Biocompatible Chemical Sensors via Nitric Oxide Release

迄今为止，开发能够准确实时监测危重患者血液中临床重要血气（pH、PCO2、PO2）和电解质（如K+、Ca++等）水平的血管内化学传感器的努力失败了，原因是传感器表面开始凝血以及局部动脉收缩会减少植入部位的血流量。这项研究的长期目标是探索和优化制造可植入的电化学和光学血气和电解质传感器所需的化学物质，这些传感器具有外部聚合物薄膜/膜，可以在植入部位局部缓慢释放低水平的一氧化氮（NO）。正如在这个新项目的第一阶段所证明的那样，NO的原位释放阻止了植入传感器表面的血小板粘附/激活，这导致了设备体内分析性能的提高。与此同时，初步数据也表明，一氧化氮的释放有可能同时扩张紧邻传感器的动脉，从而维持植入传感器周围良好的血流。拟议的II期研究将建立在迄今为止取得的重大进展的基础上，特别是关于含有重氮离体物质（作为添加剂或附加在聚合物骨架上）的新型疏水聚合物材料的合成、表征和体内评估，这些材料可以释放一氧化氮，其通量等于或高于所有正常血管内皮细胞产生的通量。将继续对这些新型NO释放材料硅橡胶、聚氨酯和聚氯乙烯的体外和体内生物相容性进行测试，并努力了解在生理条件下控制这些聚合物的储存稳定性和NO释放率的因素。将用新的NO释放材料制备电化学和光学功能化学传感器，以确定局部NO生成对器件分析性能的影响（例如，漂移，选择性等）。将使用犬模型评估植入的电化学传感器对PO2的体内分析准确性，该传感器由各种NO释放聚合物制备而成（与同一动物中无NO释放的控制传感器相比），以确定局部NO释放对植入部位血栓形成性和血流的有效性。最后，将启动新的探索性研究，以研究利用亚硝基硫代材料和化学/生物催化亚硝酸盐还原方法作为当前重氮二醇酯化学的潜在替代策略来制备新型NO释放疏水聚合物的潜力。

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.