weight-bearing status of a limb is one method of clinically altering the stress environment at a fracture site. Reports of the effects of weight bearing, however, have been conicting. Sarmiento and associates236 found that weight bearing improved fracture healing in the femurs of normal rats. Kirchen and colleagues147 suggested that microgravity, such as during space ight, may inuence fracture healing. Aro and associates9 showed no difference in fracture healing, regardless of weight bearing, in paraplegic rats. Similarly, Riggins and co-workers218 reported that weight bearing had no effect on fracture healing in chickens. Meadows and colleagues177 evaluated the effect of weight bearing on the healing characteristics of a cortical defect in canine tibias. They demonstrated an increase in the amount of woven bone formed in defects of weight-bearing tibias compared with that in nonweight-bearing tibias. This nding appeared to reect a disuse response in the underloaded bones as opposed to the formation of more bone in those that bore weight. The investigators concluded that weight bearing was a permissive factor for the formation of woven bone in tibial defects and that it may increase the formation of bone during the process of skeletal repair. The two factors that have received the most investigative attention with respect to the ways in which mechanical treatment inuences fracture healing are blood ow and interfragmentary strain. Smith and associates251 studied the blood ow to cortical bone in canine tibias that had been subjected to an experimental osteotomy and different modes of xation. They showed that when no internal xation was used after the osteotomy, blood ow to the canine tibial diaphysis was reduced. Four hours later, blood ow to the fracture site was further reduced by an additional 50%. Reaming of the tibia and insertion of a tight-tting intramedullary nail reduced the blood ow even further. On the other hand, fractures that were treated with either internal or external xation did not experience such dramatic reductions in blood ow.197 Whereas early stability appears to have a benecial effect on blood ow, instability and reaming of the endosteal bone have deleterious effects. It is possible, however, that the development of collateral vessels overcomes the latter effect. The theory of interfragmentary strain suggests that it is the balance that develops between the degree of local interfragmentary strain and the ability of the callus to withstand the strain that determines the type of healing. Granulation tissue can tolerate 100% strain; brous tissue and cartilage withstand lower amounts. Therefore, granulation tissue is best able to tolerate the changes in
*See references 36, 47, 113, 114, 116, 129, 138, 145, 172, 198, 227, 264.
interfragmentary motion that occur during early reparative stages of fracture healing. As the fracture becomes more stable, the presence of cartilage and new bone reduces the strain and allows fracture healing to proceed. Strain is usually proportional to the size of the fracture gap, but a small gap, such as that which is present in a plated femur in which the fracture ends are not actually apposed, has a high strain. As a result, resorption occurs, allowing granulation tissue and callus to form and produce a lower strain environment. The inuences of different mechanical loading conditions on tissue differentiation have been studied in a variety of skeletal settings. These investigations have led to a theory that relates mechanical loading history to tissue differentiation in the process of endochondral bone repair. It identies tissue vascularity and two key mechanical parameters, cyclic hydrostatic stress (pressure) and cyclic tensile strain, as important determinants of tissue differentiation. Using an osteotomized long bone as the experimental system, Blenman19 and Carter40 and their co-workers performed two-dimensional nite element analyses to model idealized fracture callus, including periosteal, endosteal, and fracture gap (interfragmentary) callus regions. The stress and strain histories at each location within the callus were calculated. High levels of compressive hydrostatic stress occurred within the fracture gap. At the middle of the gap, high levels of strain were present in the radial and circumferential directions. In contrast, at the periosteal and endosteal callus regions remote from the interfragmentary gap, low levels of hydrostatic stress and tensile strain were observed. These ndings suggest that an association exists among (1) intermittent compressive hydrostatic stress and chondrogenesis, (2) intermittent strain and brogenesis, and (3) low levels of mechanical stimulation and osteogenesis (with good vascularity) or chondrogenesis (with poor vascularity). In addition, these studies showed that after cartilage forms within callus, moderate levels of cyclic tensile strain (or distortional strain) accelerate endochondral ossication. Local cyclic hydrostatic stress delays endochondral ossication, however, possibly via an inhibition of revascularization. More recent research by Claes and associates54 supports similar concepts. A few investigators have attempted to design systems in which mechanical input would stimulate fracture repair. Goodship and Kenwright109 studied the inuence of controlled micromotion on fracture healing in two groups of sheep in which tibial diaphyseal fractures had been created. The tibial fractures in one group were treated with rigid external xation, and those in the other group were subjected to a regimen of controlled axial micromotion (500 cycles at 0.5 Hz) for 17 min/day. Enhanced fracture repair was demonstrated by radiographic, histologic, and biomechanical analyses in the group having micromotion. In a subsequent clinical, prospective randomized controlled trial, Kenwright and colleagues142 compared the effects of controlled axial micromotion on tibial diaphyseal fracture healing in patients who were treated with external xation and stratied according to fracture severity grade and extent of soft tissue injury. The tibias that were treated with induced micromotion were subjected to controlled longitudinal displacement and loading of the transxion
CHAPTER 22 Enhancement of Skeletal Repair
641
pins by means of a pneumatic pump interfaced to a spring module with sliding clamps (Fig. 221). Fracture healing was assessed clinically, radiographically, and by biomechanical measurement of the stiffness of the frame. The mean healing time was shortened in the tibias that had undergone micromovement compared with those in the control group. The differences in healing time were independently related to the treatment method, and no statistically signicant differences were observed in complication rates between the groups. Other studies by these and other investigators have conrmed these ndings, and even suggested that induced micromotion caused by axial loading of tibial fractures produces more rapid healing than rigid xation.141, 143, 144, 179, 234, 235
Electrical Enhancement
The ability of electricity to heal fracture nonunions was rst described in several anecdotal reports during the 19th century.117, 162 Despite these early reports, no further advances were made in this method of fracture healing augmentation until 1953, when Yasuda demonstrated the
Print Graphic
Presentation
FIGURE 221. Setup for the use of controlled axial micromotion for the treatment of tibial fractures. Two sliding clamps are attached to the external xation column and to a spring assembly. These clamps provide complete control of the longitudinal (axial) displacement and load. A pneumatic pump is attached to the spring module and to the sliding clamps, so that small controlled increments of axial displacement can be applied. (From Kenwright, J.; Richardson, J.B.; Cunningham, J.L.; et al. J Bone Joint Surg Br 73:654659, 1991.)
appearance of new bone in the vicinity of the cathode (negative electrode) when current in the microampere range was continuously applied for 3 weeks to a dry rabbit femur.287 This group of investigators also showed that stress-generated potentials develop in bone subjected to a bending load, so that the portion experiencing compressive stresses becomes electronegative and the portion experiencing tensile stresses becomes electropositive.100 Later, Friedenberg and Brighton93 described another type of electrical potential in hydrated bone, the bioelectric or steady state potential. This type of potential is electronegative and occurs in nonstressed bone in areas of active growth and repair. Since Yasudas rst report of the piezoelectric properties of bone, there has been an abundance of research on the electric properties of bone, collagen, and other biological tissues.6, 10, 12, 115, 164, 244 Although the exact mechanism by which electric and electromagnetic elds lead to osteogenesis is still being debated, it has been well documented that electrical stimulation of bone has an effect on several intracellular and extracellular regulatory systems involved in bone formation.1, 2, 86, 87, 176, 184, 293 A variety of electrical stimulation devices have been developed, and each of these can be categorized as one of three types: (1) constant direct-current stimulation using percutaneous or implanted electrodes (invasive), (2) time-varying inductive coupling produced by a magnetic eld (noninvasive), and (3) capacitive coupling (noninvasive). In direct-current stimulation, stainless steel cathodes are placed into the tissues and electrically induced osteogenesis shows a dose-response curve that relates to the amount of current delivered. Currents lower than a certain threshold result in no bone formation, whereas those higher than that threshold lead to cellular necrosis.92 In electromagnetic stimulation, an alternating current produced by externally applied coils leads to a time-varying magnetic eld, which in turn induces a time-varying electrical eld in the bone. In capacitive coupling, an electrical eld is induced in bone by an external capacitor; that is, two charged metal plates are placed on either side of a limb and attached to a voltage source.27 Most of the studies on the clinical use of electrical stimulation in orthopaedic patients have focused on the treatment of nonunions. Using constant direct current to treat nonunions, Brighton and associates28 achieve solid bone union in 84% of cases. When this study was expanded to include other clinical centers, an additional 58 out of 89 nonunions achieved solid bone union. The investigators concluded that, with the exception of patients who have synovial pseudarthrosis or an infection, application of constant direct current to nonunions could result in a rate of union that is comparable to that observed after bone grafting procedures and with fewer associated risks. Using the method of pulsing electromagnetic eld stimulation in tibial nonunions, another group of investigators showed an 87% success rate for the achievement of union.11, 13 Scott and King reported the results of a prospective double-blind trial using capacitive coupling in patients with an established nonunion of long bones.241 Their data, which was statistically signicant (P < 0.004) showed healing in 60% of the patients who had received
642
electrical stimulation but in none of the patients who had been managed with a placebo unit. More recently, Goodwin and colleagues110 performed a multicenter randomized double-blind prospective comparison to evaluate the effect of noninvasive capacitively coupled electrical stimulation on the success rate of lumbar spine fusion surgery. For the 179 patients who completed treatment and evaluation, the overall protocol success rate was 84.7% for the active patients and 64.9% for the placebo patients. According to the Yates corrected chi-square test, these results were also statistically signicant (P = 0.0043). However, the study had a 12% dropout rate due to noncompliance, the patients had varying degrees of instability of the spine, and the differences among the various surgeons with regard to experience performing internal xation of the spine were not taken into account in the study. Although these reports show that electrical stimulation may be successful in the treatment of nonunions and, in a select number of patients, spinal fusion, the application of this technology to the treatment of fresh fractures has not been clearly demonstrated. Two studies have shown that pulsed electromagnetic elds enhance bone regeneration in fresh osteotomies and fracture animal models.91, 233 In the more recent of these studies, Fredericks and colleagues performed tibial osteotomies stabilized by external xation in New Zealand white rabbits. One day after surgery, the animals were randomly assigned to receive either no exposure, 30 minutes, or 60 minutes per day of a low-frequency, low-amplitude pulsed electromagnetic eld (PEMF). Specimens were examined biomechanically and radiographically, and the results indicated that normal intact torsional strength was achieved by 14 days in the 60-minute PEMF group, by 21 days in the 30-minute PEMF group, and by 28 days in the sham controls. In addition, the 60-minute PEMF-treated osteotomies had signicantly higher torsional strength than did sham controls at 14 and 21 days postoperatively. The 30-minute PEMF-treated osteotomies were signicantly stronger than those in the sham controls only after 21 days. Lastly, maximum fracture callus area correlated with the time to reach normal torsional strength. Others have failed to reproduce these results.4, 159 To our knowledge, no published clinical study has shown that electrical stimulation enhances the repair of fresh fractures in humans. Another potential application of electrical stimulation is in the treatment of fractures that show delayed union. Sharrard247 conducted a double-blind, multicenter trial of the use of PEMFs in patients who had a delayed union of a tibial fracture. Forty-ve tibial fractures that had not united for more than 16 but less than 32 weeks were treated with immobilization in a plaster cast incorporating the coils of an electromagnetic stimulation unit. The unit was activated in 20 of these fractures. The results showed radiographic evidence of union in nine of the fractures that had undergone active electromagnetic stimulation and in only three of the fractures in the control group. Although there has been an abundance of research on the use of electrical enhancement of fracture healing, numerous questions still abound. More studies are necessary to further understand the use of this modality at both the basic science and clinical levels, especially with regard to its use in fresh fractures.
Ultrasonic Enhancement
Low-intensity pulsed ultrasound has been known for some time to stimulate fresh fracture healing in experimental animals and healing of nonunions in humans.74, 173, 206, 275, 282 Its use in enhancing the healing of fresh fractures in humans, however, is more controversial. Heckman and co-workers,123 in a prospective, randomized, double-blind evaluation, examined the use of a new ultrasound stimulating device as an adjunct to conventional treatment with a cast of 67 closed or grade-I open fractures of the tibial shaft. Thirty-three fractures were treated with the active device and 34 with a placebo control device. At the end of the treatment, there was a statistically signicant decrease in the time to clinical healing (86 5.8 days in the active-treatment group compared with 114 10.4 days in the control group) (P = 0.01) and a signicant decrease in the time to overall (clinical and radiographic) healing (96 4.9 days in the active-treatment group compared with 154 13.7 days in the control group) (P = 0.0001). The patients compliance with the use of the device was excellent, and no serious complications were reported. This study conrmed earlier studies that demonstrated the efcacy of low-intensity ultrasound stimulation in the acceleration of the normal fracture repair process. Kristiansen showed similar ndings in an investigation of patients with fresh distal radius fractures.152 Cook and associates60 investigated the ability of low-intensity ultrasound to accelerate the healing of tibial and distal radius fractures in smokers. The usual healing time for tibial fractures in smokers is 175 27 days, but with ultrasound treatment the healing time was reduced by 41% to 103 8.3 days. Smokers with distal radius fractures had a healing time of 98 30 days, which was reduced by 51% to 48 5.1 days with ultrasound treatment. Treatment with the active ultrasound device also substantially reduced the incidence of delayed unions in tibias in smokers and nonsmokers. These results have optimistic implications because they suggest that ultrasound can mitigate the delayed healing effects of smoking, which is a common risk factor associated with nonunions and delayed unions. Moreover, this study is especially noteworthy because it provides insight into the mechanism that mediates this fracture-healing modality. Although several theories of how ultrasound enhances fracture healing have been proposed,200, 285 by showing that ultrasound facilitates bony regeneration in a host that has a systemic reduction in generalized healing due to poor oxygen transport,248 one can hypothesize that ultrasound may elicit its effects, at least in part, by enhancing the delivery of oxygen. This theory is supported by an in vitro study on the effect of ultrasound on human mandibular osteoblasts, gingival broblasts, and monocytes.216 The authors of this study showed that ultrasound stimulates these cells to produce angiogenic factors such as interleukin-8 (IL-8), broblast growth factor (FGF), and vascular endothelial growth factor, therefore suggesting that the effects of ultrasound treatment are mediated by stimulation of angiogenesis, which ultimately enhances the healing environment caused by local hypoxia. Although these studies give credence to the value of ultrasound in enhancing healing of fresh human fractures
643
treated nonoperatively, a study by Emami and coworkers84 showed no effect of low-intensity ultrasound on healing time of fresh tibial fractures treated with a reamed and statically locked intramedullary rod. Therefore, to date, it appears that the clinical use of ultrasound for enhancing fracture healing has been shown to be benecial only in delayed unions and nonunions and in fresh fractures in smokers. At least one type of ultrasound device has been approved for marketing in the United States, and it is anticipated that more clinical data will be available on the use of this biophysical signal in the near future.
animals induces bone formation.270, 272 Follow-up studies of these demineralized allogeneic bone-inductive matrices21, 79, 107, 137, 181, 269 resulted in identication of a family of compounds known as the bone morphogenetic proteins (BMPs).281 Several other growth factors have since been shown to play an important role in the development, repair, and induction of bone. These compounds are currently grouped into the transforming growth factor- (TGF-) superfamily, which includes the BMPs, the FGFs, the insulin-like growth factors (IGFs), and the platelet-derived growth factors (PDGFs) (Table 221). OSTEOGENIC METHODS Naturally occurring autogenous and allogeneic bone grafts have been available for more than a century. Although
BIOLOGIC METHODS OF ENHANCEMENT
zzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzz Knowledge of the cellular and molecular biology of the musculoskeletal system has led to a better understanding of the basic processes that regulate repair of skeletal tissues. To apply this new information to the enhancement of skeletal repair, the specicity of a particular stimulus for its receptor or targeted pathway must rst be determined. Local stimulation of skeletal repair involves not only the development of specic molecules to stimulate discrete components of the healing process but also the design of delivery systems to optimize the effect of a stimulating factor. The development of systemic methods for enhancement of skeletal repair is attractive, but the introduction of a systemic agent that targets these processes requires a high degree of specicity, and this approach needs more extensive investigation. Local factors for the stimulation of skeletal healing have been evaluated, and data are available from both clinical and experimental studies.
TABLE 221
Peptide Signaling Molecules Involved in Skeletal Growth and Repair

