Biocompatible Chemical Sensors via Nitric Oxide Release

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Heretofore, efforts to develop in vivo chemical sensors for real-time clinical monitoring of blood gases, electrolytes, glucose, etc. in critically ill and diabetic patients have been stymied by the unreliable analytical results obtained owing to biocompatibility problems induced by sensor implantation (cell adhesion, thrombus, inflammatory response, etc.). The goal of this research is to explore and optimize the chemistries required to fabricate in vivo chemical sensors with outer polymeric coatings that slowly release or generate low levels of nitric oxide (NO). The local release/generation of NO is expected to greatly enhance the biocompatibility of the implanted sensors, thereby yielding more reliable and clinically useful analytical data. Results from Phase I & II studies clearly demonstrate that in-situ release of NO significantly reduces surface thrombusformation and greatly improves in the in vivo analytical accuracy of intravascular oxygen sensors. Recent data now also suggest that local NO release may be beneficial to the performance of sensors placed subcutaneously (e.g., glucose sensors) by reducing the inflammatory response of the surrounding tissue. In Phase III studies, continued biocompatibility/analytical performance testing of intravascular oxygen sensors prepared with the most promising/optimized diazeniumdiolate-based NO releasing polymeric coatings are proposed (in porcine model) to better understand the precise levels of NO required to achieve reduced platelet adhesion/activation on the sensors' surface and a concomitant improvement in analytical performance. For longer-term sensor implants, a completely new strategy to generate NO locally at the surface of the devices will be explored. New polymeric coatings that possess immobilized copper ion sites will be developed to serve as catalytic surfaces for in situ conversion of endogenous nitrosothiol species (RSNO) (e.g., nitrosoglutathione, nitrosocysteine, etc.) to NO, thereby providing sustained generation of the NO species, locally, at the surface of the implanted device. Functional intravascular oxygen sensors prepared with these new copper-based coatings will be fabricated and tested for thromboresistivity as weir as in vivo analytical accuracy. In addition, experiments will be undertaken to assess the relative variations in the levels of reactive RSNO substrates in both blood (pigs) and subcutaneous fluid (rats) using electrochemical NO sensors coated with the copper ion-based coatings. The various polymeric!materials developed thus far for in vivo sensors have also proven useful as coatings for other biomedical devices in which thromboresistant surfaces are sorely needed (e.g., vascular grafts, extracorporeal circuits, blood filters, etc.). Hence, the overall impact of this research on medicine is quite broad and significant.