Studies aimed at preparing and testing the in vivo thromboresistivity/biocompatibility of novel polymeric materials capable of biomimetically generating nitric oxide (NO) from endogenous nitrosothiol species in blood are proposed. It has been discovered recently in these laboratories that organic polymers doped with certain lipophilic Cu(II)-ligand complexes generate, via a catalytic reaction, physiologically relevant levels of NO at their interface, when bathed in solutions containing nitrite and/or various nitrosothiols. Nitric oxide is known to be a potent, naturally occurring inhibitor of platelet adhesion and activation as well as smooth muscle cell proliferation. Ongoing studies in the Pi's laboratories have already demonstrated the greatly enhanced thromboresisitivity of synthetic polymers that liberate NO from novel NO adducts (diazeniumdiolates) with fluxes = to normal endothelial cells (1 x 10-10 mol/cm2min). However, use of existing NO release polymers for long-term biomedical implants (e.g., as coatings on shunts, grafts, stents, etc.) is limited by the relatively small reservoir of NO adduct that can be loaded within thin polymeric coatings. In contrast, normal blood already possesses a substantial reservoir of NO precursors in the form of nitrosothiols; formed from the oxidation of endogenous NO produced by nitric oxide synthase (NOS). It is believed that these species can be used to generate locally enhanced NO levels for extended time periods in vivo at the interface of polymers possessing Cu(II) complexes (cyclen derivatives) either doped within or covalently linked to certain biomedical grade polyurethane (PU) polymers. Complexed copper(II) can be readily reduced to Cu(I) by thiolates (e.g., glutathione, cysteine, etc.) and ascorbate in blood. The Cu(I) is then capable of reducing nitrosothiols back to NO. The principal objectives of this program will be to prepare and examine a variety of Cu(II/I)-ligand/polyurethane materials that can carry out this novel redox chemistry and further test the resulting materials for toxicity/pyrogenicity/inflammatory response in small animals, as well as thromboresistivity/biocompatibility in a longer term (28 d) implant model for arteriovenous shunts (in pigs) by co-investigators at the University of Cincinnati Medical Center. If the proposed in vivo studies with PU polymers containing Cu(II) complexes yield the expected evidence of reduced thrombosis (vs. control coatings) due to local NO generation, it is anticipated that these new biomimetic materials would have immediate applications for preparing/coating a host of biomedical implants.
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