Transforming Growth Factor- Family Transforming growth factor-1 Transforming growth factor-2 Transforming growth factor-3 Bone Morphogenetic Protein Family Bone morphogenetic protein-2 Bone morphogenetic protein-3 Bone morphogenetic protein-4 Bone morphogenetic protein-5 Bone morphogenetic protein-6 Bone morphogenetic protein-7 (also known as osteogenic protein-1) Bone morphogenetic protein-8 (also known as osteogenic protein-2) Bone morphogenetic protein-9 Bone morphogenetic protein-10 Growth and differentiation factor-1 Growth and differentiation factor-3 Growth and differentiation factor-5 Growth and differentiation factor-6 (also known as bone morphogenetic protein-13) Growth and differentiation factor-7 (also known as bone morphogenetic protein-12) Growth and differentiation factor-9 Growth and differentiation factor-10 Inhibin/Activin Family Inhibin- Inhibin-A Inhibin-B Inhibin-C Mullerian inhibiting substance Growth and differentiation factor-8 Others Platelet-derived growth factors Alpha broblast growth factor (FGF-1) Basic broblast growth factor (FGF-2) Insulin-like growth factor I Insulin-like growth factor II
zzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzz
Local Enhancement
Local methods for the enhancement of skeletal repair can be categorized into osteogenic, osteoconductive, and osteoinductive approaches. Osteogenesis is the process of new bone formation. Osteogenic approaches to fracture healing enhancement include the use of naturally occurring materials that have been shown to induce or support bone formation, such as autologous bone marrow grafts55, 102, 246 and autologous or allogeneic bone grafts.33, 35, 96 Experience with bone grafting dates back to the early 1900s,46 and it has been estimated that there are more than 250,000 bone grafts performed annually in the United States.182 Osteoconduction is the process by which brovascular tissue and osteoprogenitor cells invade a porous structure that acts as a temporary scaffold and replace it with newly formed bone. The most widely studied osteoconductive substances are those composed of hydroxyapatite, calcium phosphate or calcium sulfate composites, and the bioactive glasses.157 Lastly, the process that promotes mitogenesis of undifferentiated mesenchymal cells, leading to formation of osteoprogenitor cells that have osteogenic capacity, is known as osteoinduction. Urist made the rst observation that implantation of demineralized lyophilized segments of bone matrix either subcutaneously or intramuscularly in
zzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzz
644
TABLE 222
Properties of Autologous Bone Grafts

