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.

项目摘要 血栓形成和感染是长期医院患者阳性健康结果的主要威慑 留下来。改善这些结果并减少血源性感染的可能性的方法 超过30天的人受到追捧。多年来，一系列活跃的一氧化氮（NO）释放 生成材料已被纳入医疗设备，以帮助减少血凝块和感染。 但是，没有释放（Norel）材料的设计存在重大限制，因为大多数材料都不 在长时间内提供非常好的持续不断的助焊剂，导致无意的感染或需要 不断交换。因此，我们提出了可以减少血栓形成的聚合物材料的开发 通过通过抑制血小板粘附/激活并预防微生物感染来模仿内皮。 我们将使用用S-硝基-N-乙酰基苯胺修饰的硅氧，3D型木材结构（Silsesquioxanes） （SNAP），一种生物相容性的无偏见，并在硅橡胶聚合物上锚定为吊坠基团。这些 吊坠笼将提供无释放组和血液之间的牢固相互作用，导致持续 Norel Fluxes。我们假设吊坠Snap-3d笼没有释放聚合物将提供更好的持续 由于其出色的生物相容性，因此没有先前Norel聚合物的通量，无释放的密度要高得多 组（〜8 no/nm3）比直接表面功能化，其极性/空间的结构非常可修改 改编。为了检验这一假设，我们提出了两个具体目标。第一个目的是开发快照 官能化的硅质粉红色作为在硅橡胶聚合物（PDMS）上的垂直无释放剂以增强 并控制Norel功能。我们将使用硫醇 - 烯化学物质将锡氏菌植物共价嫁接到 PDMS，然后在测试之前不加载它们。然后将测试Norel聚合物的无释放 性质，物理/机械性能，耐用性，浸出和存储/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）表现出较高的无通量范围，并为聚合物 在生理条件下最多可实现30天的活动的材料将进行测试和记录。这 第二个目标将评估Norel聚合物对血小板粘附和细菌感染的协同作用 使用体外生物测定验证生物系统中的聚合物无释放和兼容性。这些聚合物 将研究其抑制使用NO作为血小板的GPIIB/IIIA纤维蛋白原受体的能力 具有体外生物测定方法的抗凝剂。将在体外评估抗菌作用（生物反应器） 与常见的血源性病原体与留置医疗设备相关，这导致血液 感染（即铜绿假单胞菌）。我们希望提议的无释放聚合物能够满足或超过我们的 预计在30天内没有2-4 x 10-10 mol cm-2 min-1的通量，并提供有效的杀菌剂和抗凝剂 特性。这项研究将对减少血液凝结的负面健康后果产生深远的影响 以及长期ICU患者的感染，并使他们的主要疾病更快地恢复。