S-Nitroso-N-acetylpenicillamine (SNAP)-Based Antithrombotic and Antimicrobial Polymers for Biomedical Applications: Nitric Oxide (NO) to the Rescue

Abstract

Nitric oxide (NO) is known to be a potent inhibitor of platelet activation and adhesion. NO released by macrophages or other inflammatory cells also serves as a natural antimicrobial agent in the immune system. Therefore, polymeric materials that are capable of stable and long-term NO release should exhibit similar antithrombotic and antimicrobial properties.

In this dissertation, novel polymeric materials that can release NO at physiological relevant levels for extended time periods were examined and evaluated for their potential biomedical applications. S-Nitroso-N-acetylpenicillamine (SNAP), the NO donor compound, exhibits unprecedented shelf stability when incorporated into low water uptake polymer CarboSil 20 80A, a tri-copolymer of polyurethane, poly(dimethylsiloxane) and polycarbonate. Solid-state analysis demonstrated that SNAP can partially dissolve in CarboSil polymer (ca. 3.4-4.0 wt%) and the SNAP molecules exceeding the solubility limit crystalize via hydrogen bonding within the polymer phase to form a stable polymer-crystal composite material. The slow dissolution of the crystals ultimately contributes to the long-term NO release upon solution contact (Chapter 2). The unique NO release mechanism also directly correlates with the polymer surface area that is exposed to the aqueous solution, suggesting that a water rich layer in the outermost surfaces of the polymer material is the likely site where most of the NO is liberated from the soluble SNAP within the polymer (Chapter 3). An optimized solvent impregnation process was also developed to transform off-the-shelf medical devices, such as intravascular (IV) catheters, to NO releasing catheters (Chapter 4). For example, dip-coated CarboSil IV catheter tubing can be impregnated with up to 15 wt% SNAP loading in methanol/methyl ethyl ketone (30/70 v/v) within 2 h. Both SNAP-doped and SNAP-impregnated CarboSil catheters exhibit significantly less bacterial biofilm formation in vitro and reduced clotting in vivo when compared to the controls.

Further, dual-functional antibacterial biomaterial surfaces that combine the physical modification (e.g., topographical texture) and chemical modification (e.g., NO release) were developed, with the aim of achieving a synergistic and/or additive effect on the inhibition of bacterial adhesion. Textured CarboSil surfaces bearing ordered pillar topographies (400/400/600, 500/500/600 and 700/700/300 nm) were fabricated via a soft lithography two-stage replication process. The NO release concept was introduced either by spin-coating SNAP-doped CarboSil sub-layer in the middle of the polymer film (Chapter 5) or by impregnating SNAP into the bulk of the polymer via solvent impregnation (Chapter 6). The antibacterial results demonstrated that the dual functional polymer surfaces provide a synergistic effect in reducing bacteria adhesion of S. epidermidis and P. aeruginosa.

Overall, the stable and long-term delivery of NO from biomedical polymers provides an attractive approach to improve the hemocompatibility and antibacterial properties of a wide variety of medical devices that face biocompatibility/microbial infection challenges within the hospital setting.