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

用于血液接口装置的长期介导不释放有机硅聚合物

• 批准号: 10654071
• 负责人: Joseph Furgal
• 金额: $ 43.44万
• 依托单位: BOWLING GREEN STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-05-03 至 2026-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10654071
• 关键词: 3-Dimensional; Adhesions; Amputation; Anti-Bacterial Agents; Anticoagulants; Antimicrobial Effect; Bacteria; Bacterial Infections; Biocide; Biological; Bioreactors; Blood; Blood Platelets; Blood Vessels; Blood coagulation; Blood-Borne Pathogens; Buffers; Catheter-related bloodstream infection; Catheters; Cessation of life; Chemistry; Communities; Development; Devices; Effectiveness; Endothelial Cells; Endothelium; Engineering; Environment; Exhibits; Familiarity; Feedback; Fibrinogen Receptors; Growth; Health; Health Care Costs; Hospital Units; Hospitalization; Hospitals; Immobilization; In Vitro; Infection; Intensive Care Units; Knowledge; Liquid substance; Mediating; Medical; Medical Care Costs; Medical Device; Medical Research; Methods; Microbial Biofilms; Morbidity - disease rate; N-acetylpenicillamine; Nitric Oxide; Nitric Oxide Donors; Nose; Nosocomial Infections; Organism; Outcome; Output; Oxygen; Patients; Peripheral; Physiological; Platelet Activation; Polymers; Polyurethanes; Polyvinyl Chloride; Property; Pseudomonas aeruginosa; Recovery; Research; Research Personnel; Respiratory Tract Infections; Route; Scientist; Sepsis; Series; Silicon; Silicone Elastomers; Silicones; Sterilization; Structure; Surface; System; Testing; Thrombosis; Time; Tissues; Vasodilator Agents; Virus; Work; antimicrobial; biological systems; biomaterial compatibility; clinical application; controlled release; density; design; disability; experience; experimental study; hemocompatibility; improved; improved outcome; in vitro Bioassay; in vivo; interfacial; materials science; mechanical properties; microbial; prevent; tool

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.

项目概要 血栓形成和感染是长期住院患者取得积极健康结果的主要障碍 留下来。改善这些结果并降低血源性感染可能性的方法 超过30天的时间很受追捧。多年来，一系列活性一氧化氮（NO）释放和 生成材料已被纳入医疗设备中，以帮助凝血和减少感染； 然而，NO 释放 (NOrel) 材料的设计存在很大的局限性，因为大多数材料不 长时间提供良好且持续的一氧化氮通量，导致意外感染或需要 不断的换出。因此，我们建议开发可减少血栓形成的聚合物材料 通过抑制血小板粘附/激活来模仿内皮细胞并预防微生物感染。 我们将使用经 S-亚硝基-N-乙酰青霉胺改性的硅氧 3D 笼结构（倍半硅氧烷） (SNAP)，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 悬垂笼将在NO释放基团和血液之间提供强烈的相互作用，从而导致持续的 NOrel 通量。我们假设悬垂的 SNAP-3D 笼式 NO 释放聚合物将提供更好的持续性 由于其优异的生物相容性和更高的 NO 释放密度，NO 通量超过了以前的 NOrel 聚合物 基团（〜8 NO / nm3）比直接表面功能化，以及它们的极性/空间结构非常可修改 适应。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 NO 释放剂，以增强 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 释放情况 性能、物理/机械性能、耐久性、浸出和储存/灭菌稳定性。他们的能力 模拟内皮细胞 (2-4 x 10-10 mol cm-2 min-1) 和聚合物表现出的较高范围的 NO 通量 将测试并记录在生理条件下实现长达 30 天活性的材料。这 第二个目标是评估 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 将研究使用 NO 作为血小板抑制进入 GPIIb/IIIa 纤维蛋白原受体的能力 抗凝血剂采用体外生物测定方法。将在体外评估抗菌效果（生物反应器） 与导致血流的留置医疗器械相关的常见血源性病原体 感染（即铜绿假单胞菌）。我们预计拟议的 NO 释放聚合物能够达到或超过我们的要求 30 天内预计 NO 通量为 2-4 x 10-10 mol cm-2 min-1，并提供有效的杀菌和抗凝剂 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 和长期住院 ICU 患者的感染，并使其能够更快地从原发病中康复。