Summary of Key Points
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Bone grafting is a common procedure worldwide. Both autograft and allograft are safe and effective for use in patients. Autograft is the gold standard to which all other bone graft materials are compared.
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There are many options that act as bone graft substitutes. Osteogenesis, osteoinduction, and osteoconduction are desirable properties of bone graft. Several formulations of these properties are available for use.
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Ceramics are osteoconductive and do not intrinsically have osteoinductive properties. Depending on the specific ceramic utilized, they have varying rates of resorption and integration into the host.
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Combination biologic and composite grafts include both an osteoconductive matrix and an osteogenic or osteoinductive material. When the osteoconductive scaffold is mixed with a biologic such as bone marrow aspirate, the newly formed composite graft may acquire osteogenic and osteoinductive potential, thus providing a competitive alternative to autograft.
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Bone morphogenetic proteins are powerful osteoinductive compounds of osteogenic and angiogenic activity but they are accompanied by some limitations and side effects that must be accounted for in the decision to use them.
Among the earliest descriptions of bone grafting and fusion of the spine was that made by Dr. Fred Albee in 1911 for the treatment of Pott disease. Today, one of the most common types of graft (second only to blood) is bone, with more than 450,000 procedures using bone performed annually in the United States. Medical care costs for low back pain in the United States, which includes spine arthrodesis, exceed $100 billion per year. Spine arthrodesis is the most common reason for autogenous bone harvest. Autogenous cancellous bone is the gold standard against which all other bone graft materials are compared. The osteogenic, osteoinductive, and osteoconductive properties of autograft are unequaled in stimulating bone repair. The procurement site of choice is the iliac crest because of the quantity and quality of available bone. Nevertheless, there are significant drawbacks to autograft, including procurement morbidity, limited availability, and increased operative time. In fact, iatrogenic complications originating from the graft procurement site represent a significant source of patient and physician concern. The primary operation may be successful, but the secondary procedure can result in increased patient recovery time and disability.
Allograft is a commonly chosen alternative to autograft, especially when autografting is either impractical or impossible. However, this convenience comes at a price. Just like any organ allograft transplant, the allograft has the potential to transfer disease and trigger a host immune response. The allograft is heavily processed to mitigate these risks at the expense of impaired osteoinductivity and diminished mechanical properties. This renders allograft inferior to autograft as a bone graft material. In addition, processing adds to the already significant procurement costs.
By virtue of these drawbacks to both auto- and allograft, synthetic alternatives have been an active area of research since the 1980s. Despite the extensive research, only 10% of bone graft procedures annually performed worldwide involve synthetics, because of their perceived inferiority to native autograft and allograft. Drawbacks of many synthetics include poor resorbability, inclusion of animal or marine-derived components, variable handling characteristics, limited availability, added cost, and at times limited clinical study. Until recently, synthetic grafts provided only osteoconductive properties, lacking osteoinductive and osteogenic potential. However, composite grafts that combine a synthetic osteoconductive matrix with osteoinductive growth factors and osteogenic cells have the potential to provide the advantages of autogenous bone graft—without its disadvantages. Numerous preclinical and clinical trials are under way to determine whether these synthetic alternatives combined with osteoinductive and osteogenic elements are able to achieve the same results as native bone.
Use of Cancellous Bone Grafts Versus Substitutes
Role of Cancellous Bone
Cancellous bone is a scaffold within which a variety of cell types interact to perform a wide array of essential functions, in addition to its importance as the nurturing microenvironment for hematopoiesis, myelogenesis, and platelet formation. Cancellous bone serves as an incubator that protects and grows the sources of its own maintenance and the renewal of pluripotent osteoprogenitor stem cells. The growth, migration, and differentiation of these bone-forming cells are regulated by local growth factors that are elaborated by the cells and platelets within the cancellous bone. Cancellous bone is highly porous and vascular, which fosters its role as a cell incubator. It does have a limited weight-bearing function and in pathologic or traumatic conditions is susceptible to collapse under compressive forces. Cortical bone surrounds and protects the cancellous bone. This dense structural material makes up the bulk of the skeleton and provides for its axial load-bearing capabilities.
