Biocompatible Chemical Sensors Via Nitric Oxide Release/Generation

描述（由申请人提供）：迄今为止，由于传感器的生物相容性问题（细胞粘附、血栓形成、炎症反应等），获得的不准确的分析结果阻碍了开发临床可行的体内化学传感器，用于实时监测医院危重病人的血气、电解质、葡萄糖、乳酸等。该研究计划的目标是探索和优化制造体外聚合物涂层的体内化学传感器所需的化学物质，这些涂层可以缓慢释放或产生低水平的一氧化氮（NO）。一氧化氮的局部释放/生成模拟了发生在所有健康血管内壁的化学反应（内皮生成一氧化氮），有望大大提高植入传感器的生物相容性和伴随的分析性能。事实上，在NIH支持的前3个阶段的结果清楚地表明，原位释放和/或生成NO显著减少了表面血栓的形成，提高了血管内氧传感器的体内分析准确性，也减少了皮下植入的葡萄糖传感器的炎症反应。新开发的基于内源性s -亚硝基硫醇（RSNOs）在固定化Cu（II）或有机硒（RSe）位点上的自发催化分解的NO生成聚合物是制备植入式传感器的潜在最有吸引力的涂层。然而，血液中内源性RSNOs水平的任何显著变化可能最终决定这些NO生成型聚合物是否能提供相当于NO释放涂层的结果（NO供体掺杂或共价连接到聚合物上）。因此，在研究的最后阶段，最有希望的一氧化氮释放和一氧化氮生成涂层将通过在猪和兔子体内血管内（动脉和静脉）植入涂层传感器的体内研究同时进行评估。除氧传感器外，还将重点展示用这些涂层制备的静脉葡萄糖和乳酸电化学传感器的生物相容性/性能。在ICU和其他重症监护病房，这种传感器是非常需要的，因为严密的血糖控制可以显著改善患者的预后，而且血乳酸水平的趋势被视为患者康复的重要预测指标。还将使用改进的电化学RSNO传感器对实验动物的RSNO种类进行测量，以评估用生成NO涂层制备的传感器的分析性能/血栓形成与测量的RSNO血液水平是否存在明确的相关性。在病人床边连续可靠地测量血液中的重症监护分析物（血气、电解质、代谢物）的能力是生物医学传感器技术的“圣杯”，只有在传感器性能不受生物相容性问题影响的情况下，才能实现这一目标。因此，本研究的成功将对提高危重病人医疗质量的能力产生重大影响。

DESCRIPTION (provided by applicant): To date, efforts to develop clinically viable in vivo chemical sensors for real-time monitoring of blood gases, electrolytes, glucose, lactate, etc. in critically ill hospital patients have been stymied by the inaccurate analytical results obtained owing to sensor biocompatibility problems (cell adhesion, thrombus formation, inflammatory response, etc.). The goal of this research program 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 mimics the chemistry that occurs at the inner walls of all healthy blood vessels (NO production by endothelium) and is expected to greatly enhance the biocompatibility and concomitant analytical performance of the implanted sensors. Indeed, results during the first 3 phases of NIH support have clearly demonstrated that in situ release and/or generation of NO significantly reduces surface thrombus formation and improves in the in vivo analytical accuracy of intravascular oxygen sensors, and also reduces inflammatory response for glucose sensors implanted subcutaneously. Newly developed NO generating polymers, based on spontaneous catalytic decomposition of endogenous S-nitrosothiols (RSNOs) at immobilized Cu(II) or organoselenium (RSe) sites, are potentially the most attractive coatings for preparation implanted sensors. However, any significant variability in endogenous levels of RSNOs in blood may ultimately dictate whether these NO generation type polymers can provide results equivalent to NO release coatings (with NO donors doped or covalently linked to polymers). Therefore, in the final phase of studies, the most promising NO release and NO generation coatings will be evaluated side-by-side via in vivo studies with coated sensors implanted intravascularly (arteries and veins) within pigs and rabbits. Beyond oxygen sensors, greater emphasis will be placed on also demonstrating improved biocompatibility/performance for intravenous glucose and lactate electrochemical sensors prepared with these coatings. Such sensors are sorely needed in the ICU and other critical care hospital units where tight glycemic control of patients significantly improves outcomes, and where trends in blood lactate levels are viewed as an important prognosticator of patient recovery. Measurements of RSNO species in the test animals with improved electrochemical RSNO sensors will also be carried out to assess whether there is a clear correlation in analytical performance/thrombus formation for sensors prepared with the NO generating coatings vs. measured RSNO blood levels. The ability to reliably measure critical care analytes (blood gases, electrolytes, metabolites) in blood continuously at a patient's bedside is the "holy grail" for biomedical sensor technology, and this goal can only be achieved when sensor performance is not compromised by biocompatibility issues. Hence, the success of this research will have significant impact in the ability improve the quality of health care for critically ill patients. PUBLIC HEALTH RELEVANCE: The ability to accurately measure critical care analytes (blood gases, electrolytes, glucose, lactate, urea, etc.) in blood continuously at a patient's bedside with intravascular sensors is the "holy grail" for biomedical sensor technology. This goal can only be achieved when sensor performance is not compromised by biocompatibility issues that result in thrombus formation on the surface of the sensors, yielding inaccurate measurements of target analytes. Hence, success of the proposed research program will have significant impact on the ability enhance the quality of health care for critically ill patients by providing an approach (NO release/generation polymeric coatings) to dramatically improve the biocompatibility and concomitant analytical performance of miniaturized chemical sensing catheters implanted within blood vessels.