Wednesday, March 4, 2009


Bone Graft Substitute Materials


In 1998, slightly more than 300,000 bone graft procedures were performed in the United States. Currently, this figure exceeds 500,000 in the US and approximately 2.2 million worldwide (Giannoudis et al, 2005). The estimated cost of these procedures approaches $2.5 billion per year.
Of the 300,000 procedures performed in 1998, 9 of 10 involved the use of either autograft or allograft tissue. The current standard is for autograft tissue bone grafts, in which tissue is 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, providing an interconnected structure through which new cells can migrate and new vessels can form. Osteogenicity refers to the situation when the osteoblasts that are at the site of new bone formation are able to produce minerals to calcify the collagen matrix that forms the substrate for new bone. 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, thus creating a supply problem.
Allografts are alternatives to autografts and taken from donors or cadavers, circumventing some of the shortcomings of autografts by eliminating donor-site morbidity and issues of limited supply. However, allografts present risks as well; although allograft tissue is treated by tissue freezing, freeze-drying, gamma irradiation, electron beam radiation, ethylene oxide, etc, the risk of disease transmission from donor to recipient is not completely removed. Some (Boyce et al, 1999) have estimated that the risk of human immunodeficiency virus (HIV) transmission alone with allograft bone is 1 case in 1.6 million population. A case of hepatitis B transmission (Tomford, 1995) and 3 cases of hepatitis C transmission (Conrad et al, 1995) have been reported with allograft tissue. More recently, cases of disease transmission have been reported (Centers for Disease Control and Prevention [CDC], 2001, 2002).
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 from a common donor. Each patient developed septic arthritis from the donor tissue (CDC, 2001). In November 2001, a patient underwent reconstructive knee surgery, and within 4 days of the surgery, the patient died of infection caused by Clostridium sordellii (CDC, 2002). After these and similar cases were reported, the CDC (2002) 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 which are available for clinical use and others of which are still in the developmental stage. Many of these alternatives use a variety of materials, including natural and synthetic polymers, ceramics, and composites, whereas 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 horizon.

Bone Graft Classification System

Several categories of bone graft substitutes exist (see the Table below) and encompass a variety of materials, material sources, and origins (natural vs synthetic). Many are formed from composites of 1 or more types of material; however, the composite is usually built on a base material.

Laurencin et al (2006) 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 [AlloSource, Centennial, Colo], Opteform [Exactech, Inc, Gainesville, Fla], Grafton [BioHorizons, Birmingham, Ala], OrthoBlast [IsoTis OrthoBiologics, Irvine, Calif]).
  • Factor-based bone graft substitutes are natural and recombinant growth factors, used alone or in combination with other materials such as transforming growth factor-beta (TGF-beta), 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 are 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 [DENTSPLY Friadent CeraMed, Lakewood, Colo], Norian SRS [Synthes, Inc, West Chester, Pa], ProOsteon [Interpore Cross International, Irvine, Calif], Osteoset [Wright Medical Technology, Inc, Arlington, Tenn]).
  • Polymer-based bone graft substitutes, degradable and nondegradable polymers, are used alone or in combination with other materials (eg, Cortoss [Orthovita, Inc, Malvern, Pa], open porosity polylactic acid polymer [OPLA], Immix [Osteobiologics, Inc, San Antonio, Tex]).

Allograft basedAllograft bone, used alone or in combination with other materialsAllogro, OrthoBlast, Opteform, Grafton
Factor basedNatural and recombinant growth factors, used alone or in combination with other materialsTGF-beta, PDGF, FGF, BMP
Cell basedCells used to generate new tissue alone or seeded onto a support matrixMesenchymal stem cells
Ceramic basedIncludes calcium phosphate, calcium sulfate, and bioglass, used alone or in combinationOsteograf, Norian SRS, ProOsteon, Osteoset
Polymer basedBoth degradable and nondegradable polymers, used alone or in combination with other materialsCortoss, OPLA, Immix