The ideal implant for reconstructive surgery encourages regeneration of lost tissue and disappears quickly enough to render revision surgery unnecessary.Developing and fine- tuning such a material to match the host tissue into which it is implanted requires a clear understanding of how resorbing implant and host tissue interact. This study will investigate the responses of bone and its microvasculature to resorbing polymer as the process unfolds. It will also investigate the effect on this interaction of using the polymer as a vehicle for a cytokine, recombinant bone morphogenetic protein-2 (rBMP-2). The carrier will be 50:50 molar ratio copolymer polylactide-polyglycolide (PLGA). It will be formed into threads and inserted into bone chamber window tibial implants (BCIs) through which intravital microscopy will allow observation of bone vascularization, microcirculation, vessel leakage, neo-osteogenesis and polymer resorption. Threads will be loaded with BMP-2 by imbibition. Using fluorescent indicators, pH and BMP-2 concentration changes will be measured to test two hypotheses: (l) The pH around degrading polymer in vivo is sufficiently buffered to allow osteo conduction; and (2) BMP-2 monotonically increases the rate at which trabeculae grow into an acute bone defect. Local pH changes will be assessed using intravenous injections of the fluorescent pH indicators seminaphthorhodafluor (SNARF- 1) dextran 20kDa and rBMP-2 mixed with rhodamine-FITC dextran 20kDa. Weekly color photomicrographs of fluorescent images will show changes in rBMP-2 concentration as well as pH. Blood images will be enhanced with FITC-dextran and fluorescent 1.75 micrometer microspheres and bone images with oxytetracycline and DCAF. By alternating transmitted and epi fluorescence illumination and changing fluorescence cubes on the intravital microscope, all structures of interest will be imaged and recorded for video digitization, measurement and analysis. Data will be gathered weekly from sample sizes determined by power statistics (14 rabbits) and compared with historical as well as concurrent controls. Data from blood flow and leakage measurements will be used to interpret the mechanism of buffering. Confirmation of hypothesis l will be determined by the degree to which incorporation occurs without evidence of a foreign-body reaction and by the degree to which bone and blood vessel regeneration is not inhibited by polymer thread resorption. Confirmation of hypothesis 2 will be determined by the degree to which bone apposition exceeds that for the polymer alone and the degree to which it exceeds historical controls (BCIs without polymer or BMP).
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