Novel Biocompatible/Antimicrobial Materials Based on Nitric Oxide Release/Generation.

Abstract

Thrombus formation and bacterial infection are two major problems that are associated with indwelling biomedical devices. In this dissertation work, coatings that are capable of releasing or generating nitric oxide (NO), a potent anti-platelet and antimicrobial agent, have been developed to solve the biocompatibility issues. First, diazeniumdiolate doped-poly(lactic-co-glycolic acid) (PLGA)-based NO release coatings with controllable NO release profiles can be prepared with lifetimes of up to 15 d at room temperature and 10 d at 37°C. The NO release coatings exhibit significant antibiofilm properties after one week incubation in a CDC biofilm reactor, which provided both renewable nutrient sources and shear forces. In particular, compared to a silicone rubber surface, an NO release film with a base layer of 30 wt% dibutyhexyldiamine diazeniumdiolate (DBHD/N2O2) mixed with poly(lactic acid) (PLL) exhibited ~ 98.4% reduction in biofilm biomass of S. aureus and ~ 99.9% reduction for E. coli at 37 °C. NO can also be generated from endogenous NO donors such as S-nitrosothiols (RSNOs) by utilizing catalytic materials. A carboxyl-ebselen-based layer-by-layer (LbL) film was fabricated by alternatively assembling carboxyl-ebselen linked polyethylenimine (e-PEI) and alginate (Alg) onto substrates followed by salt annealing and cross-linking. After soaking in sheep blood for 24 h, a polyurethane catheter coated with (e-PEI/Alg)50 exhibit an NO flux of 3×10-10 mol cm-2 min-1 in a reservoir containing physiological levels of RSNO and thiols. The LbL film is also capable of generating superoxide, a potent antimicrobial agent. In-vitro antimicrobial tests demonstrated that a (e-PEI/Alg)50 film is capable of killing 98.2 % E. coli in solution and reducing ~87% E. coli surface coverage within 2 h at 37°C. In addition, a novel CuO nanoparticle-doped polyurethane film with less leaching of copper and minimized toxicity issue compared with a similar film doped with Cu nanoparticles is prepared. The film is capable of catalytically generating NO for 16 days at 37 °C. With their proven potential antithrombotic or antimicrobial properties, the developed NO release and NO generation coatings are expected to improve the biocompatibility of indwelling surfaces, reduce the medical cost and save patients’ lives.