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: 7625998
• 负责人: Charles Y Lee
• 金额: $ 63.35万
• 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 2013-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7625998
• 关键词: Abbreviations; Accident and Emergency department; Address; Adverse effects; Animal Model; Animals; Biological Preservation; Biomedical Engineering; Blood flow; Cardiac Death; Clinical; Clinical Trials; Cryopreservation; Data; Effectiveness; Equilibrium; Family suidae; Future; Goals; Graft Survival; Heart Arrest; Hepatocellular Damage; Human; Incidence; Injury; Legal patent; Letters; Liver; Membrane; Methods; Modeling; Organ; Patients; Performance; Perfusion; Phase; Preparation; Production; Rattus; Recovery; Recovery of Function; Regional Perfusion; Reperfusion Injury; Research; Scientist; Simulate; Small Business Innovation Research Grant; Solutions; Stress; System; Testing; Time; Toxic effect; Transplant Surgeon; Transplantation; Universities; Waiting Lists; Warm Ischemia; Wisconsin; base; cost; experience; improved; in vivo Model; liver function; liver transplantation; oxidation; pre-clinical; prevent; prototype; public health relevance; research clinical testing; success

DESCRIPTION (provided by applicant): The long term goal 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 increased stresses of extended warm ischemia. A new solution has been developed to restore depleted energy stores, maintain membrane stability, and minimize oxidation damage. The Phase I project was highly successful in showing that the new HMP solution improved 5hr preservation of extended warm ischemic (60 mins) rat livers in both isolated perfusion and transplant studies. The results showed improved recovery, a reduction in injury, and improved survival (7/9) compared with the UW solution alone (0/6). The main goals of this Phase II SBIR are: 1) to strengthen IP protection, 2) to minimize the potential of toxicity effects, 3) to reduce production costs, and 4) to begin testing the solution in a pre-clinical large animal DCD model. The following Specific Aims will accomplish these objectives: 1) determine the maximum sustainable warm ischemic time for livers to be reclaimed by the new perfusion solution and hypothermic machine perfusion, 2A) optimize the components and 2B) optimize the concentration of components of the new HMP solution, 3) test the new optimized HMP solution in a porcine DCD liver model. To achieve these Aims, isolated perfused liver studies in the rat and porcine and transplant studies in the rat will be utilized. Accomplishing the objectives of this project will strengthen the value of the solution, increase IP protection of the solution, lessen the potential for toxicity issues and form the basis for further testing in a pre-clinical large animal transplant and human ex vivo models in preparation for clinical trials. The success of this project will be directly related to the establishment of a critical partnership between the team of the transplant surgeon, the scientist and biomedical engineer who will collaboratively test and modify as needed the new HMP solution. In addition, HepatoSys, Inc. will collaborate with Organ Recovery Systems to test the new perfusion solution in their prototype Liver Transporter. PUBLIC HEALTH RELEVANCE: Donation after Cardiac Death (DCD) livers have the potential to increase the number of transplants 20-40%, however poor preservation methods and solutions prevent the widespread use of these organs. A new perfusion solution combined with hypothermic machine perfusion preservation has been developed to reclaim these livers that have experienced extended periods of no blood flow after cardiac death. The Phase I SBIR project was highly successful in showing that the new perfusion solution improved recovery and survival in transplant studies. This Phase II project will serve to bring this solution closer to clinical use by optimizing the solution and beginning to test it in large pre-clinical animals that simulate DCD.

描述(由申请人提供)：该项目的长期目标是通过开发一种新的低温机器灌流(HMP)溶液来恢复和保存可用于移植的心脏死亡(DCD)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，以恢复耗尽的能量存储，保持膜的稳定性，并将氧化损害降至最低。 第一阶段项目非常成功地表明，在隔离灌流和移植研究中，新的HMP溶液改善了延长热缺血(60分钟)大鼠肝脏的5小时保存期。结果显示，与单独使用UW液(0/6)相比，UW液可提高恢复率、减少损伤并提高存活率(7/9)。 这一第二阶段SBIR的主要目标是：1)加强知识产权保护，2)最大限度地减少潜在的毒性影响，3)降低生产成本，4)开始在临床前大型动物DCD模型中测试该解决方案。以下具体目标将实现这些目标：1)确定新灌注液和低温机灌流回收肝脏的最大可持续热缺血时间，2A)优化成分，2B)优化新HMP溶液的成分浓度，3)在猪DCD肝脏模型上测试新的优化HMP溶液。为了实现这些目标，将利用大鼠和猪的隔离灌流肝脏研究以及大鼠的移植研究。完成该项目的目标将增强该解决方案的价值，增加该解决方案的知识产权保护，减少潜在的毒性问题，并为进一步在临床前大型动物移植和人类体外模型中进行测试奠定基础，为临床试验做准备。该项目的成功将直接关系到移植外科医生、科学家和生物医学工程师团队之间建立关键伙伴关系，他们将根据需要合作测试和修改新的HMP解决方案。此外，肝脏系统公司将与器官恢复系统公司合作，在他们的原型肝脏传输器中测试新的灌流解决方案。公共卫生相关性：心脏死亡(DCD)后的肝脏捐赠有可能使移植的数量增加20%-40%，但糟糕的保存方法和解决方案阻碍了这些器官的广泛使用。一种新的灌注液与低温机灌流保存相结合已经被开发出来，以恢复这些在心脏死亡后经历了长时间无血流的肝脏。第一阶段SBIR项目非常成功地表明，在移植研究中，新的灌注液提高了恢复和存活率。这个第二阶段的项目将通过优化该解决方案并开始在模拟DCD的大型临床前动物中进行测试，使该解决方案更接近临床使用。