To date, efforts to develop intravascular chemical sensors capable of accurate, real-time monitoring of clinically important blood gas (pH, PCO2, PO2) and electrolyte (e.g., K+, Ca++, etc.) levels within the blood of critically ill patients have failed owing to problems associated with the initiation of clotting on the sensors' surfaces as well as localized arterial constriction that diminishes blood flow at the implant site. The long term goal of this research is to explore and optimize the chemistries required to fabricate implantable electrochemical and optical blood gas and electrolyte sensors with outer polymeric films/membranes that slowly release low levels of nitric oxide (NO) locally, at the implant site. As demonstrated during the first phase of this new program, such in-situ release of NO prevents platelet adhesion/activation on the surface of the implanted sensors, and this leads to an improvement in the in vivo analytical performance of the devices. At the same time, preliminary data also points to the potential for the NO release to concomitantly dilate the artery immediately adjacent to the sensor, thereby maintaining good blood flow around the implanted sensor. The proposed Phase II studies will build upon significant progress made to date, especially with respect to the synthesis, characterization and in vivo evaluation of novel hydrophobic polymeric materials containing diazeniumdiolated species (either as additives or appended to the polymer backbone) that can release NO with fluxes at or above those generated by endothelial cells that line all normal blood vessels. Continued in vitro and in vivo biocompatibility testing of these new NO releasing silicone rubber, polyurethane and poly(vinyl chloride) materials will continue, as will efforts to understand the factors that control their storage stability and release rates of NO from these polymers under physiological conditions. Functional chemical sensors, both electrochemical and optical, will be prepared with the new NO release materials to determine the effect of local NO generation on the analytical performance of the devices (e.g., drift, selectivity, etc.). The in vivo analytical accuracy of an implanted electrochemical sensor for PO2, prepared with the various NO-release polymers, will be assessed (vs. control sensors w/o NO release in the same animals) using a canine model, to determine the effectiveness of local NO release on thrombogenicity and blood flow at the implant site. Finally, new exploratory studies will be initiated to examine the potential to utilize nitrosothiolated materials and chemical/biocatalytic nitrite reduction approaches as potential alternate strategies to the current diazeniumdiolate chemistry to formulate novel NO release hydrophobic polymers.
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