General Characteristics of a Successful Bone Graft
A bone graft functions similarly to cancellous bone, supporting new tissue growth by providing the bone and blood cells with a matrix substrate. For a bone graft to be successful, three processes—osteogenesis, osteoconductivity, and osteoinductivity—that mimic natural events in cancellous bone must take place.
Osteogenesis
Osteogenesis is the process of bone formation through cellular osteoblastic activity, which is dependent on the presence of osteoprogenitor stem cells. Osteogenic grafts provide cells with the direct ability to form new bone.
Osteoinduction
Osteoinduction is the biologically mediated recruitment and differentiation of cell types essential for bone formation. Osteoinductive grafts supply factors that induce undifferentiated tissue to differentiate into bone.
Osteoconduction
Osteoconduction involves the apposition of growing bone to the three-dimensional surface of a suitable scaffold provided by the graft. Osteoconduction requires the structural and chemical environments that simulate those found in cancellous bone. The ideal scaffold provides dimensional stability and degrades at a rate commensurate with the speed of new bone formation.
In addition, material for a successful bone graft must have good handling characteristics, be nontoxic (e.g., not leach chemicals into the circulation), and exhibit biomechanical characteristics (e.g., tension, compression, modules of elasticity) similar to those of cancellous bone. Spine surgeons currently are using a variety of materials, both stand-alone and in combination. Table 31-1 summarizes the biologic properties that constitute a graft’s osteointegrative capabilities (i.e., the formation of bony tissue around the implant without growth of fibrous tissue at the bone-implant interface).
| Graft Material | Osteogenesis | Osteoinduction | Osteoconduction |
|---|---|---|---|
| Autograft | 2 * | 2 | 2 |
| Allograft | 0 | 1 | 2 |
| Xenograft | 0 | 0 | 2 |
| α-TCP | 0 | 0 | 1 |
| β-TCP (porous) | 0 | 0 | 2 |
| Hydroxyapatite | 0 | 0 | 1 |
| Injectable calcium phosphate cement (e.g., Norian SRS † ) | 0 | 0 | 1 |
| BMA | 3 | 2 | 0 |
| β-TCP plus BMA | 3 | 2 | 2 |
| DBM | 0 | 2 | 1 |
| Collagen | 0 | 0 | 2 |
| BMP | 0 | 3 | 0 |
| Hyaluronic acid | 0 | 0 | 0 |
| Bioactive glasses | 0 | 0 | 1 |
| Degradable polymers | 0 | 0 | 1 |
| Porous metals | 0 | 0 | 1 |
* Score range 0 (none) to 3 (excellent).
Potential Uses of Natural and Synthetic Bone Grafts
Surgeons introduce bone graft, natural or synthetic, for many types of repair procedures: in fusion (e.g., cervical fusion after discectomy, as an onlay lumbar graft, an interbody lumbar graft, and in fractures) and as a bone void filler (e.g., collapsed vertebral body, autograft donor site repair, bony defects as a result of trauma or tumor resection, osteonecrosis). Synthetic graft material also can be used in conjunction with either autograft or allograft as a bone graft extender.
Graft Materials
Autograft
Pro
Autograft includes osteogenic bone and marrow cells as well as an osteoconductive matrix of minerals, matrix proteins, and osteoinductive proteins. Neither host rejection nor disease transmission is an issue with an autograft. The combination of these properties can result in high graft success rates. Many spinal fusion procedures (e.g., dorsal cervical, thoracic, and intervertebral) that use autogenous graft produce fusion rates higher than 90%.
Con
The separation of body tissue from its blood supply can result in cell death prior to revascularization. Therefore, the viability of autogenous bone as a living graft and host is severely compromised when it is harvested. Furthermore, the quality of the donor stock is not constant; it depends on many factors, such as the patient’s age, gender, health, and genetic disposition. This opens the door for alternatives. Although some spinal fusion procedures result in high fusion rates, the results are not uniform. Many common procedures, such as dorsolateral lumbar fusion, produce fusion rates as low as 56%. Although autogenous bone is regarded as the gold standard, its biologic performance under certain conditions and in certain patients is less than ideal.
