Biocompatible Chemical Sensors Via Nitric Oxide Release/Generation

描述(申请人提供)：到目前为止，由于传感器生物兼容性问题(细胞黏附、血栓形成、炎症反应等)，开发临床可行的体内化学传感器用于实时监测重症医院患者的血气、电解质、葡萄糖、乳酸等的努力一直受到不准确分析结果的阻碍。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活体化学传感器所需的化学成分，这些涂层可以缓慢释放或产生低水平的一氧化氮(NO)。NO的局部释放/产生模拟了所有健康血管内壁发生的化学作用(内皮产生NO)，预计将极大地提高植入传感器的生物兼容性和伴随的分析性能。事实上，NIH支持的前3个阶段的结果清楚地表明，原位释放和/或产生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，还减少了植入皮下的葡萄糖传感器的炎症反应。最新开发的基于固定化铜(II)或有机硒(RSe)位上内源S-亚硝硫醇(RSNO)自发催化分解的NO生成聚合物，可能是制备植入传感器最有吸引力的涂层。然而，血液中RSNO内源性水平的任何显著变化最终可能决定这些非生成型聚合物是否能够提供等同于NO释放涂层的结果(没有供体掺杂或共价连接到聚合物)。因此，在研究的最后阶段，将通过将涂层传感器植入猪和兔的血管内(动脉和静脉)进行体内研究，对最有希望的NO释放和NO生成涂层进行评估。除了氧气传感器外，还将更加重视展示用这些涂层制备的静脉注射葡萄糖和乳酸电化学传感器的生物兼容性/性能的改善。ICU和其他重症监护医院单位迫切需要这种传感器，在这些医院，对患者严格的血糖控制显著改善了预后，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传感器测量实验动物中的RSNO物种，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显的相关性。能够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)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兼容性问题影响的情况下，才能实现这一目标。因此，这项研究的成功将对提高危重病患者的医疗保健质量产生重大影响。 与公共健康相关：能够准确测量重症监护分析物(血气、电解质、葡萄糖、乳酸、尿素等)利用血管内传感器在患者床边持续监测血液是生物医学传感器技术的“圣杯”。只有当传感器的性能不受生物兼容性问题的影响时，才能实现这一目标，生物兼容性问题会导致传感器表面形成血栓，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通过提供一种方法(无释放/代聚合物涂层)来显著提高植入血管内的微型化学传感导管的生物兼容性和伴随的分析性能，从而对提高危重患者的医疗保健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.