Perpetual Organ Preservation and Rehabilitation (POPR)

项目总结/摘要 NOSI的R21申请：心脏，肺，血液和睡眠的大胆新生物工程研究 《疾病与障碍》详细介绍了一种独特的方法来维持整个人类肺部的技术发展 在很长一段时间内，以彻底改变实体器官移植和人类转化研究。 常温离体器官灌注（EVOP）是临床上可接受的保存方法， 评估和修复整个器官以供移植。EVOP也被科学家用于 转化研究并成为研究具有完全完整的细胞-细胞相互作用的器官的重要平台， 内皮和上皮界面，以及体内可见的整个细胞区室谱。 因此，EVOP提供了一个独特的平台，以保存器官移植，以及研究人类 生理学和病理学通过临床前转化研究。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框架短，因此是有限的。因此，我们认为， 在EVOP策略中存在需要新技术的未满足的需求。调查小组有 需要在器官移植、肺生理学、生物医学工程和血管生物学方面的经验 以确保拟议的工作取得成功。目标1将利用调查人员的专业知识， 猪肺EVOP模型，通过几个关键步骤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，双重灌注，以及使用 细胞富集灌注液。猪肺被广泛用于肺EVOP的初始开发 并为翻译工作提供了一个高保真的模型。在第二年，目标2将利用和验证经验教训 在Aim 1中使用来自同意的器官捐赠者的人肺学习。本提案的总体目标是 是通过调整现有的离体肺灌注来克服目前肺EVOP的时间限制 永久性器官保存和康复策略，或POPR。POPR将从根本上 改变器官的分配和可用性，留出时间进行干预，否则可能会恢复 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 限制潜在器官捐献者使用的其他因素。因此，持久性有机污染物审查的发展将是 巨大的公共卫生重要性，我们的建议利用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，就可以在临床上被移植程序使用， 研究人员在全国各地的专业中心。重要的是，本文开发的原理可以应用于 其他实体器官，包括心脏，肾脏和小肠，以扩展实体器官移植， research.

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.