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The Journal of Bone and Joint Surgery (American). 2007;89:649-658. doi:10.2106/JBJS.F.00465 © 2007 The Journal of Bone and Joint Surgery, Inc.
Bone Grafts and Bone Graft Substitutes in Orthopaedic Trauma SurgeryA Critical Analysis
1 Department of Orthopaedic Surgery, Temple University, One Greentree Centre,
Suite 104, Marlton, NJ 08053. E-mail address:
william.delong{at}tuhs.temple.edu
Investigation performed at Temple University School of Medicine,
Marlton, New Jersey
 Osteoinduction is a
process that supports the mitogenesis of undifferentiated mesenchymal cells,
leading to the formation of osteoprogenitor cells that form new bone.
Orthopaedic trauma surgery requires the regular use of bone grafts to help provide timely healing of musculoskeletal injuries. The iliac crest autologous graft remains the gold standard. The morbidity associated with the harvest of bone graft has caused practitioners to seek methods of enhancing healing with bone graft substitutes. The term bone graft substitute describes a spectrum of products that have various effects on bone-healing. Unfortunately, there is little information in the literature about when and where to use these devices. In general, we categorize the properties of bone graft substitutes as osteoinductive, osteoconductive, or osteogenic. Going through the operating room storage areas in our institutions, we find many of these products available, with various trade names that can be misleading and confusing. The purpose of this review is to give the practicing surgeon a basic fund of knowledge on the topic of bone graft substitutes as well as an opinion on the levels of evidence in the current literature supporting the use of the various materials. The answers to the most difficult questions regarding bone graft substitutes require multicenter prospective randomized studies. These are extremely difficult to design and execute, with the cost being the most onerous obstacle. Industrial funding has been one of the ways to get this type of work completed. The full details of all of the requirements for making a project of this magnitude successful is beyond the scope of this project. The authors are all members of the Orthopaedic Trauma Association Orthobiologics Committee. Because of their expertise, they were charged by the President of the organization to provide this brief summary for use by the orthopaedic community. The opinions stated here are based on the literature, and the recommendations are based on the levels of evidence supporting claims from this body of information.
One of the unique aspects of the human skeleton is its ability to regenerate itself as part of a repair process. Skeletal repair involves a series of events that parallel embryological development. As all skeletal tissues evolve from mesenchyme, undifferentiated mesenchymal cells make a genetic commitment to a particular cellular lineage early in the developmental or repair process. In the case of repair, some stimulus must signal the undifferentiated mesenchymal cells to differentiate along a chondro-osteogenic pathway. This phenomenon, known as osteoinduction, is defined as "a process that supports the mitogenesis of undifferentiated mesenchymal cells leading to the formation of osteoprogenitor cells with the capacity to form new bone."1 Thus, any material that induces this process could be considered to be osteoinductive.
The concept of osteoinduction was introduced by Marshall R. Urist at the
time of his discovery of the so-called bone induction principle in the
1960s2. The initial
understanding was that bone matrix—demineralized bone matrix in
particular—contains some property that can induce new bone formation
when implanted into an extraskeletal site. Urist and his colleagues soon
identified a protein that they named bone morphogenetic protein
(BMP); this led to a program of investigation to identify and characterize an
entire family of osteoinductive
molecules3. By the
mid-1990s, it had become clear that this family included at least fifteen BMPs
and was part of the larger transforming growth factor-
In order to assess the quality of evidence supporting scientific knowledge regarding a therapeutic intervention, a hierarchical rating system was established to place a published report into proper context for the reader. Recently introduced into this journal, this rating system requires authors to classify their study as therapeutic, prognostic, diagnostic, or economic/decision analysis and to provide a level-of-evidence rating4. Studies with higher levels of evidence are more valuable to surgeons attempting to resolve clinical dilemmas. For example, a well-conducted, randomized controlled trial (Level I) provides excellent information to help a clinician evaluate a treatment, whereas a review article, while helpful, is essentially based on an expert's personal opinion (Level V). While the answer to a clinical question must be based on a composite assessment of all evidence of all types and no one study should be considered definitive, reports with higher levels of evidence are generally considered more appropriate for clinical decision-making. Level-of-evidence ratings for multiple studies addressing a clinical care recommendation can be summarized with use of a grades-of-recommendation table. This requires that authors not only rate the quality of the evidence reported but also provide the quality of a clinical care recommendation based on the evidence to support it.