However, probably the greatest drawback to autograft use is the need for a second fascial incision and surgical dissection, with the attendant potential for complications. In fact, minor complications such as superficial infection, seroma/hematoma, temporary sensory loss, and mild or transient pain are common. Major complications occur at the donor site range in 0.7% to 39% of patients. These include infection, prolonged wound drainage, herniation of muscle and abdominal contents through the donor defect, deep hematomas, need for reoperation, pain lasting longer than 6 months, profound sensory loss, vascular and neurologic injury, unsightly scars, subluxation, gait disturbances, sacroiliac joint destabilization, enterocutaneous fistula, pelvic or iliac fracture, and heterotopic bone formation. Life-threatening complications include major vessel or visceral injury.
Neurologic injury may occur from dissection close to several nerves in the area (e.g., sciatic, lateral femoral cutaneous, and cluneal). Vascular injury to the superior gluteal vessels may occur from dissection too close to the sciatic notch. Chronic pain at the donor site, present in up to 25% of cases, may be attributable to excessive removal of bone from the sacroiliac region with violation of the sacroiliac joint.
Hu and Bohlman reported a series of 14 patients who suffered a fracture at the iliac bone graft procurement site after spine fusion. Most of these patients were elderly women with chronic medical diseases. The authors, therefore, recommended iliac bone graft procurement with caution in this group to minimize the potential for these iatrogenic fractures. Based on subsequent cadaver studies, the authors recommended leaving at least 3 cm between the anterosuperior iliac crest and the graft procurement site and a maximum distance of 3 cm from the dorsal ilium.
Although the risk of surgical complications theoretically can be minimized, certain procurement issues remain. These include increased operative time and blood loss, temporary disruption of donor-site bone structure, pain, vascular injuries, and cosmetic defects.
Bone also can be obtained from the local decompression site or from a remote site such as the rib or tibia. These sites have their own problems, however, and typically are not a first choice for spine arthrodesis.
Osteoconductive Matrices
Most other bone grafts serve primarily as an osteoconductive matrix, with minimal to no self-supplied osteogenic or osteoinductive properties. The trade-off is greater source availability and elimination of the need for a second operative site. The structural properties of the three-dimensional scaffold matrix (especially the degree of porosity) are the primary determinants of the speed and completeness of incorporation and remodeling. The osteoconductive scaffold provides an appropriate environment into which bone cells and bone morphogenetic proteins (BMPs) can migrate, adhere, and proliferate.
Allograft
Allografts initially were used only for massive grafting where autograft use was impossible. However, by 1996 allografts constituted 34% of all bone grafts performed in the United States, an increase in use of more than 14-fold compared with just a decade earlier. Today, allograft has become the most common autograft substitute or extender.
Pro
Three factors have led to the surge in popularity of allograft. First, the National Organ Transplant Act increased overall availability. Second, donor screening and tissue processing have improved safety and quality of donated tissue. Third, the manufacture of new allograft forms (e.g., dowels) has greatly improved overall allograft utility and versatility. Perhaps the greatest advantage of allograft is its wide availability in a variety of physical forms that can be customized to specific applications. Machine tooling to shape structural allograft into forms such as wedges or threaded bone dowels can allow allograft to function as both bone graft and fixation device. Other advantages include the reduction of procurement morbidity, the potential for immediate structural support, and a reasonable success rate (> 60%) reported for specific procedures (e.g., hip revision surgery, management of tumors in bone). The success rate of allograft appears dependent on the fusion procedure performed, but success rates for ventral-spinal lumbar fusions with allograft are now close to being comparable to those with autograft.
Con
Allografts, in general, do not generate results exactly equivalent to those of autografts. Allografts can vary greatly in initial bone quality, be of higher initial expense, transmit disease, and evoke immunogenic reactions. Processing constraints, required for patient safety, do not guarantee the absence of disease transmission or immunogenic reaction, but they do minimize risks posed by these adverse responses. One study of 1146 femoral heads considered suitable for bone-bank donation found unexpected disease in 8%, including three undiagnosed malignant bone tumors. Minimal processing of allograft (i.e., freezing freshly obtained bone) is not sufficient to inactivate the AIDS virus, as HIV transmission has been reported by this means.
