The ultimate goal of this research proposal is to develop injectable orthopaedic biomaterials for treating skeletal defects with guided bone ingrowth into biodegradable polymer conduits. The biomaterial is based on a highly unsaturated linear polyester with covalently bound peptide moieties for enhancing cellular attachment to the polymer. The biomaterial also serves as a carrier for bone growth factors to stimulate the bone regeneration cascade. The proposed work involves attachment of the RGDS adhesive peptide sequence to a novel polymer, poly(propylene fumarate) (PPF), developed in our laboratory. The peptide sequence will be appropriately spaced from the polymeric backbone to provide for sufficient interaction between the peptide and stromal osteoblast receptors. The fabrication of new injectable biodegradable composite formulations will be investigated for the development of polymeric conduits for guided bone regeneration. The composite formulation will be based on PPF-co-RGDS. This unsaturated linear polyester will be crosslinked via an addition polymerization with N-vinyl pyrrolidinone. Additional components of the composite formulation will include a water soluble salt for initial porosity, a calcium phosphate matrix for formation of an osteoconductive scaffold for new bone growth, a microparticle carrier for the bone growth factor TGF-Beta1, a radical polymerization initiator and an accelerator. The combined effects of the peptide surface concentration and growth factor dose on new bone formation will be determined in vitro using a three-dimensional biodegradable polymer/stromal osteoblast model developed in our laboratory. The efficacy of the optimized peptide/growth factor composite to form new bone in an orthotopic site to restore osseous continuity will be tested using an acute segmental critical-size long- bone defect model in rats. New bone formation and graft consolidation to host bone will be assessed radiographically as a function of time. Light and fluorescence microscopy will allow quantitative and qualitative analyses of the extent, character and dynamics of new bone formation. The mechanical properties of the grafted bones will be measured to verify restoration of the integrity of the reconstituted region under functional loads. The proposed project will provide clinically valuable information regarding new injectable orthopaedic biomaterials for bone repair and replacement. It will lead to a major advance in treating skeletal defects using biocompatible and biodegradable polymers which are becoming particularly important because of the renewed concern for the safety of non-degradable implants and the potential for disease transmission with allografts.
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