Grades of Recommendation B. Fair evidence (Level-II or III studies with consistent findings) for or against recommending intervention. C. Poor-quality evidence (Level-IV or V studies with consistent findings) for or against recommending intervention. I. There is insufficient or conflicting evidence not allowing a recommendation for or against intervention.
To our knowledge, there have been no studies in which the investigators carefully evaluated the osteoinductive properties of allograft bone per se. However, there have been studies on demineralized bone matrix as a source of osteoinductive proteins and, while most of the structural aspects of an allograft are eliminated by an extensive demineralization process, demineralized bone matrix is, strictly speaking, allogeneic bone tissue. Since the true test of osteoinductivity is whether a material that has been implanted in a nonosseous site forms bone, the inability of allograft bone to do this in patients argues against its having substantial osteoinductive activity. Demineralized bone matrix has been shown to produce this effect in animal studies, but it too has never demonstrated this effect in patients. In addition, different demineralized bone matrix products have been found to vary with regard to their osteogenic response in animal models.
Demineralized bone matrix is produced by acid extraction of allograft. It
contains type-1 collagen, non-collagenous proteins, and osteoinductive growth
factors5. As noted
above, the TGF- There are numerous demineralized bone matrix formulations based on refinements of the manufacturing process. They are available as freeze-dried powder, granules, gel, putty, or strips. They have also been developed as combination products with other materials such as allogeneic bone chips and calcium sulfate granules. All have been shown to have osteoinductive effects in animals, but we are not aware of any Level-I studies of the use of demineralized bone matrix alone in humans. One prospective controlled study showed equivalent rates of spinal fusion between sides in patients who had been treated with autograft on one side and a 2:1-ratio composite of Grafton DBM (gel) and autograft on the other, suggesting a potential use of Grafton DBM as a bone-graft extender11. Only anecdotal information is available regarding similar applications in patients with long-bone fractures and nonunions. There is now evidence of differential potencies of demineralized bone matrix preparations based on the manufacturer and manufacturing process12. Because these materials were originally developed as reprocessed human tissues, clearance for marketing was achieved without the need for randomized controlled trials comparing their efficacy with that of autologous bone. However, as currently marketed formulations of these products include carrier substances such as glycerol, starch, and hyaluronic acid, the United States Food and Drug Administration (FDA) now plans to regulate demineralized bone matrix products as Class-II medical devices. Currently marketed demineralized bone matrix products will most likely be reclassified with use of the 510K pathway, which requires demonstration of substantial equivalence to a predicate device but still not does not require demonstration of efficacy comparable with that of autologous bone graft.
To our knowledge, the first reports on the use of BMP to treat clinical conditions came from the Department of Orthopaedic Surgery at the University of California at Los Angeles. Urist purified the protein in his laboratory, and Johnson and colleagues used the protein in clinical settings13. These uncontrolled retrospective series (Level-IV evidence) had encouraging results and stimulated further investigation in this area. Because extraction of purified human BMP from cadaver bone provided small yields, the ability to produce it in large quantities was limited. Therefore, companies turned to the use of recombinant gene technology to develop individual BMPs and to focus on those that have the greatest potential for bone induction in patients. Because the use of this technology is viewed by the FDA as being associated with risk, recombinant BMPs are classified as Class-III devices. At the present time, two recombinant BMPs, rhBMP-2 and rhBMP-7 (also known as osteogenic protein-1 [OP-1]) are available for clinical use. Each has been evaluated in randomized controlled trials involving trauma patients, and those studies provided data that qualify as Level-I evidence. In a large prospective, randomized, controlled, partially blinded, multicenter study, Friedlaender et al.14 assessed the efficacy of the OP-1 Device (3.5 mg of rhBMP-7 in a bovine bone-derived type-1 collagen-particle delivery vehicle; Stryker Biotech, Hopkinton, Massachusetts) in comparison with that of