Current Concepts Review
BY CHRISTOPHER G. FINKEMEIER, MD
Investigation performed at University of California Davis Medical Center, Sacramento, California
➤ The treatment of delayed unions, malunions, and nonunions requires restoration of alignment, stable fixation, and in many cases adjunctive measures such as bone-grafting or use of bone-graft substitutes.
➤ Bone-graft materials usually have one or more components: an osteoconductive matrix, which supports the in- growth of new bone; osteoinductive proteins, which support mitogenesis of undifferentiated cells; and osteo- genic cells (osteoblasts or osteoblast precursors), which are capable of forming bone in the proper environment.
➤ Autologous bone graft, usually harvested from the iliac crest, is an excellent graft material, but its availability may be limited and the procedure to harvest the material is associated with complications.
➤ Bone-graft substitutes can either replace autologous bone graft or expand an existing amount of autologous bone graft.
➤ Various forms of bone-graft substitutes are available and include allograft bone preparations such as demineral- ized bone matrix and calcium-based materials.
The treatment of posttraumatic skeletal conditions such as de- layed unions, nonunions, malunions, and other problems of bone loss is challenging. In most cases, restoration of align- ment and stable fixation of the bone is all that is necessary to achieve a successful reconstruction. However, in many cases, adjunctive measures such as bone-grafting or bone transport are required to stimulate bone-healing and fill bone defects.
When faced with a problem requiring bone replace- ment, the orthopaedic surgeon currently has several options: autologous or allogeneic cancellous or cortical bone, deminer- alized bone matrix, calcium phosphate-based bone-graft sub- stitute, or autologous bone marrow. In the future, the options will include recombinant bone morphogenetic proteins or growth factors. The biology of each of these grafts varies and may provide one or several essential components: (1) an os- teoconductive matrix, which is a scaffold or trellis that sup- ports the ingrowth of new bone; (2) osteoinductive proteins, which stimulate and support mitogenesis of undifferentiated perivascular cells to form osteoprogenitor cells; and (3) osteo- genic cells (osteoblasts or osteoblast precursors), which are ca- pable of forming bone if placed into the proper environment. The surgeon’s choice of the proper graft must be based on what is required from the graft (structural or bone-forming function, or both), the availability of the graft, the recipient bed, and the cost. The surgeon must also remember that stable fixation is necessary for the use of any of these grafts1. No bone
graft or bone-graft substitute permits the surgeon to use less than optimum orthopaedic techniques or to deviate from proper surgical principles.
Conventional bone-grafting with autologous cortical and cancellous bone harvested from the iliac crest is the stan- dard against which all other bone-graft substitutes are judged, but it has disadvantages. The supply of autologous bone graft is limited, and many patients with difficult problems requiring skeletal reconstruction may have undergone several previous harvests of bone grafts and thus have little or no additional useful iliac crest bone. In addition, the harvesting of autolo- gous bone is associated with a rate of major complications of 8.6% and a rate of minor complications of 20.6%2. Another problem is that enough autologous graft may not be available, especially if there is massive segmental bone loss. For these reasons, it is important to have various options available to augment, expand, or substitute for autologous bone graft.
Autologous Bone Grafts
Autologous bone grafts have osteogenic, osteoconductive, and osteoinductive properties. Available autologous bone grafts include cancellous, vascularized cortical, nonvascularized cor- tical, and autologous bone marrow grafts (Table I). Bone for- mation from autologous grafts is believed to occur in two phases3,4. During the first phase, which lasts approximately four weeks, the main contribution to bone formation is from the cells of the graft. During the second phase, cells from the host begin to contribute to the process. The endosteal lining cells and marrow stroma produce more than half of the new bone, whereas osteocytes make a small (10%) contribution. Free he- matopoietic cells of the marrow make a minimal contribution5.
Autologous cancellous bone is easily revascularized and is rapidly incorporated into the recipient site. Cancellous graft is a good space filler, but it does not provide substantial struc- tural support. Because only the osteoblasts and endosteal lin- ing cells on the surface of the graft survive the transplant, a cancellous graft acts mainly as an osteoconductive substrate, which effectively supports the ingrowth of new blood vessels and the infiltration of new osteoblasts and osteoblast pre- cursors5-8. Osteoinductive factors released from the graft dur- ing the resorptive process as well as cytokines released during the inflammatory phase may also contribute to healing of the graft, although this is only a prevailing theory based on cir- cumstantial evidence; it has not yet been substantiated by sci- entific documentation3,9,10. Although cancellous graft does not provide immediate structural support, it incorporates quickly and ultimately achieves strength equivalent to that of a corti- cal graft after six to twelve months11.
