Prevention of catheter related infections via photoactive nitric oxide delivery device

项目摘要/摘要 目前，血管内导管的临床应用面临着主要的挑战：1)感染；2)血小板 活化和表面诱导的血栓形成。导尿管细菌污染导致超过28,000人 美国每年的死亡人数，以及医疗行业令人震惊的23亿美元。 血栓形成可进一步导致血管阻塞、导管故障，甚至生命- 有危险的情况，如血栓。带有肝素粘结表面的商用导管可用于 防止凝血，但对预防感染作用不大。此外，防腐剂或抗生素导管涂层或锁 解决方案降低了细菌感染的风险，但不能阻止保护细菌的生物膜的形成。 抗生素。因此，有必要也有机会制定预防感染的设备战略 以及留置导管上的血栓，以增强通畅性和安全性。 我们和其他人的工作已经证明，从聚合物表面释放的一氧化氮(NO)可以防止血小板 激活和细菌感染。这项技术模拟血管内皮细胞衬里血管， 以及我们体内的其他细胞，不会在局部产生任何物质来防止凝血和细菌生物被膜。最近我们 发现所有的积极作用都可以通过与NO供体物理混合的聚合物实现 分子S-亚硝基-N-乙酰青霉胺(SNAP)，无毒、价廉、易合成。 聚合物中NO供体主动释放的NO减少了导管上的感染和血栓形成；然而， 无释放聚合物策略本身受到导管内无给体功能的有限存储空间的限制 限制不可用/发布的持续时间的墙。我们最近的研究表明， 利用具有侧面发光光纤的光活性NO释放聚合物开发导管轮毂装置 这使得可控的NO释放水平成为可能。这项提议的目标是开发一种导管集线器装置 包括利用NO给体共价结合到具有侧面发光纤维的聚合物的聚合物 提供光活性NO释放(无淋滤)的光学器件，以提供长期、可调的NO释放 导管接口提供有效的广谱抗菌性能并减少血栓形成 通过抑制血小板黏附/激活。新设备将适用于任何导管设备；然而， 本方案将长期重点研究组合式光活性NO释放导管集线器 用于预防感染和血栓形成的血管内导管。这个项目的成功完成将 允许进展到早期临床试验和开发新一代可插入的设备 在留置导尿管的管腔内，以防止这些并发症，同时改善患者护理。

Project Summary/Abstract Currently, clinical applications of intravascular catheters suffer from major challenges: 1) infection; and 2) platelet activation and surface-induced thrombosis. Bacterial contamination of catheters causes more than 28,000 deaths per year in the United States, as well as costing the healthcare industry a staggering $2.3 billion. Thrombus formation can further lead to obstruction of blood vessels, catheter malfunction, or even life- threatening situations such as embolism. Commercial catheters with heparin-bonded surfaces are available to prevent clotting, but do little to prevent infections. In addition, antiseptics or antibiotics catheter coatings or lock solutions decrease the risk of bacterial infection, but do not prevent biofilm formation that shields bacteria from antibiotics. Therefore, there is a necessity and opportunity to develop device strategies for preventing infection and thrombosis on indwelling catheters for enhanced patency and safety. Our work and others have demonstrated that nitric oxide (NO) release from polymer surfaces can prevent platelet activation and bacterial infection. This technology mimics the vascular endothelial cells lining the blood vessels, as well as other cells in our bodies, producing NO locally to prevent clotting and bacterial biofilm. Recently we discovered that all of the positive effects can be achieved from polymers physically blended with the NO donor molecule S-nitroso-N-acetylpenicillamine (SNAP), which is nontoxic, inexpensive, and easy to synthesize. Active NO release from the NO donors in polymers reduces infection and thrombosis on catheters; however, the NO-release polymer strategy alone is limited by the finite reservoir of NO donor functionalities within the catheter wall which limits the duration of the NO availability/release. Our recent work has shown the potential of developing a catheter hub device that utilizes photoactive NO-releasing polymers with side glowing fiber optics that enables controllable NO release levels. The goal of this proposal is to develop a catheter hub device comprised of a polymer utilizing a NO donor covalently bonded to the polymer with side glowing fiber optics to provide photoactive NO-release (without leaching) to provide long-term, tunable NO-release at the catheter interface to provide potent broad-spectrum antimicrobial properties and reduce thrombosis by inhibiting platelet adhesion/activation. The new device will be applicable to any catheter device; however, this proposal will focus on studying the combined photoactive NO-releasing catheter hub device in long-term intravascular catheters for the prevention of infection and thrombosis. Successful completion of this project will allow progression to early clinical trials and the development of a new generation of devices that can be inserted within the lumen of indwelling catheters to prevent these complications while improving patient care.