Processing renders the graft nonviable and mitigates osteoinduction potential by destroying proteins useful in recruiting bone cells and inducing new bone formation. Because the processed allografts are less representative of human tissue compared with autografts, allografts are not as readily received and incorporated by the host. Allografts are slower to be resorbed and not as completely replaced by new bone compared with autografts. The structural integrity of the processed bone complex also is compromised, and stability at the defect site, critical for rapid healing and return to function, is more difficult to achieve. Results are especially poor for dorsal lumbar fusion, and lower reported fusion rates for allograft implants compared with autograft-only implants were found in two studies.
The quantity of allograft material is constrained by limited supply; tissue banks report difficulty with procurement because of fear of gross disfigurement at the donor site. Donor-to-donor variation results in uncertain, nonuniform quality. Bone quality varies with donor age and gender; even same-size bones from different anatomic sites in a single donor can vary in strength by as much as 20%.
A low-grade inflammatory reaction typically is associated with allograft. This immune response may contribute to allograft failure (i.e., fracture and nonunion). Because of an initial intense inflammatory reaction, new capillaries are easily thrombosed, resulting in a delay in vascularization and osteoinduction. Even at maturation, necrotic bone can account for as much as 50% or more of the graft.
A literature review of animal studies suggests a correlation between histocompatibility difference and allograft failure, both biologically and biomechanically. In a mouse model, the immunologic reaction appears to be specific to donor antigen and consists of killer/suppressor T cells, which are associated with soft tissue rejection. In humans, alloreactivity appears similar to the animal findings, resulting in an overall sensitization rate of 67%, higher than that seen after blood transfusion (12% to 50%). The immune response system may share common bone marrow-derived precursors and cytokines with the bone remodeling system, explaining the potential interaction of the immune response with bone remodeling. The most convincing evidence of a causal relationship between immunogenicity and poorer outcome is that among 29 patients studied who received allograft, those lacking sensitization to class II antigens achieved better clinical results than did sensitized patients.
The two types of allograft in common use, fresh frozen and freeze dried, differ in their processing, which gives each different advantages and disadvantages. Fresh-frozen allografts retain BMP and are stronger and more completely incorporated in host bone than freeze-dried grafts, but they also are the most immunogenic and have produced documented HIV transfer. Freeze-dried allografts are the least immunogenic and have caused no documented HIV or viral disease transmission. However, their BMP is destroyed, and they have the most compromised mechanical integrity, with decreased graft strength of up to 50% relative to freshly frozen allografts.
In summary, although allograft tissue processing is necessary, it adds expense, reduces graft function both biologically and mechanically, and does not eliminate allograft risks entirely. Despite processing, histologic evidence of a low-grade inflammatory reaction is typical. These factors indicate that allograft is an inferior graft compared with autograft.
Demineralized Bone Matrix
Demineralized bone matrix (DBM) is thought to possess more osteoinductive properties than regular allograft because of enhanced bioavailability of growth factors following the demineralization process. DBM gels and putties have become widely used in spinal fusion surgery in the United States. The first widely available DBM preparation was a gel consisting of DBM combined with a glycerol carrier. One retrospective study assessed the augmentation of local bone autograft with a DBM/glycerol composite for dorsolateral lumbar spine fusion as a means to avoid second-site autologous bone harvest. The control group used iliac crest autograft alone. The percentage of patients undergoing fusion was similar in both groups (60% and 56% for DBM and controls, respectively; P = .83).
There are several commercially available DBM substances for clinical use. Wang and colleagues studied the osteoinductibility of several DBMs by comparing the usefulness of the different types of DBM as a bone graft substitute in an athymic rat spine fusion model. They reported that there were significant differences between some of the tested products, although all products claim to have significant osteoinductive capabilities. They noted that several factors—such as differences in preprocess handling, varying demineralization times, final particle size, terminal sterilization, the differences in the carrier, and donor viability—are expected to influence the properties of a DBM product. They also emphasized that a specific, sensitive, and reliable screening assay of the osteoinductive properties of DBM and objective information about each product’s osteoinductivity are much needed. Additionally, as a comparison to the concentration of BMPs, DBM product concentrations of BMP can be up to 10 6 less than commercial BMP products.
