Perfusion preservation solution for recovery of Donation by Cardiac Death livers

用于心脏死亡捐献肝脏回收的灌注保存液

• 批准号: 7158304
• 负责人: Charles Y Lee
• 金额: $ 17.29万
• 依托单位: HEPATOSYS, INC.
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-08-01 至 2007-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7158304
• 关键词: animal mortality; bile; bilirubin; bioenergetics; cellular pathology; cold temperature; enzyme biosynthesis; histology; hyaluronate; isolation perfusion; laboratory rat; liver cells; liver function; liver ischemia /hypoxia; liver preservation; liver transplantation; male; nonhuman therapy evaluation; respiratory oxygenation; solutions; technology /technique development; tissue donors

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.

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用于恢复和保存的新型低温机器灌注（HMP）解决方案来增加可用于移植的心死亡（DCD）肝脏捐赠的数量。目前 DCD 肝脏是可移植的，并且有可能将供体库增加 20-40%。然而，由于目前的简单冷藏（SCS）方法保存效果不佳，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长时间热缺血带来的应激增加问题。一种新的解决方案已经被开发出来，以解决能量底物耗尽、膜不稳定性增加、氧化损伤增加和微循环破坏的问题。初步研究表明，这种新的 HMP 解决方案具有恢复和保存长期热缺血肝脏的潜力。 I 期 SBIR 的目标是通过实现以下具体目标，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 HMP 解决方案在离体肝脏灌注模型中改善 60 ​​分钟热缺血肝脏恢复和保存的功效，2) 对新 HMP 解决方案保存的长期热缺血肝脏进行移植研究。在隔离灌注系统中评估功能恢复可以通过广泛的终点进行更好的控制和评估。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、耗氧量、组织学和酶的释放来评估。该系统可以评估移植物是否经历原发性无功能，这是 DCD 器官衰竭的主要原因。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建立重要的合作伙伴关系，他们将协作测试并根据需要修改新的 HMP 解决方案。该项目将为临床前动物移植模型中长期热缺血肝脏的恢复和保存的 II 期 SBIR 应用进一步测试奠定基础。此外，还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。该提案的最终目标是开发一个完整的系统，该系统将允许恢复当前未使用的潜在供体肝脏库，从而显着增加可用于移植的可行供体的数量。