Property Osteoconduction Osteoinduction Osteoprogenitor cells Immediate strength Strength at 6 mo Strength at 1 yr
zzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzz
Cancellous ++++ ++ +++ ++ +++ Nonvascularized Cortical + ? +++ ++ +++ Vascularized Cortical + ? + +++ +++ ++++
zzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzz
Source: Reprinted from the J Am Acad Orthop Surg Comp Rev 3(1): 2, 1995.
much has been written about the use of bone grafts in skeletal reconstruction, relatively little attention has been devoted to the specic application of bone grafts in the healing of fresh fractures. The scientic principles of autogenous cortical and cancellous bone graft responses suggest that the process begins with the formation of a hematoma around the implanted bone. The hematoma may release bioactive molecules such as growth factors and cytokines from degranulated platelets.20 Necrosis of the graft follows, and a local inammatory response is stimulated. Within days, a brovascular stroma develops in which host-derived blood vessels and osteogenic precursor cells migrate toward the graft. Eventually the graft is penetrated by osteoclasts, which initiate the resorptive phase of incorporation. Because only a few cells from the graft survive the transplantation, the major contributions of the graft to the process of fracture healing are its osteoconductive properties. The elaboration of any osteoinductive factors from the graft during resorption and the stimulation of an inammatory response accompanied by cytokines can also contribute to fracture healing.81 It has been suggested that the host response to cancellous bone grafts differs from the response to cortical bone grafts in terms of the rate and completeness of repair. The more porous nature of the cancellous tissue may permit a more rapid revascularization and lead to a more complete incorporation than that which occurs with cortical bone grafts. Moreover, although the present understanding of the biology of cancellous bone grafts suggests that the process of graft resorption precedes the osteoblastic bone formation response, the reverse may be true with autogenous cortical bone grafts.124 Although the resorptive phase in the incorporation of cancellous grafts appears to be small, transient, and often difcult to observe radiographically, it leads to a stimulation or triggering of new bone formation, a process involving the elaboration of factors that are specically mitogenic for osteoprogenitor cells. Initially, cancellous bone grafts have minimal structural integrity. However, this changes rapidly during the process of osteointegration (new bone formation and incorporation) within preexisting osseous elements. Conversely, Enneking and colleagues85 demonstrated that cortical grafts initially provide structural strength before the process of osteointegration begins and that while the graft is being remodeled and resorbed by osteoclastic activity it can lose up to one third of its strength over 6 to 18 months. As reconstructive efforts at limb-sparing surgery have
expanded, free vascularized cortical grafts have been used more frequently. The most common grafts involve the bula, although the ribs, iliac crest, and other bones have also been used. With vascularized grafts, there is no signicant cell necrosis, and biomechanical studies have shown that they are superior to cortical grafts for the rst 6 months of incorporation. After this initial period, no demonstrable difference exists between cortical and vascularized bone grafts as measured by torque, bending, and tension tests. In addition, when bone grafts are used to bridge gaps greater than 12 cm, vascularized grafts are superior. Vascularized grafts have a reported stress fracture rate of 25% compared with 50% for nonvascularized cortical grafts.104 Because the procedure is technically demanding, it appears that so far the use of vascularized grafting for fracture healing enhancement has had limited indications such as for nonunions involving irradiated tissue,75 or those involving the carpal scaphoid73, 101, 291 (Table 222). Although autogenous bone grafts are effective in enhancing skeletal repair, they are associated with several potential complications. The major disadvantages of autogenous bone grafting include the limited quantity of bone available for harvest and the signicant donor site morbidity. Although autogenous bone is widely used and useful, there is morbidity associated with its harvesting. Kurz and associates154 reviewed the literature for complications of harvesting autogenous iliac bone grafts, with particular attention given to different operative approaches. Younger and Chapman290 retrospectively studied the medical records of 239 patients with 243 autogenous bone grafts to document donor site morbidity. They found an 8.6% overall major complication rate and a 20.6% minor complication rate. Considerably less is known about the use of allogeneic bone in the repair of fresh fractures or even nonunions. Because of concerns regarding the transmission of bloodborne diseases through allogeneic tissue transplantation, justication for the use of these materials has become even stricter. Most allografts are either frozen or freeze-dried, although fresh allografts are also available. The latter evoke an intense immune response, and although animal experiments on the use of fresh allografts to enhance fracture healing are beginning,160 until now they have been used only as osteochondral grafts in cases of joint resurfacing.51 Frozen allografts are stored at temperatures lower than 60C, which diminishes degradation by enzymes and allows for decreased immunogenicity without changes in
645
biomechanical properties. Freeze-drying (lyophilization) involves the removal of water and vacuum packing of frozen tissue. Although the freeze-drying of allografts results in a reduction in their immunogenicity,97 this treatment also affects the mechanical integrity of the graft, resulting in a reduction in its load-bearing capacity.202 Moreover, because the donors cells die in the process of allograft preparation and preservation, whatever limited osteogenic contribution could have been provided by cells is lost with allogeneic bone grafts. Allografts can be used for structural and nonstructural purposes. Morcellation of cancellous and cortical bone has been used to reconstruct defects after curettage of bone cysts and benign neoplasms and to reconstruct periarticular defects during arthroplasty. Some surgeons have mixed allograft bone with autogenous bone graft or bone marrow in an effort to enhance osteogenesis and osteoinduction. Structurally, allografts can be used to reconstruct diaphyseal defects as intercalary segments or in arthrodeses about the ankle, hip, and spine. In addition, large segments can be conformed to replace acetabular defects. Complications with large structural allografts, however, can be numerous and can include nonunion (10%), fracture (5%15%), and infection (10%15%).249 In addition to local infections, major concerns arise regarding the potential for transmission of hepatitis and the human immunodeciency virus. The American Association of Tissue Banks has set strict standards that have decreased the risk of disease transmission. Their records indicate that of the 3 million tissue transplantations performed since the identication of the human immunodeciency virus, only two donors tissues have been linked with documented transmission. Both cases involved unprocessed, freshfrozen allografts,3 and in one of these cases, other samples from the same donor that were lyophilized and irradiated did not transmit the virus. This suggests that lyophilization and irradiation may destroy the human immunodeciency virus. Although the risk of transmission of an infectious agent is always possible, it is important to realize that owing to strict donor screening practices, procurement techniques, and serologic testing, allografts are used daily in orthopaedic practices without reports of signicant associated morbidities. A number of reports have suggested that autogenous bone marrow alone is an effective osteogenic graft.55, 102, 242, 246 This concept is based on the fact that autogenous bone marrow contains osteogenic precursors that could contribute to bone formation.71, 94, 199 Autogenous marrow has been used clinically to augment the osteogenic response to implanted allografts35 and xenogeneic bone.208, 229, 230 However, autogenous bone marrow used alone may also be an effective graft for stimulating bone formation and skeletal repair. Connolly and associates55 investigated the osteogenic capacity of autogenous bone marrow in a controlled study in rabbits. They found that osteogenesis was accelerated in diffusion chambers loaded with centrifuged and concentrated bone marrow cells that had been implanted into the peritoneal cavity (ectopic site) in a delayed union model (orthotopic site). Garg and colleagues102 treated long bone fractures in patients with plaster cast immobilization and percutaneous injection of autogenous bone marrow. Patients were kept
from weight bearing for 6 weeks after the operation, after which protected weight bearing was allowed until union was achieved. The investigators reported clinical and radiographic healing in 17 of 20 fractures. The use of autogenous bone marrow preparations for the treatment of fractures may be rened by the development of better methods for the isolation, purication, and cultural expansion of marrow-derived mesenchymal cells.37, 38 Selective adhesion methods can be used to isolate cells with osteogenic potential from the marrow cell population of hemopoietic origin. Once isolated, these cells may be added to a culture medium containing factors that stimulate cell replication but not differentiation, to ultimately yield a supply of cells that are highly osteogenic. A series of animal studies have already shown that cells prepared in this manner may be combined with a calcium phosphate ceramic delivery system to regenerate bone or enhance the repair of skeletal defects.29, 111 OSTEOCONDUCTIVE METHODS Osteoconductive materials used as bone graft substitutes are designed to provide an optimal setting for ingrowth of sprouting capillaries, perivascular tissues, and osteoprogenitor cells from the recipient host bed.14, 64, 271 Architectural characteristics of the material (e.g., pore size and pore density), as well as its biologic properties such as cell adherence capabilities, are just several factors that inuence its mechanical strength and ability for osteoconduction.70, 90, 153 The most common osteoconductive bone graft substitutes used to date are porous ceramics composed of hydroxyapatite, calcium phosphate, calcium carbonate, calcium sulfate, bioactive glass, and bovine bone. Ceramics are made by sintering, a process by which mineral salts are heated to temperatures above 1000C. Sintering has been shown to reduce the amount of carbonated apatite, an unstable and weakly soluble form of hydroxyapatite that allows signicant osteoclastic remodeling. Because of this process, many of the ceramics currently in use provide a stable biologic construct for osteoconduction to occur.83, 273 Chiroff and colleagues50 were the rst to describe the fact that corals made by marine invertebrates have a structure similar to that of cortical and cancellous bone and therefore may have a role as bone graft substitutes. The compounds reviewed below are those that have been the most extensively studied in basic science and clinical investigations. Collagraft (Zimmer, Inc., Warsaw, IN), a mixture of hydroxyapatite, tricalcium phosphate, and bovine collagen, was designed for use with autogenous bone marrow and acts as a nonstructural bone graft substitute.63 Two major prospective clinical trials have been reported and both have concluded that Collagraft is both efcacious and safe.44, 65 The more recent of these two studies, which compared the safety and efcacy of autogenous bone graft obtained from the iliac crest with those of Collagraft, was a prospective, randomized investigation conducted concurrently at 18 medical centers. Two hundred thirteen patients (249 fractures) were followed for a minimum of 24 months to monitor healing and the occurrence of complications. The results showed no signicant differences between the two treatment groups with respect to
646
rates of union (P = 0.94, power = 88%) and functional measures (use of analgesics, pain with activities of daily living, and impairment in activities of daily living; P > 0.10). The prevalence of complications did not differ between the treatment groups except for the rate of infection, which was higher in the patients who were managed with an autogenous graft. Twelve patients who were managed with a synthetic graft had a positive antibody titer to bovine collagen; seven of them agreed to have intradermal challenge with bovine collagen. One patient had a positive skin response to the challenge but had no complications with regard to healing of the fracture. Despite these two optimistic clinical trials, clinicians need to consider (1) the grafts lack of structural support; (2) the need to combine the collagen-mineral composite with the patients bone marrow, risking complications from another procedure; and (3) the potential immunogenicity and risk of disease transmission with the use of bovine collagen. Pro Osteon (Interpore Cross International, Inc., Irvine, CA) is produced by harvesting tricalcium phosphate from marine coral exoskeletons and converting it into hydroxyapatite. The coralline material is different from other hydroxyapatite implants in that it is structurally similar to cancellous bone. Owing to this architectural similarity, osteoconduction is optimized. In addition, the material can be cut to t the area being grafted, and it has been shown to have good strength in compression. Two studies in particular have conrmed the clinical advantages of this bone graft substitute, one in distal radius fractures279 and another in tibial plateau fractures.30 Some of the concerns that have been expressed by clinicians with this material include variable quality and strength, undened resorption rates,132 and persistent radiopaqueness, making it difcult to estimate fracture healing.238 Nevertheless, coralline hydroxyapatite is a very popular bone graft substitute with well-documented clinical benets. Norian SRS skeletal replacement system (Norian Corp., Cupertino, CA) is a paste consisting of powdered calcium phosphate and calcium carbonate mixed with a solution of calcium phosphate. The material can be injected into a fracture, where within about 10 minutes, it hardens owing to the formation of the mineral dahllite. After 12 hours, the dahllite formation is almost complete, giving the material an ultimate compressive strength of 55 MPa. As a result of these properties, treatment of certain fractures with Norian SRS can augment the xation that is achieved with a cast or with operative means. Animal studies have shown that Norian SRS is in many cases extensively resorbed and replaced by host bone.56, 89 Several investigators have conrmed the efcacy of Norian in fractures of the distal radius,136, 150, 231, 288 the calcaneus,239 and the hip.82, 108 This and other calcium phosphate composites will certainly have great potential as bone graft substitutes. As with other types of cement, more research is required concerning resorption rates and long-term consequences of extrusion of the material into the soft tissues. Osteoset (Wright Medical Technology, Inc., Arlington, TN) is a bone graft substitute composed of calcium sulfate pellets. The preparation is mostly resorbed by as early as 6 to 8 weeks, a property that has been criticized by some. In fact, the manufacturer states that the material does not
provide structural support and that it should not be a substitute for internal or external xation. To our knowledge, no controlled studies have been published to date regarding the clinical efcacy of this product. This is in part because Osteoset was marketed in the United States before the institution of the current Food and Drug Administration approval process. In an effort to introduce a bone graft substitute with osteoconductive and osteoinductive properties, the manufacturer of Osteoset has also introduced Allomatrix Injectable Putty, a combination of AlloGro demineralized bone matrix and Osteoset. To our knowledge, no clinical trials with this product have been reported. Although this and other previously described bone graft substitutes are relatively safe with respect to inducing an immune response or transmitting an infectious disease, there has been a report of three inammatory reactions associated with the use of Osteoset following resection of bone tumors.222 Well-designed clinical trials on the use of Osteoset in humans are still needed to better understand the safety and efcacy of this product. Bioactive glass and bovine bonederived ceramics are two types of bone graft substitutes that have not yet undergone enough testing to make them clinically useful products. To our knowledge, Novabone and Biogran are the two bioactive glass products that have been developed to act as bone graft substitutes. Neither of these products has been studied extensively, although animal studies have proven bioglass materials to be promising.195 Although nonphysiologic and offering little structural support, these two products need to be further studied. Endobon, a bovine cancellous bonederived ceramic, is marketed in Europe as a bone graft substitute. Although anecdotal reports of its success exist, to our knowledge, no clinical trials on this product have been performed. OSTEOINDUCTIVE METHODS Demineralized Allograft Bone Matrix To our knowledge, four commercially available products containing demineralized allograft bone matrix exist. Grafton DBM (Osteotech, Inc., Eatontown, NJ) and DynaGraft (GenSci Regeneration Sciences, Inc., Mississauga, Ontario, Canada) contain only demineralized human bone matrix. Osteol (Sofamor Danek Group, Inc., Memphis, TN) and Opteform (Exactech, Inc., Gainesville, FL) contain demineralized human bone matrix mixed with either porcine gelatin or compacted corticocancellous human bone chips, respectively. All of these products have osteoinductive effects. The last two have the advantage of hardening at body temperature and the potential for remodeling to normal bone. To date, Grafton DBM and DynaGraft are indicated primarily for nonunions and delayed unions and for patients with potentially poor healing potential such as smokers and diabetics. Although all have the potential for disease transmission, the manufacturers claim that this has not yet occurred. Although Grafton is manufactured with glycerol, which has been suggested to be neurotoxic, no reports of neural toxicity have been made to date. Because of their ability to harden, Osteol and Opteform have the potential for offering structural integrity to fractures and other bony defects.
647
Bone Morphogenetic Proteins and Other Growth Factors The TGF- superfamily of proteins, which includes the BMPs, FGFs, IGFs, and PDGFs, elicit their actions by binding to transmembrane receptors that are linked to gene sequences in the nucleus of various cells by a cascade of chemical reactions.171, 265 Because these cascades activate several genes at once, specic growth factors generate multiple effects, both within a single cell type as well as in different cell types.161, 243 Osteoinduction has been described as occurring in three major phases: chemotaxis, mitosis, and differentiation.215 The aforementioned growth factors, all polypeptide molecules, provide a mechanism for stimulative and regulative effects on these phases. Transforming Growth Factor-. TGF-, a peptide rst identied by its ability to cause phenotypic transformation of rat broblasts,220 has been shown to be a fundamental, multifunctional, regulatory protein that can either stimulate or inhibit several critical processes of cell function.255 Since then, ve different isomers of TGF- have been identied (three of these are found in humans), as have several other related polypeptide growth factors. These are now all a part of the TGF- superfamily, which also includes other ubiquitous compounds such as the BMPs, activins, inhibins, and growth and differentiation factors. The largest source of TGF- in the body is the extracellular matrix of bone, and platelets probably represent the second largest reservoir for this peptide.42, 251 All the TGF-s are disulde-linked dimers comprising 12- to 18-kD subunits.146 Most are homodimers (TGF-1, TGF-2, and TGF-3), but some are heterodimers (TGF-1.2 and TGF-2.3).193 TGF-s are secreted in a latent propeptide form that requires activation by extracellular proteolytic activity. In bone, it is thought that this occurs within the acidic microenvironment formed by the sealing zone directly beneath bone-resorbing osteoclasts.196 Chondrocytes and osteoblasts have been shown to produce TGF-,135, 221 which itself affects protein synthesis in these cell lines.223 Joyce and associates134 were the rst to investigate the endogenous expression of TGF- in organ cultures of fracture callus. Using immunohistochemical and recombinant DNA techniques, they analyzed fresh femur fractures made in male rats at four distinct histologic stages: immediately after the injury, during intramembranous bone formation, during chondrogenesis, and during endochondral ossication. Using immunolocalization, TGF- was found to persist for up to 10 days after the fracture was created. During intramembranous bone formation, TGF- was localized both intracellularly in osteoblasts and proliferating mesenchymal cells, as well as extracellularly. TGF- was localized to mesenchymal cells, immature chondrocytes, and mature chondrocytes during chondrogenesis, as well as to the extracellular matrix surrounding chondrocyte precursors. During endochondral ossication, ossied matrix on the bone side of the ossication front no longer stained for TGF-, whereas the extracellular matrix surrounding the hypertrophic chondrocytes that bordered the ossication front stained intensely for TGF-. Gene expression of TGF- was
evaluated by Northern blot analysis from eight pooled fracture calluses, microdissected into soft (brous and cartilaginous) and hard (osseous) callus, at 3-day intervals. TGF- messenger RNA (mRNA) levels peaked in the soft callus 13 days after fracture, corresponding to the histologic progression of chondrogenesis. TGF- mRNA levels in the hard callus were highest at 5 and 15 days after fracture, corresponding to intramembranous bone formation and endochondral ossication, respectively. Since then, several other investigators have added information to this original report.7, 224 Some studies have shown that TGF- decreases rat osteoblast differentiation and mineralization.260 Overall, however, the in vitro studies indicate that TGF- increases the expression of osteoblast differentiation markers such as alkaline phosphatase, type I collagen, and osteonectin, and acts in synergy with 1,25-dihydroxyvitamin D3 to increase alkaline phosphatase levels.130, 277 To our knowledge, Mustoe and co-workers183 were the rst to show that TGF- applied exogenously enhances healing of tissues. They applied this peptide directly to linear incisions made through the dorsal skin of rats and demonstrated a 220% increase in maximal wound strength after 5 days and acceleration in the rate of healing by at least 3 days. Numerous investigations on the effect of exogenously introduced TGF- into injured bone have also been performed.15, 16, 120, 205 We focus on the three published reports available to date that have evaluated the effect of TGF- using fracture healing models.67, 163, 190 Critchilow and associates studied the effect of TGF-2 on rat tibial fracture healing. The tibiae were fractured and immobilized with either a six-hole stainless steel dynamic compression plate (stable mechanical conditions) or a plastic plate designed to leave a 0.5-mm gap at the fracture site (unstable mechanical conditions). TGF-2 was injected into the fracture site as a one-time dose (either 60 or 600 ng) 4 days after the injury was produced. The fractures were examined at 5, 7, 10, and 14 days after the fracture. The callus of fractures healing under stable mechanical conditions consisted almost entirely of bone, whereas those of the fractures healing under unstable mechanical conditions had a large area of cartilage over the fracture site with bone on each side. Under stable mechanical conditions, 60 ng of TGF-2 had an insignificant effect on callus development, whereas the higher dose of 600 ng led to a larger callus. Under unstable mechanical conditions, the quantity of tissue components changed, but the size of the callus remained unaffected. At the lower dose of 60 ng of TGF-2, the callus contained more brous tissue and less bone and cartilage. The amounts of bone, cartilage, and brous tissue in callus treated with 600 ng of TGF-2 were similar to those in the control group, although the lack of bone between the cartilage and periosteum indicated that the callus is less mature. The investigators concluded that TGF-2 does not enhance fracture healing. Lind and colleagues163 studied the effect of TGF- administered continuously using an osmotic minipump to unilaterally plated adult rabbit tibial osteotomies. For 6 weeks, the experimental groups received either 1 or 10 g per day, and the control group received injections without TGF-. At 6 weeks, fracture healing was evaluated by
648
mechanical tests, histomorphometry, and densitometry. Markedly increased callus volume and statistically signicant maximal bending strengths were demonstrated in the groups receiving 1 g of TGF- per day. In the group administered 10 g of TGF- per day, there was no statistically signicant increase in bending strength, although the callus volume persisted to be greater than that in the control group. There was no statistically signicant effect in any of the experimental groups on bending stiffness, bone mineral content, cortical thickness, or Haversian canal diameter. The investigators concluded that exogenous administration of TGF- might enhance fracture healing in rabbits by increasing callus size but that the callus created may be too immature to enhance the mechanical strength of the osteotomy. Nielson and associates190 studied the effect of TGF- administered locally around the fracture line of healing rat tibial fractures stabilized with an intramedullary pin. TGF- was injected at a dose of either 4 ng or 40 ng every other day for 40 days. The strength, stiffness, energy absorption, and deection of the fractures were measured. Biomechanical testing showed an increase in load to failure and callus diameter in the group treated with higher (40 ng) dose of TGF-. The researchers concluded that TGF- increases callus formation and strength in rat tibial fractures after 40 days of healing. Comparing these and other studies and making clinically relevant conclusions is difcult owing to differences in models, dose regimens, delivery systems, and isoforms of TGF- used.41 Overall, TGF- appears to have some efcacy in augmenting fracture healing if the fracture is stable. More research using validated and consistent models is needed to further assess the role of TGF- on enhancement of normal fracture healing. Bone Morphogenetic Proteins. The BMPs are a subfamily of the TGF- superfamily of polypeptides. BMPs are distinguished from other members of the superfamily by having, in general, seven rather than nine conserved cysteines in the mature region.228 Several known members of this family of osteoinductive growth factors can be subdivided into several classes based on structure.127 BMPs play crucial roles in growth, differentiation, and apoptosis in a variety of cells during development, including chondrocytes and osteoblasts. Compared with TGF-, however, BMPs have been shown to have more selective and powerful effects on bone healing in animal models. During fracture repair, endogenously expressed BMPs include BMP-2, BMP-3 (osteogenin), BMP-4, and BMP-7 (osteogenic protein, OP-1). In humans, BMP-2 and BMP-7 have been the most extensively studied, and they have been isolated, sequenced, and manufactured using recombinant DNA technology. The importance of BMPs during bone healing has been demonstrated using numerous in vitro48, 263, 284 and in vivo models.23, 119, 131, 186, 194, 289 Several investigators have also studied the ability of exogenously administered BMPs to promote bone regeneration in osseous locations. BMP-2,106, 148, 149, 240, 286 BMP-7,58, 59, 61 and BMP-3257 have all been shown to promote fracture healing of critical-sized defects. A critical-sized defect may be dened as the smallest intraosseous wound that would not heal by bone forma-
tion in the lifetime of the animal. Critical-sized diaphyseal defect models mimic a clinical situation in which so much bone is lost that even normal mechanisms cannot repair it, such as a result of trauma or bone resection for musculoskeletal tumors. Although these defects do not heal without intervention, they are not truly models of normal or impaired bone healing, as it is the inherent size of the defect that leads to failed healing rather thanas in the case of a delayed union or nonunionthe host characteristics or the local fracture environment. Although signicant developments in fracture repair enhancement have been achieved using critical-sized diaphyseal defect models, they do not simulate the more common clinical situation in which the cause of a nonunion is a compromised healing environment other than massive bone loss. Therefore, we provide a review of some of the literature that has supported the use of BMPs to enhance the healing of fractures. Einhorn and co-workers investigated the effects of percutaneously injecting recombinant BMP-2 into standardized, closed mid-diaphyseal femur fractures in rats 6 hours after injury.80 First, 278 male rats were divided into three groups of 96 animals, each receiving either no injection at all, injection of an aqueous buffer, or injection of the buffer plus 80 g of rhBMP-2. Animals in each of these groups were then further sub-divided into four groups and were sacriced at 7, 14, 21, and 28 days after fracture. At the conclusion of the experiment, 18 femora from each subgroup were tested biomechanically and 6 were analyzed histologically. A statistically signicant increase in stiffness in the rhBMP-2treated fractures was observed by day 14 and continued at 21 and 28 days after fracture compared with that in the other two groups. There was also a signicant increase in strength in the rhBMP2treated fractures at day 28. A robust subperiosteal membranous bone response, greater than that seen in either of the control groups, was demonstrated histologically in the fractures treated with rhBMP-2. In addition, compared with that in controls, there was relative maturation of osteochondrogenic cells in the rhBMP-2 treated fractures. Bridging callus appeared earlier in the rhBMP-2treated groups, and relatively increased peripheral woven bone was seen in these groups as well. The investigators concluded that local percutaneous injection of rhBMP-2 into fresh fractures might accelerate the rate of normal fracture healing. Bostrom and Camacho22 and Turek and co-workers266 studied BMP-2 combined with an absorbable collagen sponge and applied as an onlay graft in a rabbit ulnar osteotomy and conrmed its effects on the healing of fresh fractures described by Einhorn and associates. Exogenously administered BMP-7 has been evaluated in animal noncritical-sized defect models by three groups of investigators. Using a closed diaphyseal tibial fracture model in the goat, den Boer and colleagues69 investigated the effect of BMP-7 introduced into a fresh fracture gap and concluded that injections of BMP-7 solution in these fractures accelerates their healing during the rst 2 weeks. Cook57 and Poplich and colleagues209 created bilateral 3-mm noncritical-sized defects in the midulna of 35 adult male dogs and also showed that BMP-7 enhanced fracture healing as measured by several parameters.
649
Although the effect of exogenously administered BMP into acute bony defects has been studied for some time, it has not been until recently that investigators have studied the effect of BMPs on the treatment of nonunions. Whereas in acute defects, the species specicity of a BMP does not appear to be important,292 its effect on the ability of a BMP to enhance healing of a nonunion has been shown in a canine model.121 Heckman and associates122 performed standardized nonunions in the midportion of the radial diaphysis in 30 mature mongrel dogs. The nonunion was treated with implantation of a carrier consisting of poly (DL-lactic acid) and polyglycolic acid polymer (50:50 polylactic acidpolyglycolic acid [PLG50]) containing canine-puried BMP or TGF-1, or both, or the carrier without BMP or TGF-1. Five groups, consisting of six dogs each, were treated with (1) implantation of the carrier alone, (2) implantation of the carrier with 15 mg of BMP, (3) implantation of the carrier with 1.5 mg of BMP, (4) implantation of the carrier with 15 mg of BMP and 10 ng of TGF-1, or (5) implantation of the carrier with 10 ng of TGF-1. The specimens were examined radiographically and histomorphometrically 12 weeks after implantation. The radii treated with either 1.5 mg or 15 mg of BMP showed signicantly increased periosteal and endosteal bone formation. No signicant radiographic or histomorphometric evidence of healing was observed after implantation of the polylactic acidpolyglycolic acid carrier alone or in combination with 10 ng TGF-1. The investigators concluded that species-specic BMP incorporated into a polylactic acidpolyglycolic acid carrier implanted at the site of an ununited diaphyseal fracture increases bone formation. In addition, TGF-1 at the dose used in the study did not have a similar effect and did not potentiate the effect of BMP. The investigators suggested that the biodegradable implant containing BMP that was used in their study was an effective bone-graft substitute. This study conrmed the biocompatibility of polylactic acid polyglycolic acid composites, the bioavailability of BMP and TGF-1 released from this implant, and, most important, the capability of BMP to augment bone healing in chronic nonunions. Clinical experience with exogenously administered BMPs in bony defects or fresh fractures is somewhat limited. To date, only preliminary results exist on the effects of BMP-2 and BMP-7 to enhance bony regeneration in humans. Recently described is an open label safety and feasibility trial using BMP-2 with an absorbable collagen sponge carrier.217 Twelve patients with Gustillo grade II, IIIA, or IIIB open tibia fractures from four major trauma centers were treated with 3.4 or 6.8 mg of BMP-2. Eight of the 12 patients were treated with a nonreamed tibial rod, and 4 were treated with an external xator. At the time of denitive wound closure (median, 4 days postoperatively), one or two Helistat (Colla-tec, Plainsboro, NJ) absorbable collagen sponges soaked with 0.43 mg/mL of BMP-2 were applied to the fracture site. Independent radiologists and orthopaedic surgeons reviewed radiographs of the fractures 4 months postoperatively. Nine (75%) of the fractures healed without additional intervention, and three (25%) required a secondary bone graft procedure. Aside from two patients in whom transient serum antibodies against BMP-2 developed, no signicant complications
were encountered. Although these results showed that the use of BMP-2 in these types of injuries is safe, feasible, and probably efcacious, the nal results of a larger prospective randomized clinical trial are not yet complete. Friedlaender reported preliminary results of a multicenter clinical trial using NOVOS (Styrker Biotech, Natick, MA), a form of BMP-7 associated with a bovine-derived collagen carrier.95 In this trial, 124 tibial nonunions in 122 patients were treated in 18 centers. Inclusion criteria were nonunion of at least 9 months and the surgeons choice of intramedullary xation with bone graft as the most appropriate method of treatment. None of these nonunions was expected to heal if left untreated. Patients received either autograft or NOVOS. A successful result was dened as a return to full weight bearing, reduction in pain, and radiographic union by 9 months. Preliminary results of this trial indicated that NOVOS was comparable to autogenous grafting in achieving success. The healing rate, however, was not 100% in either group. Geesink and colleagues investigated the osteogenic potential of BMP-7 in a critically sized human bony defect model.105 Twenty-four patients undergoing high tibial osteotomy for osteoarthritis of the knee were divided into four groups. In the rst group the bular osteotomy had been left untreated, and in the second group demineralized bone had been used to ll the defect. Radiologic and dual-energy x-ray absorptiometry parameters measured during the rst postoperative year showed no evidence of bony changes in the untreated group, whereas matrix formation of new bone was observed from 6 weeks onward in the group treated with demineralized bone. The third group received 2.5 mg of recombinant BMP-7 combined with a collagen type I carrier, and the fourth group received collagen type I carrier only. The results of this part of the study showed that all but one of the patients treated with the BMP-7 exhibited formation of new bone from 6 weeks on as compared with insignicant formation of new bone observed in those who received the collagen carrier alone. The investigators concluded that recombinant human BMP-7 is effective in healing human critical-sized bony defects. Fibroblast Growth Factors. The FGF family, to our knowledge, currently includes 19 members.283 The most abundant types in normal adult tissues are acidic broblast growth factor (aFGF) and basic broblast growth factor (bFGF), also named FGF-1 and FGF-2. Both are heparinbinding polypeptides that have been shown to bind to the same receptor.188 These molecules are best known for their effects on endothelial cell replication and neovascularization.34 The expression of FGFs during fracture repair, however, has been well documented,25, 232 and their role in fracture healing and its enhancement has been investigated in several animal studies.24 Although one report18 has questioned the ability of FGF to enhance fracture healing, the results of most experiments to date have been positive with respect to their effects. Jingushi and associates, using a rat bilateral femoral fracture model, explored the effect of exogenous aFGF on normal fracture healing.133 Compared with controls, the animals that had received injections of aFGF showed enlarged calluses in the cartilage formation stage of healing, and these calluses remained enlarged until 4
650
weeks after fracture. Nakamura and associates tested the effects of bFGF on healing tibial fractures in dogs185 and concluded that bFGF promotes fracture healing in dogs by the stimulation of bone remodeling. Radomsky and co-workers, rst in rabbits212 and more recently in baboons,211 showed evidence that FGF-2, delivered in a hyaluronan gel, accelerates fracture healing. In the latter study, FGF-2 (4 mg/mL) and hyaluronan (20 mg/mL) were combined into a viscous gel formulation and percutaneously injected as a one-time dose into a 1-mm gap osteotomy that was surgically created in the bulae of baboons. Radiographically, this combination led to a statistically signicant increase in callus area at the treated site. Histologic analysis revealed a signicantly greater callus size, periosteal reaction, vascularity, and cellularity in the treated groups compared with those in the untreated controls. Furthermore, specimens treated with 0.1, 0.25, and 0.75 mL of hyaluronan/FGF-2 demonstrated a 48%, 50%, and 34% greater average load at failure and an 82%, 104%, and 66% greater energy to failure than the untreated controls, respectively. Although the aforementioned studies on the effects of exogenously delivered FGF are promising, it does not appear that this class of molecules is as specic or as potent as the BMPs. In addition, only minimal research has been reported on the side effects of high doses of FGF 174 . Platelet-Derived Growth Factor. PDGF is the major mesenchymal cell mitogen present in serum.225 PDGF is a dimeric molecule consisting of disulde-bonded A- and B-polypeptide chains. Both homodimeric (PDGF-AA and PDGF-BB) and heterodimeric (PDGF-AB) forms exist.125 A PDGF-like peptide has been found in bovine bone,118 and it has been shown to have in vitro effects on several lines of osteoblastic cells.43, 112, 261 Early in the course of fracture healing, it has been shown to be released by degranulating platelets in the fracture hematoma, possibly acting as a chemotactic agent.8 Later in fracture repair, PDGF protein is detectable in both young and mature hypertrophic chondrocytes and osteoblasts.20 The effects of exogenously administered PDGF on fracture healing are controversial. Marden and colleagues showed that PDGF inhibits the bone regeneration induced by osteogenin in rat craniotomy defects.167 Nash and associates tested the effects of exogenously administered PDGF on bone healing using a rabbit tibial osteotomy model.187 Although histologically the treated groups appeared to have increased callus density and volume, three-point bending to failure testing failed to show an improvement in strength.
Systemic Enhancement
Numerous reports have shown that patients who have sustained traumatic brain injury experience faster fracture healing with more callus than healthy patients,103, 203, 250, 254 although the mechanism by which this may occur remains unclear. Bidner and colleagues17 showed that the serum of patients who have sustained a head injury contains a mitogenic activity that is specic for osteoblastic cells. They suggested that there might be a humoral mechanism for the enhanced osteogenesis that accompanies head injury. No conclusive evidence exists for
the molecular identication of this factor. A review article insightfully suggested, in fact, that contrary to common belief, fracture healing is not necessarily accelerated in the patient with traumatic brain injury. Hypertrophic callus, myositis ossicans, and heterotopic ossication, however, do occur frequently and are often misperceived as accelerated healing.155 IGFs and growth hormone (GH) have been suggested to play a role in skeletal growth and remodeling. IGFs derive their name from observations that they produce insulinlike biochemical effects that are not suppressed by anti-insulin antiserum. IGFs exert biologic activity via both IGF cell surface receptors and insulin-like growth factor binding proteins.68, 213 IGF-1 and IGF-2 are the two most important factors of their kind, the former having the higher growth-promoting activity. IGF-1, also known as somatomedin-C, mediates the effect of GH on the skeleton.62 Because IGF-1 is known to be GH dependent, it is possible that IGF levels may be increased in vivo by administration of GH. Several studies have been conducted to determine the role of GH in the repair of skeletal tissues. Some showed that GH stimulates skeletal repair,151 and others failed to show an effect.192 An investigation of the biomechanics of fracture healing in a rabbit tibial model showed that GH treatment was unsuccessful in the stimulation of fracture healing. However, the animals in this experiment were shown to have a persistent nutritional decit, so it is possible that the failure of GH to inuence skeletal repair resulted from an inability to signicantly stimulate circulating levels of IGF-I in this nutritional state.39 Therefore, the roles of GH and IGF-1 in the systemic enhancement of skeletal repair remain unclear. IGF-2, on the other hand, is one of the most abundant growth factors in bone, circulates at higher concentrations than IGF-1, and binds to the same cell surface receptors but with a lower afnity.99 The observation that IGF-2 is stimulated in response to externally applied magnetic elds88 suggests that this molecule may play a role in skeletal repair. The systemic effects of these and other related molecules on the enhancement of skeletal repair may depend not only on their direct effects on the responding cells but also on the concentrations and environmental conditions under which they are permitted to act. Raschke and co-workers214 studied the effect of systemic administration of homologous recombinant GH on bone regenerate consolidation in distraction osteogenesis. Tibiae of 30 mature Yucatan micropigs were osteomized at the mid-diaphyseal level. Starting 5 days after surgery, the limbs were distracted using an external xator at the rate of 2 mm/day for 10 consecutive days. Animals in the treatment group received a daily subcutaneous injection of 100 g of recombinant porcine GH (rpGH) per kilogram of body weight, and those in the control group received sodium chloride. Nondestructive in vivo torsional stiffness (IVTS) measurements were conducted after surgery and on days 1, 2, 3, 4, 6, 8, and 10 of consolidation. After the animals were euthanized, destructive biomechanical testing was performed. Serum levels of IGF-1 were measured once during the latency period (days 15), four times during distraction (days 615), and seven times during consolidation (days 1625) to determine the endocrine
651
response to rpGH. Throughout the consolidation phase, the mean in vivo torsional stiffness of the treatment group was 125% higher than that of the control group on day 16, increased to 207% higher on day 19, and reached 145% on the day after killing. Final regenerate torsional failure load was 131% higher and ultimate torsional stiffness was 231% higher in the treatment group than in the control group. The mean serum level of IGF-1 increased to 440% of preoperative basal level in the treatment group and remained unchanged in the control group. These researchers concluded that systemic administration of growth hormone greatly accelerates ossication of bone regenerate in distraction osteogenesis. Prostaglandins are another important class of compounds that may be considered for eventual use in the systemic enhancement of skeletal repair. Over the past two decades, almost every skeletal metabolic effect has been described after prostaglandin administration, from increased bone resorption to increased bone formation.168 The rst reports of bone formation after prostaglandin treatment described cortical thickening of the limb bones and ribs of neonatal infants who had been treated systemically with prostaglandin E1 for the purpose of maintaining a patent ductus arteriosus.253, 267 Subsequent investigations in which prostaglandin E2 was administered systemically showed increased cortical and trabecular bone formation in dogs126, 191 and restoration of normal skeletal mass in ovariectomized rats who had lost cancellous and cortical bone mass.139, 140 The fact that these effects can be blocked by the administration of indomethacin, an inhibitor of prostaglandin synthesis, supports the contention that prostaglandins directly enhance bone formation.252 Finally, several studies have shown that normal fracture healing is impaired by administration of prostaglandin inhibitors.5, 219, 259 Although these reports suggest that prostaglandins may be useful in enhancing fracture healing, the clinical safety and efcacy of systemically administered prostaglandins to enhance skeletal repair in humans have yet to be described.
CLINICAL APPLICATIONS
zzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzz Although strategies to enhance skeletal repair are the subject of ongoing research, such advances should not be envisioned as substitutes for optimal orthopaedic management. Appropriate internal or external xation and the attainment of adequate alignment and stability will always be the mainstays of fracture care. Moreover, because of cost-containment and monitoring of practice patterns, physicians will be able to use specic new products only in situations in which their use has been carefully studied, the data scrutinized by peer review, and the indications and labeling approved by a federal regulatory agency. With these considerations in mind, our current recommendations and visions for future possibilities are presented.
Fresh Fractures
Enhancement of fresh fracture healing at the time of initial treatment may be indicated in situations in which the
mechanical or physiologic environment predisposes to delayed union or nonunion. In addition, an enhanced healing process could lead to a quicker return of patients to productive work. Although adequate xation and alignment through traditional orthopaedic principles are sufcient in most cases, even these traditional principles are subject to change. For example, Sarmiento and associates237 demonstrated successful healing of closed diaphyseal tibial fractures with the use of cast bracing and early weight bearing, but Kenwright and colleagues142 showed that external xation augmented by controlled micromotion accelerated the healing process. For more than 100 years, autogenous cancellous bone grafting has been the standard of care for augmentation of both initial fracture repair and the treatment of a nonunion.104 As noted previously, it provides osteogenic, osteoinductive, and osteoconductive properties but is limited in its quantity and in its ability to provide immediate structural rigidity. In addition, harvesting of autogenous bone graft is not risk free. Physical methods of enhancing acute fracture healing have varying benets. Bone graft substitutes have revolutionized fracture treatment and will continue to do so. No single graft substitute, however, is ideal for all injuries, and it is important for the surgeon to be knowledgeable about the advantages and disadvantages of all the available materials. To summarize, the only physical method that has been shown to enhance the healing of fresh fractures is low-intensity ultrasound. This modality has been shown to be effective clinically only in the treatment of closed tibial and distal radius fractures in smokers. With regard to osteogenic methods of augmenting skeletal repair, it appears that autogenous bone graft is the most benecial and poses the least risk of infection and complications. Vascularized cortical graft harvesting is highly demanding and has limited indications, perhaps only in the face of infection or for areas that are known to be devoid of adequate blood ow. Allografts have been shown to have up to a 15% rate of infection and therefore should be used with caution. Autogenous bone marrow preparations have not been shown to be efcacious in clinical trials, but these preparations certainly have great theoretical appeal. It is very difcult to form conclusions as to which of the commercially available bone graft substitutes is the most effective. This is in part because clinical experience is limited, and large clinical trials are lacking. The clinical experience of the authors with coralline hydroxyapatite (ProOsteon) for tibial plateau fractures has proven it to be extremely useful. Evaluating healing radiographically, however, is often difcult when using this material. We have also used injectable calcium phosphate cement (Norian SRS) for distal radius fractures with promising results as well. There has been anecdotal evidence that injecting demineralized allograft bone matrices into fresh fractures of patients who have poor healing potential, such as diabetics and smokers, enhances fracture healing in these patients. Statistically signicant clinical data supporting these reports are lacking. Early human experiments have shown that injectable BMP has a role in accelerating healing of fresh fractures. Follow-up studies of these and other growth factors are awaited (Table 223).
652
TABLE 223
Management of Fresh Fractures: Recommendations and Future Possibilities

