Nitric oxide (NO) is known to be a potent inhibitor of platelet activation and adhesion. Healthy endothelial cells that line the inner walls of all blood vessels exhibit a NO flux of 0.5~4×10−10 mol cm−2 min−1 that helps prevent thrombosis. Materials with a NO flux that is equivalent to this level are expected to exhibit similar anti-thrombotic properties. In this study, five biomedical grade polymers doped with S-nitroso-N-acetylpenicillamine (SNAP) were investigated for their potential to control the release of NO from the SNAP within the polymers, and further control the release of SNAP itself. SNAP in the Elast-eon E2As polymer creates an inexpensive, homogeneous coating that can locally deliver NO (via thermal and photochemical reactions) as well slowly release SNAP. Furthermore, SNAP is surprisingly stable in the E2As polymer, retaining 82% of the initial SNAP after 2 months storage at 37°C. The E2As polymer containing SNAP was coated on the walls of extracorporeal circuits (ECC) and exposed to 4 h blood flow in a rabbit model of extracorporeal circulation to examine the effects on platelet count, platelet function, clot area, and fibrinogen adsorption. After 4 h, platelet count was preserved at 100±7% of baseline for the SNAP/E2As coated loops, compared to 60±6% for E2As control circuits (n=4). The SNAP/E2As coating also reduced the thrombus area when compared to the control (2.3±0.6 and 3.4±1.1 pixels/cm2, respectively). The results suggest that the new SNAP/E2As coating has potential to improve the thromboresistance of intravascular catheters, grafts, and other blood contacting medical devices, and exhibits excellent storage stability compared to previously reported NO release polymeric materials.

Biomedical devices are essential for patient diagnosis and treatment; however, when blood comes in contact with foreign surfaces or homeostasis is disrupted, complications including thrombus formation and bacterial infections can interrupt device functionality, causing false readings and/or shorten device lifetime. Here, we review some of the current approaches for developing antithrombotic and antibacterial materials for biomedical applications. Special emphasis is given to materials that release or generate low levels of nitric oxide (NO). Nitric oxide is an endogenous gas molecule that can inhibit platelet activation as well as bacterial proliferation and adhesion. Various NO delivery vehicles have been developed to improve NO’s therapeutic potential. In this review, we provide a summary of the NO releasing and NO generating polymeric materials developed to date, with a focus on the chemistry of different NO donors, the polymer preparation processes, and in vitro and in vivo applications of the two most promising types of NO donors studied thus far, N-diazeniumdiolates (NONOates) and S-nitrosothiols (RSNOs).

The prolonged and localized delivery of nitric oxide (NO), a potent antithrombotic and antimicrobial agent, has many potential biomedical applications. In this work, the origin of the long-term storage stability and sustained NO release mechanism of S-nitroso-N-acetyl-d-penicillamine (SNAP)-doped CarboSil 20 80A polymer, a biomedical thermoplastic silicone-polycarbonate-urethane, is explored. Long-term (22 days) localized NO release is achieved by utilizing a cross-linked silicone rubber as topcoats, which can greatly reduce the amount of SNAP, NAP, and NAP disulfide leaching from the SNAP-doped CarboSil films, as measured by LC–MS. Raman spectroscopy and powder X-ray diffraction characterization of SNAP-doped CarboSil films demonstrate that a polymer–crystal composite is formed during the solvent evaporation process when SNAP exceeds its solubility in CarboSil (ca. 3.4–4.0 wt %). Further, when exceeding this solubility threshold, SNAP exists in an orthorhombic crystal form within the bulk of the polymer. The proposed mechanism of sustained NO release in SNAP-doped CarboSil is that the solubilized SNAP in the polymer matrix decomposes and releases NO, primarily in the water-rich regions near the polymer/solution interface, and the dissolved SNAP in the bulk polymeric phase becomes unsaturated, resulting in the dissolution of crystalline SNAP within the bulk of the polymer. This is a very slow process that ultimately leads to NO release at the physiological flux levels for >3 weeks. The increased stability of SNAP within CarboSil is attributed to the intermolecular hydrogen bonds between the SNAP molecules that crystallize. This crystallization also plays a key role in maintaining RSNO stability within the CarboSil polymer for >8 months at 37 °C (88.5% remains). Further, intravascular catheters fabricated with this new material are demonstrated to significantly decrease the formation of Staphylococcus aureus biofilm (a leading cause of nosocomial bloodstream infections) (in vitro) over a 7 day period, with 5 log units reduction of viable cell count on catheter surfaces. It is also shown that the NO release catheters can greatly reduce thrombus formation on the catheter surfaces during 7 h implantation in rabbit veins, when compared to the control catheters fabricated without SNAP. These results suggest that the SNAP-doped CarboSil system is a very attractive new composite material for creating long-term NO release medical devices with increased stability and biocompatibility.