Intravascular Chemical Sensors with Improved Biocompatiblity/Performance via Nitric Oxide Release

摘要 迄今为止，开发用于实时监测血气的临床上可行的体内化学传感器的努力， 电解质、葡萄糖、乳酸盐等在重症医院患者中的不准确分析 由于传感器生物相容性问题（细胞粘附、血栓形成等）导致的结果而且很有可能 感染我们在过去15年的研究一直在探索和优化所需的化学物质， 制造体内化学传感器，缓慢释放低水平的一氧化氮（NO）。当地释放NO 模拟所有健康血管内壁发生的化学反应（内皮细胞产生NO） 和免疫细胞（巨噬细胞、嗜中性粒细胞）的作用，并预期大大增强生物相容性， 血管内传感器的杀菌特性。这将导致改进的分析性能， 植入式传感器和更低的感染风险。事实上，在先前NIH支持下获得的结果显然 表明原位释放NO显著减少表面血栓形成，并改善血管内血栓形成。 血管内氧和葡萄糖传感器的体内分析准确性。最近，一种全新的 已经开发了释放NO的聚合物材料（S-亚硝基硫醇（RSNO）浸渍的导管）， 具有非常理想的长期贮存稳定性、长期NO释放、易于用ETO灭菌，和 低毒性。我们现在希望利用这种简单且低成本的NO释放化学来实施新的阶段 我们预计将导致这项技术的翻译为实时传感器技术， 在拟议的4年项目期结束时，重症监护病房（ICU）。我们的首要目标是评估 这些新材料是否可以容易地用于制造导管型电化学传感器（用于 氧、葡萄糖和乳酸盐），其表现出极大增强的体内分析性能（在猪和羊中）。 除了NO的释放，我们还将探索结合新的RSNO- 浸渍化学与固定的CD 47在传感器的表面上。CD 47是一种有效的抗- 炎症/抗血小板活化剂，结合许多炎性细胞表面的SIRPα受体 细胞，包括血小板。最佳NO释放和组合NO释放/CD 47修饰传感器用于监测 氧（PO 2）、葡萄糖和乳酸盐将首先被并排评估（相对于相应的非NO释放 对照）在麻醉猪的动脉和静脉内体内（超过24小时）。最有前途的 然后，将在完全清醒的绵羊中进行10天以上的试验，以证明 由于这种新的抗血栓形成/抗微生物特性， 可植入电化学传感器的产生。能够可靠地测量重症监护分析物， 在病人床边连续采集血液是生物医学传感器技术的“圣杯”，这一目标可以 只有当传感器性能不受生物相容性和感染问题影响时才能实现。

ABSTRACT 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 inaccurate analytical results due to sensor biocompatibility problems (cell adhesion, thrombus formation, etc.) and a high risk of infection. Our research over the past 15 years has been to explore and optimize the chemistry required to fabricate in vivo chemical sensors that slowly release low levels of nitric oxide (NO). The local release of NO mimics the chemistry that occurs at the inner walls of all healthy blood vessels (NO production by endothelium) and by immune cells (macrophages, neutrophils) and is expected to greatly enhance the biocompatibility and bactericidal properties of the intravascular sensors. This will lead to improved analytical performance of the implanted sensors and less risk of infection. Indeed, results obtained with prior NIH support have clearly demonstrated that in situ release of NO significantly reduces surface thrombus formation and improves the in vivo analytical accuracy of intravascular oxygen and glucose sensors. Very recently, a completely new type of NO releasing polymer material (S-nitrosothiol (RSNO) impregnated catheter tubing) has been developed that possesses highly desirable long-term shelf stability, long-term NO release, ease of sterilization with ETO, and low toxicity. We now wish to utilize this simple and low cost NO release chemistry to implement a new phase of research that we anticipate will lead to translation of this technology to real-time sensor technology for the intensive care units (ICU) at the end of the proposed 4-year project period. Our primary goal will be to assess whether these new materials can be readily used to fabricate catheter type electrochemical sensors (for oxygen, glucose, and lactate) that exhibit greatly enhanced in vivo analytical performance (in pigs and sheep). In addition to NO release, we will also explore the potential advantages of combining the new RSNO- impregnation chemistry with immobilized CD47 on the surface of the sensors. CD47 is a potent anti- inflammatory/anti-platelet activation agent that binds to the SIRPα receptor on surfaces of many inflammatory cells, including platelets. Optimal NO release and combined NO release/CD47 modified sensors for monitoring oxygen (PO2), glucose, and lactate will first be evaluated side-by-side (vs. corresponding non-NO release controls) in vivo within arteries and veins of anesthetized pigs (over 24 h period). The most promising approach derived from this initial screening will then be tested in fully awake sheep over 10 d periods to prove the enhanced analytical performance resulting from the antithrombotic/antimicrobial properties of this new generation of implantable electrochemical sensors. The ability to reliably measure critical care analytes 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 and infection issues.