Perfusion preservation solution for recovery of Donation by Cardiac Death livers

描述(由申请人提供)：项目摘要/摘要：该项目的长期目标是通过开发一种用于恢复和保存的新的低温机器灌流(HMP)解决方案，增加心脏死亡(DCD)后可供移植的肝脏的捐赠数量。目前，DCD肝脏是可移植的，有可能使供体池增加20%-40%。然而，由于目前的简单冷藏(SCS)方法保存得很差，它们在很大程度上没有得到充分利用。研究表明，HMP可以提高动物模型移植物的存活率。然而，随着热缺血时间的增加，初步研究表明，目前的HMP溶液不足以应对延长的热缺血增加的应激。一种新的解决方案已经被开发出来，以解决能量底物的耗尽、膜的不稳定性增加、氧化损伤增加和微循环中断。初步研究表明，这种新的HMP溶液具有恢复和保存延长的热缺血肝脏的潜力。这一阶段SBIR的目标是通过实现以下特定目标来测试新HMP恢复和保存延长的热缺血肝脏的可行性：1)确定新的HMP溶液在隔离肝灌流模型中提高60min热缺血肝脏恢复和保存的有效性，2)用新的HMP溶液保存延长的热缺血肝脏的移植研究。在隔离的灌流系统中评估的功能恢复允许更好地控制和评估广泛的终点。肝细胞和内皮细胞的功能和损伤将通过胆汁产生、透明质酸摄取、组织能量状态、氧气消耗、组织学和酶的释放来评估。这个系统可以评估移植物是否经历了原发无功能，这是DCD器官失败的主要原因。在移植研究中，将评估存活率、酶释放、胆红素和组织学。该项目的成功将直接关系到移植外科医生团队、科学家和生物医学工程师之间关键伙伴关系的建立，他们将合作测试并根据需要修改新的HMP解决方案。该项目将为在临床前动物移植模型中恢复和保存延长的热缺血肝脏的第二阶段SBIR应用程序的进一步测试奠定基础。此外，将对解决方案进行优化，并确定恢复的时间限制。项目简介：虽然肝移植被认为是治疗终末期肝病的唯一权威疗法，但由于缺乏可行的供体肝脏，许多需要移植的患者无法接受移植。这项提议的最终目标是开发一个完整的系统，使目前未使用的潜在捐赠者肝库得以恢复，从而大大增加可供移植的可行捐赠者的数量。

DESCRIPTION (provided by applicant): Project Summary/Abstract: The long term goals of this project is to increase the number of Donation after Cardiac Death (DCD) livers available for transplantation by developing a new hypothermic machine perfusion (HMP) solution for recovery and preservation. Currently DCD livers are transplantable and have the potential to increase the donor pool 20-40%. However, they are largely under utilized due to poor preservation by the current method of simple cold storage (SCS). Studies show that HMP can improve graft survival in animal models. However, as warm ischemic time is increased, preliminary studies show that the current HMP solution is not sufficient to address the increase stresses of extended warm ischemia. A new solution has been developed to address depletion of energy substrates, increased membrane instability, increased oxidation damage, and microcirculation disruption. Preliminary studies suggest that this new HMP solution has the potential to recover and preserve extended warm ischemic livers. The goal of this Phase I SBIR is to test the feasibility of a new HMP to recover and preserve extended warm ischemic livers in the rat model by accomplishing the following Specific Aims: 1) Determine the efficacy of the new HMP solution to improve recovery and preservation of 60 minutes warm ischemic livers in an isolated liver perfusion model, 2) transplantation study of extended warm ischemic livers preserved by the new HMP solution. Functional recovery evaluated in an isolated perfusion system allows greater control and assessment with a broad spectrum of endpoints. Hepatocellular and endothelial cell functions and damage will be assessed by bile production, hyaluronic acid uptake, tissue energy state, oxygen consumption, histology, and release of enzymes. This system can assess whether grafts experience primary non-function, a major cause of failure in DCD organs. In the transplant studies, survival, enzyme release, bilirubin, and histology will be evaluated. The success of this project will be directly related to the establishment of a critical partnership between the team of transplant surgeons, the scientist and biomedical engineer who will collaboratively test, and modify as needed the new HMP solution. This project will form the basis for further testing in a Phase II SBIR application for recovery and preservation of extended warm ischemic livers in a pre-clinical animal transplant model. In addition, the solution will be optimized and a time limit for recovery will be determined. Project Narrative: Although liver transplantation is considered the only definitive therapy for endstage liver disease, many patients who require transplants cannot receive them because of the shortage of viable donor livers. The ultimate goal of this proposal is to develop a complete system that will allow recovery of a pool of currently unused potential donor livers resulting in a significant expansion in the number of viable donors available for transplant.