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），所获得的分析结果不准确，阻碍了开发用于实时监测危重医院患者血气、电解质、葡萄糖、乳酸盐等的临床可行的体内化学传感器的努力。该研究计划的目标是探索和优化制造具有外部聚合物涂层的体内化学传感器所需的化学物质，这些涂层缓慢释放或产生低水平的一氧化氮（NO）。NO的局部释放/生成模拟了在所有健康血管内壁发生的化学反应（内皮细胞产生NO），预计将大大增强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个阶段期间的结果已经清楚地证明，NO的原位释放和/或产生显著减少了表面血栓形成，并提高了血管内氧传感器的体内分析准确性，并且还减少了皮下植入的葡萄糖传感器的炎症反应。新开发的NO生成聚合物，基于自发催化分解内源性S-亚硝基硫醇（RSNOs）在固定化Cu（II）或有机硒（RSe）的网站，是潜在的最有吸引力的涂层用于制备植入式传感器。然而，血液中RSNO的内源性水平的任何显著变化可能最终决定这些NO生成型聚合物是否可以提供与NO释放涂层（NO供体掺杂或共价连接到聚合物）等同的结果。因此，在研究的最后阶段，最有希望的NO释放和NO生成涂层将通过体内研究进行并行评价，其中将涂层传感器植入猪和兔的血管内（动脉和静脉）。除氧传感器外，还将更加重视证明用这些涂层制备的静脉内葡萄糖和乳酸盐电化学传感器的生物相容性/性能得到改善。在ICU和其他重症监护病房中迫切需要这样的传感器，在这些病房中，患者的严格血糖控制显著改善了结果，并且血液乳酸水平的趋势被视为患者恢复的重要指标。还将使用改进的电化学RSNO传感器测量试验动物中的RSNO物质，以评估使用NO生成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。在患者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”，只有当传感器性能不受生物相容性问题影响时，才能实现这一目标。因此，这项研究的成功将对提高危重患者的医疗质量产生重大影响。 公共卫生相关性：准确测量重症监护分析物（血气、电解质、葡萄糖、乳酸盐、尿素等）的能力在病人床边用血管内传感器连续检测血液是生物医学传感器技术的“圣杯”。只有当传感器性能不受生物相容性问题的影响时，才能实现这一目标，生物相容性问题会导致传感器表面形成血栓，从而导致目标分析物的测量不准确。因此，拟议研究计划的成功将对通过提供一种方法（NO释放/生成聚合物涂层）来显著改善植入血管内的小型化化学传感导管的生物相容性和伴随分析性能的能力提高危重患者的医疗保健质量产生重大影响。

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.