Perpetual Organ Preservation and Rehabilitation (POPR)

项目概要/摘要 NOSI 的 R21 应用：针对心脏、肺、血液和睡眠的大胆新生物工程研究 疾病和疾病详细介绍了维护整个人类肺部的独特方法的技术开发 长期致力于实体器官移植和人类转化研究的彻底变革。 常温异位或离体器官灌注（EVOP）是一种临床上接受的保存、 评估和修复用于移植的整个器官。 EVOP 也被科学家用于 转化研究并成为研究具有完整细胞间相互作用的器官的重要平台， 内皮和上皮界面，以及体内看到的整个细胞区室谱。 因此，EVOP 提供了一个独特的平台来保存移植器官以及研究人类 通过临床前转化研究进行生理学和病理学。不幸的是，EVOP 目前严重 由于该技术目前提供的器官健康稳定性的时间范围很短，因此受到限制。因此， EVOP 战略中存在未满足的需求，需要新技术。调查组拥有 所需的器官移植、肺生理学、生物医学工程和血管生物学经验 以确保拟议工作的成功。目标 1 将利用研究人员的专业知识 猪肺EVOP模型通过几个关键措施将稳定的器官保存时间延长至至少5天 技术进步，包括代谢底物支持、废物去除、双灌注和使用 细胞富集的灌注液。猪肺被广泛用于肺 EVOP 的初步开发 并为翻译工作提供高保真模型。在第二年，目标 2 将利用和验证经验教训 在目标 1 期间使用来自同意的器官捐赠者的人肺了解到。本提案的总体目标 是通过适应现有的离体肺灌注来消除目前肺 EVOP 的时间限制 允许永久器官保存和康复（POPR）的策略。 POPR 将从根本上 改变器官的分配和可用性，为可以恢复的干预措施留出时间 无法使用的器官，通过免疫调节或微生物清除改善器官，并可能减轻 限制使用潜在器官捐献者的其他因素。因此，POPR的发展将是 巨大的公共卫生重要性，我们的提案利用了肺的跨学科专业知识 移植、器官保存、血管内皮健康和生物医学工程专家。的 本文提出的技术一旦开发出来，就可以用于临床移植计划和 全国各地专门中心的研究人员。重要的是，本文开发的原理可以应用 到其他实体器官，包括心脏、肾脏和小肠，以扩大实体器官移植和 研究。

Project Summary/Abstract This R21 application for the NOSI: Bold New Bioengineering Research for Heart, Lung, Blood and Sleep Disorders and Diseases details the technical development of a unique method to maintain whole human lungs for an extended period in order to revolutionize solid organ transplantation and human translational research. Normothermic ex situ, or ex vivo, organ perfusion (EVOP) is a clinically accepted method of preserving, evaluating, and rehabilitating whole organs for transplantation. EVOP has also been utilized by scientists for translational research and emerged as an important platform to study organs with fully intact cell-cell interactions, endothelial and epithelial interfaces, and with the entire spectrum of cellular compartments seen in vivo. Therefore, EVOP provides a unique platform to preserve organs for transplantation, as well as to study human physiology and pathology through preclinical translational studies. Unfortunately, EVOP is currently severely limited due to the short time frame of organ health stability currently provided by the technology. Therefore, there is an unmet need in EVOP strategies that requires new technology. The investigative team has the needed experience in organ transplantation, pulmonary physiology, biomedical engineering and vascular biology in order to ensure success of the proposed work. Aim 1 will leverage the expertise of the investigators with a porcine model of lung EVOP to extended stable organ preservation to at least 5 days through several key technology advances, including metabolic substrate support, waste product removal, dual perfusion, and the use of cellular enriched perfusate. Porcine lungs were utilized extensively for the initial development of lung EVOP and provide a high-fidelity model for translational work. In Year 2, Aim 2 will leverage and validate lessons learned during Aim 1 using human lungs from consented organ donors. The overall objective of this proposal is to obviate the current limitation of time for lung EVOP by adapting existing ex vivo lung perfusion strategies to allow for perpetual organ preservation and rehabilitation, or POPR. POPR would radically change allocation and availability of organs, allow time for interventions that could rehabilitate otherwise unusable organs, improve organs via immunomodulation or microbiologic clearance, and potentially mitigate other factors that limit the use of potential organ donors. Therefore, the development of POPR would be of tremendous public health importance and our proposal leverages the transdisciplinary expertise of lung transplantation, organ preservation, vascular endothelial health and biomedical engineering specialists. The technology proposed herein, once developed, could be used by transplant programs clinically and by researchers in specialized centers across the country. Importantly, principals developed herein can be applied to other solid organs, including heart, kidney, and small bowel, to extend solid organ transplantation and research.