Autologous cancellous bone is commonly harvested from the iliac crest, which can provide a large supply of bone (especially the posterior iliac crest). Other sources are Gerdy’s tubercle, the distal part of the radius, and the distal part of the tibia. Autologous cancellous bone graft is an excellent choice for nonunions with <5 to 6 cm of bone loss and that do not re- quire structural integrity from the graft. It can also be used to fill bone cysts or bone voids after reduction of depressed ar- ticular surfaces such as in a tibial plateau fracture. However, bone-graft substitutes may be preferable in these cases to avoid donor site morbidity. Stable internal or external fixation is also required, to provide the optimum environment for graft con- solidation and successful fracture-healing.
Sources of autologous cortical grafts include the fibula, ribs, and iliac crest. These grafts can be transplanted with or without their vascular pedicle. Autologous cortical grafts have little or no osteoinductive properties and are mostly osteocon- ductive, but the surviving osteoblasts do provide some osteogenic properties as well12,13. Autologous cortical grafts provide excellent structural support at the recipient site as well. Al- though nonvascularized cortical grafts provide immediate structural support, they become weaker than vascularized cor- tical grafts during the initial six weeks after transplantation as a result of resorption and revascularization12,14. However, by six to twelve months there is little difference in strength between vascularized and nonvascularized cortical grafts12. Vascular- ized cortical grafts heal rapidly at the host-graft interface, and their remodeling is similar to that of normal bone. Unlike nonvascularized grafts, these grafts do not undergo resorption and revascularization and, therefore, they provide superior strength during the first six weeks12. Despite their initial strength, cortical grafts still must be supported by internal or external fixation to protect them from fracture while they hy- pertrophy in response to Wolff ’s law15 and mechanical load- ing. Autologous cortical bone grafts are good choices for segmental defects of bone of >5 to 6 cm, which require imme- diate structural support. For defects of >12 cm, vascularized grafts are superior to nonvascularized grafts as indicated by failure rates of 25% and 50%, respectively11. The harvest of large cortical grafts has been associated with some problems. Tang et al. reported that, of thirty-nine patients who had a free fibular graft harvested for treatment of avascular necrosis of the femoral head, 42% had a subjective sense of instability and 37% had a subjective sense of weakness in the lower ex- tremity16. Only mild weakness of great toe extension and flex- ion could be measured in 43% and 29% of these patients, respectively. Only 2% of the patients required a reoperation for a problem at the donor site. Bone transport may be a bet- ter option for defects of >6 cm17,18.
The advantages of autologous cancellous or cortical bone grafts are their excellent success rate, low risk of trans- mitting disease, and histocompatibility. However, as noted above, there is a limited quantity of autologous bone graft and there is the potential for donor site morbidity.
Another source of autologous material is the osteoblastic stem cells found in bone marrow. Injections of autologous bone marrow provide a graft that is osteogenic and potentially os- teoinductive through cytokines and growth factors secreted by the transplanted cells. Bone marrow can be aspirated from the posterior iliac wing in volumes of 100 to 150 mL and can be injected into a fracture or nonunion site to stimulate heal- ing. When it is to be used in small bones such as the scaphoid, the bone marrow aspirate can be centrifuged19 to concentrate the marrow cells and to maximize osteogenic stromal colony- forming efficiency while decreasing the volume injected. Muschler et al. showed that a 2-mL aspirate from a human anterior iliac crest has a mean of 2400 alkaline phosphatase- positive colony-forming units20. The larger the volume of the aspirate, the greater the total number of alkaline phosphatase- positive colony-forming units, but they are more diluted. An increase in the volume of the aspirate from 1 to 4 mL de- creases the concentration of alkaline phosphatase-positive colony-forming units by 50%. Thus, the maximum number of alkaline phosphatase-positive colony-forming units can be delivered to the recipient site in four 1-mL aliquots as op- posed to one 4-mL aliquot20.
