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阻碍因素 留下来。改善这些结果并减少血液感染的可能性的方法 超过30天的人非常受追捧。多年来，一系列活性一氧化氮(NO)的释放和 发电材料已被纳入医疗设备，以帮助减少血液凝块和感染； 然而，无释放(NOREL)材料的设计有很大的局限性，因为大多数材料不 在很长一段时间内提供非常好且持续的无感染，导致意外感染或需要 不断换出。鉴于此，我们建议开发可减少血栓形成的聚合物材料。 通过抑制血小板黏附/激活和防止微生物感染来模拟内皮。 我们将使用S-亚硝基-N-乙酰青霉胺修饰的硅-氧，三维笼状结构(倍半硅氧烷) (Snap)是一种生物相容的NO供体，并作为侧基固定在硅橡胶聚合物上。这些 悬挂式笼子将提供不释放基团和血液之间的强烈相互作用，从而导致持续 诺雷尔通量。我们推测，悬挂式SNAP-3D笼型无释放聚合物将提供更好的持久性 与以前的Norel聚合物相比，由于其出色的生物兼容性，没有助熔剂，NO的释放密度要高得多 基团(~8NO/Nm~3)比直接表面官能化，以及它们的极性/立体非常可改变的结构 改编。为了检验这一假设，我们提出了两个具体目标。第一个目标是开发SNAP 功能化倍半硅氧烷作为硅橡胶聚合物(PDMS)上的悬浮型缓释剂 并控制诺雷尔的能力。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。然后将对Norel聚合物进行NO释放测试 性能、物理/机械性能、耐用性、浸出性和储存/灭菌稳定性。他们有能力 模拟内皮细胞表现出的较高范围的NO通量(2-4x10-10molcm-2min-1)和聚合物 将对在生理条件下实现长达30天的活动的材料进行测试和记录。这个 第二个目标是评估诺瑞尔聚合物在血小板黏附和细菌感染方面的协同作用。 使用体外生物测定来验证生物系统中聚合物的非释放性和兼容性。这些聚合物 将研究它们利用一氧化氮作为血小板抑制GPIIb/IIIa纤维蛋白原受体的能力 抗凝剂采用体外生物测定方法。抗菌效果将在体外(生物反应器)进行评估。 与留置导致血液流动的医疗器械有关的常见血源性病原体 感染(即铜绿假单胞菌)。我们期望建议的不释放聚合物达到或超过我们的 预计30天内无流量2-4 x 10-10molcm-2min-1，并提供有效的杀菌和抗凝血剂 属性。这项研究将对减少血液凝结对健康的负面影响产生深远的影响 和感染，使长期住院的ICU患者能够更快地从原发病中恢复过来。

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.