Management Nonoperative Operative Currently Available Techniques Ultrasound (distal radius, tibia) Autogenous bone grafts Calcium phosphate ceramics External xationinduced micromotion
Nonunions
Nonunion is the clinical entity that most orthopaedists equate with the need for enhanced bone healing. As with delayed unions of tibial fractures, reamed intramedullary nailing has been shown to stimulate the healing process and to lead to union in more than 90% of cases.262 The mainstay of treatment for nonunions remains autogenous cancellous bone grafting.201 There is currently no evidence to suggest that osteoconductive substances (ceramics or composites) or ultrasound is effective in the healing of nonunions. On the other hand, electrical and electromagnetic stimulation has gained Food and Drug Administration approval for the treatment of certain nonunions (Table 225).
Future Possibilities
Osteoinductive factor Expanded bone marrow osteoprogenitor cells
Delayed Unions
Traditionally, orthopaedists have referred to a delayed union as a fracture that heals more slowly than average.169 Although this is somewhat of a vague denition, delayed union of fractures, however measured, continues to be a problem. Current nonoperative means of augmenting healing of delayed unions include electromagnetic eld stimulation. Bone marrow grafting has been proposed to augment healing in a delayed union setting, but its effectiveness has not been proved in a controlled study. Autogenous iliac grafting has repeatedly been shown to stimulate the healing process in delayed unions.178 Injection of demineralized bone matrix as well as genetically engineered bone morphogenetic proteins into a fracture that is healing slower than average may greatly enhance the rate of fracture healing; although no detrimental effects of these treatments have been reported to date, more clinical trials are needed to prove their efcacy. Despite the attraction that some of these modalities may hold for augmenting healing, the literature is replete with data demonstrating the efcacy of more standard operative interventions. For example, reamed intramedullary nailing262 and dynamization of fracture xation systems76, 278 remain the mainstays of the management of delayed union (Table 224).
Fresh Fractures with Bone Loss and Reconstruction of Segmental Metaphyseal or Diaphyseal Defects
Large bone defects can be created by severe comminution or impaction at the time of initial injury or by operative resection in the treatment of bone tumors or infections. The critical determinants in choosing a material to bridge the gap or ll the defect include the biologic environment in the gap, its location (metaphyseal or diaphyseal), and the size of the defect. Previously infected or irradiated gaps and areas of extensive soft tissue loss create unfavorable biologic milieus. For metaphyseal defects, autogenous cancellous bone grafts have been shown to be successful180 and can be combined with calcium phosphate ceramics as volume expanders if necessary (Table 226). If a defect is not surrounded by bone on all sides, or if its volume is greater than 30 cc, ceramics should not be used alone because they offer no osteoinductive or osteogenic potential. The reconstruction of diaphyseal defects requires systems that can provide immediate structural rigidity (see Table 226). Small defects (12 cm) can be managed adequately with rigid xation and autogenous cancellous bone grafts201 or possibly with shortening of the involved bone.52 Larger defects may be treated with autologous cortical grafts, but vascularized autologous grafts are preferable because they enhance local healing by improving blood ow and providing osteogenic cells.158, 207, 256
TABLE 224
Management of Delayed Unions: Recommendations and Future Possibilities

