Omniphobic Coating of Extracorporeal Life Support Systems for Improved Thromboresistance

项目摘要 体外膜肺氧合（ECMO）通常用于重症监护病房的气体交换， 重度呼吸和心力衰竭事件。这种回路由一个或多个血管通路组成 插管、血泵和由一束微孔中空纤维膜组成的氧合器 （HFM）。血流通过泵从循环系统中抽出，并被引导通过HFM束， 氧合和CO2去除，然后返回给患者。然而，ECMO的发生率很高， 血栓形成和器械失效，这与凝血级联反应的激活有关，主要是由于 体外回路的非生物血液接触表面。这种血栓形成的临床表现 如深静脉血栓形成、肺栓塞、氧合器血栓形成和小血管血栓形成。因此，我们认为， 需要全身抗凝剂，这导致出血和相关并发症。体外膜肺氧合- 相关静脉血栓形成率高达85%，氧合器血栓形成率为10 - 16%， 患者年龄和氧合器设计的影响ECMO有40%的高重度出血率，其中16 - 21%是 颅内出血尽管先进的生物材料的发展，ECMO的使用仍然是 受到出血和血栓并发症的阻碍。 FreeFlow Medical Devices（FFMD）正在优化和商业化系留液体全氟化碳（TLP） 医疗器械上的涂层。该SBIR项目的目标是验证我们的TLP涂层 ECMO膜将减少血栓形成。我们的长期目标是改善患者的预后， ECMO通过降低血栓形成和出血引起的并发症发生率。我们的全憎涂层 阻止所有生物成分（细菌、真菌、血液成分）粘附在医疗器械表面， 通过固定高度惰性和生物相容性的全氟化液体薄层，我们 优化的涂层技术在各种表面上结合了薄的含氟聚合物层， 化学气相沉积技术。 第一阶段提案的目的是获得我们的TLP-氧合膜将 降低临床相关条件下的血栓形成性。一旦获得概念证明，我们将 进入TLP-氧合器cGMP生产的第II阶段，并继续FDA推荐的 生物相容性测试，使其准备上市前批准。第一阶段申请的目标是 通过研究以下具体目标来实现。目的1：优化PMP膜上的TP涂层， 保持其原有的微孔性和气体交换能力。目的2：优化LP涂层，以实现 血栓形成性最高。目的3：确定优化的TLP涂层氧合的抗血栓性 膜在ECMO相关的流动诱导剪切应力下的平均使用持续时间。一旦证明 我们将进入第二阶段，进行TLP氧合器的cGMP生产， 血液灌注管，并继续进行FDA推荐的生物相容性试验， 上市前批准。

PROJECT SUMMARY Extracorporeal membrane oxygenation (ECMO) is commonly used in the critical care unit for gas exchange in the event of severe respiratory and cardiac failure. Such circuits consist of one or more vascular access cannulae, a blood pump, and an oxygenator composed of a bundle of microporous hollow fiber membranes (HFM). Blood flow is drawn from the circulatory system via a pump and directed through the HFM bundle for oxygenation and CO2 removal prior to being returned to the patient. However, ECMO has high incidence of thrombosis and device failure, which are associated with activation of the coagulation cascade primarily due to the non-biological blood-contacting surface of the extracorporeal circuit. Such thrombosis manifests clinically as deep vein thrombosis, pulmonary embolism, oxygenator thrombosis, and small vessel thrombosis. Hence, systemic anticoagulants are necessary, which leads to hemorrhage and associated complications. The ECMO- associated venous thrombosis rate is as high as 85% and oxygenator thrombosis rate is 10–16% depending on patient age and oxygenator design. ECMO has high severe hemorrhage rate of 40%, of which 16–21% is intracranial hemorrhage. Despite the development of advanced biomaterials, ECMO use continues to be hampered by bleeding and thrombosis complications. FreeFlow Medical Devices (FFMD) is optimizing and commercializing tethered liquid perfluorocarbon (TLP) coatings on medical devices. The goal of this SBIR project is to validate the hypothesis that our TLP-coated ECMO membranes will reduce thrombosis. Our long-term goal is to improve outcomes for patients requiring ECMO by reducing the rate of complications caused by thrombosis and bleeding. Our omniphobic coating stops the adhesion of all biological components (bacteria, fungi, blood components) to the surface of medical devices through the immobilization of a thin layer of highly inert and biocompatible perfluorinated liquid. Our optimized coating technology incorporates a thin fluoropolymer layer on various surfaces with the help of chemical vapor deposition technique. The objective of this phase I proposal is to obtain the proof of concept that our TLP-oxygenation membrane will reduce thrombogenicity under clinically relevant conditions. Once proof of concept has been obtained, we will progress to Phase II for cGMP manufacturing of TLP-oxygenator and proceed with FDA-recommended biocompatibility testing to make this ready for premarket approval. The goals of this phase I application will be achieved by investigating the following Specific Aims. Aim 1: Optimize TP coating on PMP membrane to maintain its original microporosity and gas exchange capacity. Aim 2: Optimize the LP coating to achieve the highest thrombogenicity. Aim 3: Determine thromboresistance of the optimized TLP-coated oxygenation membrane under ECMO-relevant flow-induced shear stress for the period of average use duration. Once proof of concept has been obtained, we will progress to Phase II for cGMP manufacturing of TLP-oxygenator and blood perfusion tubing and proceed with FDA-recommended biocompatibility testing to make this ready for premarket approval.