Development of novel nitric oxide releasing materials and polymeric coatings for blood contacting biomedical applications.

摘要

To devise more biocompatible materials for use in blood contacting devices, novel polymers with either nitric oxide (NO) release alone or NO release in concert with surface-bound active heparin have been developed, with the goal of mimicking the nonthrombogenic properties of the endothelial cell (EC) layer that lines all blood vessels.; New NO releasing polymethacrylates with pendant N-diazeniumdiolated alkyldiamine moieties were synthesized and characterized. The NO releasing polymeric coatings were formulated by doping such polymer-based NO donors within PVC and silicone rubber matrices, and employing a biodegradable poly(lactide- co-glycolide) as a harmless proton-generating additive to greatly prolong the NO release of such coatings. Polymer coatings with a desired NO surface flux at/above intact EC NO levels (0.5-4 x 10-10 mol·cm-2·min-1 for at least 24 h could be prepared using this approach. Such coatings may be employed to improve blood compatibility of some short-term biomedical devices via the sustained NO release with minimal potential toxicity.; A new approach to potentially resolve serious thrombosis issues associated with hemodialysis therapies was also developed. New water-soluble polymeric NO donors, based on the diazeniumdiolated branched poly(ethylenimine)s and their derivatives, were prepared and characterized. These macromolecular NO donors (with up to 4.15 mumol/mg of total NO release) were utilized as additives to the dialysate solution of model dialysis filters. It was demonstrated that steady, controllable and physiologically relevant NO fluxes could be generated at the high surface area dialysis fiber/blood interface within hemodialysis filters. Such localized increase in NO levels may greatly decrease the risk of thrombosis.; Finally, a new polymeric coating that combines NO release with surface-bound active heparin was developed, with the aim of more closely mimicking the normal functions of the EC layer. The dual acting polymeric coatings, using PVC and polyurethanes as model matrices, were formulated to be capable of releasing tunable and physiological levels of NO for up to one week. The outermost layer of the coating also possesses surface-bound heparin with synergistic anticoagulant activity. Such EC biomimetic coatings are capable of functioning by two complementary anti-thrombosic mechanisms and, therefore, are expected to exhibit greatly enhanced thromboresistivity compared to polymers that utilize either immobilized heparin or NO release alone.