Bactericidal, Nonthrombogenic Intravascular Catheters

 描述：血管内导管上的感染和血栓形成是医疗实践中的主要、昂贵的问题。在过去的十年里，我们已经证明了表面一氧化氮(NO)的释放可以解决这些问题，将各种NO供体分子(如重氮二醇、S-亚硝硫醇)掺入到聚合物导管中。这项技术是基于这样一个事实，即鼻窦腔内以及中性粒细胞和巨噬细胞释放的NO是一种强大的天然抗菌和抗病毒药物。此外，正常内皮细胞分泌的NO通过阻止血小板黏附和激活来防止凝血。在相关的血管内导管动物模型中，我们已经开发出持续产生NO的聚合物，以防止生物膜形成、血小板黏附和血栓形成。尽管有效，但迄今为止使用的供体分子的成本、毒性和制备方法阻碍了临床应用。我们最近发现，NO供体分子S-亚硝基-N-乙酰青霉胺(SNAP)可以实现NO释放的所有积极作用。与早期的NO释放材料相比，掺杂/浸渍SNAP的聚合物易于制备、无毒、廉价且非常稳定。我们将开发用聚合物稳定的SNAP制作NO释放导管的新方法(例如，溶剂浸渍、NO释放多腔导管等)。Meyerhoff博士领导的化学实验室将创建和评估加载到聚氨酯和硅胶导管中的SNAP组合，优化21天的NO释放率，减少淋失率，增强耐用性，并展示在无负荷情况下进行无显著损失灭菌的能力。习博士在公共卫生学院的实验室将检测新的NO释放导管对几种已知与住院患者血管内导管感染相关的微生物的抗菌/抗生物膜活性。由巴特利特博士领导的大型动物实验室将在慢性动物试验中评估优化的NO分泌导管，以评估对生物膜和血栓形成的影响。这项生物工程研究拨款(BRG)结合了生物医学聚合物中基于RSNO的NO释放剂的新基础化学，利用这种化学制造实用设备的生物工程，证明对目标细菌菌株的有效性的微生物学研究，以及动物模型的生物学评估，所有这些都导致了临床翻译 四年了。

 DESCRIPTION: Infection and thrombosis on intravascular catheters are major, expensive problems in medical practice. Over the last ten years we have demonstrated that surface nitric oxide (NO) release can solve these problems, using various NO donor molecules (e.g., diazeniumdiolates, S-nitrosothiols (RSNOs)) incorporated into polymeric catheter tubing. This technology is based on the fact that NO released within the sinus cavities and by neutrophils and macrophages functions as a potent natural antimicrobial and antiviral agent. Further, NO secretion by the normal endothelium prevents clotting by preventing platelet adhesion and activation. We have developed polymers that continuously produce NO to prevent biofilm formation, platelet adhesion, and thrombosis in relevant animal models of intravascular catheters. Although effective, the cost, toxicity, and preparation of the donor molecules used to date have prevented clinical application. We have recently discovered that all of the positive effects of NO release can be achieved with the NO donor molecule S-nitroso-N-acetylpenicillamine (SNAP). In contrast to earlier NO release materials, polymers that are doped/impregnated with SNAP are easy to fabricate, nontoxic, inexpensive, and very stable. We will develop new methods of fabricating NO release catheters with polymer stabilized SNAP (e.g., solvent impregnation, NO releasing multilumen catheters, etc.). The chemistry laboratory directed by Dr. Meyerhoff will create and evaluate combinations of SNAP loaded into polyurethane and silicone catheters, optimize NO release rates for 21 d, reduce leaching rates, enhance durability, and demonstrate the ability to sterilize without significant loss in NO loading Dr. Bull, a bioengineer, will model NO release from certain multi-lumen catheter configurations and also oversee testing of the physical properties of the catheters (e.g., durometer, surface roughness, etc.), in terms of potential changes in such parameters as a result of SNAP impregnation. Dr. Xi's laboratory in the School of Public Health, will examine the antimicrobial/antibiofilm activity of the new NO release catheters against several microbes known to be associated with infections caused by intravascular catheters in hospitalized patients. The large animal laboratory, directed by Dr. Bartlett, will evaluate the optimized NO secreting catheters in chronic animal testing to evaluate effect on biofilm and thrombosis formation. This bioengineering research grant (BRG) combines new basic chemistry of RSNO-based NO release agents in biomedical polymers, the bioengineering to use this chemistry to make practical devices, the microbiological studies to prove effectiveness against targeted bacterial strains, and biologic evaluation in animal models, all leading to clinical translation in four years.