autografting in the treatment of 122 patients with a total of 124 tibial nonunions. All of the nonunions were at least nine months old and had shown no progress toward healing for the three months prior to the patient's enrollment in the study. All patients were treated with reamed intramedullary nailing of the nonunion and were then randomized to have either autograft bone or OP-1 implanted at the nonunion site. Despite randomization, there were more smokers in the OP-1 group. Nine months after the surgery, 81% of the sixty-three nonunions treated with OP-1 and 85% of the sixty-one treated with autograft had clinical evidence of union. Radiographic assessments suggested healing of 75% and 84% of these nonunions, respectively. As statistical analysis of these results showed equivalent efficacy between OP-1 and autograft, the authors concluded that OP-1 was a safe and effective alternative to bone graft in the treatment of tibial nonunions. A limitation of the study was that the investigators could not control for the potential healing effects produced by reamed intramedullary nailing of tibial nonunions. It is noteworthy that half of the nonunions treated in this study were of fractures that had failed to heal following reamed nailing as primary treatment. Another positive effect of the use of OP-1 was that there was a reduction in the rate of infections compared with that in the control group. More recently, the BMP-2 Evaluation in Surgery for Tibial Trauma (BESTT) Study Group reported the results of a large multinational, prospective, randomized, controlled study of the effects of INFUSE (rhBMP-2 on an absorbable type-1 collagen sponge; Medtronic Sofamor Danek, Memphis, Tennessee) in the treatment of open tibial fractures15. Four hundred and fifty patients with such an injury were initially managed with irrigation, débridement, and intramedullary nail fixation. At the time of definitive wound closure, the patients were randomized to one of three groups: standard closure, standard closure and the addition of 6 mg of rhBMP-2 to the fracture site, or standard closure and the addition of 12 mg of rhBMP-2 to the fracture site. The primary outcome measure in this study was the rate of secondary interventions (returns to the operating rooms for additional treatment). The group treated with the higher dose of rhBMP-2 (1.5 mg/kg) had fewer secondary interventions. Interestingly, although not used as primary outcome measures, an accelerated time to union, improved wound-healing, and a reduced infection rate were also found in the patients treated with the high dose of rhBMP-2. In a similar study, McKee et al.16 investigated the use of OP-1 in the treatment of open tibial fractures. The fracture was treated initially with irrigation, débridement, and locked intramedullary nailing and, at the time of definitive wound closure, the patient was randomized to be managed with either standard closure or standard closure and the addition of 3.4 mg of OP-1 to the fracture site. One hundred and twenty-two patients with a total of 124 tibial fractures were enrolled in the study. There was a significant decrease in the rate of secondary interventions for delayed unions and nonunions (the primary outcome measure) in the OP-1-treated group (p = 0.02). There was a corresponding improvement in patient function, with 80% of the OP-1 group having no or mild pain with activity at twelve months postinjury compared with 65% of the control group (p = 0.04).
Allograft Approximately one-third of the bone grafts used in North America are allografts17. Allograft bone is an attractive alternative to autogenous bone as it avoids donor site morbidity, is relatively abundant, and can be used off the shelf. Fresh allograft bone is less frequently used than processed allograft because of an inadequate time for disease screening. Disease transmission is the major risk and disadvantage of the use of allograft materials, and the risk is increased when fresh allografts are used. However, one must keep in mind that, although there is a risk of bacterial and viral infection transmission, there have been relatively few reported cases considering the large number of allograft procedures done each year. Frozen allografts are stored at temperatures below –60°C, which decreases enzyme degradation and host immune response. Freeze-drying involves removal of water from the tissue with subsequent vacuum packing and storage at room temperature. This destroys all osteogenic cells and leaves only limited osteoinductive capability. The host immune response is less robust than the response to fresh or fresh-frozen allograft. Allografts can be processed as a powder, cancellous or cortical chips, wedges, pegs, dowels, or struts. In addition, they can be machined into shapes, such as screws, for specific