Long-term and Mediated NO-Release Silicone Polymers for Blood Interface Devices

项目摘要 血栓形成和感染是长期住院患者积极健康结局的主要障碍 留下来改善这些结果并降低血液传播感染可能性的方法， 超过30天的都很抢手。多年来，一系列活性一氧化氮（NO）的释放和 已将生成材料并入医疗装置中以帮助减少血凝块和感染; 然而，NO释放（NOrel）材料的设计存在显著的限制，因为大多数材料不 在长时间内提供非常好的和持续的NO通量，导致意外感染或需要 不断的交换。因此，我们建议开发聚合物材料，以减少血栓形成 通过抑制血小板粘附/活化来模拟内皮并防止微生物感染。 我们将使用S-亚硝基-N-乙酰基青霉胺修饰的硅-氧，3D笼状结构（倍半硅氧烷 SNAP是一种生物相容性NO供体，并作为侧基锚定在硅橡胶聚合物上。这些 悬垂笼将提供NO释放基团和血液之间的强烈相互作用，导致持续的 NOrel通量。我们假设悬挂式SNAP-3D笼状NO释放聚合物将提供更好的持续释放。 NO通量超过以前的NOrel聚合物，因为它们具有优异的生物相容性， 基团（~8 NO/nm 3）比直接表面官能化，以及它们对于极性/空间位阻的非常可修改的结构 适应为了验证这一假设，我们提出了两个具体目标。第一个目标是开发SNAP 官能化的倍半硅氧烷作为侧基NO释放剂在硅橡胶聚合物（PDMS）上， 并控制NOrel功能。我们将使用硫醇-烯化学将倍半硅氧烷共价接枝到 PDMS，然后在测试前加载NO。然后将测试NOrel聚合物的NO释放 性能、物理/机械性能、耐久性、浸出和储存/灭菌稳定性。的能力 模拟内皮细胞表现出的较高范围的NO通量（2-4 × 10-10 mol cm-2 min-1）， 将测试和记录在生理条件下达到30天活性的材料。的 第二个目的是评价NOrel聚合物对血小板粘附和细菌感染的协同作用 使用体外生物测定来验证聚合物NO释放和生物系统中的相容性。这些聚合物 将研究它们使用NO作为血小板抑制接近GPIIb/IIIa纤维蛋白原受体的能力 抗凝剂体外生物测定法。将在体外评价抗菌作用（生物反应器） 与导致血液流动的留置医疗器械相关的常见血源性病原体 感染（即绿脓杆菌）。我们期望所提出的NO释放聚合物达到或超过我们的 在30天内，预期NO通量为2-4 x 10-10 mol cm-2 min-1，并提供有效的生物杀灭剂和抗凝剂 特性.这项研究将对减少血液凝固对健康的负面影响产生深远的影响 和感染的长期入住ICU的病人，使他们更快地从原发病恢复。

Project Summary Thrombosis and infection are major deterrents to positive health outcomes in hospital patients with long-term stays. Methods to improve these outcomes and reduce the possibility of bloodborne infection for stays up to and beyond 30 days are highly sought after. Over the years a series of active nitric oxide (NO) releasing and generating materials have been incorporated into medical devices to aid in blood clot and infection reduction; however, there are significant limitations with the designs of NO release (NOrel) materials in that most do not offer a very good and sustained NO flux over long periods of time, leading to inadvertent infections or needing constant swap outs. Due to this, we propose the development of polymeric materials that will reduce thrombosis by mimicking the endothelium via inhibition of platelet adhesion/activation and preventing microbial infections. We will use silicon-oxygen, 3D-cage structures (silsesquioxanes) modified with S-nitroso-N-acetylpenicillamine (SNAP), a biocompatible NO-donor, and anchored as pendant groups on silicone rubber polymers. These pendant cages will offer strong interactions between NO-release groups and blood fluids leading to sustained NOrel fluxes. We hypothesize that the pendant SNAP-3D cage NO release polymers will offer better sustained NO flux over previous NOrel polymers due to their excellent biocompatibility, a much higher density of NO release groups (~8 NO/nm3) than direct surface functionalization, and their very modifiable structures for polarity/steric adaptations. To test this hypothesis, we propose two specific aims. The first aim is to develop SNAP functionalized silsesquioxanes as pendent NO-release agents on silicone rubber polymers (PDMS) to enhance and control NOrel capabilities. We will use thiol-ene chemistries to covalently graft the silsesquioxanes onto PDMS, and then load them with NO before testing. The NOrel polymers will then be tested for NO-release properties, physical/mechanical properties, durability, leaching, and storage/sterilization stability. Their ability to mimic the higher range of NO flux exhibited by endothelial cells (2-4 x 10-10 mol cm-2 min-1) and for the polymer materials to achieve activity for up to 30 d under physiological conditions will be tested and documented. The second aim will evaluate the synergistic effects of the NOrel polymers on platelet adhesion and bacterial infection using in vitro bioassays for verifying polymer NO-release and compatibility in biological systems. These polymers will be studied for their ability to inhibit access to GPIIb/IIIa fibrinogen receptors using NO as a platelet anticoagulant agent with in vitro bioassay methods. The antimicrobial effects will be evaluated in vitro (bioreactor) with common bloodborne pathogens associated with indwelling medical devices which lead to bloodstream infections (i.e. Pseudomonas aeruginosa). We expect the proposed NO-release polymers to meet or exceed our expected NO flux of 2-4 x 10-10 mol cm-2 min-1 over 30 days and offer effective biocidal and anticoagulant properties. This research will have profound impact on reducing negative health consequences of blood clotting and infection of long-stay ICU patients and enable faster recovery from their primary ailments.