Management Nonoperative Operative Currently Available Techniques Electromagnetic eld Autogenous bone grafting Reamed intramedullary nailing/dynamization
TABLE 225
Management of Nonunions: Recommendations and Future Possibilities

Management Currently Available Techniques Electromagnetic eld Autogenous bone grafting Reamed intramedullary nailing Future Possibilities
Future Possibilities Osteoinductive factor Osteoinductive factor Nonoperative Operative
Osteoinductive factor Osteoinductive factor
CHAPTER 22 Enhancement of Skeletal Repair TABLE 226
653
Management of Reconstruction of Segmental Metaphyseal or Diaphyseal Defects: Recommendations and Future Possibilities
Finding Currently Available Techniques
Future Possibilities
Metaphyseal Defects <30 cc Autogenous cancellous graft Calcium phosphate ceramics >30 cc Calcium phosphate ceramic/autogenous composite graft Diaphyseal Defects <2 cm 26 cm >6 cm Autogenous cancellous graft Nonvascularized cortical autograft Bone transport Vascularized cortical autograft
Osteoinductive implant Osteoinductive implant
Osteoinductive implant Osteoinductive implant Osteoinductive implant
to be clinically useful for the treatment of nonunions and delayed unions in all patients and for accelerating fracture healing in smokers. Future investigations on these physical methods need to be directed at their effectiveness in accelerating healing of fresh fractures. Knowledge about biologic methods of fracture healing enhancement has increased tremendously over the past decade. New ceramics and allogeneic bone matrices are being developed and have been found anecdotally to be useful, although large clinical trials evaluating their efcacy and safety are lacking. As our understanding of intracellular and extracellular signaling cascades expands, the use of genetically engineered endogenous compounds such as BMPs to enhance fracture healing will progress as well. It is possible that in the future orthopaedic surgeons will give patients an oral medication that ultimately accelerates fracture healing. Given that fracture care costs societies millions of dollars yearly, such augmentation of fracture healing can be tremendously cost-effective and therefore both clinically and economically benecial.
REFERENCES 1. Aaron, R.K.; Ciombor, D.; Jolly, G. Stimulation of experimental endochondral ossication by low-energy pulsing electromagnetic elds. J Bone Miner Res 4:227233, 1989. 2. Aaron, R.K.; Ciombor, D.; Jones, A.R. Bone induction by decalcied bone matrix and mRNA of TGFb and IGF-1 are increased by ELF eld stimulation. Trans Orthop Res Soc 22:548, 1997. 3. AATB Information Alert, vol. 3, no. 6. McLean, VA, American Association of Tissue Banks, December 15, 1993. 4. Akai, M.; Yabuki, T.; Tateishi, T.; Shirasaki, Y. Mechanical properties of the electrically stimulated callus: An experiment with constant direct current in rabbit bulae. Clin Orthop 188:293302, 1984. 5. Allen, H.L.; Wase, A.; Bear, W.T. Indomethacin and aspirin: Effect of nonsteroidal anti-inammatory agents on the rate of fracture repair in the rat. Acta Orthop Scand 51:595600, 1980. 6. Anderson, J.C.; Eriksson, C. Electrical properties of wet collagen. Nature 227:166168, 1968. 7. Andrew, J.G.; Hoyland, J.; Andrew, S.M.; et al. Demonstration of TGF-beta 1 mRNA by in situ hybridization in normal human fracture healing. Calcif Tissue Int 52:7478, 1993. 8. Andrew, J.G.; Hoyland, J.; Freemont, A.J.; et al. Platelet-derived growth factor expression in normally healing human fractures. Bone 16:455460, 1995. 9. Aro, H.; Eerola, E.; Aho, A.J. Fracture healing in paraplegic rats. Acta Orthop Scand 56:228232, 1985. 10. Bassett, C.A.L.; Becker, R.O. Generation of electric potentials in bone in response to mechanical stress. Science 137:10631064, 1962. 11. Bassett, C.A.L.; Mitchell, S.N.; Gaston, S.R. Treatment of ununited tibial diaphyseal fractures with pulsing electromagnetic elds. J Bone Joint Surg Am 63:511523, 1981. 12. Bassett, C.A.L.; Pawluck, R.J. Electrical behavior of cartilage during loading. Science 814:575577, 1974. 13. Bassett, C.A.L.; Valdes, M.G.; Hernandez, E. Modication of fracture repair with selected pulsing electromagnetic elds. J Bone Joint Surg Am 64:888895, 1982. 14. Bauer, T.W.; Muschler, G.F Bone graft materials. An overview of the . basic science. Clin Orthop 371:1027, 2000. 15. Beck, L.S.; DeGuzman, L.; Lee, W.P.; et al. Bone marrow augments the activity of transforming growth factor beta 1 in critical sized bone defects. Trans Orthop Res Soc 21:626, 1996. 16. Beck, L.S.; DeGuzman, L.; Lee, W.P.; et al. Transforming growth factor beta 1 bound to tricalcium phosphate persists at segmental radial defects and induces bone formation. Trans Orthop Res Soc 20:593, 1995. 17. Bidner, S.M.; Rubins, I.M.; Desjardins, J.V.; et al. Evidence for a humoral mechanism for enhanced osteogenesis after head injury. J Bone Joint Surg Am 72:11441149, 1990. 18. Bland, Y.S.; Critchlow, M.A.; Ashhurst, D.E. Exogenous broblast
Vascularized cortical autografts are more appropriate for large diaphyseal defects (>6 cm). The advantages of vascularized grafts are more rapid and complete incorporation, which provides immediate structural support, and the ability of the transplanted bone to form new bone.276 They also have the ability to hypertrophy (increasing size up to 100%) and to withstand large functional loads.49 The bula has been used successfully to bridge large defects in the humerus, tibia, or femur.245 Allografts can be used in these settings, but their incorporation is markedly slower than that of autografts, and they therefore remain signicantly weaker for longer periods after implantation.98 Delayed fracture healing (up to 3 years after surgery) has been reported to occur in up to 19% of allografted fractures. In addition, complications related to rejection, usually manifest as rapid osteolysis, infection (11%), and nonunion (17%), may occur.166 Nonvascularized cortical autografts are replaced by creeping substitution, but they eventually become completely replaced at more rapid rates than allografts. Allografts are contraindicated in the setting of a poor local blood supply because they are at increased risk for infection and may become a sequestrum.45, 258 Bone transport is also an option and has been used successfully in many clinical studies.72, 170 Limitations of this technique include pain, pintract problems, angulation, docking site nonunion, and poor patient cooperation. Distraction lengths greater than 6 cm are sometimes difcult to achieve.
EXPECTATIONS FOR THE FUTURE
zzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzzz Because not all fractures heal uneventfully, research directed at discovering new methods for fracture healing enhancement will continue to be important. Physical modalities of enhancing fracture healing have been shown
654
SECTION I General Principles growth factors-1 and -2 do not accelerate fracture healing in the rabbit. Acta Orthop Scand 66:543548, 1995. Blenman, P.R.; Carter, D.S.; Beaupre, G.S. Role of mechanical loading in the progressive ossication of the fracture callus. J Orthop Res 7:398407, 1989. Bolander, M.E. Regulation of fracture repair by growth factors. Proc Soc Exp Biol Med 200:165170, 1992. Bolander, M.E.; Balian, G. The use of demineralized bone matrix in the repair of segmental defects: Augmentation with extracted matrix proteins and a comparison with autologous grafts. J Bone Joint Surg Am 68:12641274, 1986. Bostrom, M.P.G.; Camacho, N.P. Potential role of bone morphogenetic proteins in fracture healing. Clin Orthop 355S:274282, 1998. Bostrom, M.P.; Lane, J.M.; Berberian, W.S.; et al. Immunolocalization and expression of bone morphogenetic proteins 2 and 4 in fracture healing. J Orthop Res 13:357367, 1995. Bostrom, M.P.; Saleh, K.J.; Einhorn, T.A. Osteoinductive growth factors in preclinical fracture and long bone defects models. Orthop Clin North Am 30:647658, 1999. Bourque, W.T.; Gross, M.; Hall, B.K. Expression of four growth factors during fracture repair. Int J Dev Biol 37:573579, 1993. Boyd, H.B.; Lipinski, S.W.; Wiley, J.H. Observations on non-union of the shaft of long bones, with statistical analysis of 842 patients. J Bone Joint Surg Am 43:159168, 1961. Brighton, C.T. Current concepts review: The treatment of nonunions with electricity. J Bone Joint Surg Am 63:847851, 1981. Brighton, C.T.; Black, J.; Friedenberg, Z.B.; et al. A multicenter study of the treatment of non-union with constant direct current. J Bone Joint Surg Am 62:213, 1981. Bruder, S.P.; Fink, D.J.; Caplan, A.I. Mesenchymal stem cells in bone development: Bone repair and skeletal regeneration. J Cell Biochem 56:283294, 1994. Bucholz, R.W.; Carlton, A.; Holmes, R. Interporous hydroxyapatite as a bone graft substitute in tibial plateau fractures. Clin Orthop 240:5362, 1989. Buckwalter, J.A. Activity vs. rest in the treatment of bone, soft tissue and joint injuries. Iowa Orthop J 15:2942, 1995. Buckwalter, J.A.; Einhorn, T.A.; Bolander, M.E.; Cruess, R.L. Healing of the musculoskeletal tissues. In: Rockwood, C.A., Jr.; Green, D.P.; Bucholz, R.W.; Heckman, J.D., eds. Rockwood and Greens Fractures in Adults. Philadelphia, J.B. Lippincott, 1996, pp. 261304. Burchardt, H. The biology of bone graft repair. Clin Orthop 174:2842, 1983. Burgess, W.H.; Maciag, T. The heparin-binding (broblast) growth factor family of proteins. Annu Rev Biochem 58:575606, 1989. Burwell, R.G. Studies in the transplantation of bone: VII. The fresh composite homograft-autograft of cancellous bone: An analysis of factors leading to osteogenesis in marrow transplants and in marrow-containing bone grafts. J Bone Joint Surg Br 46:110140, 1964. Buschmann, M.D.; Gluzband, Y.A.; Grodzinky, A.J.; Hunziker, E.B. Mechanical compression modulates matrix biosynthesis in chondrocyte/agarose culture. J Cell Sci 108:14971508, 1995. Caplan, A.I. Mesenchymal stem cells. J Orthop Res 9:641650, 1991. Caplan, A.I. The mesengenic process. Clin Plast Surg 21:429435, 1994. Carpenter, J.E.; Hipp, J.A.; Gerhart, T.N.; et al. Failure of growth hormone to alter fracture healing biomechanics in a rabbit model. J Bone Joint Surg Am 74:359367, 1992. Carter, D.R.; Blenman, P.R.; Beaupre, G.S. Correlations between mechanical stress history and tissue differentiation in initial fracture healing. J Orthop Res 6:736748, 1988. Centrella, M.; Horowitz, M.C.; Wozney, J.M.; McCarthy, T.L. Transforming growth factor- gene family members and bone. Endocr Rev 15:2739, 1994. Centrella, M.; McCarthy, T.L.; Canalis, E. Transforming growth factor-beta and remodeling of bone. J Bone Joint Surg Am 73:14181428, 1991. Centrella, M.; McCarthy, T.L.; Kusmik, W.F et al. Relative binding .; and biochemical effects of heterodynamic and homodynamic isoforms of platelet-derived growth factor in osteoblast-enriched cultures from foetal rat bone. J Cell Physiol 146:420426, 1991. 44. Chapman, M.W.; Bucholz, R.; Cornell, C. Treatment of acute fractures with a collagen-calcium phosphate graft material: A randomized clinical trial. J Bone Joint Surg Am 79:495502, 1997. 45. Charnell, M.J.; McAndrew, M.P.; Thomas, R.; Schwartz, H.S. Structural allografts for reconstruction of lower extremity open fractures with ten centimeters or more of acute segmental defects. J Orthop Trauma 9:222226, 1995. 46. Chase, W.S.; Herndon, C.H. The fate of autogenous and homeogeneous bone grafts: A historical review. J Bone Joint Surg Am 37:809841, 1955. 47. Chen, C.S.; Ingber, D.E. Tensegrity and mechanoregulation. Osteoarthritis Cartilage 7:8194, 1999. 48. Chen, P.; Carrington, J.L.; Hammonds, R.G.; Reddi, A.H. Stimulation of chondrogenesis in limb bud mesoderm cells by recombinant human bone morphogenetic protein 2B (BMP-2B) and modulation by transforming growth factor-1 and 2. Exp Cell Res 195:509 515, 1991. 49. Chew, W.Y.C.; Low, C.K.; Tan, S.K. Long term results of free vascularized bular grafts. Clin Orthop Rel Res 311:258261, 1995. 50. Chiroff, R.; Weber, J.; White, E. Tissue ingrowth of replamineform implants. J Biomed Mater Res 9:2945, 1975. 51. Chu, C.R.; Convery, F .R.; Akeson, W.H. Articular cartilage transplantation. Clinical results in the knee. Clin Orthop 360:159168, 1999. 52. Cierny, G.; Zorn, K.E. Segmental tibial defects: Comparing conventional and Ilizarov methodologies. Clin Orthop 301:118 123, 1994. 53. Claes, L.; Augat, P.; Suger, G.; Wilke, H.J. Inuence of size and stability of the osteotomy gap on success of fracture healing. J Orthop Res 15:577584, 1997. 54. Claes, L.E.; Heigele, C.A.; Neidlinger-Wilke, C.; et al. Effects of mechanical factors on the fracture healing process. Clin Orthop 355:S132S147, 1998. 55. Connolly, J.; Guse, R.; Lippiello, L.; Dehne, R. Development of an osteogenic bone marrow preparation. J Bone Joint Surg Am 71:684691, 1989. 56. Constantz, B.R.; Ison, I.C.; Fulmer, M.T.; et al. Skeletal repair by in situ formation of the mineral phase of bone. Science 267:1796 1799, 1995. 57. Cook, S.D. Acceleration of bone healing with OP-1 in a canine noncritical size defect model. Abstract. Second International OP-1 Conference, Boston, MA, 1997. 58. Cook, S.D.; Baffes, G.C.; Wolfe, M.W.; et al. The effect of recombinant human osteogenic protein-1 on healing of large segmental bone defects. J Bone Joint Surg Am 76:827838, 1994. 59. Cook, S.D.; Baffes, G.C.; Wolfe, M.W.; et al. Recombinant human bone morphogenetic protein-7 induces healing in a canine long-bone segmental defect model. Clin Orthop 301:302312, 1994. 60. Cook, S.D.; Ryaby, J.P.; McCabe, J.; Frey, J.J.; et al. Acceleration of tibia and distal radius fracture healing in patients who smoke. Clin Orthop 337:198207, 1997. 61. Cook, S.D.; Wolfe, M.W.; Salkeld, S.L.; et al. Effect of recombinant human osteogenic protein-1 on healing of segmental defects in non-human primates. J Bone Joint Surg Am 77:734750, 1995. 62. Copeland, K.C.; Underwood, L.E.; Van Wyk, J.J. Induction of imunoreactive somatomedin C in human serum by growth hormone: Dose response relationships and effects on chromatographic proles. J Clin Endocrinol Metab 50:690697, 1980. 63. Cornell, C.N. Initial clinical experience with use of collagraft as a bone graft substitute. Tech Orthop 7:5563, 1992. 64. Cornell, C.N.; Lane, J.M. Current understanding of osteoconduction in bone regeneration. Clin Orthop 355:S267S273, 1998. 65. Cornell, C.N.; Lane, J.M.; Chapman, M.; et al. Multicenter trial of Collagraft as bone graft substitute. J Orthop Trauma 5:18, 1991. 66. Court-Brown, C.; McQueen, M. Compartment syndrome delays tibial union. Acta Orthop Scand 58:249252, 1987. 67. Critchlow, M.A.; Bland, Y.S.; Ashhurst, D.E. The effect of exogenous transforming growth factor-beta 2 on healing fractures in the rabbit. Bone 16:521527, 1995. 68. Czech, M.P. Signal transmission by the insulin-like growth factors. Cell 59:235238, 1989.
19. 20. 21.
22. 23. 24. 25. 26. 27. 28. 29. 30. 31. 32.
33. 34. 35.
36. 37. 38. 39. 40. 41. 42. 43.
CHAPTER 22 Enhancement of Skeletal Repair 69. den Boer, F .C.; Bramer, J.A.M.; Blokhius, T.J.; et al. The effect of recombinant human osteogenic protein-1 on the healing of fresh closed diaphyseal fracture. Abstract. Second International OP-1 Conference, Boston, MA, 1997. 70. Dennis, J.E.; Caplan, A.I. Porous ceramic vehicles for rat marrow derived (Rattus norvegicus) osteogenic cell delivery: Effects of pretreatment with bronectin or laminin. J Oral Implant 19:106 115, 1993. 71. Diduch, D.R.; Coe, M.R.; Joyner, C.; et al. Two cell lines from bone marrow that differ in terms of collagen synthesis, osteogenic characteristics, and matrix mineralization. J Bone Joint Surg Am 75:92105, 1993. 72. DiPasquale, D.; Ochsner, M.G.; Kelly, A.M.; Maloney, D.M. The Ilizarov method for complex fracture non-unions. J Trauma 37:629634, 1994. 73. Doi, K.; Oda, T.; Soo-Heong, T.; Nanda, V. Free vascularized bone graft for non-union of the scaphoid. J Hand Surg [Am] 25:507519, 2000. 74. Duarte, L.R. The stimulation of bone growth by ultrasound. Arch Orthop Trauma Surg 101:153159, 1983. 75. Duffy, G.P.; Wood, M.B.; Rock, M.G.; Sim, F Vascularized free .H. bular transfer combined with autografting for the management of fracture non-unions associated with radiation therapy. J Bone Joint Surg Am 82:544554, 2000. 76. Egger, E.L.; Gottsauner, F Palmer, J.; et al. Effects of axial .; dynamization on bone healing. J Trauma 34:185192, 1993. 77. Einhorn, T.A. Current concepts review: Enhancement of fracturehealing. J Bone Joint Surg Am 77:940956, 1995. 78. Einhorn, T.A.; Bonnarens, F Burnstein, A.H. The contributions of .; dietary protein and mineral to the healing of experimental fractures: A biomechanical study. J Bone Joint Surg Am 68:13891395, 1986. 79. Einhorn, T.A.; Lane, J.M.; Burstein, A.H.; et al. The healing of segmental bone defects induced by demineralized bone matrix: A radiographic and biomechanical study. J Bone Joint Surg Am 66:274279, 1984. 80. Einhorn, T.A.; Majeska, R.J.; Oloumi, G.; et al. Enhancement of experimental fracture healing with a local percutaneous injection of rhBMP-2. Abstract. American Academy of Orthopaedic Surgeons Annual Meeting, San Francisco, California, 1997. 81. Einhorn, T.A.; Majeska, R.J.; Rush, E.B.; et al. The expression of cytokine activity by fracture callus. J Bone Miner Res 10:1272 1281, 1995. 82. Elder, S.; Frankenburg, E.; Goulet, J.; et al. Biomechanical evaluation of calcium phosphate cementaugmented xation of unstable intertrochanteric fractures. J Orthop Trauma 14:386393, 2000. 83. Ellies, L.G.; Nelson, D.G.; Featherstone, J.D. Crystallographic structure and surface morphology of sintered carbonated apatites. J Biomed Mater Res 22:541553, 1988. 84. Emami, A.; Petren-Mallmin, M.; Larsson, S. No effect of lowintensity ultrasound on healing time of intramedullary xed tibial fractures. J Orthop Trauma 13:252257, 1999. 85. Enneking, W.F Burchardt, H.; Puhl, J.J.; Piotrowski, G. Physical .; and biological aspects of repair in dog cortical bone transplants. J Bone Joint Surg Am 57:237252, 1975. 86. Fitzsimmons, R.J.; Ryaby, J.T.; Magee, F Baylink, D.J. IGF-II .P.; receptor number is increased in TE-85 cells by low amplitude, low frequency, electromagnetic eld exposure. J Bone Miner Res 10:812819, 1995. 87. Fitzsimmons, R.J.; Ryaby, J.T.; Magee, F et al. Combined magnetic .P.; elds increase IGF-II secretion in osteoblast cultures. Endocrinology 136:31003106, 1995. 88. Fitzsimmons, R.J.; Ryaby, J.T.; Mohan, S.; et al. Combined magnetic elds increase insulin-like growth factor II in TE85 human osteosarcoma bone cell cultures. Endocrinology 136:31003106, 1995. 89. Frankenburg, E.P.; Goldstein, S.A.; Bauer, T.W; et al. Biomechanical and histological evaluation of a calcium phosphate cement. J Bone Joint Surg Am 80:11121124, 1998. 90. Frayssinet, P.; Mathon, D.; Lerch, A.; et al. Osseointegration of composite calcium phosphate bioceramics. J Biomed Mater Res 50:125130, 2000. 91. Fredericks, D.C.; Nepola, J.V.; Baker, J.T.; et al. Effects of pulsed electromagnetic elds on bone healing in a rabbit tibial osteotomy model. J Orthop Trauma 14:93100, 2000.
