Injectable Osteoinductive Biodegradable Composites

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DESCRIPTION (provided by applicant): Many clinical situations, such as spinal arthodesis, total joint arthroplasty, osteoprotic insufficiency fractures, and bone loss after skeletal trauma, may be addressed by biodegradable scaffolds that can be injected and crosslinked in situ. For injectable biodegradable materials for bone tissue engineering, design parameters include biocompatibility, viscosity, gelation time, setting time, mechanical properties in compression, torsion, and bending, and promotion of tissue formation. For minimally invasive applications, injectable systems that can be crosslinked in situ by chemical redox initiation, can promote tissue growth, and have improved torsional and bending strength are required. Recently developed injectable materials use crosslinking agents that can affect the biocompatibility of the injectable system. We hypothesized that 1) if fumaryl chloride, which contains carbon-carbon double bonds for in situ crosslinking, is copolymerized with a biocompatible macromer that has a flexible backbone such as poly(caprolactone), the copolymer may self-crosslink in the absence of a crosslinking agent; 2) covalent bonding of hydroxyapatite filler to the polymer matrix would significantly improve the torsional and bending strength of the injectable system; 3) the use of hydrogel microspheres in place of salt as porogen would significantly improve the rheological properties of the material before injection; and 4) controlled delivery of growth factors would promote tissue formation in situ. Therefore, we propose to address the issues of self-crosslinking, injectability, and covalent bonding of hydroxyapatite to the polymer scaffold. In the first aim of this project, the effect of copolymerization and crosslinking parameters on self-crosslinking and degradation characteristics of a novel poly(epsilon-caprolactone fumarate) (PCLF) macromer will be investigated to eliminate the use of a crosslinking agent in injectable systems. In the second aim, hydroxyapatite nanoparticles will be grafted with methacryloxydimethylchlorosilane to covalently bond the particulate phase to the matrix by reacting the carbon-carbon double bonds of the graft with those of the fumarate groups in the PCLF matrix. The goal of this aim is to improve the torsional and bending strengths of the composite. In the third aim, gelatin or olio(poly(ethylene glycol) fumarate) hydrogel microspheres will be used as porogen in place of salt to improve the rheological properties of the injectable formulation. In the fourth aim, the composite material will serve as a carrier for recombinant human bone morphogenic protein-2 (rhBMP-2), and the effects of composite composition and loading on release kinetics and bioactivity of rhBMP-2 will be determined.