Novel Nitric Oxide (NO)-Releasing Polymers and Their Biomedical Applications

Two common factors that can cause complications with indwelling biomedical devices are thrombus and infection. Nitric oxide (NO) is known to be a potent inhibitor of platelet activation and adhesion. Healthy endothelial cells exhibit a NO flux into the bloodstream of 0.5∼4x10-10 mol cm -2 min-1. In addition, NO that is released within the sinus cavities and by neutrophils/macrophages functions as a potent natural antimicrobial agent. Therefore, polymer materials that release NO are expected to have similar anti-thrombotic and antimicrobial properties.;In this dissertation work, two novel approaches to achieving long-term NO release from polymers were studied and evaluated for their potential biomedical applications. In the first approach, S-nitroso-N -acetypenicillamine (SNAP)-doped polymers were studied for potential hemocompatibility. The SNAP-doped Elast-eon E2As (block copolymer of poly(dimethylsiloxane) and polyurethane) creates an inexpensive polymer that can locally deliver physiologically relevant levels of NO (via thermal and photochemical reactions). SNAP was also found to be surprisingly stable in the E2As polymer during shelf-life stability and ethylene oxide sterilization studies. The SNAP/E2As polymer was coated on the inner walls of extracorporeal circulation (ECC) circuits and was found to preserve the platelet count at ∼100% of baseline and reduce thrombus area after 4 h blood flow in a rabbit model. The SNAP/E2As polymer was also used to fabricate NO-releasing catheters that were implanted in sheep veins for 7 d. The SNAP/E2As catheters significantly reduced the amount of thrombus and bacterial adhesion (in comparison to E2As control catheters).;In the second approach, the NO release from diazeniumdiolated dibutylhexanediamine (DBHD/N2 O 2)-doped polymers was significantly improved using various poly(lactic-co-glycolic acid) (PLGA) additives. Using acid-capped PLGA additives was found to cause high initial bursts of NO, while using an ester-capped PLGA additive extended the NO release for up to 14 d. The pH changes corresponding to the NO release profiles from these films was visualized by doping films with pH indicator dyes. Poly(vinyl chloride)- and Elast-eon E2As were used as the base polymers for combined DBHD/N 2 O 2 and PLGA coatings on the inner walls of ECC circuits. After 4 h of blood flow in a rabbit model, the E2As-based NOrel circuits preserved platelets at a higher level than PVC-based NOrel circuits (97% and 80% of baseline, respectively). This demonstrates that the inherent hemocompatibility properties of the base polymer can also influence the efficiency of the NO release coatings. A DBHD/N2 O 2-doped SG-80A polymer material was also studied and used to fabricate patches that were applied to scald burn wounds infected with Acinetobacter baumannii. The NO released from these patches applied to the wounds is shown to significantly reduce the A. baumannii infection after 24 h (∼4 log reduction).;The results for both of types of NO-releasing polymers studied here demonstrated greatly enhanced biocompatibility properties, in terms of reducing thrombus and infection. These materials have the potential for improving the hemocompatibility of a wide variety of blood-contacting medical devices.