Biocompatible Coating for Pediatric Blood Oxygenators - Phase II

描述（由申请人提供）：临床上可用于儿科（和成人）体外膜氧合（ECMO）的许多氧合器在设备表面（包括微孔中空纤维）上使用肝素涂层（例如Carmeda BioActive Surface），以提高生物相容性。尽管应用了这些涂层，但显著的炎症和凝血相关并发症以及血浆泄漏仍然与延长的ECMO支持相关。此外，当前肝素涂层的应用降低了下面的中空纤维膜的渗透性，影响其转移氧气和二氧化碳的能力。由这些涂层引起的气体交换效率的降低导致更大的总生物材料表面积需求（更大的微孔中空纤维表面积氧合器），从而加剧了涂层旨在减轻的炎症反应问题，以及导致增加的预充体积。在本工作的第一阶段，设计了五种离子化等离子体（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。两个第一阶段涂层超过了我们第一阶段建议中规定的标准，以判定可行性。每一种都证明了足够水平的活性肝素和血浆阻力，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提升到涂层成分和沉积工艺稳健且足够一致的水平，以实现一种或两种涂层的商业化。拟定的开发计划将涉及：1）涂层成分优化，2）涂层工艺优化，3）全面的体外性能评估，4）人血液中的体外生物相容性评价，以及5）动物体内长期试验。在完成该II期项目后，我们将生产并验证基于肝素的生物相容性涂层，该涂层具有透气性、高生物活性，在灭菌后保持其生物活性，并在使用前储存，并防止或延迟血浆泄漏。这样的涂层具有显著的潜力来减少与现有的血液氧合器和其他血液接触医疗装置相关的炎症反应和随后的发病率。Ension将儿科血液氧合器作为使用这种改进的生物相容性涂层的第一个细分市场，尽管它只占该产品整体市场的一小部分，因为它将允许快速开发，并作为进入其他细分市场的其他应用的垫脚石。体外膜肺氧合（ECMO）与儿科患者的严重并发症和潜在不良结局相关，因为血液-生物材料相互作用导致血液变化。公共卫生相关性：该II期项目代表了实现基于肝素的生物相容性涂层的主要研发工作，该涂层具有高度生物活性、成本效益，并在使用前灭菌和储存后保持其生物活性。这样的涂层具有显著的潜力来减少由使用现有的血液氧合器和其他血液接触医疗装置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.