Perfusion preservation solution for recovery of Donation by Cardiac Death livers

描述（由申请人提供）：项目总结/摘要：本项目的长期目标是通过开发一种新的低温机器灌注（HMP）恢复和保存解决方案，增加可用于移植的心源性死亡（DCD）肝脏捐赠数量。目前，DCD肝脏是可移植的，并有可能增加20- 40%的供体库。然而，由于目前的简单冷藏（SCS）方法保存不佳，它们在很大程度上未得到充分利用。研究表明，HMP可以提高动物模型中移植物的存活率。然而，随着热缺血时间的增加，初步研究表明，目前的HMP解决方案不足以解决延长的热缺血的应力增加。已经开发了一种新的解决方案来解决能量底物的耗尽、增加的膜不稳定性、增加的氧化损伤和微循环中断。初步研究表明，这种新的HMP溶液有可能恢复和保存延长的热缺血肝脏。本I期SBIR的目的是通过实现以下特定目标，测试新HMP在大鼠模型中恢复和保存长期热缺血肝脏的可行性：1）确定新的HMP溶液在隔离的肝脏灌注模型中改善60分钟热缺血肝脏的恢复和保存的功效，（2）新型HMP液保存的长期热缺血肝脏的移植研究。在隔离灌注系统中评估的功能恢复允许更好的控制和评估，具有广泛的终点。将通过胆汁产生、透明质酸摄取、组织能量状态、耗氧量、组织学和酶释放来评估肝细胞和内皮细胞功能和损伤。该系统可以评估移植物是否经历原发性无功能，这是DCD器官失败的主要原因。在移植研究中，将评价存活率、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建立关键的合作伙伴关系，他们将合作测试并根据需要修改新的HMP解决方案。该项目将成为在临床前动物移植模型中恢复和保存长期热缺血肝脏的II期SBIR应用中进一步测试的基础。此外，将优化解决方案，并确定恢复时限。项目叙述：虽然肝移植被认为是终末期肝病的唯一确定性治疗方法，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。该提案的最终目标是开发一个完整的系统，该系统将允许回收目前未使用的潜在供体肝脏，从而显著增加可用于移植的可行供体数量。

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.