Perpetual Organ Preservation and Rehabilitation (POPR)

项目摘要/摘要 R21在鼻部的应用：大胆的心、肺、血和睡眠生物工程研究 《疾病与紊乱》详细介绍了一种维护整个人类肺部的独特方法的技术开发 为了给实体器官移植和人类翻译研究带来革命性的变化。 常温体外器官灌流(EVOP)是一种临床公认的保存方法， 评估和修复移植的整个器官。EVOP还被科学家用于 翻译研究，并成为研究细胞与细胞相互作用完全完整的器官的重要平台， 内皮细胞和上皮细胞的界面，以及体内所见的整个细胞室的光谱。 因此，EVOP为保存器官供移植以及研究人类提供了一个独特的平台 生理学和病理学通过临床前翻译研究。不幸的是，EVOP目前严重 由于目前该技术提供的器官健康稳定的时间框架很短，因此受到限制。因此， 在EVOP战略中有一个需要新技术的未得到满足的需求。调查组已经掌握了 在器官移植、肺生理学、生物医学工程和血管生物学方面需要经验 以确保拟议工作的成功。目标1将利用调查人员的专业知识 猪肺EVOP模型通过几个关键因素将稳定器官保存延长到至少5天 技术进展，包括代谢底物支持、废物去除、双重灌流和使用 富含细胞的灌流液。猪肺被广泛用于肺EVOP的早期发展 并为翻译工作提供高保真的模型。在第二年，AIM 2将利用和验证经验教训 在AIM 1期间使用同意的器官捐赠者的人肺学习到的。这项提案的总体目标是 是通过适应现有的体外肺灌流来消除目前肺EVOP的时间限制 允许器官永久保存和康复的战略，或POPR。波普尔会从根本上 改变器官的分配和可获得性，为原本可以恢复的干预留出时间 不可用的器官，通过免疫调节或微生物清除来改善器官，并有可能减轻 其他限制使用潜在器官捐赠者的因素。因此，POPR的发展将是 对公众健康的巨大重要性和我们的建议利用了肺科的跨学科专业知识 移植、器官保存、血管内皮健康和生物医学工程专家。这个 这里提出的技术，一旦开发出来，就可以用于临床移植计划，并通过 全国各地专门中心的研究人员。重要的是，这里开发的原则可以应用 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.