This technique has potential problems because of the tendency for the injected material to wash away from the frac- ture site. Many authors have studied the effect of composite grafts formed from a combination of bone-graft substitutes and autologous bone marrow 21-25. Demineralized bone matrix is an excellent carrier because of its osteoconductive and os- teoinductive properties. Connolly et al. used autologous bone marrow mixed with 10 mg of demineralized bone matrix, which forms a sand-like material, to fill bone defects19,26. This composite graft can be injected percutaneously as well. Injec- tion of autologous bone marrow, with or without a carrier, has been used to treat nonunion and delayed union of several bones (i.e., the carpal bones, tibia, femur, humerus, etc.). The Type-IIIB open tibial fracture may be the ideal fracture for this technique because of its high frequency of healing prob- lems and the possible benefits of not having to expose the fracture site to deliver the graft. Connolly reported that eigh- teen (90%) of twenty delayed unions of the tibia united after utilization of this technique19. He recommended waiting six to twelve weeks after the acute fracture to allow the initial in- flammatory reaction and osteoclastic resorption to subside before injecting the autologous bone marrow19. Injection of autologous bone marrow does not promote healing more rap- idly or to a greater extent than do traditional bone-grafting techniques27-29, but it has been shown to be as successful in one small series19. Injection of autologous bone marrow offers sev- eral advantages: (1) the technique is relatively simple and can be done as an outpatient procedure and should, therefore, be cost-effective19,25; (2) it is associated with fewer complications at the donor and recipient sites than is harvesting of autograft from the iliac crest19,25, although I am not aware of any direct comparison studies upon which to base a final conclusion; and (3) because the approach is less invasive, clinicians may be encouraged to perform early treatment of delayed unions, ul- timately expediting healing and decreasing the complications of prolonged immobilization.
Techniques for Harvesting Autologous
Cortical and Cancellous Bone Graft
Bone can be harvested from either the anterior or the posterior iliac crest. Harvesting from the anterior iliac crest is usually more convenient because the patient is typically in a supine position for most operations involving the extremities. However, only a limited amount of bone can be obtained from the anterior iliac crest, and this site should not be used when >20 to 30 cc of graft is required. The posterior iliac crest, on the other hand, has an abundant supply of both cortical and cancellous bone and is an ideal location from which to harvest large amounts of bone-graft material. The general technique for harvesting bone from the ilium is similar regardless of whether the bone is taken anteriorly or posteriorly. When bone is harvested from the anterior iliac crest, I recommend that the most anterior extent be at least 2 to 3 cm posterior to the anterior superior iliac spine to avoid predisposing it to an avulsion fracture. It is important to take advantage of the relatively large amount of cancellous bone under the iliac tubercle. When bone is taken from the posterior iliac crest, I recommend that the most posterior extent be at least 4 cm from the posterior superior iliac spine to decrease the chance of violating the sacroiliac joint.
For illustrative purposes, I will describe my technique for harvesting corticocancellous bone graft from the posterior iliac wing (Fig. 1). The patient is placed in the prone position, over bolsters, and all osseous prominences are well padded.
The buttock and flank ipsilateral to the operative site is prepared and draped. A vertical incision is made, centered over the proposed harvest area. Transverse incisions that parallel the posterior iliac crest should not be used routinely, as they may injure the cluneal nerves. The length of the incision is determined by the amount of bone-graft material that is needed.
The deep fascia overlying the posterior iliac crest is incised over the crest down to the bone. With use of a sharp Cobb elevator and either a knife or an electrocautery, the fascia is then elevated off the iliac wing, exposing either the outer table or the inner table, depending on the surgeon’s preference. A lap sponge placed over the sharp edge of a Cobb elevator can be used to assist in clearing the periosteum. I typically expose the outer table for harvesting. I then use a 0.5-in (12.7-mm) sharp straight osteotome to cut a line into the iliac crest, starting 4 cm anterior to the posterior superior iliac spine and extending as far anteriorly as needed. From this corticotomy, I then use a straight 0.5-in osteotome to cut vertical lines toward the sciatic notch (Fig. 1, A). It is imperative to be careful not to violate the sciatic notch to avoid injury to the neurovascular pedicle, which lies adjacent to the iliac wing in the sciatic notch. Strips of graft of various widths can then be cut with the straight osteotome through the extent of the proposed harvest area.
Using a gouge of the same diameter as the cortical strip, I remove corticocancellous strips with abundant cancellous bone attached to a thin layer of cortical bone from the iliac wing (Fig. 1, B). These strips are placed into a sterile basin and covered with a damp sponge or towel. The remaining portion of the cancellous bone within the iliac wing is then removed.
A: Posterior view of the pelvis. Strips of corticocancellous bone as well as cancellous bone can be harvested, with the most posterior extent of the harvest being no closer than 4 cm from the posterior superior iliac spine. B: Corticocancellous strips consist of cancellous bone attached to a thin layer of cortical bone. C: Cancellous bone can be removed from between the inner and outer tables of the ilium and is best stored in a container where it can be kept moist with use of a combination of gouges or large curets (Fig. 1, C). Abundant cancellous bone is also available underneath the iliac crest itself. More cancellous graft can be removed by un- dermining in each direction from the harvest site.