situations. Sterility is a major concern with the use of allografts, highlighting the need for aseptic tissue retrieval and adequate donor screening. However, even those safeguards do not eliminate the risk of infection. Therefore, serological testing must be performed. The FDA requires testing for HIV-1 (human immunodeficiency-1), HIV-2, and HCV (hepatitis-C virus) antibody. Many states also require testing for hepatitis-B core antibody. The AATB (American Association of Tissue Banks) requires additional testing for HTLV-I (human T-cell lymphotropic virus-I) and HTLV-II antibodies. Additional testing for HIV with use of polymerase chain reaction and for hepatitis with use of nucleic acid amplification as well as testing for cytomegalovirus and syphilis antibodies is frequently done. Grafts may be processed or terminally sterilized. Terminal sterilization involves the treatment of the tissue with a single modality at the completion of the harvest and processing to provide sterility. This is commonly done with techniques such as gamma irradiation or ethylene oxide sterilization. Ethylene oxide sterilization is more cost-efficient, but it may negatively affect the mechanical strength or biologic activity of the graft. Terminal sterilization with gamma radiation has been found to have greater effects on the mechanical properties of allografts, whereas ethylene oxide affects the osteoinductive properties. The risk of disease transmission with fresh allografts and the difficulty with storage and distribution of these grafts have led to the predominant use of fresh-frozen and freeze-dried allografts. These allografts are primarily osteoconductive, but they retain a variable number of osteoinductive proteins. The osteoinductive properties vary according to the type of allograft and the processing methods used to prepare, sterilize, and store the allograft material prior to implantation. Incorporation of allograft bone begins with passive osteoconduction. Bone formation is then further stimulated through osteoinduction. Incorporation of allograft bone differs according to the type of graft that is used. Cortical strut grafts are incorporated by creeping substitution through the process of intramembranous bone formation at the cortical junctions18,19. Cortical graft ends with an exposed medullary canal are incorporated by enchondral ossification. This process involves weakening of the initial structural strength of the cortical graft as it is resorbed. Strength is recovered as new bone formation occurs20. In contrast, cancellous allograft chips or powders are incorporated solely by enchondral bone formation along the osteoconductive framework of the graft, which strengthens the construct over time20. The use of allograft has become widespread. Potential applications in the trauma setting include reconstruction of skeletal defects, augmentation of fracture repair, and treatment of nonunion. The primary application of allografts in trauma surgery consists of use of cancellous or corticocancellous chips as an osteoconductive filler for metaphyseal defects such as occur with tibial plateau fractures. Assessment of their efficacy in this application is extremely difficult. Van Houwelingen and McKee reported on a case series of six humeral nonunions treated with a combination of compression plate fixation and cortical onlay allografts21. All six nonunions had united at a mean of 3.4 months. Hornicek et al. reported on a series of nine humeral nonunions treated in a similar fashion; union was achieved in all patients at an average of 2.9 months22. Haddad et al. reported on a retrospective case series of forty patients in whom a femoral fracture around a well-fixed prosthetic femoral stem was treated with cortical onlay strut allografts, with or without plate fixation and without revision of the femoral component23. Thirty-nine of the forty fractures united. Wang and Weng reported the results of a retrospective study of nine patients in whom a distal femoral shaft nonunion had been treated with internal fixation combined with cortical allograft strut grafts24. All fractures united at an average of five months. Herrera et al. reported the results of a retrospective study of unstable distal radial fractures treated with cancellous allograft augmentation of both internal and external fixation25. None of seventeen patients evaluated after treatment with this protocol had a poor result. The authors concluded that cancellous allograft was a useful adjunct for treatment of unstable distal radial fractures with metaphyseal comminution. There is Level-IV evidence supporting the use of cortical and cancellous allografts in reconstructive trauma surgery21,24,25. Additional research is needed to determine the ideal material for encouraging bone formation with these applications.
