The preparation, characterization, and preliminary biomedical application of various nitric oxide (NO)-releasing fumed silica particles (0.2-0.3 microm) are reported. The tiny NO-releasing particles are synthesized by first tethering alkylamines onto the surface of the silica using amine-containing silylation reagents. These amine groups are then converted to corresponding N-diazeniumdiolate groups via reaction with NO(g) at high pressure in the presence of methoxide bases (e.g., NaOMe). N-Diazeniumdiolate groups were found to form more readily with secondary amino nitrogens than primary amino nitrogens tethered to the silica. Different alkali metal cations of the methoxide bases, however, have little effect on the degree of N-diazeniumdiolate formation. The N-diazeniumdiolate moieties attached on the silica surface undergo a primarily proton-driven dissociation to NO under physiological conditions, with an "apparent" reaction order somewhat greater than 1 owing to local increases in pH at the surface of the particles as free amine groups are generated. The rates of N-diazeniumdiolate dissociation are further related to the parent amine structures and the pH of the soaking buffer. The N-diazeniumdiolate groups also undergo slow thermal dissociation to NO, with zero-order dissociation observed at both -15 and 23 degrees C. It is further shown that the resulting NO-releasing fumed silica particles can be embedded into polymer films to create coatings that are thromboresistant, via the release of NO at fluxes that mimic healthy endothelial cells (EC). For example a polyurethane coating containing 20 wt % of NO-releasing particles prepared with pendant hexane diamine structure (i.e., Sil-2N[6]-N(2)O(2)Na) is shown to exhibit improved surface thromboresistivity (compared to controls) when used to coat the inner walls of extracorporeal circuits (ECC) employed in a rabbit model for extracorporeal blood circulation.

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The synthesis, characterization, and biomedical application in preparing more thromboresistant polymeric coatings for a series of lipophilic dialkyldiamine-based diazeniumdiolatesare described. Dialkylhexamethylenediamine diazeniumdiolates of the form RN[N(O)NO](-)(CH(2))(6)NH(2)(+)R, where R = CH(3), CH(2)CH(3), (CH(2))(2)CH(3), (CH(2))(3)CH(3), (CH(2))(4)CH(3,) (CH(2))(5)CH(3), and (CH(2))(11)CH(3), are prepared via reaction of the corresponding diamine with NO. The more lipophilic diazeniumdiolates [e.g., R = (CH(2))(3)CH(3)] can be incorporated into hydrophobic polymeric films (e.g., plasticized PVC), and the resulting materials release NO for extended periods of time upon exposure to PBS buffer. The mechanism of NO release from these films is examined in detail. More stable initial NO release can be achieved by adding lipophilic anionic species (e.g., tetraphenylborate derivative) to the polymeric material to buffer the activity of protons within the organic phase. It is shown that the use of these new lipophilic NO-donors in polymers provides the ability to tailor NO release rates for a variety of medical applications. As an example, polymers doped with N,N'-dibutylhexamethylenediamine diazeniumdiolate and a tetraphenylborate derivative are employed as coatings for vascular grafts in sheep. The NO release grafts exhibited enhanced performance and had an average 95% thrombus-free surface area compared to 42% for the corresponding control grafts when examined after 21d of implantation.