Development of Hemocompatible Polymeric Materials for Blood-Contacting Medical Devices.

Abstract

The research in this dissertation focuses on the development of novel multifunctional polymeric coatings that incorporate multiple antithrombogenic and/or anti-proliferative bioactive agents. The incorporated bioactive agents, whether endogenous small molecules (nitric oxide), polysaccharides (heparin), proteins (thrombomodulin), or drugs (sirolimus), are intended to function synergistically to prevent the formation of thrombus and the proliferation of smooth muscle cells, which are considered to be two of the major causes for the failure of various blood-contacting implantable devices. New multifunctional bilayer polyurethane coatings were developed that exhibit both controlled NO release (via use embedded diazeniumdiolate NO donors) and surface-bound active TM or combined TM and heparin. Both TM and heparin’s activity were evaluated by chromogenic assays and found to be at clinically significant levels. The NO release rate could be tuned by changing the thickness of top coatings. The duration of NO release at physiologically relevant levels (1×10-10mol/min/cm^2) could be as long as 2 weeks. To control the rate of NO release of polymers containing diazeniumdiolate NO donors, more stable and less toxic lipophilic tetrapenylborate species were examined to help buffer the pH in the polymeric phase of the coatings. Furthermore, in order to completely eliminate the leaching and possible toxicity issues associated with small molecules, a new sulfonated PU was synthesized with sulfonic anionic sites covalently tethered to the PU backbones as a potential replacement for borate additives. In vitro endothelial cell and SMC studies demonstrated that such coatings exhibit much improved biocompatibility compared to films prepared with conventional tetrakis(p-chlorophenyl)borate. In addition to thrombus formation, SMC proliferation is another important cause for medical device failure, especially for stents and small-diameter vascular grafts. The use of NO, in combination with an anti-cell proliferation agent, might provide the ideal solution to reduce both clotting and restenosis risks. Thus, the first dual-functional polymeric coatings that released both sirolimus and NO were prepared. NO is released at physiologically relevant levels with simultaneous release of sirolimus from 3.00 to 0.10μgcm^2/h over a period of 2 weeks. The possibility of combining catalytic NO generation and sirolimus release was also explored by doping a selenium-derivatized PU with sirolimus.