Hemostasis can be obtained by packing a combination of Gelfoam (Upjohn, Kalamazoo, Michigan) and thrombin into the iliac wing, or bone wax can be applied to the raw os- seous surfaces to stop the bleeding. Packing with lap sponges also helps to control the bleeding. I recommend placing a me- dium-sized suction drain deep to the fascia and then closing the fascia with an absorbable heavy suture. The wound can be closed according to the surgeon’s preference.
Other potential areas for harvesting bone include meta- physeal regions of the skeleton, such as the distal part of the radius, Gerdy’s tubercle, the tibial plafond, and the greater trochanter. The harvesting technique is similar for all of these areas, and I recommend a technique similar to that used to perform a bone biopsy. A small drill bit should be used to create perforations in an elliptical pattern. These perforations are then connected with a small osteotome or a small curet to remove the cortical roof. Beneath this roof there is a supply of cancellous bone in various quantities, depending on the ana- tomic region of the body from which the graft is being har- vested. Once the graft is harvested, the small cortical roof can be replaced, or it can be used as part of the bone graft. Hemo- stasis can be obtained by packing with a sponge or with some thrombin-impregnated Gelfoam. I usually do not use suc- tion drainage in these locations. A compression dressing works well to obtain hemostasis. Harvesting of any of the var- ious vascularized pedicle flaps, such as the fibula or the iliac crest, requires specialized techniques and is beyond the scope of this review.
Allogeneic bone, with variable biologic properties, is available in many preparations: demineralized bone matrix, morselized and cancellous chips, corticocancellous and cortical grafts, and osteochondral and whole-bone segments.
Demineralized Bone Matrix
Demineralized bone matrix acts as an osteoconductive, and possibly as an osteoinductive, material. It does not offer structural support, but it is well suited for filling bone defects and cavities. Demineralized bone matrix revascularizes quickly. It also is a suitable carrier for autologous bone marrow as discussed previously. Demineralized bone matrix is prepared by a standardized process, as originally described by Urist et al.31,32 and modified by Reddi and Huggins33, in which allogeneic bone is crushed or pulverized to a consistent particle size (74 to 420 µm) followed by demineralization in 0.5N HCL mEq/g for three hours. The residual acid is eliminated by rinsing in sterile water, ethanol, and ethyl ether. Current methods of processing demineralized bone matrix follow the same basic steps, but refinements of the technique, many of which have been patented, have been developed by several companies and tissue banks. Process variables may include demineralization time, acid application, temperature, application of defatting agents, and use of either aseptic processing methods or irradiation or ethylene oxide sterilization of the final product. The companies and tissue banks market these variations in processing with the claim that they provide unique advantages and superior performance over other products, although little comparative scientific data are available to support many of the claims.
The biologic activity of demineralized bone matrix ispresumably attributable to proteins and various growth fac- tors present in the extracellular matrix and made available to the host environment by the demineralization process. The osteoinductive capacity of demineralized bone matrix can be affected by storage, processing, and sterilization methods and can vary from donor to donor. For example, sterilization by ethylene oxide under certain conditions and 2.5 Mrad of gamma irradiation substantially reduce osteoinductivity34,35. Because the osteoinductive capacity differs from donor to do- nor and because of safety reasons, the American Association of Tissue Banks and the United States Food and Drug Admin- istration require each batch of demineralized bone matrix to be obtained from a single human donor36. Demineralized bone matrix is available as a freeze-dried powder, as crushed granules or chips, and as a gel or paste (Table II).
Demineralized bone matrix is an excellent grafting ma- terial with which to induce bone formation within contained, stable skeletal defects such as bone cysts and cavities26,37,38. Oth- ers have reported that application of demineralized bone ma- trix to long-bone nonunions and acute bone defects from fractures results in successful healing similar to that following autologous bone-grafting26,39-41. Demineralized bone matrix can also be used to enhance healing of arthrodeses in the spine and elsewhere26,32. The most successful grafts may be compos- ites of demineralized bone matrix and autologous bone marrow19,26 when used with stable fixation. A dilute mixture of demineralized bone matrix and autologous bone marrow can be injected with a syringe, and this method has been used suc- cessfully in many challenging situations19,26. Demineralized bone matrix can also augment and expand autologous cancel- lous bone graft when the supply of autogenous bone is limited or the defect is very large.
