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.

摘要 到目前为止，开发临床上可行的体内化学传感器用于实时监测血气的努力， 危重病人体内的电解质、葡萄糖、乳酸等因分析不准确而受阻。 结果由于传感器生物兼容性问题(细胞粘连、血栓形成等)并且有很高的风险 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)。NO在当地的释放 模拟所有健康血管内壁发生的化学物质(内皮细胞不产生) 并通过免疫细胞(巨噬细胞、中性粒细胞)，有望大大提高生物相容性和 血管内传感器的杀菌性能。这将导致改进分析性能 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显然已经 研究表明，NO的原位释放显著减少了表面血栓的形成，并改善了动脉粥样硬化。 血管内氧气和葡萄糖传感器的活体分析准确性。最近，一种全新的类型 开发了一种释放NO的聚合物材料(S-亚硝硫醇浸渍导管管材)。 具有非常理想的长期货架稳定性，长期不释放，使用ETO易于灭菌，以及 低毒。我们现在希望利用这种简单和低成本的无释放化学物质来实现新的阶段 我们预期的研究将导致将这项技术转化为用于 在拟议的4年项目期结束时建立重症监护病房(ICU)。我们的主要目标将是评估 这些新材料是否可以容易地用来制造导管型电化学传感器(用于 氧、葡萄糖和乳酸)，大大提高了活体分析性能(在猪和羊身上)。 除了NO释放，我们还将探索结合新的RSNO- 固定化CD47在传感器表面的浸渍化学。CD47是一种强大的抗肿瘤药物 炎症/抗血小板激活剂，与许多炎症性疾病表面的Sirpα受体结合 细胞，包括血小板。最佳的NO释放和组合的NO释放/CD47修饰传感器用于监测 将首先并排评估氧气(PO2)、葡萄糖和乳酸(与相应的不释放NO相比 对照)在体动、静脉内注射(24小时以上)。最有希望的 从这种初步筛选中得出的方法将在完全清醒的绵羊身上进行为期10天的测试，以证明 这一新的抗血栓/抗菌性能带来的分析性能增强 植入式电化学传感器的产生。能够可靠地测量危重护理分析物 持续在患者床边的血液是生物医学传感器技术的“圣杯”，这一目标可以 只有在传感器性能不受生物兼容性和感染问题影响的情况下才能实现。