Of the 300,000 procedures performed in 1998, 9 of 10 involved the use of either autograft tissue or allograft tissue. The current standard for bone grafts is the autograft, in which tissue harvested from the patient, usually from the iliac crest, but possibly from the distal femur or the proximal tibia. The graft is then placed at the injury site. This tissue is ideal as a bone graft because it possesses all of the characteristics necessary for new bone growth, namely osteoconductivity, osteogenicity, and osteoinductivity.

Osteoconductivity refers to the situation in which the graft supports the attachment of new osteoblasts and osteoprogenitor cells. It provides an interconnected structure through which new cells can migrate and new vessels can form. Osteoinductivity refers to the ability of a graft to induce nondifferentiated stem cells or osteoprogenitor cells to differentiate into osteoblasts.

Harvesting the autograft requires an additional surgery at the donor site that can result in its own complications, such as inflammation, infection, and chronic pain that occasionally outlasts the pain of the original surgical procedure. Quantities of bone tissue that can be harvested are also limited, creating a supply problem as well.

Alternatives to autografts are allografts. Taken from donors or cadavers, allografts circumvent some of the shortcomings of autografts by eliminating donor site morbidity and issues of limited supply. However, allografts present risks as well. Because the tissue is obtained from a donor, a risk of disease transmission from donor to recipient exists. Although allograft tissue is treated by tissue freezing, freeze-drying, gamma irradiation, electron beam radiation, and ethylene oxide, to name a few methods, the risk of disease transmission is not completely removed. Some have estimated that the risk of HIV transmission alone with allograft bone is 1 case in 1.6 million population (Boyce, 1999). One case of hepatitis B transmission and 3 cases of hepatitis C transmission have been reported with allograft tissue; the latest case occurred in 1992.

Although rigorous donor screenings and tissue treatments have greatly reduced the incidence of HIV and hepatitis transmission, other diseases have been passed on as recently as 2000 and 2001. In April 2000, 2 different patients received bone-tendon-bone allografts for anterior cruciate ligament reconstruction. They received their allografts from a common donor. Each patient developed septic arthritis from the donor tissue. In November 2001, a patient underwent reconstructive knee surgery, and within 4 days of the surgery, the patient died from infection due to Clostridium sordellii.

After this and similar cases were reported, the Centers for Disease Control and Prevention began an investigation that revealed 25 other cases of allograft-related infection or illness. Although many methods can reduce the risk of disease transmission, the treatments used to sterilize the tissue remove proteins and factors, reducing or eliminating the osteoinductivity of the tissue.

Despite the benefits of autografts and allografts, the limitations of each have necessitated the pursuit of alternatives. Using the 2 basic criteria of a successful graft, osteoconduction and osteoinduction, investigators have developed several alternatives. Some of these are available for clinical use, and others are still in the developmental stage. Many of these alternatives use a variety of materials, including natural and synthetic polymers, ceramics, and composites. Others have incorporated factor- and cell-based strategies that are used either alone or in combination with other materials. This article reviews what is currently available and what is on the

Several categories of bone graft substitutes exist. These encompass varied materials, material sources, and origins (natural vs synthetic). Bone graft substitutes are composed of various materials, and many are formed from composites of 1 or more types of material. However, in each case, the composite is usually built on a base material.

Laurencin et al have suggested a classification scheme of material-based groups. Allograft-based bone graft substitutes involve allograft bone used alone or in combination with other materials (eg, AlloGro, Opteform, Grafton, Orthoblast). Factor-based bone graft substitutes are natural and recombinant growth factors used alone or in combination with other materials such as transforming growth factor–b [TGF-b], platelet-derived growth factor (PDGF), fibroblast growth factor (FGF), and bone morphogenetic protein (BMP).

Cell-based bone graft substitutes use cells to generate new tissue alone or seeded onto a support matrix (eg, mesenchymal stem cells).

