Bone Void Fillers: Bone and Bone Substitutes

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Chapter 18 Bone Void Fillers

Bone and Bone Substitutes

One of the most common types of graft (second only to blood) is bone, with over 450,000 procedures using bone performed annually in the United States, and 2.2 million worldwide.1 Spine arthrodesis is the most common reason for autogenous bone harvest, with approximately 250,000 spinal fusions performed in the United States each year.2 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.36

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 a very active area of research over the past 30 years. Nevertheless, only about 10% of the 2.2 million bone graft procedures annually performed worldwide involve synthetics, because of their perceived inferiority to native autograft and allograft.1 Drawbacks of many synthetics include poor resorbability, inclusion of animal or marine-derived components, variable handling characteristics, limited availability, and added cost. 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 this potential can be realized.

Use of Cancellous Bone Grafts versus Substitutes

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.


Osteoconduction involves the apposition of growing bone to the three-dimensional surface of a suitable scaffold provided by the graft.8 Osteoconduction requires the structural and chemical environments that simulate those found in cancellous bone.9 The ideal scaffold provides dimensional stability and degrades at a rate commensurate with the speed of new bone formation.1

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 18-1 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).10,11

Graft Materials



Autograft includes osteogenic bone and marrow cells as well as an osteoconductive matrix of cartilage, minerals, matrix proteins, and osteoinductive proteins associated with the matrix.12 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%.2


Because the separation of body tissue from its blood supply results in cell death,2 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. Thus, the use of autograft does not always effect repair. 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%.2,13 Although autogenous bone is regarded as the gold standard, its biologic performance is less than ideal.14

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.15 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.2,16 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.1719 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).6 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,20 may be attributable to excessive removal of bone from the sacroiliac region with violation of the sacroiliac joint.6

Hu and Bohlman6 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, recommend iliac bone graft procurement with caution in this group to minimize the potential for these iatrogenic fractures. Based on subsequent cadaver studies, the authors recommend leaving at least 3 cm between the anterosuperior iliac crest and the graft procurement site21 and a maximum distance of 3 cm from the dorsal ilium.22

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.12,20

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 a choice of last resort.


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.14 Allograft has become the most common autograft substitute or extender for autograft.


Three factors have led to the surge in popularity of allograft.14 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.2 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).23 Success rates for ventral-spinal lumbar fusions with allograft are comparable to those with autograft.24


Allografts do not generate results equivalent to those of autografts.24 Allografts can vary greatly in initial bone quality, be of higher initial expense, transmit disease, and evoke immunogenic reactions.25 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.26 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.24

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.24 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.2,27 Results are especially poor for dorsal lumbar fusion,24 and lower reported fusion rates for allograft implants compared with autograft-only implants were found in two studies.2

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.28 Donor-to-donor variation results in uncertain, nonuniform quality.29 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%.27

A low-grade inflammatory reaction typically is associated with allograft.25 This immune response may contribute to allograft failure (i.e., fracture and nonunion).24,30,31 Because of an initial intense inflammatory reaction, new capillaries are easily thrombosed, resulting in a delay in vascularization and osteoinduction.24 Even at maturation, necrotic bone can account for as much as 50% or more of the graft.24

A literature review of animal studies suggests a correlation between histocompatibility difference and allograft failure, both biologically and biomechanically.30 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.30 In humans, alloreactivity appears similar to the animal findings, resulting in an overall sensitization rate of 67%, higher than that seen after blood transfusion (12–50%).23,32 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.30 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.23

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, are stronger and more completely incorporated in host bone than freeze-dried grafts,24 but also are the most immunogenic and have produced documented HIV transfer. Freeze-dried allograft is the least immunogenic and has caused no documented HIV or viral disease transmission. However, its BMP is destroyed, and it has the most compromised mechanical integrity, with decreased graft strength of up to 50% relative to freshly frozen allograft.2,27

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.2,25 DBM gels and putties have become widely used in spinal fusion surgery since 1990, with about 500,000 mL used for implants each year in the United States.2 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).33 Although prospective clinical studies are under way, available data suggest a role for DBM as a bone-graft extender, rather than as a bone-graft substitute, in spinal surgery.2 Now there are several commercially available DBM substances for clinical use. Wang et al. studied the osteoinductibility of each DBM by comparing the usefulness of the different types of DBM as a bone graft substitute in an athymic rat spine fusion model. He reported that there are significant differences between some of the tested products, although all products claim to have significant osteoinductive capabilities. He 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. He 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.34


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.35 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.