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

通过一氧化氮释放改善生物相容性/性能的血管内化学传感器

• 批准号: 9525342
• 负责人: MARK E MEYERHOFF
• 金额: $ 39.47万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-09-21 至 2020-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9525342
• 关键词: Adhesions; Anti-inflammatory; Arteries; Bacteria; Binding; Blood; Blood Circulation; Blood Platelets; Blood Vessels; Blood gas; Blood specimen; CD47 gene; Catheters; Cell Adhesion; Cells; Chemicals; Chemistry; Clinical; Critical Care; Critical Illness; Detection; Devices; Electrolytes; Endothelium; Enzymes; Exhibits; Exposure to; Family suidae; Foundations; Generations; Glucose; Goals; Grant; Hospitals; Hour; Human; Hydrogen Peroxide; Immobilization; Immune; Implant; In Situ; In Vitro; Infection; Infection prevention; Inflammatory; Inflammatory Response; Integral Membrane Protein; Intensive Care; Intensive Care Units; Measurement; Measures; Microbial Biofilms; Monitor; Nitric Oxide; Oxygen; Patient Care; Patients; Pediatric Hospitals; Penicillamine; Performance; Phase; Philadelphia; Physiological; Platelet Activation; Polymers; Polyurethanes; Production; Property; Proteins; Receptor Signaling; Recombinants; Research; Research Support; Risk; S-Nitrosothiols; SHPS-1 protein; Sheep; Side; Silicones; Solvents; Sterilization; Surface; Swelling; Technology; Temperature; Testing; Thrombus; Time; Toxic effect; Translating; Translations; United States National Institutes of Health; Veins; Work; animal data; antimicrobial; awake; bactericide; biomaterial compatibility; clinical practice; cost; experimental study; glucose sensor; health care quality; high risk; implantable device; implanted sensor; improved; in vivo; innovation; macrophage; miniaturize; neutrophil; novel; prevent; real time monitoring; receptor; response; scaffold; screening; sensor; sensor technology; success

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.

抽象的 迄今为止，人们正在努力开发临床上可行的体内化学传感器来实时监测血气， 危重医院患者的电解质、葡萄糖、乳酸等因分析不准确而受阻 由于传感器生物相容性问题（细胞粘附、血栓形成等）和高风险 感染。我们过去 15 年的研究一直是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）。本地发布NO 模拟所有健康血管内壁发生的化学反应（内皮细胞产生一氧化氮） 以及免疫细胞（巨噬细胞、中性粒细胞）的作用，有望大大增强生物相容性和 血管内传感器的杀菌特性。这将提高分析性能 植入传感器，感染风险更低。事实上，在 NIH 之前的支持下获得的结果已经清楚地表明 证明原位释放 NO 显着减少表面血栓形成并改善体内血栓形成 血管内氧和葡萄糖传感器的体内分析准确性。最近，一种全新的类型 已开发出 NO 释放聚合物材料（S-亚硝基硫醇 (RSNO) 浸渍导管） 具有非常理想的长期储存稳定性、长期 NO 释放、易于使用 ETO 灭菌，以及 低毒。我们现在希望利用这种简单且低成本的 NO 释放化学来实施新阶段 我们预计的研究将导致该技术转化为实时传感器技术 重症监护病房 (ICU) 在拟议的 4 年项目期结束时。我们的主要目标是评估 这些新材料是否可以很容易地用于制造导管型电化学传感器（例如 氧、葡萄糖和乳酸），表现出大大增强的体内分析性能（在猪和羊中）。 除了NO释放之外，我们还将探索结合新RSNO-的潜在优势 将 CD47 固定在传感器表面的浸渍化学。 CD47 是一种有效的抗 炎症/抗血小板活化剂，可与许多炎症表面的 SIRPα 受体结合 细胞，包括血小板。用于监测的最佳 NO 释放和组合 NO 释放/CD47 改良传感器 氧气 (PO2)、葡萄糖和乳酸将首先并排评估（与相应的非 NO 释放相比） 对照）在麻醉猪的动脉和静脉体内（超过24小时）。最有前途的 然后，将在完全清醒的绵羊身上测试 10 天以上的初步筛选方法，以证明 这种新产品的抗血栓/抗菌特性提高了分析性能 植入式电化学传感器的产生。能够可靠地测量重症监护分析物 在患者床边持续提供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。