I recommend demineralized bone matrix for filling sta- ble, well-contained bone defects and cysts and as a bone-graft expander when the defect is large. Although to my knowledge no prospective, randomized controlled studies have been done to prove the efficacy of demineralized bone matrix for the treatment of nonunions, there may be some nonunion situa- tions in which the use of demineralized bone matrix could be considered. First, it can be used to augment autologous can- cellous or corticocancellous grafts. Demineralized bone ma- trix may also be an alternative for a patient who has no autologous bone available for use as a graft or for a patient who does not wish to undergo an extensive open procedure or for whom the open procedure carries a very high risk. In this case, a percutaneous procedure utilizing demineralized bone matrix and autologous bone marrow could be considered. I recommend using demineralized bone matrix as a composite graft with autologous bone marrow to provide an immediate supply of osteoprogenitor cells in combination with a matrix that is both conductive and inductive22,24. However, while some studies have shown successful outcomes with composite grafts19,26,42, experience with these grafts is limited and their ef- fectiveness is currently unproven.
Demineralized bone matrix has several potential disad- vantages. Because it is an allogeneic material, there is the po- tential to transmit human immunodeficiency virus (HIV). However, the decalcification process appears to inactivate and eliminate HIV43, so even if infected tissue got through the ex- tensive donor screening process, the risk of transmission is very low. According to one manufacturer, there have been no reported cases of infectious disease transmission in 1.5 mil- lion procedures with the use of one particular preparation of demineralized bone matrix44. Similarly, one large tissue bank that processes demineralized bone matrix reported in its liter- ature that no infectious disease transmission had occurred from more than 20,000 donors45. Another potential limitation of demineralized bone matrix is that different batches may have different potencies because of the wide variety of donors used to supply the graft. Finally, although many authors have reported healing similar to that following autologous cancel- lous bone-grafting, I am not aware of any prospective, ran- domized studies that would allow a true comparison of the two graft types.
Morselized and Cancellous Allografts
Morselized and cancellous allografts are osteoconductive and provide some mechanical support, mainly in compression. They are most often preserved by freeze-drying (lyophilization) and vacuum-packing, and they undergo stages of incorporation similar to those of autologous cancellous bone. I recommend using morselized allograft for packing bone defects such as bone cysts after curettage or in periarticular metaphyseal locations to support elevated articular surfaces after articular depression such as occurs with tibial plateau or tibial pilon fractures. Morselized allograft is also useful to aug- ment autogenous cancellous bone and to fill larger defects when the supply of autologous bone is limited. Allograft bone is associated with a very small risk of infectious disease trans- mission, but its use will eliminate the need to harvest iliac crest bone and its associated morbidity.
Osteochondral and Cortical Allografts
Osteochondral and cortical allografts are harvested from various regions of the skeleton, such as the pelvis, ribs, femur, tibia, and fibula, for reconstruction after major bone or jointloss. The grafts are available as whole-bone or joint segments (i.e., as the whole or part of the tibia, humerus, femur, talus, acetabulum, ilium, or hemipelvis) for limb salvage procedures or as cortical struts to buttress existing bone, to stabilize and reconstitute cortical bone after periprosthetic fractures, and to fill bone defects. These grafts are osteoconductive and provide immediate structural support. They are preserved by either deep-freezing or freeze-drying. Deep-frozen allografts retain their material properties and can be implanted immediately after thawing, whereas freeze-dried allografts can be friable and weak in torsion and bending, even after rehydra- tion prior to implantation. Again, transmission of infectious disease is a risk when osteochondral and cortical allografts are used. However, of the three million tissue transplants per- formed since identification of the HIV virus, only two cases of HIV transmission have occurred and both involved trans- plantation of unprocessed fresh-frozen allografts36. I recom- mend the use of cortical allografts to fill bone voids and for reconstructive procedures requiring immediate structural support in patients who wish to avoid harvest of an autolo- gous fibular graft.
Fresh allografts that require no preservation are avail- able, but they incite an intense immune reaction, making them less attractive than autografts. These fresh allografts have limited applications and are currently being used mainly for joint resurfacing.
Ceramics and Ceramic Composites
Fig. 2-A Preoperative anteroposterior radiograph of a depressed intra-articular tibial plateau fracture. The depressed articular surface is indicated by the arrow. Fig. 2-B Postoperative anteroposterior radiograph made after reduction of the articular surface and coralline hydroxyapatite grafting of the metaphyseal defect left behind after elevation of the articular surface, as indicated by the arrow.
