Biocompatible Coating for Pediatric Blood Oxygenators - Phase II

描述（由申请人提供）：临床上用于儿科（和成人）体外膜氧合（ECMO）的许多氧合器在器械表面使用肝素涂层，如Carmeda BioActive Surface，包括微孔中空纤维，以提高生物相容性。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，当前肝素涂层的应用降低了底层中空纤维膜的通透性，影响了它们转移氧气和二氧化碳的能力。这些涂层导致的气体交换效率的降低导致了更大的总生物材料表面积要求（更大的微孔中空纤维表面积充氧器），从而加剧了涂层旨在缓解的炎症反应问题，并导致了注入体积的增加。在这项工作的第一阶段，设计了五种离子等离子体（IP）沉积涂层，以克服这些限制，并提供增强的生物活性和稳定性，进行了原型设计和评估。两个一期涂料超过了我们一期提案中规定的标准，以确定可行性。每位患者均表现出足够水平的活性肝素和血浆抵抗，以减轻与长期使用膜氧合相关的并发症，而不会过度降低纤维的气体渗透性。这一可行性证明保证了正式的第二阶段研究和开发工作，其总体目标是将涂层技术从概念验证推进到涂层成分和沉积工艺稳健且足够一致的水平，以追求一种或两种涂层的商业化。拟议的开发计划将涉及：1)涂层成分的优化，2)涂层工艺的优化，3)全面的体外性能评估，4)人体血液中的体外生物相容性评估，以及5)长期的动物体内试验。二期项目完成后，我们将生产并验证一种基于肝素的生物相容性涂层，该涂层具有透气性，高度生物活性，在使用前灭菌和储存后保持其生物活性，并防止或延迟等离子体泄漏。这种涂层具有显著的潜力，可以减少与现有血液氧合器和其他血液接触医疗设备相关的炎症反应和随后的发病率。Ension已经将儿童血液氧合器作为第一个细分市场，尽管它只占该产品整体市场的一小部分，因为它将允许快速发展，并作为进入其他细分市场的其他应用的垫脚石。体外膜氧合（ECMO）与儿科患者的严重并发症和潜在的不良预后有关，因为血液-生物材料相互作用导致血液发生变化。公共卫生相关性：该二期项目代表了实现基于肝素的生物相容性涂层的主要研究和开发工作，该涂层具有高度生物活性，成本效益高，并且在使用前消毒和储存后保持其生物活性。这种涂层具有显著的潜力，可以减少因使用现有的血液氧合器和其他血液接触医疗装置而引起的炎症反应和随后的发病率。

DESCRIPTION (provided by applicant): Many oxygenators clinically available for pediatric (and adult) extracorporeal membrane oxygenation (ECMO) utilize heparin coatings such as Carmeda BioActive Surface on device surfaces, including the microporous hollow fibers, to improve biocompatibility. Despite application of these coatings, significant inflammatory and coagulation-related complications, as well as plasma leakage, remain associated with extended ECMO support. Furthermore, application of current heparin coatings reduces permeance of the underlying hollow fiber membranes affecting their capacity to transfer oxygen and carbon dioxide. Reductions in gas exchange efficiency caused by these coatings result in greater total biomaterial surface area requirements (a larger microporous hollow fiber surface area oxygenator) thus exacerbating the inflammatory response problem the coating is intended to mitigate, as well as leading to increased priming volumes. During Phase I of this work five ionized plasma (IP) deposited coatings designed to overcome these limitations and to provide enhanced bioactivity and stability were prototyped and evaluated. Two Phase I coatings exceeded the criteria outlined in our Phase I proposal to adjudicate feasibility. Each demonstrated sufficient levels of active heparin and plasma resistance to mitigate complications associated with long-term use of membrane oxygenation, without unduly decreasing the gas permeance of the fibers. This demonstration of feasibility warrants a formal Phase II research and development effort with the overall objective of advancing the coating technology from proof-of-concept to a level where coating composition and deposition processes are robust and sufficiently consistent to pursue commercialization of one or both coatings. The proposed development program will address: 1) optimization of coating composition, 2) optimization of coating processes, 3) comprehensive in vitro performance assessments, 4) in vitro biocompatibility evaluations in human blood, and 5) prolonged in vivo testing in animals. Upon completion of this Phase II project we will have produced and validated a heparin-based, biocompatible coating that is gas permeable, highly bioactive, maintains its bioactivity after being sterilized and stored prior to use, and prevents or delays plasma leakage. Such a coating has significant potential to reduce inflammatory response and subsequent morbidity associated with existing blood oxygenators and other blood-contacting medical devices. Ension has targeted pediatric blood oxygenators as the first market segment to be addressed with this improved biocompatible coating, even though it represents only a small portion of the overall market for this product, because it will permit rapid development and serve as a stepping stone for access to other applications in other market segments. Extracorporeal membrane oxygenation (ECMO) is associated with serious complications and potentially poor outcomes in pediatric patients due to changes to the blood resulting from blood- biomaterial interaction. PUBLIC HEALTH RELEVANCE: This Phase II project represents the main research and development effort for realization of a heparin-based biocompatible coating that is highly bioactive, cost- effective, and maintains its bioactivity after being sterilized and stored prior to use. Such a coating has significant potential to reduce inflammatory response and subsequent morbidity resulting from use of existing blood oxygenators and other blood-contacting medical devices.