Calcium Phosphate Synthetic Substitutes
Calcium phosphate is available in a variety of forms and products, including ceramics, powders, and cements. Ceramics are highly crystalline structures created by heating nonmetallic mineral salts at temperatures greater than 1000°C, a process known as sintering. These phosphate materials have variable rates of osteointegration based on their crystalline size and stoichiometry. They have the advantage of incorporating at a slower rate than calcium sulfate materials. One of the commonly available resorbable ceramics is tricalcium phosphate. These ceramics can be obtained in block, granular, powder, or putty form. Coralline ceramics are formed by thermochemically treating coral with ammonium phosphate, leaving tricalcium phosphate with a structure and porosity that are similar to those of cancellous bone. Pore size and porosity are important characteristics of bone graft substitutes. No osseous ingrowth occurs with pore sizes of 15 to 40 µm. Osteoid formation requires minimum pore sizes of 100 µm, with pore sizes of 300 to 500 µm reported to be ideal for osseous ingrowth28. Some authors, however, have reported that pore size may be less critical than the presence of interconnecting pores for osseous ingrowth. Interconnecting pores prevent the formation of blind alleys, which are associated with low oxygen tension; low oxygen tension prevents osteoprogenitor cells from differentiating into osteoblasts29. Synthetic hydroxyapatite is a crystalline calcium phosphate osteoconductive bone substitute that is also manufactured as a ceramic through a sintering process. Animal studies have suggested that hydroxyapatite may have some osteoinductive properties in addition to its osteoconductive capabilities30,31. However, because of slow in vivo resorption and a high brittleness, which have caused clinicians to be concerned about slow bone formation, hydroxyapatite is not commonly used alone as an osteoconductive bone substitute. Tricalcium phosphate is less brittle and has a faster resorption rate than hydroxyapatite. Animal studies have demonstrated that 95% of calcium phosphate is resorbed in twenty-six to eighty-six weeks32,33. Tricalcium phosphate and hydroxyapatite have been combined into a biphasic calcium phosphate composite that has a faster resorption rate than pure hydroxyapatite. Calcium phosphate can also be manufactured as a cement, by adding an aqueous solution to dissolve the calcium, which is followed by a precipitation reaction in which the calcium phosphate crystals grow and the cement hardens. The primary advantage of cements over blocks, granules, or powders is the ability to custom-fill defects and increased compressive strength. However, cement can be extruded beyond the boundaries of the fracture, potentially damaging the surrounding tissue. This presents a potential disadvantage of these phosphate materials, as they will not dissolve if they happen to migrate into the joint. The ability of calcium phosphate bone substitutes to act as a bone-void filler has been documented in animal studies and human case series34-36. Cameron evaluated the incorporation time of tricalcium phosphate by placing an 8.5 by 3-mm disk of the material into the cut surface of tibiae in a series of twenty patients undergoing total knee replacement37. The disks of tricalcium phosphate could not be detected radiographically at six months, and the authors concluded that tricalcium phosphate was a useful resorbable bone-filler material. In a retrospective case series, forty-three patients with traumatic bone defects or nonunion of the femur, tibia, calcaneus, humerus, ulna, or radius had treatment augmented with tricalcium phosphate38. Ninety percent of the fractures and 85% of the nonunions had united at the time of follow-up, at an average of twelve months (minimum duration, six months). The authors concluded that tricalcium phosphate was a useful substitute for cancellous bone. In a prospective randomized study of forty closed tibial plateau fractures with metaphyseal defects conducted by Bucholz et al.39, patients were randomized to have the defect filled with either autogenous bone or porous hydroxyapatite. At an average of 15.4 months postoperatively, no significant radiographic or clinical differences were appreciated between the two groups. The more recent availability of calcium phosphate as a cement has increased the applications of this osteoconductive material because of its increased compression strength and improved custom-filling of bone defects. Investigators have evaluated the use of calcium phosphate cement products for augmentation of the repair of fractures of the distal radial metaphysis, tibial plateau, calcaneus, hip, and spine. Several randomized studies40, including one multicenter randomized controlled trial involving forty patients with a distal radial fracture41, have shown that patients treated with cement augmentation and immobilization had a faster regain of grip strength and range of motion than did patients treated with external fixation. Zimmermann et al. performed a prospective study of fifty-two postmenopausal, osteoporotic women in whom a distal radial fracture had been treated with either percutaneous pinning alone or percutaneous pinning supplemented by injection of calcium phosphate cement42. The patients treated with cement augmentation had superior functional outcomes at two years after the surgery. In a randomized study of 323 distal radial fractures treated with closed reduction and a cast or with percutaneous pinning, augmentation with calcium phosphate cement was compared with treatment without such augmentation43. At the time of early follow-up, the patients with cement augmentation were found to have improved grip strength, range of motion, and social functioning and decreased swelling. However, by one year, no clinical differences between the groups were detected. In a prospective study of twenty-six patients in whom a tibial plateau fracture had been treated with open reduction and internal fixation with injection of calcium phosphate cement into the residual bone defect, only two patients had radiographic evidence of loss of reduction at a mean of 19.7 months44. In another series, of fourteen patients in whom a lateral