Expanding the Liver Transplant Organ Pool through Ex Vivo Liver Perfusion

项目总结/摘要 肝移植为终末期肝病患者提供了挽救生命的治疗。但 这种疗法的潜力受到死亡供体肝脏供应不足的限制，无法治疗所有可能的患者。 效益这导致肝移植的适应症狭窄，等待名单死亡率高， 使用边缘器官，使移植后存活率恶化并增加成本。我们认为 移植前离体供体肝灌注（EVLP）具有改变这种模式的无与伦比的潜力。 与目前标准的静态冷藏（SCS）肝脏保存不同， 缺氧条件下的代谢活动导致细胞能量储存逐渐耗尽， 移植物质量恶化，在EVLP下，通过充氧灌注恢复细胞有氧呼吸 允许正常的代谢过程在体外进行。这将允许移植物损伤的移植前恢复 通过热缺血（例如来自DCD供体的那些），诊断适合移植物与不适合移植物的移植物。 器官移植和器官移植库的显著净扩张。 在这个拟议的项目中，我们寻求定义EVLP在肝脏中的最合适和最有效的应用 移植我们将研究允许EVLP恢复的器官损伤的边界，并将描述 肝脏灌注的理想参数。这些研究还将提供丰富的数据，为未来的设计提供信息。 识别器官移植适宜性的多参数判别器。在本项目的最终目标中， 我们利用目标I和II中获得的信息，使用以下方法对SCS和EVLP进行随机比较： DCD肝脏作为临床试验的前奏。总的来说，这些研究将产生至关重要的数据， 离体肝脏灌注领域的最佳发展。

PROJECT SUMMARY / ABSTRACT Liver transplantation provides life saving treatment for patients with end-stage liver disease. However, the potential of this therapy is limited by an inadequate supply of deceased donor livers to treat all those who could benefit. This has resulted in narrow indications for liver transplantation, high waiting list mortality, and increased use of marginal organs that worsen post transplant survival rates and increase costs. We believe that pretransplant ex vivo donor liver perfusion (EVLP) has unparalled potential to alter this paradigm. Unlike the current standard liver preservation by static cold storage (SCS) in which incompletely arrested metabolic activity under anoxic conditions leads to gradual exhaustion of cellular energy stores and progressive deterioration of graft quality, under EVLP, cellular aerobic respiration is restored by oxygenated perfusion allowing normal metabolic processes to ensue ex vivo. This will permit pretransplant recovery for grafts injured by warm ischemia (such as those from DCD donors), diagnosis of grafts suitable from those nonsuitable for transplant and a marked net expansion of the organ pool for transplantation. In this proposed project, we seek to define the most appropriate and effective application of EVLP to liver transplants. We will investigate the boundaries of organ injury that allows recovery by EVLP and will delineate the ideal parameters of liver perfusion. These studies will also provide a wealth of data to inform future designed to identify multi parameter discriminators of organ suitability for transplantation. In the final aim of of this project, we utilize the information gained in Aims I and II to conduct a randomized comparison of SCS and EVLP using DCD livers as a prelude to a clinical trial. Collectively, these studies will generate data critically necessary in optimal development of the field of ex vivo liver perfusion.