Calcium phosphate ceramics may be used as osteoconductive matrices in orthopaedic surgical settings (Table III). Many of the current calcium phosphate biomaterials can be classified as polycrystalline ceramics. The material structure of ceramics is derived from individual crystals of a highly oxidized substance that have been fused together at the crystal grain boundaries by a high-temperature process called sintering46. Ceramics are brittle and have poor tensile strength, making their primary clinical application one of filling contained bone defects or restoring areas of bone loss resulting from a fracture such as an articular fracture with joint depression. Calcium phosphate biomaterials should be placed in intact bone or rigidly stabilized bone in order to protect the ceramic from shear stresses, and they should be tightly packed into the adjacent host bone to maximize ingrowth47. Calcium phosphate ceramics are available as porous or nonporous blocks of various sizes or as porous granules. Calcium phosphate ceramics do not elicit a foreign-body reaction and are well tolerated by host tissues.
Tricalcium phosphate is a random porous ceramic that undergoes partial conversion to hydroxyapatite once it is implanted into the body11. Tricalcium phosphate is more porous and is resorbed faster than hydroxyapatite, making it mechanically weaker in compression46. After conversion, the hydroxyapatite is resorbed slowly and, therefore, large segments of hydroxyapatite remain in place for years. Because tricalcium phosphate has an unpredictable biodegradation profile, it has not been popular as a bone-graft substitute48. However, Bucholz et al. showed that tricalcium phosphate is effective for filling bone defects resulting from trauma, benign tumors, and cysts47.
Coralline hydroxyapatite is processed by a hydrothermal exchange method that converts the coral calcium phosphate to crystalline hydroxyapatite with pore diameters between 200 and 500 μm and in a structure very similar to that of human trabecular bone. Bucholz et al. reported that the clinical performances of autologous cancellous bone graft and coralline hydroxyapatite are equivalent when the substances are used to fill bone voids resulting from articular surface depression in tibial plateau fractures49. Other studies have demonstrated successful healing of cortical defects greater than one-third of the diaphyseal circumference of long-bone fractures, although the results are less predictable than those following treatment of metaphyseal fractures47. To avoid donor site morbidity, I occasionally use coralline hydroxyapatite granules or blocks of various size, depending on the size of the defect, to fill metaphyseal defects after reduction of depressed articular segments (Figs. 2-A and 2-B). A contraindication to the use of this material is a joint surface defect that would allow the grafting material to migrate into the joint. In these cases, I prefer to use autologous or allograft cancellous bone, which is more adhesive to itself and to the surrounding metaphyseal bone.
Another ceramic bone-graft substitute currently in clinical use is a calcium-collagen graft material. This osteoconductive composite of hydroxyapatite, tricalcium phosphate, and Type-I and III collagen is mixed with autologous bone marrow to provide osteoprogenitor cells and other growth factors. The composite does not provide structural support, but it serves as an effective bone-graft substitute or bone-graft
Preoperative anteroposterior radiograph of a shotgun injury to the left tibial plateau, which was previously debrided and stabilized in an exter- nal fixator.
expander to augment acute fracture-healing. Chapman et al. performed a prospective, randomized comparison of autolo- gous iliac crest bone graft and calcium-collagen graft material in the treatment of acute long-bone fractures with both bone- grafting (<30 cm3 volume required) and internal or external fixation50. The authors observed no differences between the two groups with regard to the union rate or functional mea- sures, and they concluded that calcium-collagen graft material with autologous bone marrow can be used instead of autolo- gous bone graft for patients who have an acute traumatic de- fect of a long bone. There is no scientific evidence that calcium-collagen graft materials can effectively substitute for autologous bone graft to stimulate healing of nonunions. I recommend the use of this material with autologous bone marrow as a replacement for autologous bone graft for acute long-bone fractures with enough comminution or cortical bone loss to require bone-grafting when internal or external fixation is planned. I do not recommend using it to fill meta- physeal bone defects resulting from articular fractures because it does not offer structural support. Finally, I do not recom- mend it for the treatment of nonunions except in the role of a bone-graft expander when the supply of autologous bone graft is limited.
Calcium sulfate graft material with a patented crystal- line structure described as an alphahemihydrate acts primarily
Anteroposterior (Fig. 3-B) and lateral (Fig. 3-C) radiographs made ten months after fibular strut allogeneic bone-grafting of the massive metaphyseal bone defect as an osteoconductive bone-void filler that completely resorbs as newly formed bone remodels and restores anatomic fea- tures and structural properties. Potential uses of calcium sul- fate graft material include the filling of cysts, bone cavities, and segmental bone defects; expansion of grafts used for spi- nal fusion; and filling of bone-graft harvest sites. Currently, very limited information is available on the use of this mate- rial in humans; no published controlled studies are available, to my knowledge.