tibial plateau fracture with a metaphyseal defect had been treated with open reduction and internal fixation and filling of the defect with calcium phosphate cement, only one patient had had an altered fracture reduction at an average of thirty months45. Schildhauer et al. reported on a series of thirty-six joint-depression-type calcaneal fractures that had been treated with internal fixation augmented by calcium phosphate cement46. They found that patients who had been allowed to bear weight as early as three weeks after the surgery had no radiographic evidence of loss of reduction, and there was no significant difference in functional outcome scores between patients who had been allowed to begin bearing weight before six weeks and those who began it after six weeks. However, the authors did note an 11% infection rate. Seventy-five percent of the infections developed in smokers, and histological evaluation of tissue from those patients demonstrated no giant cells or eosinophils to suggest a foreign body or allergic reaction. Although this infection rate is an important outcome to consider, the authors concluded that cement augmentation of internal fixation of joint-depression-type calcaneal fractures allowed earlier weight-bearing with no change in postoperative outcomes. Early results have demonstrated that augmentation of femoral neck and intertrochanteric hip fractures with calcium phosphate cement is feasible, with no substantial increase in complications47. A randomized prospective study showed that femoral neck fractures treated with cannulated screws augmented with calcium phosphate cement had less postoperative displacement than those treated with cannulated screws alone48. The magnitude of this difference in displacement was decreased at six weeks after the surgery compared with the average difference at one week after the surgery. No authors of human studies have been able to clearly demonstrate the resorption rate of calcium phosphate cement. Animal studies have shown that up to 80% of the cement is resorbed at ten weeks, with resorption and replacement with bone continuing for as long as thirty weeks49,50. This process occurs by dissolution as well as by osteoclast resorption. The lack of osteoprogenitor cells and osteoinductive potential of calcium-based bone substitutes has led to the development of composite grafts in an attempt to accelerate bone formation. A composite graft is created by adding an osteoinductive factor to an osteoconductive calcium phosphate matrix to theoretically increase bone formation. A prospective, randomized, multicenter trial of 249 long-bone fractures in patients followed for a minimum of two years was conducted to compare autogenous bone graft with a composite graft consisting of biphasic calcium phosphate ceramic mixed with bovine collagen and autogenous bone marrow51. No significant differences in union rates, functional outcomes, or complications were found between the two groups. The authors concluded that a calcium phosphate composite graft was as effective as an autogenous iliac crest bone graft for the treatment of long-bone fractures requiring bone graft augmentation (Level-I evidence). Table I lists some of the commercially available osteoconductive products that are commonly used.
Humans require three elements for bone-healing: extracellular matrix, growth factors, and cells. The results of healing are usually quite remarkable, but when it fails the biology must be reestablished to reflect the injury condition or embryological development such that healing may once again begin. There is no formal definition of materials with osteogenic properties. The term has evolved as the entire field of tissue engineering has expanded into the musculoskeletal system52. For the purpose of this paper, the working definition of osteogenesis is the generation of bone from bone-forming cells. Thus, the presence of adult mesenchymal stem cells in an autograft helps to prepare a bone to respond to injury. Orthopaedic surgeons have employed this approach for decades through the use of autologous bone and bone marrow grafts. The critical component necessary to all bone formation is the ability to provide viable osteoprogenitor cells.
Bone Morphogenesis Cascade
Historic Perspective Bone marrow aspirate often is diluted twenty to forty-fold with blood elements. The aspiration technique is very specific in order to maximize the number of effective progenitor cells per unit volume. Muschler et al.54 studied this issue and reported that no more than 2 mL of blood should be aspirated from any given area in the iliac crest to avoid dilution with peripheral blood. On the basis of these data, a selective retention system was developed that has the ability to concentrate progenitor cells three to four times and load them onto an allograft substrate for delivery.
Substantiation by In Vitro and Animal Models A sheep tibial defect model was used to evaluate hydroxyapatite combined with either rhBMP-7 or bone marrow63. Treatment with the composite grafts yielded results that were as good as those in an autograft control group and were superior to those in either a void group or a group treated with hydroxyapatite alone. Muschler et al.64 reported on the use of a selective cell-retention method of enriching allograft (Cellect) in a canine spine fusion model. The selective cell process allows the concentration of connective tissue progenitors to be increased three to fourfold. A union score, quantitative computed tomography, and mechanical testing were used to measure the results, and all three showed the use of the selective-retention-enriched bone matrix and bone-marrow clot to be superior to the use of bone matrix alone or nonenriched bone matrix and bone-marrow clot. The results from animal studies provide a compelling sense that application of bone marrow is effective for the promotion of bone-healing. The combination of cells with a ceramic substance seems to work very well. When bone marrow is mixed with matrix and BMP there seems to be a strong synergistic effect, as one would expect because all three elements necessary for bone-healing are plentiful. Despite these findings, history has shown that positive results in animals do not guarantee the same in humans.