655
92. Friedenberg, Z.B.; Andrews, E.T.; Smolenski, B.I.; et al. Bone reaction to varying amounts of direct current. Surg Gynecol Obstet 131:894899, 1970. 93. Friedenberg, Z.B.; Brighton, C.T. Bioelectric potentials in bone. J Bone Joint Surg Am 48:915923, 1966. 94. Friedenstein, A.J.; Chailakhyan, R.K.; Gerasimov, U.V. Bone marrow osteogenic stem cells in vitro cultivation and transplantation in diffusion chambers. Cell Tissue Kinet 20:263272, 1987. 95. Friedlaender, G. Treatment of established tibial non-unions using recombinant osteogenic protein-1 (OP-1). Abstract. Second International OP-1 Conference, Boston, MA, 1997. 96. Friedlaender, G.E. Bone grafts: The basic science rationale for clinical applications. J Bone Joint Surg Am 69:786790, 1987. 97. Friedlaender, G.E. Immune responses to osteochondral allografts: Current knowledge and future directions. Clin Orthop 174:5868, 1983. 98. Friedlaender, G.E.; Goldberg, V.M., eds. Bone and Cartilage Allografts: Biology and Clinical Applications. Park Ridge, IL, American Academy of Orthopaedic Surgeons, 1991. 99. Frolik, C.A.; Ellis, L.F Williams, D.C. Isolation and characteriza.; tion of insulin-like growth factor II from human bone. Biochem Biophys Res Comm 151:10111018, 1988. 100. Fukada, E.; Yasuda, I. On the piezoelectric effect of bone. J Physiol Soc Jpn 12:121128, 1957. 101. Gabl, M.; Reinhart, C.; Lutz, M.; et al. Vascularized bone graft from the iliac crest for the treatment of non-union of the proximal part of the scaphoid with an avascular fragment. J Bone Joint Surg Am 81:14141428, 1999. 102. Garg, N.K.; Gaur, S.; Sharma, S. Percutaneous autogenous bone marrow grafting in 20 cases of ununited fracture. Acta Orthop Scand 64:671672, 1993. 103. Garland, D.E.; Toder, L. Fractures of the tibial diaphysis in adults with head injuries. Clin Orthop 150:198202, 1980. 104. Gazdag, A.R.; Lane, J.M.; Glaser, D.; Forster, R.A. Alternatives to autogenous bone graft: Efcacy and indications. J Am Acad Orthop Surg 3:18, 1995. 105. Geesink, R.G.T.; Hoefnagels, N.H.M.; Bulstra, S.K. Osteogenic activity of OP-1 bone morphogenetic protein (BMP-7) in a human bular defect. J Bone Joint Surg Br 81:710718, 1999. 106. Gerhart, T.N.; Kirker-Head, C.A.; Kriz, M.J. Healing segmental femoral defects in sheep using recombinant human bone morphogenetic protein. Clin Orthop 293:317326, 1993. 107. Glowacki, J.; Kaban, L.B.; Murray, J.E.; et al. Application of the biological principle of induced osteogenesis for craniofacial defects. Lancet 1:959963, 1981. 108. Goodman, S.B.; Bauer, T.W.; Carter, D.; et al. Norian SRS cement augmentation in hip fracture treatment. Laboratory and initial clinical results. Clin Orthop 348:4250, 1998. 109. Goodship, A.E.; Kenwright, J. The inuence of induced micromovement upon the healing of experimental fractures. J Bone Joint Surg Br 67:650655, 1985. 110. Goodwin, C.B.; Brighton, C.T.; Guyer, R.D.; et al. A double-blind study of capacitively coupled electrical stimulation as an adjunct to lumbar spinal fusions. Spine 24:13491356, 1999. 111. Goshima, J.; Goldberg, V.M.; Caplan, A.I. The origin of bone formed in composite grafts of porous calcium phosphate ceramic loaded with marrow cells. Clin Orthop 269:274283, 1991. 112. Graves, D.T.; Antoniades, H.N.; Williams, S.R.; et al. Evidence for functional platelet-derived growth factor receptors on MG-63 human osteosarcoma cells. Cancer Res 44:29662970, 1984. 113. Gray, M.L.; Pizzanelli, A.M.; Grodzinsky, A.J.; et al. Mechanical and physicochemical determinants of the chondrocyte biosynthetic response. J Orthop Res 6:777792, 1988. 114. Grodzinsky, A.J. Electromechanical and physicochemical properties of connective tissue. Crit Rev Biomed Eng 9:133199, 1983. 115. Grodzinsky, A.J.; Lipshitz, H.; Glimcher, M.J. Electromechanical properties of articular cartilage during compression and stress relaxation. Nature 275:448450, 1978. 116. Guilak, F Compression-induced changes in the shape and vol. ume of the chondrocyte nucleus. J Biomech 28:15291541, 1995. 117. Hartshorne, E. On the cause of pseudoarthrosis and especially that form of it sometimes called supernumerary joint. Am J Med 1:121156, 1841.
656
SECTION I General Principles 142. Kenwright, J.; Richardson, J.B.; Cunningham, J.L.; et al. Axial movement and tibial fractures. J Bone Joint Surg Br 73:654659, 1991. 143. Kenwright, J.; Richardson, J.B.; Goodship, A.E.; et al. Effect of controlled axial microenvironment on healing of tibial fractures. Lancet 2:11851187, 1986. 144. Kershaw, C.J.; Cunningham, J.L.; Kenwright, J. Tibial external xation, weight bearing, and fracture movement. Clin Orthop 293:2836, 1993. 145. Kim, Y.J.; Grodzinsky, A.J.; Plaas, A.H. Compression of cartilage results in differential effects on biosynthetic pathways for aggrecan, link protein and hyaluronan. Arch Biochem Biophys 328:331340, 1996. 146. Kingsley, D.M. The transforming growth factor beta superfamily: New members, new receptors, and new genetic tests of function in different organisms. Genes Dev 8:133146, 1994. 147. Kirchen, M.E.; OConnor, K.M.; Gruber, H.E.; et al. Effects of microgravity on bone healing in a rat bular osteotomy model. Clin Orthop 318:231242, 1995. 148. Kirker-Head, C.A.; Gerhart, T.N.; Armstrong, R.; et al. Healing bone using recombinant human bone morphogenetic protein 2 and copolymer. Clin Orthop 349:205217, 1998. 149. Kirker-Head, C.A.; Gerhart, T.N.; Schelling, S.H.; et al. Long term healing of bone using recombinant human bone morphogenetic protein 2. Clin Orthop 318:222230, 1995. 150. Kopylov, P.; Runnqvist, K.; Jonsson, K.; Aspenberg, P. Norian SRS versus external xation in redisplaced distal radial fractures. A randomized study in 40 patients. Acta Orthop Scand 70:15, 1999. 151. Koskinen, E.V.S.; Lindholm, R.V.; Nieminen, R.A.; et al. Human growth hormone in delayed union and non-union of fracture. Int Orthop 1:317322, 1978. 152. Kristiansen, T.K.; Ryaby, J.P.; McCabe, J; et al. Accelerated healing of distal radial fractures with the use of specic, low-intensity ultrasound. A multicenter, prospective, randomized, double-blind placebo-controlled study. J Bone Joint Surg Am 79:961973, 1997. 153. Kurioka, K.; Umeda, M.; Teranobu, O.; Komori, T. Effect of various properties of hydroxyapatite ceramics on osteoconduction and stability. Kobe J Med Sci 45:149163, 1999. 154. Kurz, L.T.; Garn, S.R.; Booth, R.E. Harvesting autogenous iliac bone grafts: A review of complications and techniques. Spine 14:13241331, 1989. 155. Kushwaha, V.P.; Garland, D.G. Extremity fractures in the patient with a traumatic brain injury. J Am Acad Orthop Surg 6:298307, 1998. 156. Kwiatkowski, T.C.; Hanley, E.N.; Ramp, W.K. Cigarette smoking and its orthopaedic consequences. Am J Orthop 9:590595, 1996. 157. Ladd, A.L.; Pliam, N.B. Use of bone-graft substitutes in distal radius fractures. J Am Acad Orthop Surg 7:279290, 1999. 158. Lai-Toh, C.; Jupiter, J.B. The infected non-union of the tibia. Clin Orthop 315:176191, 1995. 159. Law, H.T.; Annan, I.; McCarthy, I.D.; et al. The effect of induced electric currents on bone after experimental osteotomy in sheep. J Bone Joint Surg Br 67:463469, 1985. 160. Lee, F Hazan, E.J.; Gebhardt, M.C.; Mankin, H.J. Experimental .Y.; model for allograft incorporation and allograft fracture repair. J Orthop Res 18:303306, 2000. 161. Lein, P.; Johnson, M.; Guo, X.; et al. Osteogenic protein-1 induces dendritic growth in rat sympathetic neurons. Neuron 15:597605, 1995. 162. Lente, R.W. Cases of ununited fracture treated by electricity. N Y State J Med 5:317319, 1850. 163. Lind, M.; Schumacker, B.; Soballe, K.; et al. Transforming growth factor- enhances fracture healing in rabbit tibiae. Acta Orthop Scand 64:553556, 1993. 164. Lotke, P.A.; Black, J.; Richardson S. Electromechanical properties in human articular cartilage. J Bone Joint Surg Am 56:10401048, 1974. 165. Macey, L.R.; Kana, S.M.; Jingushi, S.; et al. Defects of early fracture healing in experimental diabetes. J Bone Joint Surg Am 71:722 733, 1989. 166. Mankin, H.J.; Gebhardt, M.C.; Jennings, L.C.; et al. Long-term results of allograft replacement in the management of bone tumors. Clin Orthop 324:8697, 1996.
118. Hauschka, P.V.; Mavrakos, A.E.; Iafrati, M.D.; et al. Growth factors in bone matrix: Isolation of multiple types of afnity chromatography on heparin-sepharose. J Biol Chem 261:1266512674, 1986. 119. Hayashi, K.; Ishidou, Y.; Yonemori, K.; et al. Expression and localization of bone morphogenetic proteins (BMPs) and BMP receptors in ossication of the ligamentum avum. Bone 21:2330, 1997. 120. Heckman, J.D.; Aufdemorte, T.B.; Athanasiou, K.A.; et al. Treatment of acute ostectomy defects in the dog radius with rhTGF-1. Trans Orthop Res Soc 20:590, 1995. 121. Heckman, J.D.; Boyan, B.D.; Aufdemorte, T.B.; et al. The use of bone morphogenetic protein in the treatment of non-union in a canine model. J Bone Joint Surg Am 73:750764, 1991. 122. Heckman, J.D.; Ehler, W.; Brooks, B.P.; et al. Bone morphogenetic protein but not transforming growth factor- enhances bone formation in canine diaphyseal non-unions implanted with a biodegradable composite polymer. J Bone Joint Surg Am 81:1717 1729, 1999. 123. Heckman, J.D.; Ryaby, J.P.; McCabe, J.; et al. Acceleration of tibial fracture-healing by noninvasive low-intensity pulsed ultrasound. J Bone Joint Surg Am 76:2634, 1994. 124. Heiple, K.G.; Chase, S.W.; Herndon, C.H. A comparative study of the healing process following different types of bone transplantation. J Bone Joint Surg Am 45:15931616, 1963. 125. Heldin, C.H.; Ostman, A.; Ronnstrand, L. Signal transduction via platelet-derived growth factor receptors. Biochim Biophys Acta 1378:F79F113, 1998. 126. High, W. Effects of orally administered prostaglandin E1 on cortical bone turnover in adult dogs: A histomorphometric study. Bone 8:363374, 1987. 127. Hogan, B.L.M. Bone morphogenetic proteins: Multifunctional regulators of vertebrate development. Genes Dev 10:15801594, 1996. 128. Ilizarov, G.A. The tension-stress effect on the genesis and growth of tissues: Part I. Clin Orthop 238:249281, 1989. 129. Ingber, D.E. Tensegrity: The architectural basis of cellular mechanotransduction. Annu Rev Physiol 59:575599, 1997. 130. Ingram, R.T.; Bonde, S.K.; Riggs, B.L.; et al. Effects of transforming growth factor beta (TGF-) and 1,25 dihydroxyvitamin D3 on the function, cytochemistry, and morphology of normal human osteoblast-like cells. Differentiation 55:153163, 1994. 131. Ishidou, Y.; Kitajima, I.; Obama, H.; et al. Enhanced expression of type I receptors for bone morphogenetic proteins during bone formation. J Bone Miner Res 10:16511659, 1995. 132. Jensen, S.S.; Aaboe, M.; Pinholt, E.M.; et al. Tissue reaction and material characteristics of four bone substitutes. Int J Oral Maxillofac Implants 11:5556, 1996. 133. Jingushi, S.; Heydemann, A.; Kana, S.K.; et al. Acidic broblast growth factor (aFGF) injection stimulates cartilage enlargement and inhibits cartilage gene expression in rat fracture healing. J Orthop Res 8:364371, 1990. 134. Joyce, M.E.; Jingushi, S.; Bolander, M.E. Transforming growth factor-beta in the regulation of fracture repair. Orthop Clin North Am 21:199209, 1990. 135. Joyce, M.E.; Nemeth, G.G.; Jingushi, S.; et al. Expression and localization of transforming growth factor- in a model of fracture healing. Proceedings of the 35th Annual Meeting of the Orthopedic Research Society. Orthop Trans 13:460, 1989. 136. Jupiter, J.B.; Winters, S.; Sigman, S.; et al. Repair of ve distal radius fractures with an investigational cancellous bone cement: A preliminary report. J Orthop Trauma 11:110116, 1997. 137. Kaban, L.B.; Mulliken, J.B.; Glowacki, J. Treatment of jaw defects with demineralized bone implants. J Oral Maxillofac Surg 40:623 626, 1982. 138. Kawata, A.; Mikuni-Takagaki, Y. Mechanotransduction in stretched osteocytes: Temporal expression of immediate early and other genes. Biochem Biophys Res Commun 246:404408, 1998. 139. Ke, H.Z.; Li, M.; Jee, W.S. Prostaglandin E2 prevents ovariectomyinduced cancellous bone loss in rats. Bone Miner 19:4562, 1992. 140. Ke, H.Z.; Li, X.J.; Jee, W.S. Partial loss of anabolic effect of prostaglandin E2 on bone after its withdrawal in rats. Bone 12:173183, 1991. 141. Kenwright, J; Goodship, A.R. Controlled mechanical stimulation in the treatment of tibial fractures. Clin Orthop 241:3647, 1989.
CHAPTER 22 Enhancement of Skeletal Repair 167. Marden, L.J.; Fan, R.S.P.; Pierce, G.F et al. Platelet derived growth .; factor inhibits bone regeneration induced by osteogenin, a bone morphogenetic protein, in rat craniotomy defects. J Clin Invest 92:28972905, 1993. 168. Marks, S.C., Jr.; Miller, S.C. Effects of prostaglandins on the skeleton. In: Hollinger, J.; Seyfer, A.E., eds. Portland Bone Symposium 1993. Portland, Oregon Health Sciences University, 1993, pp. 3960. 169. Marsh, J.L.; Buckwalter, J.A.; Evarts, C.M. Non-union, delayed union, malunion and avascular necrosis. In: Epps, C.H., ed. Complications in Orthopaedic Surgery. Philadelphia, J.B. Lippincott, 1994, pp. 183211. 170. Marsh, J.L.; Prokuski, L.; Biermann, J.S. Chronic infected tibial non-unions with bone loss: Conventional techniques versus bone transport. Clin Orthop 301:139146, 1994. 171. Massague, J. TGF-B signaling: Receptors, transducers, and mad proteins. Cell 85:947950, 1996. 172. Matyas, J.R.; Anton, M.G.; Shrive, N.G.; Frank, C.B. Stress governs tissue phenotype at the femoral insertion of the rabbit MCL. J Biomech 28:147157, 1995. 173. Mayr, E.; Frankel, V.; Ruter, A. UltrasoundAn alternative healing method for non-unions. Arch Orthop Trauma Surg 120:18, 2000. 174. Mazue, G.; Bertolero, F Garofano, L.; et al. Experience with the .; preclinical assessment of basic broblast growth factor (bFGF). Toxicol Lett 64:329338, 1992. 175. McKibbin, B. The biology of fracture healing in long bones. J Bone Joint Surg Br 60:150162, 1978. 176. McLeod, K.J.; Rubin, C.T. The effect of low-frequency electrical elds on osteogenesis. J Bone Joint Surg Am 74:920929, 1992. 177. Meadows, T.H.; Bronk, J.T.; Chao, E.Y.S.; Kelly, P.J. Effect of weight bearing on healing of cortical defects in the canine tibia. J Bone Joint Surg Am 72:10741080, 1990. 178. Meiser, K.; Segal, D.; Whitelaw, G.P. The role of bone grafting in the treatment of delayed unions and non-unions of the tibia. Orthop Rev 19:260271, 1990. 179. Mooney, V.; Nickel, V.L.; Harvey, J.P., Jr.; et al. Cast-brace treatment for fractures of the distal part of the femur: A prospective controlled study of one hundred and fty patients. J Bone Joint Surg Am 52:15631578, 1970. 180. Moore, T.M.; Patzakis, M.J.; Harvey, J.P. Tibial plateau fractures: Denition, demographics, treatment rationale, and long-term results of closed traction management of operative reduction. J Orthop Trauma 1:97119, 1987. 181. Mulliken, J.B.; Glowacki, J.; Kaban, L.B.; et al. Use of demineralized allogeneic bone implants for the correction of maxillocraniofacial deformities. Ann Surg 194:366372, 1981. 182. Muschler, G.F Lane, J.M. Orthopaedic surgery. In: Habal, M.B.; .; Reddi, A.H., eds. Bone Grafts and Bone Substitutes. Philadelphia, W.B. Saunders, 1992, pp. 375407. 183. Mustoe, T.A.; Glenn, F Thomason, A.; et al. Accelerated healing .P.; of incisional wounds in rats induced by transforming growth factor. Science 237:13331336, 1987. 184. Nagai, M.; Ota, M. Pulsating electromagnetic eld stimulates mRNA expression of bone morphogenetic protein-2 and-4. J Dent Res 73:16011605, 1994. 185. Nakamura, T.; Hara, Y.; Tagawa, M.; et al. Recombinant human broblast growth factor accelerates fracture healing by enhancing callus remodeling in experimental dog tibial fracture. J Bone Miner Res 13:942949, 1988. 186. Nakase, T.; Nomura, S.; Yoshikawa, H.; et al. Transient and localized expression of bone morphogenetic protein 4 messenger RNA during fracture healing. J Bone Miner Res 9:651659, 1994. 187. Nash, T.J.; Howlett, C.R.; Steele, J.; et al. Effect of platelet-derived growth factor on tibial osteotomies in rabbits. Bone 15:203208, 1994. 188. Neufeld, G.; Gospodarowicz, D. Basic and acidic broblast growth factors interact with the same cell surface receptors. J Biol Chem 261:56315637, 1986. 189. Nicoll, E.A. Fractures of the tibial shaft: A survey of 705 cases. J Bone Joint Surg Br 46:373387, 1964. 190. Nielson, H.M.; Andreassen, T.T.; Ledet, T.; Oxlund, H. Local injection of TGF-beta increases the strength of tibial fractures in the rat. Acta Orthop Scand 65:3741, 1994.