Xenograft
Xenograft bone tissue is harvested from animals. Because of their immunogenicity, xenograft preparations generally have proven impractical for clinical use. Removal of proteinaceous and fatty materials during processing, as is done in the preparation of Kiel bone, Bio-Oss (Osteohealth, New York), or Oswestry bone, reduces immunogenicity to a degree. However, the processing required to produce this type of graft removes the osteoinductive matrix proteins. To guarantee viral inactivation, all such proteins must be removed. Processing strategies, such as freezing and freeze-drying, are less common than in the past because of unacceptable disease-transmission risk. Chemical washes have become more prevalent, but these tend to reduce or eliminate osteoinductivity.
Ceramics
Noninjectable Ceramics
Synthetic ceramics are osteoconductive but do not intrinsically possess any osteoinductive potential. The most common ceramics in current use are hydroxyapatite [Ca 10 (PO 4 ) 6 (OH) 2 ], tricalcium phosphate [Ca 3 (PO 4 ) 2 ], calcium sulfate dihydrate [CaSO 4 2(H 2 O)], and combinations thereof.
Although they exhibit different chemical properties from tissue grafts, ceramics provide off-the-shelf availability of consistently high-quality synthetic materials that have no biologic hazards. After incorporation, the strength of the repaired defect site is comparable to that of cancellous bone. Therefore, ceramics can be used as an alternative or as an addition to either cancellous autograft or allograft or as a cancellous bone void filler or bone graft extender or in sites where compression is the dominant mode of mechanical loading.
In a randomized, prospective study of 341 patients undergoing dorsal spinal fusion for idiopathic scoliosis, patients received autograft or synthetic porous ceramic blocks (macroporous biphasic calcium phosphate [MBCP], Triosite, Zimmer, Inc., Warsaw, IN; a mixture of hydroxyapatite and tricalcium phosphate). Curve correction, curve maintenance, pain, and function were comparable between the two groups 18 months postoperatively. On the other hand, wound complications were more common in the autograft group—14 patients experienced delayed healing, infection, or hematoma compared with only three wound complications in the MBCP group. In addition, 15 autograft patients had pain at the donor site at 3 months. Other donor-site complications at 3 months included seven infections, two hematomas, and four cases of delayed healing. Histologic findings showed new bone incorporating into the MBCP—evidence of good osteoconduction. These results suggest that synthetic porous ceramic is a safe and effective substitute for iliac graft autograft in this patient population.
Another prospective study of 106 cases of lumbar spinal fusion used MBCP granules mixed with autogenous bone chips and bone marrow obtained from the local spine. Dorsal deformity correction using semirigid instrumentation was performed in all patients. Only six nonunions were observed (three resulting from primary spondylolisthesis), suggesting a high success rate for MBCP in spinal fusion involving a semirigid instrumentation. The authors concluded that because the degenerative spine is not favorable to fusion, this technique offers an alternative to autograft to reduce patient morbidity from iliac bone harvest. A systematic review of ceramic used as extenders to lumbar fusion found an overall fusion rate of 86.4% regardless of ceramic product used. However, ceramics used in combination with local autograft resulted in significantly higher fusion rates compared with all other adjuncts, bone marrow aspirate, and platelet-rich plasma.
Ceramics can be costly and, in some cases, may prove prohibitive for certain surgical applications.
Rapidly Resorbing Ceramics
Scaffolds of tricalcium phosphate (the α and β forms have different crystalline structures but the same elemental and stoichiometric characteristics; the α form is formulated at 1200° C and the β form is formulated at 800° C) and calcium sulfate have been used as synthetic bone void fillers since the 1980s. Calcium phosphate contains stoichiometric amounts of calcium and phosphorus, 39% and 20% by weight, respectively, similar to those found in natural bone. It produces calcium-phosphate–rich microenvironments that stimulate osteoclastic resorption and then osteoblastic new bone formation, resulting in new bone formation within the resorbed implant. Less porous formulations resorb before complete bone ingrowth is achieved. The rate of resorption and the porosity of several bone substitutes are presented in Tables 31-2 and 31-3 .
| Ceramic | Speed of Resorption |
|---|---|
| Hydroxyapatite | Slow |
| β-Tricalcium phosphate | Intermediate |
| α-Tricalcium phosphate | Rapid |
| Calcium sulfate | Very rapid |
| Ceramic | Porosity/Osteoconductivity |
|---|---|
| Calcium phosphate | Very little |
| Hydroxyapatite | Little |
| α-Tricalcium phosphate | Intermediate |
| β-Tricalcium phosphate | Very high |
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