Clinical Application of Autologous Bone Marrow Using a bone marrow aspirate is another way to apply connective tissue progenitors to enhance bone growth and repair. This is done intraoperatively with ease and is associated with a low morbidity rate. To our knowledge, Connolly et al. were the first surgeons to report on the use of bone marrow aspirate as a clinical alternative to autograft57,66. However, their work represents Level-IV evidence at best. Garg et al.67 reported good results in their series of twenty patients in whom a nonunion had been treated with bone marrow injection. This was a single-surgeon experience with no historic or case-matched controls (Level IV). Similarly, Healey et al.68 successfully treated nonunions in a group of children with cancer by simply injecting a bone marrow aspirate. Wientroub et al.69 also reported on the use of autologous marrow to improve the effectiveness of allografts in children. Goel et al.70 reported that they employed bone marrow injections, with use of local anesthesia, for patients who were on waiting lists for open repair of a nonunion. They used the procedure in an attempt to provide a low-cost alternative treatment, and they claimed success in fifteen of twenty patients; however, no control group was evaluated. In summary, to our knowledge, there currently is no Level-I evidence documenting the effectiveness of bone marrow for the enhancement of bone-healing. Recently, Hernigou et al. reported on sixty patients with a noninfected nonunion who had undergone bone marrow aspiration from both iliac crests followed by injection into the nonunion site71. Each nonunion site received a relatively constant volume of 20 mL of concentrated bone marrow. The number of progenitor cells that was transplanted was estimated by counting the fibroblast colony-forming units. The volume of mineralized bone formation was determined by comparing preoperative computerized tomography scans with scans made four months following the injection. The results showed union in fifty-three of the sixty patients, with positive correlations between the volume of mineralized callus at four months and the number and concentration of colony-forming units. The seven patients in whom the fracture did not unite had lower numbers and concentrations of colony-forming units. This study provided Level-III evidence for the use of autologous bone marrow, which seems to be the best evidence thus far for the potential efficacy of this osteogenic material.
Use of Platelet-Rich Plasma and Related Peripheral Blood Concentrates It would seem intuitive that, in orthopaedic surgery, the ability to deliver a concentrated amount of platelets would contribute to the early stages of bone repair and thus initiate the entire fracture-healing cascade. Several strategies for platelet concentration and delivery have been developed on the basis of this assumption, but we are not aware of any published prospective comparative studies of these strategies. Current indications are based only on multiple case reports, longitudinal series, and abstracts documenting the effectiveness of platelet gels and concentrates74. This material appears to function best as a physiologic carrier for other autogenous, allogeneic, or alloplastic graft materials.
The use of autologous bone, the so-called gold standard for augmentation of bone-healing, is actually supported by very little direct clinical evidence. We are not aware of any studies in the literature in which the effectiveness of autograft was compared with that of no graft. That is not to say that autograft is not an efficacious material. Indeed, surgeons have used it for over a century with great success. As such, it remains the standard against which all bone substitutes are measured. Clinical evidence for the use of currently available bone graft substitutes ranges from Level I to Level IV. The Orthopaedic Trauma Association Orthobiologics Committee provided a summary of the levels of recommendation regarding various bone graft substitutes, which can be found in Table II. The osteoinductive effects of rhBMP-2 and 7 are well documented, and Level-I evidence supports their clinical use. There is less documentation for many of the osteoconductive bone substitutes. Some are supported by Level-I evidence, whereas others made their way into the marketplace simply by showing equivalent efficacy to a predicate medical device and have not been subjected to clinical analysis. At least one such osteoconductive material, when used as a composite with autologous bone, has shown efficacy equivalent to that of autograft. Data regarding the use of autologous bone marrow are inconsistent. Recent information suggests that methods to increase the number and concentration of osteoprogenitor cells may lead to an effective bone marrow graft material. Information regarding the clinical efficacy of autologous blood concentrates such as platelet gels is still lacking. Similarly, there are few studies in the literature in which one type of bone graft substitute was measured against another substitute for a specific indication. There remains a great need for controlled, prospective, randomized studies to provide reliable information regarding the use of these materials.
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Introduction
Osteoinductive Bone Substitutes
(TGF-