Bioinspired antifouling and thromboresistant polymers for blood-contacting interfaces

项目摘要/摘要 目前，血管内导管的临床应用面临着主要挑战：1)血小板活化和 表面诱导的血栓形成，2)表面蛋白质和细菌的生物污损，以及3)感染。血栓 形成可进一步导致血管阻塞、导管故障，甚至危及生命的情况 比如栓塞症。在美国，导管的细菌污染每年导致超过2.8万人死亡 各州，以及医疗保健行业损失了惊人的23亿美元。使用肝素的商用导管- 粘合表面可以防止凝血，但对预防感染作用很小。此外，导管被涂上了 使用防腐剂或抗生素可降低细菌感染的风险，但不能防止生物被膜的形成 保护细菌免受抗生素的侵害。因此，有必要也有机会将战略结合起来，以 防止血栓形成和感染进入单一的植入性设备涂层，以增强通透性和安全性。 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，局部不产生任何物质来防止凝血和细菌生物膜以及随后的 感染。最近我们发现，所有的正效应都可以从聚合物中掺杂 NO供体分子S-亚硝基-N-乙酰青霉胺(SNAP)，无毒、价廉、易得 合成。单独释放一氧化氮可以抑制聚合物/血液界面的局部血小板功能，但它 不能阻止纤维蛋白原的吸附和纤维蛋白的形成，而纤维蛋白在血栓形成中起着关键作用。液体- 注入的表面表现出对生物污垢和蛋白质吸附的抵抗性。我们最近的研究表明， 将光滑的系留液体全氟化碳(TLP)表面与浸渍有NO释放的聚合物相结合 部分减少蛋白质吸附和血小板黏附/活化的效果明显优于NO释放 只有聚合物。该提案的目标是开发、优化和评估一种新型聚合物，这种聚合物将 通过注入NO释放分子抑制血小板黏附和激活的联合药物，如 并使用注入液体的TLP表面来抑制生物污垢。他领导的生物材料实验室。 Brisbois将开发合成和聚合物制造方法，优化NO释放水平，评估 耐久性能，杀菌/储存稳定性研究，抗菌性能评价 与导管感染有关的常见微生物。汉达博士的实验室将研究血液物质 并进行慢性动物研究，以评估导管的血栓形成和感染。 新的聚合物将适用于任何血液接触设备；然而，这项提议将集中在研究 长期(长达30d)血管内导管的抗垢和NO释放对凝血的联合作用 和感染。该项目的成功完成将使其进入早期临床试验和开发阶段。 新一代导尿管可以减少并发症，同时提高患者护理的成功率。

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.