657
191. Norrdin, R.W.; Shih, M. Systemic effects of prostaglandin E2 on vertebral trabecular remodeling in beagles used in a healing study. Calcif Tissue Int 42:363368, 1988. 192. Northmore-Ball, M.D.; Wood, M.R.; Meggitt, B.E. A biomechanical study of the effects of growth hormone in experimental fracture healing. J Bone Joint Surg Br 62:391396, 1980. 193. Ogawa, Y.; Schmidt, D.K.; Dasch, J.R.; et al. Purication and characterization of transforming growth factor-2.3 and 1.2 heterodimers from bovine bone. J Biol Chem 267:23252328, 1992. 194. Onishi, T.; Ishidou, T.; Nagamine, K.; et al. Distinct and overlapping patterns of localization of bone morphogenetic protein (BMP) family members and a BMP type II receptor during fracture healing in rats. Bone 22:605612, 1998. 195. Oonishi, H.; Kushitani, S.; Yasukawa, E.; et al. Particulate bioglass compared with hydroxyapatite as a bone graft substitute. Clin Orthop 334:316325, 1997. 196. Oreffo, R.O.; Mundy, G.R.; Seyedin, S.M.; Bonewald, L.F Activation . of the latent bone derived TGF beta complex by isolated osteoclasts. Biochem Biophys Res Commun 158:817823, 1989. 197. OSullivan, M.E.; Chao, E.Y.S.; Kelly, P.J. Current concepts review: The effects of xation on fracture healing. J Bone Joint Surg Am 71:306310, 1989. 198. Owan, I.; Burr, D.B.; Turner, C.H.; et al. Mechanotransduction in bone: Osteoblasts are more responsive to uid forces than mechanical strain. Am J Physiol 273:C810C815, 1997. 199. Owen, M. Lineage of osteogenic cells and their relationship to the stromal system. In: Peck, W.A., ed. Bone and Mineral Research, 3rd ed. New York, Elsevier, 1985, pp. 125. 200. Parvizi, J.; Wu, C.C.; Lewallen, D.G.; et al. Low-intensity ultrasound stimulates proteoglycan synthesis in rat chondrocytes by increasing aggrecan gene expression. J Orthop Res 17:488494, 1999. 201. Patzakis, M.J.; Scilaris, T.A.; Chon, J.; et al. Results of bone grafting for infected tibial non-union. Clin Orthop Rel Res 315:192198, 1995. 202. Pelker, R.R; Friedlaender, G.E.; Markham, T.C.; et al. Effects of freezing and freeze drying on the biomechanical properties of rat bone. J Orthop Res 1:405411, 1984. 203. Perkins, R.; Skirving, A.P. Callus formation and the rate of healing of femoral fractures in patients with head injuries. J Bone Joint Surg Br 69:521524, 1987. 204. Perren, S.M. Physical and biological aspects of fracture healing with special reference to internal xation. Clin Orthop 138:138195, 1979. 205. Peterson, D.R.; Glancy, T.P.; Bacon-Clarke, R.; et al. A study of delivery timing and duration on the transforming growth factor beta 1 induced healing of critical-size long bone defects. Abstract. J Bone Miner Res 12:S304, 1997. 206. Pilla, A.A.; Mont, M.A.; Nasser, P.R.; et al. Noninvasive lowintensity pulsed ultrasound accelerates bone healing in the rabbit. J Orthop Trauma 4:246253, 1990. 207. Pirela-Cruz, M.A.; DeCoster, T.A. Vascularized bone grafts. Orthopaedics 17:407412, 1994. 208. Plenk, H.; Hollmann, K.; Wilfert, K.H. Experimental bridging of osseous defects in rats by the implantation of Kiel bone containing fresh autologous marrow. J Bone Joint Surg Br 54:735743, 1972. 209. Poplich, L.S.; Salfeld, S.L.; Rueger, D.C.; et al. Critical and noncritical size defects healing with osteogenic protein-1. Abstract. Trans Orthop Res Soc 22:600, 1997. 210. Praemer, A.; Furner, S.; Rice, D.P. Musculoskeletal injuries. In: Musculoskeletal Conditions in the United States. Park Ridge, IL, American Academy of Orthopaedic Surgeons, 1992, pp. 85124. 211. Radomsky, M.L.; Aufdemorte, T.B.; Swain, L.D.; et al. Novel formulation of broblast growth factor-2 in a hyaluronan gel accelerates fracture healing in nonhuman primates. J Orthop Res 17:607614, 1999. 212. Radomsky, M.L.; Thompson, A.Y.; Spiro, R.C.; et al. Potential role of broblast growth factor in enhancement of fracture healing. Clin Orthop 355S:283293, 1998. 213. Rajaram, S.; Baylink, D.J.; Mohan, S. Insulin-like growth factor binding proteins in serum and other biological uids: Regulation and functions. Endocr Rev 18:801831, 1997. 214. Raschke, M.J.; Bail, H.; Windhagen, H.J.; et al. Recombinant growth hormone accelerates bone regenerate consolidation in distraction osteogenesis. Bone 24:8188, 1999.
658
SECTION I General Principles protein-2 in a canine segmental defect model. Trans Orthop Res Soc 20:594, 1995. Scott, G.; King, J.B. A prospective, double-blind trial of electrical capacitive coupling in the treatment of non-union of long bones. J Bone Joint Surg Am 76:820826, 1994. Sebecic, B.; Gabelica, V.; Patrlj, L.; Sosa, T. Percutaneous autologous bone marrow grafting on the site of tibial delayed union. Croat Med J 40:429432, 1999. Shah, N.M.; Groves, A.K.; Anderson, D.J. Alternative neural crest cell fates are instructively promoted by TGFB superfamily member. Cell 85:331343, 1996. Shamos, M.H.; Lavine, L.S. Piezoelectricity as a fundamental property of biological tissues. Nature 212:267268, 1967. Shapiro, M.S.; Endrizzi, D.P.; Cannon, R.M.; Dick, H.M. Treatment of tibial defects and non-unions using ispilateral vascularized bular transposition. Clin Orthop 296:207212, 1993. Sharma, S.; Garg, N.K.; Veliath, A.J.; et al. Percutaneous bonemarrow grafting of osteotomies and bony defects in rabbits. Acta Orthop Scand 63:166169, 1992. Sharrard, W.J.W. A double-blind trial of pulsed electromagnetic elds for delayed union of tibial fractures. J Bone Joint Surg Br 72:347355, 1990. Silverstein, P. Smoking and wound healing. Am J Med 93(1A):22S 24S, 1992. Sim, F .H.; Frassica, F Use of allografts following resection of .J. tumors of the musculoskeletal system. Instr Course Lect 42:405 413, 1993. Smith, R. Head injury, fracture healing and callus. J Bone Joint Surg Br 69:518520, 1987. Smith, S.R.; Bronk, J.T.; Kelly, P.J. Effects of xation on fracture blood ow. Orthop Trans 11:294295, 1987. Solheim, E.; Pinholt, E.M.; Bang, O.G.; et al. Inhibition of heterotopic osteogenesis in rats by a new bio-erodable system for local delivery of indomethacin. J Bone Joint Surg 74:705712, 1992. Sone, K.; Tashiro, M.; Fujinaga, R.; et al. Long-term low-dose prostaglandin E1 administration. J Pediatr 97:866867, 1980. Spencer, R.F The effect of head injury on fracture healing: A . quantitative assessment. J Bone Joint Surg Br 69:525528, 1987. Sporn, M.B.; Roberts, A.B. Peptide growth factors are multifunctional. Nature 332:217219, 1988. Springeld, D.S. Autogenous bone grafts: Nonvascular and vascular. Orthopaedics 15:12371241, 1992. Stevenson, S.; Cunningham, N.; Toth, J.; et al. The effect of osteogenin (a bone morphogenetic protein) on the formation of bone in orthotopic segmental defects in rats. J Bone Joint Surg Am 76:827838, 1994. Stoffelen, D.; Lammens, J.; Fabry, G. Resection of a periosteal osteosarcoma and reconstruction using the Ilizarov technique of segmental transport. J Hand Surg [Br] 18:144146, 1993. Sudman, E.; Bang, G. Indomethacin-induced inhibition of haversian remodelling in rabbits. Acta Orthop Scand 50:621627, 1979. Talley-Ronsholdt, D.J.; Lajiness, E.; Nagodawithana, K. Transforming growth factor-beta inhibition of mineralization by neonatal rat osteoblasts in monolayer and collagen gel culture. In Vitro Cell Dev Biol Anim 31:274282, 1995. Tashjian, A.H.; Hohmann, E.L.; Antoniades, H.N.; et al. Plateletderived growth factor stimulates bone resorption via a prostaglandin mediated mechanism. Endocrinology 111:118124, 1982. Templeman, D.; Thomas, M.; Vasecka, T.; Kyle, R. Exchange reamed intramedullary nailing for delayed union and non-union of the tibia. Clin Orthop 315:5663, 1995. Thies, R.S.; Bauduy, M.; Ashton, B.A.; et al. Recombinant human morphogenetic protein-2 induces osteoblastic differentiation in W-2017 stromal cells. Endocrinology 130:13181324, 1992. Toma, C.D.; Ashkar, S.; Gray, M.L.; et al. Signal transduction of mechanical stimuli is dependent on microlament integrity: Identication of osteopontin as a mechanically induced gene in osteoblasts. J Bone Miner Res 12:16261636, 1997. Trippel, S.B. Growth factors as therapeutic agents. Instr Course Lect 46:473476, 1997. Turek, T.; Bostrom, M.P.G.; Camacho, N.P.; et al. The acceleration of fracture healing in a rabbit ulnar osteotomy model with bone morphogenetic protein 2. Abstract. Trans Orthop Res Soc 22:526, 1997.
215. Reddi, A.H. Extracellular matrix and development. In: Piez, K.A.; Reddi, A.H., eds. Extracellular Matrix Biochemistry. New York, Elsevier, 1984, pp. 375412. 216. Reher, P.; Doan, N.; Bradnock, B.; et al. Effect of ultrasound on the production of IL-8, basic FGF and VEGF Cytokine 11:416423, . 1999. 217. Riedel, G.E.; Valentin-Opran, A. Clinical evaluation of rhBMP-2/ ACS in orthopedic trauma: A progress report. Orthopedics 22:663665, 1999. 218. Riggins, R.S.; Simanonok, C.; Lewis, D.W.; Smith, A.H. Weight bearing: Its lack of effect on fracture healing. Int Orthop 9:199203, 1985. 219. Ro, J.; Sudman, E.; Marton, P.F Effect of indomethacin on fracture . healing in rats. Acta Orthop Scand 47:588599, 1976. 220. Roberts, A.B.; Anzano, M.A.; Lamb, L.C.; et al. New class of transforming growth factors potentiated by epidermal growth factor: Isolation from non-neoplastic tissues. Proc Natl Acad Sci U S A 78:53395343, 1981. 221. Robey, P.G.; Young, M.F Flanders, K.C.; et al. Osteoblasts .; synthesize and respond to transforming growth factor- in vitro. J Cell Biol 105:457463, 1987. 222. Robinson, D.; Alk, D.; Sandbank, J.; et al. Inammatory reactions associated with a calcium sulfate bone substitute. Ann Transplant 4:9197, 1999. 223. Rosen, D.M.; Stempien, S.A.; Thompson, A.Y.; et al. Transforming growth factor- modulates the expression of osteoblasts and chondrocyte phenotypes in vitro. J Cell Physiol 134:337346, 1988. 224. Rosier, R.N.; OKeefe, R.J.; Hicks, D.G. The potential role of transforming growth factor beta in fracture healing. Clin Orthop 355:S294S300, 1998. 225. Ross, R.; Raines, E.W.; Boewn-Pope, D. The biology of platelet derived growth factor. Cell 46:155169, 1986. 226. Rothman, R.H.; Klemek, J.S.; Toton, J.J. The effect of iron deciency anemia on fracture healing. Clin Orthop 77:276283, 1971. 227. Rubin, C.; Gross, T.; Qin, Y.X.; et al. Differentiation of the bone-tissue remodeling response to axial and torsional loading in the turkey ulna. J Bone Joint Surg Am 78:15231533, 1996. 228. Sakou, T. Bone morphogenetic proteins: From basic studies to clinical approaches. Bone 22:591603, 1998. 229. Salama, R.; Burwell, R.G.; Dickson, I.R. Recombined grafts of bone and marrow: The benecial effect upon osteogenesis of impregnating xenograft (heterograft) bone with autologous red marrow. J Bone Joint Surg Br 55:402417, 1973. 230. Salama, R.; Weissman, S.L. The clinical use of combined xenografts of bone and autologous red marrow: A preliminary report. J Bone Joint Surg Br 60:111115, 1978. 231. Sanchez-Sotelo, J.; Munuera, L.; Madero, R. Treatment of fractures of the distal radius with a remodellable bone cement: A prospective, randomized study using Norian SRS. J Bone Joint Surg Br 82:856863, 2000. 232. Sandberg, M.M.; Aro, H.T.; Vuorio, E.I. Gene expression during bone repair. Clin Orthop 289:292312, 1993. 233. Sarker, A.B.; Nashimuddin, A.N.; Islam, K.M.; et al. Effect of PEMF on fresh fracture-healing in rat tibia. Bangladesh Med Res Counc Bull 19:103112, 1993. 234. Sarmiento, A. A functional below-the-knee cast for tibial fractures. J Bone Joint Surg Am 49:855875, 1967. 235. Sarmineto, A. On the behavior of closed tibial fractures: Clinical/ radiological correlations. J Orthop Trauma 14:199205, 2000. 236. Sarmiento, A.; Schaeffer, J.F Beckerman, L.; et al. Fracture healing .; in rat femora as affected by functional weightbearing. J Bone Joint Surg Am 59:369375, 1977. 237. Sarmiento, A.; Sharpe, F .E.; Ebramzadeh, E.; et al. Factors inuencing outcome of closed tibial fractures treated with functional bracing. Clin Orthop 315:824, 1995. 238. Sartoris, D.J.; Gershuni, D.H.; Akeson, W.H.; et al. Coralline hydroxyapatite bone graft substitutes: Preliminary report of radiographic evaluation. Radiology 159:133137, 1986. 239. Schildhauer, T.A.; Bauer, T.W.; Josten, C.; Muhr, G. Open reduction and augmentation of internal xation with an injectable skeletal cement for the treatment of complex calcaneal fractures. J Orthop Trauma 14:309317, 2000. 240. Sciadini, M.F Dawson, J.M.; Berman, L.M.; et al. Dose-response .; characteristics of recombinant human bone morphogenetic
241. 242. 243. 244. 245. 246. 247. 248. 249. 250. 251. 252.
253. 254. 255. 256. 257.
258. 259. 260.
261. 262. 263. 264.
265. 266.
CHAPTER 22 Enhancement of Skeletal Repair 267. Ueda, K.; Saito, A.; Nakano, H.; et al. Cortical hyperostosis following long-term administration of prostaglandin E1 in infants with cyanotic congenital heart disease. J Pediatr 97:834836, 1980. 268. Uhthoff, H.K.; Rahn, B.A. Healing patterns of metaphyseal fractures. Clin Orthop 160:295303, 1981. 269. Upton, J.; Boyajian, M.; Mulliken, J.B.; Glowacki, J. The use of demineralized xenogeneic bone implants to correct phalangeal defects: A case report. J Hand Surg [Am] 9:388391, 1984. 270. Urist, M.R. Bone: Formation by autoinduction. Science 150:893 899, 1965. 271. Urist, M.R. Bone transplants and implants. In: Urist, M.R., ed. Fundamental and Clinical Bone Physiology. Philadelphia, J.B. Lippincott, 1980, pp. 331368. 272. Urist, M.R.; Strates, B.S. Bone morphogenetic protein. J Dent Res 50:13921406, 1971. 273. Vaes, G. Cellular biology and biochemical mechanism of bone resorption: A review of recent developments on the formation, activation, and mode of action of osteoclasts. Clin Orthop 231:239271, 1988. 274. Walsh, W.R.; Sherman, P.; Howlett, C.R.; et al. Fracture healing in the rat osteopenia model. Clin Orthop 342:218227, 1997. 275. Wang, S.J.; LeWallen, D.G.; Bolander, M.E.; et al. Low intensity ultrasound treatment increases strength in a rat femoral fracture model. J Orthop Res 12:4047, 1994. 276. Weiland, A.J. Current concepts review: Vascularized free bone transplant. J Bone Joint Surg Am 63:166169, 1981. 277. Wergedal, J.E.; Matsuyama, T.; Strong, D.D. Differentiation of normal human bone cells by transforming growth factor-beta and 1,25 (OH)2 vitamin D3. Metabolism 41:4248, 1992. 278. Wiss, D.A.; Stetson, W.B. Unstable fractures of the tibia treated with reamed intramedullary interlocking nail. Clin Orthop 315:5663, 1995. 279. Wolfe, S.W.; Pike, L.; Slade, J.F Katz, L.D. Augmentation of distal .; radius fracture xation with coralline hydroxyapatite bone graft substitute. J Hand Surg [Am] 24:816827, 1999. 280. Wolff, J. Das Gaesetz der Transformation der Knochen. Berlin, A. Hirchwald, 1892. 281. Wozney, J.M.; Rosen, V.; Celeste, A.J.; et al. Novel regulators of bone formation: Molecular clones and activities. Science 242:1528 1534, 1988.
659
282. Xavier, C.A.M.; Duarte, L.R. Treatment of non-unions by ultrasound stimulation: First clinical applications. Presented at the meeting of the Latin-American Orthopaedic Association and at the annual meeting of the American Academy of Orthopaedic Surgeons, San Francisco, CA, January 25, 1987. 283. Xie, M.H.; Holcomb, I.; Deuel, B.; et al. FGF-19, a novel broblast growth factor with unique specicity for FGFR4. Cytokine 11:729735, 1999. 284. Yamaguchi, A.; Katagiri, T.; Ikeda, T.; et al. Recombinant human bone morphogenetic protein-2 stimulates osteoblastic maturation and inhibits myogenic differentiation in vitro. J Cell Biol 113:681 687, 1991. 285. Yang, K.H.; Parvizi, J.; Wang, S.J.; Lewallen, D.G.; et al. Exposure to low-intensity ultrasound increases aggrecan gene expression in a rat femur fracture model. J Orthop Res 14:802809, 1996. 286. Yasko, A.W.; Lane, J.M.; Fellinger, E.J.; et al. The healing of segmental bone defects induced by recombinant human morphogenetic protein (rhBMP-2). A radiographic, histological and biomechanical study in rats. J Bone Joint Surg Am 74:659670, 1992. 287. Yasuda, I. [Fundamental aspects of fracture treatment]. J Kyoto Med Soc 4:395406, 1953. 288. Yetkinler, D.N.; Ladd, A.L.; Poser, R.D.; et al. Biomechanical evaluation of xation of intra-articular fractures of the distal part of the radius in cadavers: Kirschner wires compared with calciumphosphate bone cement. J Bone Joint Surg Am 81:391399, 1999. 289. Yonemori, K.; Imamura, T.; Ishidou, Y.; et al. Bone morphogenetic protein receptors and activin receptors are highly expressed in ossied ligament tissues of patients with ossication of the posterior longitudinal ligament. Am J Pathol 150:13351347, 1997. 290. Younger, E.M.; Chapman, M.W. Morbidity at bone graft donor sites. J Orthop Trauma 3:192195, 1989. 291. Zaidemberg, C.; Siebert, J.W.; Angrigiani, C. A new vascularized bone graft for scaphoid non-union. J Hand Surg [Am] 16:474478, 1991. 292. Zegzula, H.D.; Buck D.C.; Brekke J.; et al. Bone formation with use of rhBMP-2 (recombinant human bone morphogenetic protein-2). J Bone Joint Surg Am 79:17781790, 1997. 293. Zhuang, H.; Wang, W.; Seldes, R.M.; et al. Electrical stimulation induces the level of TGF-B1 mRNA in osteoblastic cells by a mechanism involving calcium/calmodulin pathway. Biochem Biophys Res Comm 237:225229, 1997.

