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: 7486439
• 负责人: Charles Y Lee
• 金额: $ 76.36万
• 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 2010-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7486439
• 关键词: Abbreviations; Accident and Emergency department; Address; Adverse effects; Animal Model; Animals; Biological Preservation; Biomedical Engineering; Blood flow; Cardiac Death; Class; 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; Numbers; Organ; Patients; Performance; Perfusion; Phase; Preparation; Production; Public Health; Rattus; Recovery; Recovery of Function; Regional Perfusion; Reperfusion Injury; Research; Scientist; Simulate; Small Business Funding Mechanisms; Small Business Innovation Research Grant; Solutions; Stress; System; Testing; Time; Toxic effect; Transplant Surgeon; Transplantation; Universities; Waiting Lists; Warm Ischemia; Wisconsin; base; cost; day; experience; improved; in vivo Model; liver function; liver transplantation; oxidation; pre-clinical; prevent; prototype; 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）：本项目的长期目标是通过开发一种用于恢复和保存的新型低温机器灌注（HMP）溶液，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增加的应力。已经开发出一种新的解决方案来恢复耗尽的能量储存，保持膜稳定性，并最大限度地减少氧化损伤。 I期项目非常成功地表明，在隔离灌注和移植研究中，新的HMP溶液改善了延长的热缺血（60分钟）大鼠肝脏的5小时保存。结果显示，与单独使用UW溶液（0/6）相比，恢复改善，损伤减少，存活率提高（7/9）。 该II期SBIR的主要目标是：1）加强IP保护，2）最大限度地减少潜在的毒性作用，3）降低生产成本，以及4）开始在临床前大型动物DCD模型中测试该溶液。以下特定目的将实现这些目标：1）确定新灌注溶液和低温机器灌注回收肝脏的最大可持续热缺血时间，2A）优化新HMP溶液的组分，2B）优化新HMP溶液的组分浓度，3）在猪DCD肝脏模型中测试新优化的HMP溶液。为了实现这些目标，将利用大鼠和猪的离体灌注肝脏研究以及大鼠的移植研究。实现该项目的目标将增强解决方案的价值，增加解决方案的IP保护，减少毒性问题的可能性，并为临床前大型动物移植和人类离体模型中的进一步测试奠定基础，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的合作伙伴关系，他们将根据需要合作测试和修改新的HMP解决方案。此外，HepatoSys，Inc.将与器官恢复系统公司合作，在他们的原型肝脏转运器中测试新的灌注溶液。公共卫生关系：心脏性死亡（DCD）肝脏捐赠有可能增加20- 40%的移植数量，然而，不良的保存方法和解决方案阻止了这些器官的广泛使用。一种新的灌注溶液结合低温机器灌注保存已经开发出来，以回收这些肝脏，经历了心脏死亡后长时间无血流。I期SBIR项目非常成功，表明新的灌注溶液改善了移植研究中的恢复和存活。该II期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。