Biocompatible Chemical Sensors via Nitric Oxide Release

通过一氧化氮释放的生物相容性化学传感器

基本信息

批准号：
7036025
负责人：
MARK E MEYERHOFF
金额：
$ 24.84万
依托单位：
UNIVERSITY OF MICHIGAN AT ANN ARBOR
依托单位国家：
美国
项目类别：
财政年份：
1998
资助国家：
美国
起止时间：
1998-01-01 至 2009-12-31
项目状态：
已结题

项目摘要

DESCRIPTION (provided by applicant): Heretofore, efforts to develop in vivo chemical sensors for real-time clinical monitoring of blood gases, electrolytes, glucose, etc. in critically ill and diabetic patients have been stymied by the unreliable analytical results obtained owing to biocompatibility problems induced by sensor implantation (cell adhesion, thrombus, inflammatory response, etc.). The goal of this research 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 is expected to greatly enhance the biocompatibility of the implanted sensors, thereby yielding more reliable and clinically useful analytical data. Results from Phase I & II studies clearly demonstrate that in-situ release of NO significantly reduces surface thrombus formation and greatly improves in the in vivo analytical accuracy of intravascular oxygen sensors. Recent data now also suggest that local NO release may be beneficial to the performance of sensors placed subcutaneously (e.g., glucose sensors) by reducing the inflammatory response of the surrounding tissue. In Phase III studies, continued biocompatibility/analytical performance testing of intravascular oxygen sensors prepared with the most promising/optimized diazeniumdiolate-based NO releasing polymeric coatings are proposed (in porcine model) to better understand the precise levels of NO required to achieve reduced platelet adhesion/activation on the sensors' surface and a concomitant improvement in analytical performance. For longer-term sensor implants, a completely new strategy to generate NO locally at the surface of the devices will be explored. New polymeric coatings that possess immobilized copper ion sites will be developed to serve as catalytic surfaces for in situ conversion of endogenous nitrosothiol species (RSNO) (e.g., nitrosoglutathione, nitrosocysteine, etc.) to NO, thereby providing sustained generation of the NO species, locally, at the surface of the implanted device. Functional intravascular oxygen sensors prepared with these new copper-based coatings will be fabricated and tested for thromboresistivity as weir as in vivo analytical accuracy. In addition, experiments will be undertaken to assess the relative variations in the levels of reactive RSNO substrates in both blood (pigs) and subcutaneous fluid (rats) using electrochemical NO sensors coated with the copper ion-based coatings. The various polymeric materials developed thus far for in vivo sensors have also proven useful as coatings for other biomedical devices in which thromboresistant surfaces are sorely needed (e.g., vascular grafts, extracorporeal circuits, blood filters, etc.). Hence, the overall impact of this research on medicine is quite broad and significant.

描述（由申请人提供）：迄今为止，开发体内化学传感器的努力，用于实时临床监测血液，电解质，葡萄糖等。在重症患者和糖尿病患者中，由于传感器植入传感器引起的生物相容性问题而获得的不可靠的分析结果（细胞植入型，粘附，动力疗法，动力，发域），因此所获得的不可靠的分析结果受到了阻碍。这项研究的目的是探索和优化用外聚合物涂层制造体内化学传感器所需的化学成分，这些化学传感器可以缓慢释放或产生低水平的一氧化氮（NO）。预计本地释放/NO的生成将大大提高植入传感器的生物相容性，从而产生更可靠且在临床上有用的分析数据。 I和II期研究的结果清楚地表明，原位释放无明显降低表面血栓形成，并大大提高了血管内氧气传感器的体内分析准确性。最近的数据现在还表明，局部没有释放可能会通过减少周围组织的炎症反应来皮下置换传感器的性能（例如葡萄糖传感器）。在第三阶段的研究中，提出（在猪模型中）提出了最有前途的/优化的二醇酸盐（在猪模型中），持续的生物相容性/分析性能测试，该传感器的持续生物相容性/分析性能测试没有释放的聚合物涂层（在猪模型中），以更好地理解无法确切的水平，以确切的水平以实现降低的表面和分析性降低的降低的血小板粘附/激活。对于长期传感器植入物，将探索一种在设备表面不本地生成的全新策略。将开发具有固定铜离子位点的新的聚合涂层，以作为催化表面，用于原位转化内源性硝基硫醇种类（RSNO）（例如，硝基硫酸硫酸硫代，硝基硫酸盐，硝基细胞状态等），从而无需提供持续的物种。用这些新的基于铜的涂层制备的功能性血管内氧气传感器将被制造并测试，以作为堰，如体内分析精度。此外，将进行实验，以评估血液（猪）和皮下液（大鼠）使用电化学NO传感器涂有基于铜离子的涂层的反应性RSNO底物水平的相对变化。迄今为止，用于体内传感器开发的各种聚合物材料也已被证明可作为其他生物医学设备的涂层，其中迫切需要血栓抗体表面（例如，血管移植物，体外电路，血液过滤器等）。因此，这项研究对医学的总体影响非常广泛和重要。