Chapter 2. Review of the literature

Table of Contents
2.1. Bone grafting and bone substitutes
2.2. Osteoinduction
2.3. Bone morphogenetic protein
2.4. Canine ulnar segmental defect
2.5. Treatment of a segmental bone defect with BMP
2.6. Gene therapy in a bone defect model
2.7. Other animal models with BMP
2.8. Clinical use of BMP
2.9. Other applications under development

2.1. Bone grafting and bone substitutes

In the reconstruction of skeletal defects, it often is necessary to transplant cancellous or cortical bone to restore skeletal integrity and to enhance bone healing. The clinical outcome of the grafting procedure depends on many factors, including the type of graft, the type of fixation and the host site. All bone grafts are resorbed initially, and cancellous grafts generally resorb faster than cortical grafts (Goldberg & Stevenson 1987). The materials used in bone grafting can be broadly divided into autografts, allografts, xenografts, synthetic materials, and combinations of these (Bauer & Muschler 2000). Autogenous graft has been shown to be superior to allograft in many studies, as remodelling and bone healing takes place more slowly in allografts compared to autografts (Friedlander 1987, Goldberg & Stevenson 1987, Gross et al. 1991, Kienapfel et al. 1992, Johnson & Stein 1988, Virolainen et al. 1993). The amount of autogenous bone is limited, and the additional surgical procedure causes increased morbidity in the host, which is why allografts are being used widely. Allograft bone is not without problems, however. Firstly, it includes the risks of viral diseases, such as HIV and hepatitis, and secondly, it may cause immunological reactions that interfere with the bone healing process (Burchardt 1983, Stevenson 1987).

Allografts can be processed in various ways for long-term preservation. Bone banking allows allograft bone to be widely used in clinical orthopaedics (von Versen 1992, Malinin 1992, Tomford & Mankin 1999). Freezing and freeze-drying are associated with reduced immunogenicity, and in the latter case the mechanical strength of the graft is decreased (Friedlaender 1983, Pelker et al. 1984, Wolfe & Cook 1994). In spite of wide use of bank bone woldwide, there are still many unanswered questions in allograft immunology, incorporation and remodelling (Garbuz et al. 1998, Bauer & Muschler 2000).

Xenograft bone represents an unlimited supply of available material if it could be processed to be safe for transplantation in a human host (Block & Poser 1995). Xenograft bone or xenograft collagen material have been used by some authors as a bone substitute experimentally (Salama & Weissman 1978, Salama 1983, Mehlisch et al. 1988, Hashizume et al. 1998, Young et al. 1999), but the procedure has never gained wider acceptance. Xenograft has the same inherent problems as allografts, and being from a different species, it may cause even more pronounced immunological problems. Human allograft materials are considered more effective and more widely available compared to xenografts at the present (Bauer & Muschler 2000).

Demineralized bone matrix (DBM) is an interesting option, which has been shown to have an osteoinductive potential (Urist 1965, Oikarinen & Korhonen 1979, Oikarinen 1982, Einhorn 1984, Lindholm TS et al. 1988). It is hypothesized that the rigid structure of nondecalcified bone does not permit the release of bone-inducing proteins, which become available when bone is demineralized (Guizzardi et al. 1992). Furthermore, demineralization is considered advantageous because it destroys the antigenic surface structures of bone. There is, however, marked variation in the results of various studies with DBM. In some studies DBM has been comparable to autograft bone (Oikarinen 1982, Hopp et al. 1989, Guizzardi et al. 1992), while in some others it has proven to be ineffective (Schwarz et al. 1991). Obviously, the processing techniques are important and should be standardized (Russell & Block 1999). It has also been proposed that DBM should be bioassayed prior to use due to the variation in the osteoinductive effect (Wilkins et al. 1999).

Various synthetic materials have been developed as bone substitutes and as alternatives to bone materials. These include natural coral, hydroxyapatite, tricalcium phosphate, bioactive glasses and synthetic polymers. They have been used as filling material in bone defects in experimental animal studies and also clinically (Bucholz et al. 1987, Elsinger & Leal 1995, Guillemin et al. 1987, Heise et al. 1990, Peltola 2001). The incorporation of these materials in the host bone is clearly inferior to autogenous bone grafts. They enhance osteoconduction, which is a three-dimensional process of the growth of capillaries, perivascular tissue, and osteoprogenitor cells of the host into the graft (Goldberg & Stevenson 1987). The synthetic materials are not osteoinductive, however, i.e. they do not induce the formation of new bone.

In the future, graft materials together with osteoinductive agents, i.e. proteins that induce bone, will be available for bone grafting, and their effect will probably be superior to that of autograft bone.