CH 22

Uploaded by

Document Information

Original Description:

Original Title

Copyright

Available Formats

Share this document

Share or Embed Document

Sharing Options

Did you find this document useful?

Is this content inappropriate?

Copyright:

Available Formats

CH 22

Uploaded by

Copyright:

Available Formats

C H A P T E R zzzzzzzzzzzzzzzzzzzzzzzzzzz

PHYSICAL METHODS OF ENHANCEMENT

Copyright 2003 Elsevier Science (USA). All rights reserved.

SECTION I General Principles

Copyright 2003 Elsevier Science (USA). All rights reserved.

CHAPTER 22 Enhancement of Skeletal Repair

Copyright 2003 Elsevier Science (USA). All rights reserved.

SECTION I General Principles

Copyright 2003 Elsevier Science (USA). All rights reserved.

CHAPTER 22 Enhancement of Skeletal Repair

BIOLOGIC METHODS OF ENHANCEMENT

Peptide Signaling Molecules Involved in Skeletal Growth and Repair

Copyright 2003 Elsevier Science (USA). All rights reserved.

SECTION I General Principles

Properties of Autologous Bone Grafts

Copyright 2003 Elsevier Science (USA). All rights reserved.

CHAPTER 22 Enhancement of Skeletal Repair

Copyright 2003 Elsevier Science (USA). All rights reserved.

SECTION I General Principles

Copyright 2003 Elsevier Science (USA). All rights reserved.

CHAPTER 22 Enhancement of Skeletal Repair

Copyright 2003 Elsevier Science (USA). All rights reserved.

SECTION I General Principles

Copyright 2003 Elsevier Science (USA). All rights reserved.

CHAPTER 22 Enhancement of Skeletal Repair

Copyright 2003 Elsevier Science (USA). All rights reserved.

SECTION I General Principles

Copyright 2003 Elsevier Science (USA). All rights reserved.

CHAPTER 22 Enhancement of Skeletal Repair

Copyright 2003 Elsevier Science (USA). All rights reserved.

SECTION I General Principles

Management of Fresh Fractures: Recommendations and Future Possibilities

Osteoinductive factor Expanded bone marrow osteoprogenitor cells

Management of Delayed Unions: Recommendations and Future Possibilities

Management of Nonunions: Recommendations and Future Possibilities

Future Possibilities Osteoinductive factor Osteoinductive factor Nonoperative Operative

Osteoinductive factor Osteoinductive factor

Copyright 2003 Elsevier Science (USA). All rights reserved.

CHAPTER 22 Enhancement of Skeletal Repair TABLE 226

Osteoinductive implant Osteoinductive implant

Osteoinductive implant Osteoinductive implant Osteoinductive implant

EXPECTATIONS FOR THE FUTURE

Copyright 2003 Elsevier Science (USA). All rights reserved.

19. 20. 21.

33. 34. 35.

36. 37. 38. 39. 40. 41. 42. 43.

Copyright 2003 Elsevier Science (USA). All rights reserved.

Copyright 2003 Elsevier Science (USA). All rights reserved.

Copyright 2003 Elsevier Science (USA). All rights reserved.

Copyright 2003 Elsevier Science (USA). All rights reserved.

253. 254. 255. 256. 257.

258. 259. 260.

261. 262. 263. 264.

Copyright 2003 Elsevier Science (USA). All rights reserved.

Copyright 2003 Elsevier Science (USA). All rights reserved.

Copyright 2003 Elsevier Science (USA). All rights reserved.

You might also like