The control of keratinocyte, fibroblast, and endothelial cell (EC) migration behavior are important steps in dermal wound healing. In this proposal, we hypothesize that heparan sulfate (HS), as a plurifunctional glycoasminoglycan which can act as a reservoir for dermal cell chemoattractants and mitogens, including FGF-1 and FGF-2, establishes an important biomimetic paradigm for the generation of neoglycopolymers with tailored biological and structural properties for use in controlled regeneration of the skin. We anticipate that these model materials will also provide important tools for defining the molecular mechanisms which control the behavior of dermal fibroblasts, ECs, and keratinocytes on natural, as well as synthetic surfaces. Specifically, we intend to: 1) Synthesize and characterize heparan sulfate based glycopolymers as synthetic matrix components which potentiate receptor specific activities of FGF-1 and FGF-2. Heparan-sulfate mimicking glycopolymers will be synthesized utilizing vinyl functionalized oligosaccharide monomers. Confirmation of polymer structure will be obtained by 1H and 13C NMR, IR spectroscopy, and gel permeation chromatography. FGF-1 and FGF-2 binding and receptor activating properties will be investigated using both cellular and cell free systems. The capacity of soluble HS-mimetic glycopolymers to enhance the proliferative and migratory properties of keratinocytes and fibroblasts, as well as dermal microvascular endothelial cells will be defined in vitro. 2) Define the biomimetic material properties of neoglycopolymer/gelatin matrices which mediate dermal and epidermal cell migration and proliferation in vitro. Glycopolymer/gelatin blends will be formulated. The ability of these matrix formulations, with or without added FGF-1 and FGF-2, to modulate the adhesive, proliferative, and migratory properties of keratinocytes and fibroblasts, as well as dermal microvascular endothelial cells will be determined.
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