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

描述（由申请人提供）：每年有超过43,000名美国人死于肝脏疾病，使其成为美国第十大与疾病相关的死亡原因。肝硬化伴肝脏不可逆损伤和瘢痕形成是导致肝功能衰竭的最普遍原因，可归因于酗酒和肝炎。虽然酒精一直是肝硬化的主要原因，但疾病控制中心预测，除非改进治疗方法，否则与肝炎相关的死亡人数将增加到每年38,000人。移植器官的短缺仍然是为终末期肝衰竭患者提供最佳治疗的主要障碍。对于这些患者没有透析等效的治疗方法，在等待移植器官的过程中死亡的可能性是现实的。这项SBIR提案的长期目标是通过开发一种临床可用的、便携式的、低温灌注的肝脏保存方法来增加可用于移植的供肝的数量和质量，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估。本I期提案的目的是测试并确定中间近室温，18-22℃，深度低温氧合血灌注策略与肝脏运输装置原型相结合的可行性，以保存猪心脏跳动供体肝脏功能24小时。与常温和4-6℃低温保存策略相比，该装置概念具有潜在的优势。在实验过程中，将对原型肝转运装置进行设计审查，以优化其设计。实验肝脏将与使用现行临床方法冷冻保存的对照肝脏进行比较。对照组和实验低温灌注组均采用37℃体外氧合血灌注法进行评估。恒温灌注试验回路将包括具有额外热交换和氧合能力的肝脏运输装置。在测试过程中，将经常收集灌注液和胆汁样本，并进行优先终点分析，以测量(1)代谢性酸中毒和低血糖，(2)胆汁生成减少或缺失，(3)库普弗细胞激活，(4)窦内皮细胞功能障碍，这将导致再灌注时血流量减少。如果我们在一期可行性研究中取得成功，我们随后将提出一项二期研究，尝试猪肝保存48小时，并结合体外和体内试验，优化灌注液。48小时的猪肝保存将提供临床前安全性和有效性数据，以支持FDA许可的人类肝脏长达24小时保存的临床研究的进展。

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.