This project seeks to develop and investigate methods to inhibit platelet deposition onto damaged arterial surfaces by reacting polymer segments with surface proteins exposed at sites of tissue damage. The investigators hypothesize that covalently attached polymer segments will sterically inhibit cell receptor interaction with adhesive surface ligands, thus reducing platelet deposition. Preliminary data indicates that polyethylene glycols (PEGs) with end groups reactive toward proteins can be applied to damaged arterial segments under conditions and times which would be applicable in a clinical setting. Further preliminary data shows that such covalently attached PEG segments inhibit acute platelet deposition onto these damaged human arterial segments in vitro and in balloon damaged rabbit femoral arteries in vivo. The proposed experimentation will focus on developing and refining methods for the creation of molecular barriers to thrombosis on damaged arterial surfaces, since intravascular thrombosis and the physiologic responses it potentiates remain obstacles to the success of a variety of vascular procedures and create widespread clinical morbidity and mortality. The molecular barrier technology will be developed specifically by first determining the degree of covalent PEG attachment achievable to model adhesive proteins and damaged arterial tissue surface in vitro, (under conditions tolerable in vivo). The influence of reactive PEG chemistry on this attachment will be studied. The ability of various molecular weights and surface concentrations of covalently attached PEGs to inhibit platelet deposition on to adsorbed adhesive proteins and damaged arterial surfaces will be examined. Finally, studies will be performed in a rabbit model to examine how covalent PEG attachment can interrupt acute thrombotic deposition following balloon arterial damage, prevent neointimal hyperplasia exacerbated by this acute thrombosis, and prevent restenosis following balloon angioplasty of a stenotic lesion. At the completion of this project, the investigators hope to understand how molecular parameters of tissue reactive PEGs affect the formation of molecular barriers to cell-tissue interactions. They also hope to have developed and tested a novel strategy for inhibiting acute cell-tissue interactions and plan to have specifically examined the ability of this technique to address the important clinical problem of arterial thrombosis.
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