Feasibibility of deep hypothermic (18-22C) perfusion storage of livers for transp

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。该装置还可用于生理条件下的体外肝脏质量评价。这项第一阶段计划的目的是测试和确定一种接近室温、温度18-22oC的中低温深低温充氧血液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。与常温和深4-6℃低温保存策略相比，这种设备概念具有潜在的优势。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。实验肝脏将与储存在冰上的对照肝脏进行比较，使用目前的临床方法。对照组和实验低温灌注组将通过37℃的体外氧合血液灌流进行评估。常温灌流测试电路将包括具有额外热交换和充氧能力的肝脏传输装置。在测试期间，将频繁收集灌流液和胆汁样本，并优先进行终点分析，以测量(1)代谢性酸中毒和低血糖，(2)胆汁生成减少或消失，(3)库普弗细胞激活，以及(4)肝窦内皮细胞功能障碍，这将导致再灌注时血流减少。如果我们在这项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，并结合体内外测试和灌注液优化。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。 公共卫生相关性：该提案中的创新技术突破将对国家对可移植肝脏的关键需求产生重大影响。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%。器官供应的增加应该会减少患者等待器官的时间，以及等待肝脏而死亡的患者数量。

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 device can also be employed for liver quality evaluation ex vivo under physiologic conditions. The objective of this Phase I proposal is to test and determine feasibility of an intermediate near room temperature, 18-22oC, deep hypothermic oxygenated blood perfusion strategy in combination with a prototype liver transport device for preservation of porcine heart beating donor liver functions for 24 hours. This device concept has potential advantages compared with both normothermic and profound, 4-6oC hypothermic preservation strategies. 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 control livers stored on ice using current clinical methods. Both controls and experimental hypothermic perfusion groups will be assessed by oxygenated blood perfusion ex vivo at 37oC. The normothermic perfusion test circuit will include the liver transport device with additional heat exchange and oxygenation capacity. During testing perfusate and bile samples will be collected at frequent intervals and prioritized end point assays performed to measure (1) metabolic acidosis and hypoglycemia, (2) reduced or absent bile production, (3) Kupffer cell activation, and (4) sinusoidal endothelial cell dysfunction which would lead to reduced blood flow upon reperfusion. 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 ex vivo 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: The innovative technical breakthroughs in this proposal will have a significant impact on 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. This increase in organ supply should decrease patient waiting times for organs and the number of patients who die waiting for a liver.