Another option available for filling bone voids after acute fractures is injectable calcium phosphate. One such material, Skeletal Repair System (SRS; Norian, Cupertino, California) is an injectable paste of inorganic calcium and phosphate that hardens within minutes, forming a carbonated apatite of low crystallinity and small grain size similar to that found in the mineral phase of bone51. After twelve hours, this material hardens to form dahlite with a compressive strength of 55 MPa, and, because of its crystalline structure, it can eventually be resorbed and replaced by host bone51. This material may be useful as a bone-graft substitute to augment cast treatment or internal fixation of impacted metaphyseal fractures. One indication for use of such a material is an im- pacted, extra-articular distal radial fracture that would nor- mally require pinning after reduction to avoid dorsal settling. At least one study has demonstrated that this calcium phos- phate material can be injected into the fracture site after re- duction, and after a few minutes a below-the-elbow cast is applied52. After two weeks, the cast can be replaced by a volar wrist splint until the fracture is healed52. Several authors have reported promising results with this approach for distal radial fractures52-54. However, while a multicenter study showed that patients treated with injectable calcium phosphate and cast immobilization had earlier functional return than patients treated with cast immobilization or external fixation alone, the advantage diminished by three months and no advantage was detectable after one year55. Additional potential applica- tions of injectable calcium phosphate materials include treat- ment of hip56, spine, calcaneal, and other extra-articular metaphyseal fractures at risk for hardware failure or for redis- placement under compressive loads. Several injectable pastes are available, but little data are available to make comparisons based on clinical outcomes.
Several variations of glass beads called Bioglass (USBiomateri- als, Alachua, Florida) are currently being developed, and one formulation (PerioGlas) has been approved in the United States for periodontal use. The beads are composed of silica (45%), calcium oxide (24.5%), disodium oxide (24.5%), and pyrophosphate (6%). When implanted, they bind to collagen, growth factors, and fibrin to form a porous matrix to allow in- filtration of osteogenic cells. The matrix provides some com- pressive strength, but it does not provide structural support. I have no experience with this material.
Author’s Recommendations for Specific Problems
The attainment of proper axial alignment and adequate sta- bility and the preservation of vascular supply remain the most important factors for successful treatment of acute fractures as well as delayed unions and nonunions. In fractures that do not heal or that heal slowly, there is an abnormality of either the biology or the mechanical environment, or both. There- fore, unless the mechanical environment of the fracture site is optimized, usually by increasing the stability of the fracture, manipulation of the biology at the fracture site with bone graft or bone-graft substitute will have limited success. In cases of hypertrophic nonunion, successful healing can usu- ally be accomplished simply by stabilizing the fracture. If the mechanical environment has been optimized and a nonunion still exists, the next step for the surgeon is to choose an appro- priate grafting material depending on the biology of the frac- ture site.
The first step in matching the graft to the clinical prob- lem is to decide whether the problem is a lack of osteoinduc- tion and/or osteogenesis or one of structural bone loss requiring a load-bearing graft. Well-contained, stable metaphyseal defects with a good vascular supply are well suited for osteoconductive bone-graft substitutes that can resist com- pressive forces. Allograft chips or any of the calcium-based bone-graft substitutes would be appropriate in this setting. If a nonunion is present and a stimulus for new bone formation is needed, an autologous cancellous graft is ideal. There is no bi- ologic rationale for using a purely osteoconductive graft in a nonunion or delayed union that requires new bone formation or when the vascularity of the grafting bed is marginal. Autol- ogous cancellous bone or composite grafts of demineralized bone matrix and bone marrow, or demineralized bone matrix and one of the calcium-based substitutes, are appropriate in these situations.
If a diaphyseal defect is too large to heal reliably with cancellous bone-grafting, then a structural graft such as a cor- tical autograft or allograft may be needed. For these large de- fects (approximately ≥6 cm in my experience), vascularized cortical autografts are a better choice than nonvascularized autografts or allografts because of their more rapid and com- plete incorporation as well as their ability to hypertrophy. Cortical allografts are best reserved for use in areas with an excellent vascular supply (such as metaphyseal locations [Figs. 3-A, 3-B, and 3-C] or around the femur), whereas vascularized cortical autografts should be reserved for use in areas of marginal blood supply (such as the scaphoid, femoral neck, or talus) or for reconstructing diaphyseal segmental bone defects. For smaller defects (<6 cm), autologous cancellous bone used with stable internal fixation is adequate for nonunions or fresh fractures with bone loss.