Ceramic-based bone graft substitutes include calcium phosphate, calcium sulfate, and bioglass used alone or in combination (eg, OsteoGraf, Norian SRS, ProOsteon, Osteoset).

With polymer-based bone graft substitutes, both degradable and nondegradable polymers are used alone and in combination with other materials (eg, Cortoss, open porosity polylactic acid polymer [OPLA], Immix).

Bone Graft Substitutes

The use of allografts for bone repair often requires the sterilization and deactivation of proteins normally found in healthy bone. Contained in the extracellular matrix of bone tissue are the full cocktail of bone growth factors, proteins, and other bioactive materials necessary for osteoinduction and, ultimately, successful bone healing. To capitalize on this cocktail of proteins, the desired factors and proteins are removed from the mineralized tissue by using a demineralizing agent such as hydrochloric acid. The mineral content of the bone is degraded away, and the osteoinductive agents remain in a demineralized bone matrix (DBM).

The factors and proteins that exist in bone are responsible for regulating cellular activity. Growth factors bind to receptors on cell surfaces, stimulating the intracellular environment to act. Generally, this activity translates to a protein kinase that induces a series of events resulting in the transcription of messenger ribonucleic acid (mRNA) and, ultimately, into the formation of a protein to be used intracellularly or extracellularly.

With current techniques, in vitro differentiation of mesenchymal stem cells toward the osteoblast lineage is possible. To do so, stem cells are cultured in the presence of various additives such as dexamethasone, ascorbic acid, and b-glycerophosphate to direct the undifferentiated cell towards the osteoblast lineage.

The addition of TGF-b and BMP-2, BMP-4, and BMP-7 to the culture media can also influence the stem cells toward the osteogenic lineage. In research laboratories, marrow cells containing mesenchymal stem cells have been combined with porous ceramics and implanted into rat and canine critical segmental defects, with bony growth in as little as 2 months. Mesenchymal stem cells have also been seeded onto bioactive ceramics conditioned to induce differentiation to osteoblasts. These have been proposed for use in bone repair prosthetic coatings.

Approximately 60% of the bone graft substitutes currently available involve ceramics, either alone or in combination with another material. These include calcium sulfate, bioactive glass, and calcium phosphate. The use of ceramics, especially calcium phosphates, is driven in part because the primary inorganic component of bone is calcium hydroxyapatite (HA), a subset of the calcium phosphate group. In addition, calcium phosphates are osteoconductive; osteointegrative; and, in some cases, osteoinductive. They often require high temperatures for scaffold formation and have brittle properties. Therefore, they are frequently combined with other materials to form a composite.

The final group of bone graft substitutes is the polymer-based group. Polymers present some options that the other groups do not. For instance, many polymers that are potential candidates for bone graft substitutes represent different physical, mechanical, and chemical properties. These polymers used today can be loosely divided into natural polymers and synthetic polymers. These, in turn, can be divided further into degradable and nondegradable types.

New materials and approaches

Despite the many advances in bone graft substitutes, new materials and approaches to bone healing continue to be investigated. One exciting area is tissue engineering, which can be defined as the application of biological, chemical, and engineering principles to the repair, restoration, or regeneration of living tissues by using biomaterials, cells, and factors alone or in combination.

Applying the philosophy of tissue engineering to the healing of bone, Laurencin laboratories has developed biocompatible biodegradable matrices that possess many of the properties essential to successful healing. Using a microsphere-based design, Laurencin et al have created a porous biomimetic matrix that provides an osteoconductive surface for osteoblast attachment and an interconnected pore system to allow cellular proliferation and migration.

This basic design has also been combined with a ceramic to form a composite matrix. The strategy behind the composite would allow the benefits of both materials to be included in one design. By using both previously synthesized hydroxyapatite and calcium phosphate synthesized within the matrix itself, the polymer-ceramic composite fosters the mineralization of newly forming bone. A similar polymer-ceramic composite was also shown to be a viable surface for attachment and factor production of mouse stromal cells transfected to produce BMP-7.

Future directions