The development and characterization of thromboresistant nitric oxide releasing polymeric films.

Abstract

The preparation and characterization of hydrophobic polymer films containing nitric oxide (NO) releasing diazeniumdiolates are reported. Such an approach is examined as a means of improving the thromboresistivity of polymeric materials for biomedical applications. Several different schemes for preparing NO releasing polymer films are presented, and each is examined in terms of total amount and rate of NO generation, mechanism of NO release, biocompatibility (both <italic> in vitro</italic> and <italic>in vivo</italic>), and potential biomedical applications. The first approach involves dispersion of either methylaminohexylmethylamine diazeniumdiolate (MAHMA/N₂O₂) or linear polyethylenimine diazeniumdiolate (LPEI/N₂O₂) within the polymer matrix. The potential utility of these polymer films for improving the thromboresistivity of potentiometric ion-selective electrodes, amperometric oxygen sensors and extracorporeal circuitry tubing is demonstrated. The fundamental mechanism of NO generation from MAHMA/N₂O₂ and LPEI/N₂O₂ polymer films is also determined. In both cases, leaching of intact diazeniumdiolates and/or amine by-products from the polymer matrices is shown to occur, potentially limiting clinical applications of such materials. A second approach to preparing NO-releasing polymer materials involves covalent attachment of the diazeniumdiolate to the polymer backbone. This method is demonstrated via studies with methoxymethylpiperazine-poly(vinyl chloride)/N₂O₂ (mompip-PVC/N₂O₂). The quantitative NO release profiles from different mompipPVC/N₂O₂ formulations, biocompatibility testing and application to electrochemical sensors are presented. Several of the factors influencing NO release are also examined, including water uptake, basicity of the polymer matrix and nitrosamine formation. These parameters are further confirmed using novel heparin-based diazeniumdiolates, doped into the polymer matrix via ion-pair formation with tridodecylmethylammonium cations (TDMA<super>+</super>). The resulting films are shown to release NO at rates highly dependent on the water uptake properties of the polymer matrix (polyurethane, PVC, silicone rubber) employed. Finally, the apparent diffusion coefficients of NO through different polymer materials are measured in order to help guide the appropriate selection of polymer materials for administering or detecting NO in many applications. Transport coefficients in the range of 0.2--3.0 x10<super>-5 </super> cm<super>2</super>/sec were determined for NO in a variety of plasticized and nonplasticized polymer matrices.