Biocompatible Chemical Sensors via Nitric Oxide Release

到目前为止，开发血管内化学传感器的努力能够准确、实时地监测临床上重要的血气(pH、PCO2、PO2)和电解质(如K+、Ca++等)。危重患者的血液中的水平已经下降，原因是传感器表面开始凝结以及局部动脉收缩减少了植入部位的血液流动。这项研究的长期目标是探索和优化所需的化学成分，以制造具有外部聚合物膜/膜的植入式电化学和光学血气和电解质传感器，在植入部位局部缓慢释放低水平的一氧化氮(NO)。正如在这一新计划的第一阶段所展示的那样，这种原位释放NO防止了植入的传感器表面的血小板黏附/激活，这导致了设备体内分析性能的改善。与此同时，初步数据还表明，NO的释放可能会同时扩张传感器附近的动脉，从而维持植入传感器周围的良好血流。拟议的第二阶段研究将建立在迄今取得的重大进展的基础上，特别是在含有重氮二醇化物种(作为添加剂或附加在聚合物主干上)的新型疏水聚合物材料的合成、表征和体内评估方面，这些材料可以释放NO，其产生的通量等于或高于所有正常血管内皮细胞产生的通量。将继续对这些新的释放NO的硅橡胶、聚氨酯和聚氯乙烯材料进行体外和体内生物相容性测试，并努力了解控制它们在生理条件下的储存稳定性和NO从这些聚合物中释放的因素。将用新型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生成对设备分析性能(如漂移、选择性等)的影响。用不同的NO释放聚合物制备的植入型PO2电化学传感器的体内分析准确性将使用犬模型进行评估(在相同动物中有/无NO释放的对照传感器)，以确定局部NO释放对植入部位血栓形成和血流的有效性。最后，将启动新的探索性研究，以考察利用亚硝基硫醇材料和化学/生物催化亚硝酸盐还原方法作为当前重氮二铵盐化学的潜在替代策略来制备新型NO释放疏水聚合物的可能性。

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.