The development of novel synthetic materials based upon biomimetic principles may be an important step in the generation of a biologically functional small diameter arterial prosthesis. The investigators believe that a composite structure with both membrane- and glycosaminoglycan (GAG)-mimetic components provides a rational design strategy for such an approach. Specifically, they intend to: (1) Synthesize and characterize a membrane-mimetic glycocalyx for controlled endothelial regeneration in a thromboresistant microenvironment. Integrin and GAG binding peptide sequences, as well as FGF-2 activating oligosaccharides, derived from heparan sulfate (HS), will be used as pendant groups on polymerizable phospholipid macromolecules. Substrate supported membrane assemblies will be produced, polymerized in situ, and both physiochemical and biological properties defined in vitro. (2) Define the structural and physiochemical features of a heparan sulfate based glycopolymer as a tissue regenerating matrix. Heparan-sulfate mimicking glycopolymers will be synthesized utilizing vinyl functionalized oligosaccharide monomers. FGF-2 binding and receptor activating properties will be investigated using both cellular and cell free systems. Glycopolymer/gelatin networks will be formulated with both biologically stable and proteolytically sensitive crosslinks. The ability of these matrix formulations, with or without added FGF-2, to modulate the adhesive, proliferative, and migratory properties of endothelial and smooth muscle cells will be defined. (3) Characterize the biomimetic material properties which influence thromboresistance and spontaneous endothelialization in vivo. A small diameter vascular prosthesis will be functionalized with using a baboon ex vivo shunt model and primate implant studies performed to characterize endothelial regeneration and graft patency.
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