NOVEL APPROACH TO NONTHROMBOGENIC POLYMER SURFACES

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Over the past several years, we have made significant progress in the mechanistic study of surface thrombus formation and prevention using novel surface modification methods. In the precious application, heparin immobilized polymer surfaces using dynamic hydrophilic spacer groups (by in situ surface immobilization and coating of SPUU-PEO-Heparin graft copolymer) demonstrated a significant reduction in thrombus formation on surfaces in in vitro, ex vivo and in vivo studies. In this renewal application, we propose to modify medical polymer surfaces using surface immobilized genetically engineered antithrombotic agent (Hirudin) and fibrinolytic (t-PA) agents. Hirudin and t-PA will be used because they demonstrate distinct pharmacologic advantages over the more commonly used heparin and urokinase, respectively. Novel surface amplification chemistry will be introduced to immobilize Hirudin or t-PA on the polymer surfaces, based on our hydrophilic spacer hypothesis. It is expected that the use of amplifying polymer and PEO spacer can increase surface bioactivity as well as the surface concentration of the immobilized agents. In addition, the dynamic hydrophilic environment at the blood/polymer interface can reduce protein absorption and platelet interaction. Hirudin (or t-PA) immobilized surfaces should suppress the formation of surface-induced thrombi by Hirudin's thrombin inhibitation (i.e., platelet activation and fibrin formation) or by t-PA's fibrinolytic activity. The detailed suppression mechanism will be investigated in both in vitro and vivo studies. Obtained results will be correlated with results form our previous studies of heparin immobilized surfaces. This valuable information will be used to provide a more effective model for surface behavior using genetically engineered bioactive agents and to design blood contacting medical devices.