Bioinspired antifouling and thromboresistant polymers for blood-contacting interfaces

项目总结/摘要 目前，血管内导管的临床应用遭受主要挑战：1）血小板活化和血小板聚集。 表面诱导的血栓形成，2）蛋白质和细菌对表面的生物污染，以及3）感染。血栓 形成可进一步导致血管阻塞、导管故障或甚至危及生命的情况 例如栓塞。在美国，导管的细菌污染每年导致超过28，000人死亡 美国，以及成本医疗保健行业惊人的23亿美元。市售肝素导管- 粘合表面可用于防止凝血，但对防止感染作用不大。此外，涂层导管 使用防腐剂或抗生素可降低细菌感染的风险，但不能防止生物膜的形成， 保护细菌免受抗生素的侵害。因此，有必要和机会进行联合收割机战略， 防止血栓形成和感染到单个可植入装置涂层中，以增强开放性和安全性。 我们的工作和其他人已经证明，从聚合物表面释放的一氧化氮（NO）可以防止血小板聚集。 激活和细菌感染。这项技术模拟了血管内皮细胞， 以及我们体内的其他细胞，局部产生NO以防止凝血和细菌生物膜以及随后的 感染.最近，我们发现，所有的积极效果都可以从掺杂有 NO供体分子S-亚硝基-N-乙酰青霉胺（SNAP），其无毒、廉价且易于 合成。一氧化氮的释放单独可以抑制血小板在聚合物/血液界面的局部功能，但它 不能阻止纤维蛋白原吸附和纤维蛋白形成，而纤维蛋白形成在凝块形成中起关键作用。液体- 灌注表面表现出对生物污染和蛋白质吸附的抗性。我们最近的工作表明， 将光滑的拴系液体全氟化碳（TLP）表面与浸渍有释放NO的聚合物相结合， 部分降低蛋白质吸附和血小板粘附/活化显著优于NO释放 聚合物单独。该提案的目标是开发、优化和评估一种新型聚合物， 通过浸渍NO释放分子抑制血小板粘附和活化的联合收割机试剂， 以及使用注入液体的TLP表面抑制生物污垢。生物材料实验室由Dr。 Escherbois将开发合成和聚合物制造方法，优化NO释放水平，评估 耐久性，研究灭菌/储存稳定性，并评价抗微生物性能， 与导管感染相关的常见微生物。半田博士的实验室将研究血液成分 相互作用，并进行慢性动物研究，以评价导管的血栓形成和感染。 新聚合物将适用于任何血液接触器械;然而，该提案将重点研究 在长期（长达30天）血管内导管中对凝血的联合作用 和感染该项目的成功完成将使进展到早期临床试验和开发 新一代的导管，可以减少并发症，同时提高病人护理的成功。

Project Summary/Abstract Currently, clinical applications of intravascular catheters suffer from major challenges: 1) platelet activation and surface-induced thrombosis, 2) biofouling of surfaces with proteins and bacteria, and 3) infection. Thrombus formation can further lead to obstruction of blood vessels, catheter malfunction, or even life-threatening situations such as embolism. 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. Commercial catheters with heparin- bonded surfaces are available to prevent clotting, but do little to prevent infections. In additions, catheters coated with antiseptics or antibiotics 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 combine strategies for preventing thrombosis and infection into single implantable device coatings 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 and subsequent infections. Recently we discovered that all of the positive effects can be achieved from polymers doped with the NO donor molecule S-nitroso-N-acetylpenicillamine (SNAP), which is nontoxic, inexpensive, and easy to synthesize. Nitric oxide release alone can inhibit platelet function locally at the polymer/blood interface, but it does not prevent fibrinogen adsorption and fibrin formation which plays a key role in a clot formation. Liquid- infused surfaces exhibit resistance to biofouling and protein adsorption. Our recent work has shown that combining slippery tethered liquid-perfluorocarbon (TLP) surfaces with polymers impregnated with NO-releasing moieties reduces protein adsorption and platelet adhesion/activation significantly better than NO-releasing polymers alone. The goal of this proposal is to develop, optimize, and evaluate a novel polymer that will combine agents that inhibit platelet adhesion and activation via impregnated NO-releasing molecules as well as inhibit biofouling using the liquid-infused TLP surfaces. The biomaterials laboratory directed by Dr. Brisbois will develop the synthesis and polymer fabrication methods, optimize the NO release levels, evaluate the durability properties, study the sterilization/storage stability, and evaluate the antimicrobial properties against common microbes associated with catheter infections. Dr. Handa’s laboratory will study the blood-material interactions and also conduct the chronic animal studies to evaluate the catheters for thrombosis and infection. The new polymers will be applicable to any blood-contacting device; however, this proposal will focus on studying the combined antifouling and NO-releasing effects in long-term (up to 30 d) intravascular catheters on clotting and infection. Successful completion of this project will allow progression to early clinical trials and development of a new generation of catheters that can reduce complications while improving the success of patient care.