Biocompatible Coating for Pediatric Blood Oxygenators

项目摘要/摘要：临床上用于成人和儿童体外膜氧合（ECMO）的许多氧合器在微孔中空纤维上使用肝素涂层来提高生物相容性。尽管应用了这些涂层，明显的炎症和凝血相关并发症，以及血浆泄漏，仍然与延长ECMO支持有关。此外，肝素涂层的应用降低了底层中空纤维膜的渗透性，影响了它们转移氧气和二氧化碳的能力。在某些应用中，涂层引起的气体交换效率降低可能导致气体交换的总表面积要求（表面积更大的氧合器）增加，从而加剧了涂层旨在缓解的炎症反应问题。该项目的目标是开发一种改良的血液兼容表面，用于儿科ECMO的初始应用。提出的开发计划将同时解决涂层中空纤维膜的血液相容性和气体渗透特性的优化问题。据推测，这些生物相容性的具体改进也将导致防止或实质上延迟血浆泄漏的表面。将被评估的基于肝素的涂层将是非常薄的电离等离子体（IP）沉积涂层，不覆盖中空纤维膜壁上的孔隙。该涂层将在膜表面和肝素分子之间加入“间隔分子”，以确保固定的肝素在设备使用期间保持生物活性。该涂层有望通过提高整体生物相容性来减少或防止血浆泄漏，从而减少对循环血液元素的损害，以及通过防止或延迟磷脂在纤维表面的吸附。使用中空纤维氧合膜的前期I期工艺试验证实了肝素与改性膜的共价偶联成功。我们选择儿科ECMO作为我们最初的目标市场有两个主要原因；首先，由于在如此小的市场中缺乏财政激励，这一患者群体得不到行业的充分服务。从申请人的经验来看，利用SBIR赠款等资金是在这个市场中推进技术的少数几种方法之一。其次，我们相信在非常苛刻的儿科ECMO应用中成功使用这些涂层将令人信服地证明我们涂层的有效性。对于没有替代治疗的患者群体，在要求苛刻的应用中首次使用，将使我们能够将这项技术的应用扩展到更大的市场，例如急性呼吸窘迫综合征（ARDS）。项目简介：需要体外膜氧合（ECMO）的儿童的血液暴露于大量外来物质中。ECMO中使用的血液氧合器是这种外来物质的最大来源，并且经常被涂覆以使其表面看起来对血液“看不见”。然而，这些涂层有害地影响了氧合器的性能，因为它们从未在设计时考虑到这种特定的应用。第一阶段SBIR提出开发一种专门为血液氧合器设计的涂层。

DESCRIPTION (provided by applicant): Project Summary/Abstract: Many oxygenators clinically available for adult and pediatric extracorporeal membrane oxygenation (ECMO) employ heparin coatings on microporous hollow fibers to improve biocompatibility. Despite application of these coatings, significant inflammatory and coagulation-related complications, as well as blood plasma leakage, remain associated with extended ECMO support. In addition, application of heparin coatings reduces permeance of the underlying hollow fiber membranes affecting their capacity to transfer oxygen and carbon dioxide. The reduction in gas exchange efficiency caused by the coating can, in some applications, result in greater total surface area requirements (a larger surface area oxygenator) for gas exchange, thus exacerbating the very inflammatory response problem the coating is intended to mitigate. The goal of this project is to develop an improved blood-compatible surface for initial use in pediatric ECMO. The proposed development program will simultaneously address optimization of blood compatibility and gas permeance characteristics of coated hollow fiber membranes. It is hypothesized that these specific improvements in biocompatibility will also result in a surface that prevents or substantially delays blood plasma leakage. The heparin-based coatings that will be evaluated will be very thin ionized plasma (IP)-deposited coatings that do not cover the pores in the wall of the hollow fiber membrane. The coatings will incorporate "spacer molecules" between the membrane surface and the heparin molecules to ensure that the immobilized heparin remains bioactive during use of the device. The coatings are expected to reduce or prevent blood plasma leakage by improving overall biocompatibility-thereby reducing damage to circulating blood elements-as well as by preventing or delaying adsorption of phospholipids on the fiber surfaces. Pre-Phase I process trials using hollow fiber oxygenator membranes have confirmed successful covalent coupling of heparin to the modified membranes. We have chosen pediatric ECMO as our initial target market for 2 key reasons; first, this patient population is underserved by industry due to lack of financial incentive in such a small market. From the applicant's experience, leveraging funding such as SBIR grants is 1 of the few ways to advance technology within this market. Secondly, we believe that successful use of these coatings in the very demanding pediatric ECMO application will convincingly demonstrate the effectiveness of our coating. Initial use in a demanding application, for a patient population without alternative treatments, will allow us to expand applications of this technology to larger markets such as acute respiratory distress syndrome (ARDS). Project Narrative: Children requiring extracorporeal membrane oxygenation (ECMO) have their blood exposed to large amounts of foreign material. The blood oxygenator used in ECMO is the largest source of this foreign material and is often coated to make the surface appear, "invisible" to the blood. However, these coatings deleteriously affect the performance of the oxygenator since they were never designed with this specific application in mind. This Phase I SBIR proposes development of a coating specifically designed for the blood oxygenator.