Feasibility of Hypothermic Liver Perfusion

描述(申请人提供)：每年有超过43,000名美国人死于肝病，使其成为美国第十大与疾病相关的死因。肝硬变伴有不可逆转的肝脏损伤和疤痕，是导致肝功能衰竭的最常见原因，可归因于酗酒和肝炎。尽管酒精一直是肝硬化的主要原因，但疾病控制中心预测，除非开发出更好的治疗方法，否则与肝炎相关的死亡人数将增加到每年3.8万人。供移植的器官短缺仍然是为终末期肝功能衰竭患者提供最佳治疗的主要障碍。对于这些患者来说，没有等同于透析的疗法，在等待可移植器官的过程中死亡的前景是一个现实的可能性。这项SBIR建议的长期目标是通过开发一种临床可用的、便携式的低温肝脏保存方法来提高可供移植的供体肝脏的数量和质量，这种方法将可靠地保存人类肝脏至少24小时。该第一阶段方案的目标是测试和确定中温、12-14oC低温充氧灌流策略与原型肝脏传输装置相结合的可行性，以保存猪心脏跳动中的供体肝脏功能24小时。在这些实验过程中，原型肝脏传输装置将接受设计审查，以优化其设计。实验肝脏将与新鲜的未经处理的对照组和在其他相同条件下以4-60摄氏度灌流的肝脏进行比较。新鲜对照组、对照组和实验低温灌注组将通过体外37℃的氧合血液灌流进行评估。这一常温灌流测试电路将包括具有额外热交换能力的肝脏传输装置和氧合器。在体外测试期间，将分析血气，并定期收集胆汁和灌流液样本。电解质、因子V、氨、尿素、纤维蛋白原、透明质酸、吲哚青绿清除率和肝酶将在适当时在灌流液或胆汁样本中进行评估。如果我们在第一阶段可行性研究中取得成功，我们将随后提出第二阶段研究，尝试将猪肝脏保存48小时，并将体外和体内测试与灌注液优化相结合。48小时的猪肝脏保存将提供临床前的安全性和有效性数据，以支持在FDA允许的情况下，进行长达24小时的人类肝脏临床研究。与公共卫生相关：这项提案旨在实现技术突破，有可能满足国家对可移植肝脏的关键需求。保守地说，死后长期肝脏保存策略的可用性可能会产生大量来自扩大标准心脏跳动供者和短期热缺血非心脏跳动供者的可移植肝脏，相当于增加约25%。

DESCRIPTION (provided by applicant): More than 43,000 Americans die each year from liver disease, making it the 10th leading disease- related cause of death in the US. Cirrhosis with irreversible injury and scarring of the liver, is the most prevalent cause of liver failure and is attributable to alcohol abuse as well as hepatitis. Although alcohol has been the primary cause of cirrhosis, the Center for Disease Control has predicted that hepatitis-related deaths will increase to 38,000 a year unless improved treatments are developed. The shortage of organs for transplantation continues to be a major impediment to providing optimal treatment for patients with end stage liver failure. There is no dialysis-equivalent therapy for these patients and the prospect of death while waiting for a transplantable organ is a realistic probability. The long-term goal of this SBIR proposal is to increase the number and quality of donor livers available for transplantation by developing a clinically usable, portable, hypothermic perfusion method of liver preservation that will reliably preserve human livers for at least 24 hours. The objective of this Phase I proposal is to test and determine feasibility of an intermediate temperature, 12-14oC, hypothermic oxygenated perfusion strategy in combination with a prototype liver transport device for preservation of porcine heart beating donor liver functions for 24 hours. The prototype liver transport device will be subjected to design review to optimize its design during the course of these experiments. The experimental livers will be compared with fresh untreated controls and livers perfused at 4-6oC under otherwise identical conditions. Both fresh controls and control and experimental hypothermic perfusion groups will be assessed by oxygenated blood perfusion in vitro at 37oC. This normothermic perfusion test circuit will include the liver transport device with additional heat exchange capacity and an oxygenator. During in vitro testing blood gases will be analyzed and both bile and perfusate samples will be collected at frequent intervals. Electrolytes, factor V, ammonia, urea, fibrinogen, hyaluronic acid, indocyanine green clearance and liver enzymes will be assessed in the perfusate or bile samples, as appropriate. If we are successful in this Phase I feasibility study, we will subsequently propose a Phase II study in which porcine liver preservation for 48 hours is attempted and in vitro and in vivo testing is combined with perfusion solution optimization. Forty-eight hours of porcine liver preservation would provide preclinical safety and efficacy data to support progression, with FDA permission, to clinical studies of human livers for up to 24 hours of preservation. PUBLIC HEALTH RELEVANCE: This proposal aims at technical breakthroughs with the potential to address critical national needs for transplantable livers. Conservatively the availability of longer term liver preservation strategies post-mortem may generate significant numbers, equivalent to ~25% more transplantable livers, from expanded criteria heart beating donors and short-term warm ischemic non-heart beating donors.