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，努力开发临床上可行的体内化学传感器以实时监测血液， 电解质，葡萄糖，裂缝等。病重患者患者因分析不准确而受阻 结果是由于传感器生物相容性问题（细胞粘合剂，血栓形成等）以及高风险 感染。在过去的15年中，我们的研究是探索和优化所需的化学反应 制造体内化学传感器，缓慢释放低水平的一氧化氮（NO）。本地版本否 模仿所有健康血管内壁发生的化学（无内皮产生） 并通过免疫细胞（巨噬细胞，中性粒细胞），并有望大大提高生物相容性和 血管内传感器的杀菌特性。这将导致改善的分析性能 植入传感器和感染风险较小。实际上，先前的NIH支持获得的结果显然具有 证明原位释放无明显地减少表面血栓形成并改善IN 血管内氧和葡萄糖传感器的体内分析精度。最近，一种全新的类型 尚未开发出释放聚合物材料（S-硝基硫醇（RSNO）浸渍导管管） 具有高度理想的长期货架稳定性，长期无释放，用ETO进行灭菌和 低毒性。我们现在希望利用这种简单而低成本的没有释放化学来实施新阶段 我们期望的研究将导致该技术转化为实时传感器技术 在拟议的4年项目期结束时，重症监护病房（ICU）。我们的主要目标是评估 这些新材料是否可以轻易用于制造导管型电化学传感器（用于 氧气，葡萄糖和乳酸）暴露了体内分析性能非常增强（在猪和绵羊中）。 除了没有释放外，我们还将探讨将新的rsno-合并的潜在优势 在传感器表面上用固定的CD47浸渍化学。 CD47是一种潜在的抗 在许多炎症表面上与SIRPα受体结合的炎症/抗血小板激活剂 细胞，包括血小板。最佳无释放，并组合无版本/CD47修改传感器进行监视 氧（PO2），葡萄糖和葡萄酸盐将首先并排评估（相对于相应的非释放 对照）在麻醉猪的动脉和静脉内体内（在24小时内）。最有前途的 然后，将在10 d期间完全清醒的绵羊中测试此初始筛查的方法，以证明 该新的抗重蛋/抗菌特性产生的分析性能增强 产生可植入的电化学传感器。可靠测量重症监护分析物的能力 在患者的床边连续血液是生物医学传感器技术的“圣杯”，这个目标可以 仅当没有因生物相容性和感染问题而损害传感器性能时才能实现。