Feasibility of Hypothermic Liver Perfusion

低温肝脏灌注的可行性

• 批准号: 7536720
• 负责人: Kelvin G.M. Brockbank
• 金额: $ 21.55万
• 依托单位: CELL AND TISSUE SYSTEMS, INC.
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-09-01 至 2010-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7536720
• 关键词: Address; Alcohol abuse; Alcohols; American; Ammonia; Authorization documentation; Bile fluid; Biological Preservation; Blood gas; Buffers; Cause of Death; Cells; Centers for Disease Control and Prevention (U.S.); Cessation of life; Cicatrix; Cirrhosis; Clinical Data; Clinical Research; Condition; Data; Devices; Dialysis procedure; Disease; Electrolytes; Endothelial Cells; Engineering; Enzymes; Evaluation; Factor V; Family suidae; Feasibility Studies; Fibrinogen; Goals; Heart; Heating; Hemoglobin; Hepatitis; Hepatocyte; Hour; Human; Hyaluronic Acid; In Vitro; Indocyanine Green; Injury; Knowledge; Life; Literature; Liver; Liver Failure; Liver diseases; Logic; Measurement; Methods; Modeling; Numbers; Organ; Organ Transplantation; Oxygen; Oxygenators; Patients; Performance; Perfusion; Phase; Phase II Clinical Trials; Physical Dialysis; Preclinical Testing; Probability; Public Health; Range; Regional Perfusion; Relative (related person); Safety; Sampling; Scientist; Small Business Funding Mechanisms; Small Business Innovation Research Grant; Solutions; Staging; Statistically Significant; Surgeon; System; Temperature; Testing; Transplantation; United States Food and Drug Administration; Urea; Veterinarians; Work; base; blood perfusion; cell injury; clinical application; design; improved; in vitro Model; in vivo; liver function; liver preservation; pre-clinical; prototype; research study; success

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.

描述（由申请人提供）：每年有超过 43,000 名美国人死于肝病，使其成为美国第十大疾病相关死因。肝硬化具有不可逆的肝脏损伤和疤痕，是肝衰竭的最常见原因，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，除非开发出改进的治疗方法，否则与肝炎相关的死亡人数每年将增加到 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。这些患者没有透析等效疗法，在等待可移植器官期间死亡的可能性是现实的。该 SBIR 提案的长期目标是通过开发一种临床可用的便携式低温灌注肝脏保存方法来增加可用于移植的供体肝脏的数量和质量，该方法将可靠地保存人类肝脏至少 24 小时。该第一阶段提案的目的是测试并确定中温 12-14oC 低温氧合灌注策略与原型肝脏运输装置相结合的可行性，以保存猪心跳供体肝功能 24 小时。在这些实验过程中，原型肝脏运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以及在其他相同条件下在 4-6oC 下灌注的肝脏进行比较。新鲜对照以及对照和实验低温灌注组都将通过 37oC 体外含氧血液灌注进行评估。该常温灌注测试回路将包括具有额外热交换能力的肝脏运输装置和氧合器。在体外测试期间，将分析血气，并定期收集胆汁和灌注液样本。将酌情评估灌注液或胆汁样品中的电解质、因子 V、氨、尿素、纤维蛋白原、透明质酸、吲哚菁绿清除率和肝酶。如果我们在这一阶段的可行性研究中取得成功，我们随后将提出一项II期研究，其中尝试将猪肝脏保存48小时，并将体外和体内测试与灌注溶液优化相结合。 48 小时的猪肝脏保存将提供临床前安全性和有效性数据，以支持在 FDA 许可下进行长达 24 小时保存的人类肝脏的临床研究。公共卫生相关性：该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，尸检后长期肝脏保存策略的可用性可能会从扩大标准的心跳供体和短期热缺血非心跳供体中产生大量的可移植肝脏，相当于增加约 25% 的可移植肝脏。