Although gender has no bearing on the choice of which graft to use, the age of the patient should be taken into consideration. Skeletally immature patients rarely have nonunion of acute injuries, but they may require bone-grafting after the removal of a benign or malignant bone tumor or for anothercondition such as congenital pseudarthrosis of the tibia. Most benign tumors require some type of bone to fill the defect fol- lowing curettage. In skeletally immature patients, the volume of autogenous bone graft available in the iliac crests is limited. Therefore, these patients are potential candidates for treat- ment with demineralized bone matrix, allograft cancellous bone, or another osteoconductive void-filling bone-graft substitute. At present, there are limited data to support the use of demineralized bone matrix in combination with freshly harvested bone marrow in children.
Christopher G. Finkemeier, MD
Department of Orthopaedic Surgery, University of California Davis Medical Center, 4860 Y Street, Suite 3800, Sacramento, CA 95817
The author did not receive grants or outside funding in support of his research or preparation of this manuscript. He did not receive payments or other benefits or a commitment or agreement to provide such benefits from a commercial entity. No commercial entity paid or directed, or agreed to pay or direct, any benefits to any research fund, foundation, educational institution, or other charitable or nonprofit organization with which the author is affiliated or associated.
1. Sauer HD, Schoettle H. The stability of osteosyntheses bridging defects. Arch Orthop Trauma Surg. 1979;95:27-30.
2. Younger EM, Chapman MW. Morbidity at bone graft donor sites. J Orthop Trauma. 1989;3:192-5.
3. Axhausen W. The osteogenetic phases of regeneration of bone. A historical and experimental study. J Bone Joint Surg Am. 1956;38:593-600.
4. Axhausen W. Die Knochenregeneration—ein Zweiphasisches Geschehen. Zentralble Chir. 1952;77:435-42.
5. Gray JC, Elves MW. Early osteogenesis in compact bone isografts: a quan- titative study of contributions of the different graft cells. Calcif Tissue Int. 1979;29:225-37.
6. Heslop BF, Zeiss IM, Nisbet NW. Studies on the transference of bone. I. A comparison of autologous and homologous bone implants with refer- ence to osteocyte survival, osteogenesis and host reaction. Br J Exp Pathol. 1960;41:269-87.
7. Burwell RG. Studies in the transplantation of bone. VII. The fresh composite homograft autograft of cancellous bone. An analysis of factors leading to os- teogenesis in marrow transplants and in marrow-containing bone grafts.
J Bone Joint Surg Br. 1964;46:110-40.
8. Williams R. Comparison of living autografts and homogenous grafts of cancel- lous bone heterotopically placed in rabbits. Anat Rec. 1962;143:93-105.
9. Vainio S. Observation on the regeneration of an autogenous transplant of the bone. Acta Chir Scand. 1950;100:86-109.
10. Einhorn TA, Majeska RJ, Rush EB, Levine PM, Horowitz MC. The expression of cytokine activity by fracture callus. J Bone Miner Res. 1995;10:1272-81.
11. Gazdag AR, Lane JM, Glaser D, Forster RA. Alternatives to autogenous bone graft: efficacy and indications. J Am Acad Orthop Surg. 1995;3:1-8.
12. Dell PC, Burchardt H, Glowczewskie FP Jr. A roentgenographic, biomechani- cal, and histological evaluation of vascularized and non-vascularized segmen- tal fibular canine autografts. J Bone Joint Surg Am. 1985;67:105-12.
13. Doi K, Tominaga S, Shibata T. Bone grafts with microvascular anastomosis of vascular pedicles: an experimental study in dogs. J Bone Joint Surg Am. 1977;59:806-15.
14. Enneking WF, Burchardt H, Puhl JJ, Piotrowski G. Physical and biological aspects of repair in dog cortical-bone transplants. J Bone Joint Surg Am. 1975;57:237-52.
15. Wolff J. Das Gaesetz der Transformation der Knochen. Berlin: A. Hirschwald; 1892.
16. Tang CL, Mahoney JL, McKee MD, Richards RR, Waddell JP, Louie B. Donor site morbidity following vascularized fibular grafting. Microsurgery. 1998;18:383-6.
17. Green SA. Skeletal defects. A comparison of bone grafting and bone trans- port for segmental skeletal defects. Clin Orthop. 1994;301:111-7.
18. Duman H, Sengezer M, Celikoz B, Turegun M, Isik S. Lower extremity sal- vage using a free flap associated with the Ilizarov method in patients with massive combat injuries. Ann Plast Surg. 2001;46:108-12.
19. Connolly JF. Injectable bone marrow preparations to stimulate osteogenic re- pair. Clin Orthop. 1995;313:8-18.
20. Muschler GF, Boehm C, Easley K. Aspiration to obtain osteoblast progenitor cells from human bone marrow: the influence of aspiration volume. J Bone Joint Surg Am. 1997;79:1699-709. Erratum. 1998; 80:302.