High subzero preservation of liver for transplantation

移植用肝脏的高度低温保存

• 批准号: 10815970
• 负责人: Mehmet Toner
• 金额: $ 4.39万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-01 至 2025-12-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10815970
• 关键词: Address; Animals; Antioxidants; Bacteria; Bioenergetics; Blood Vessels; Cell Survival; Cells; Cellular Morphology; Charge; Chimerism; Circulation; Citric Acid Cycle; Crystallization; Data; Endothelial Cells; Endothelium; Engineering; Exhibits; Extracellular Space; Fatty Acids; Freezing; Funding; Glutathione; Hour; Human; Ice; Injury; Legal patent; Length; Liver; Location; Measures; Metabolic; Methods; Microscopic; Modeling; Molecular; Movement; Nature; Operative Surgical Procedures; Organ; Organ Donor; Organ Preservation; Organ Transplantation; Oxygen; Patients; Perfusion; Permeability; Protocols documentation; Public Health; Rana; Rattus; Recovery; Reperfusion Injury; Research; Rodent; Signal Transduction; System; Technology; Temperature; Time; Tissue Engineering; Tissues; Toxic effect; Transplantation; Trehalose; Vascular Endothelium; Vascular resistance; Viscosity; Waiting Lists; Wood material; animation; cell injury; cold temperature; cost; experience; extracellular; improved; inhibitor; innovation; ischemic injury; liver preservation; liver transplantation; metabolomics; natural hypothermia; organ injury; oxidation; point of injury; preconditioning; preservation; prevent; programs; public health relevance; scale up; shear stress; success; transcriptome sequencing; vascular injury; wasting

ABSTRACT With more than five times the number of patients on the wait list than will receive a donor organ in the USA, the field of transplantation is facing a serious donor shortage crisis. Despite decades of research, a major critical bottleneck is the current preservation times for whole organs are limited to few hours of storage. Longer preservation times are required to enable global matching programs, eliminate unnecessary waste of organs, and reduce costs associated with unplanned surgeries, and are enabling for mixed-chimerism based tolerance induction protocols which require the donor organ to be kept viable for days so that recipient preconditioning can be done safely. Consequently, the focus of this application is to address a major unmet need in transplantation by prolonging the length of time organs can be kept in “suspended animation” ex vivo. Our approach is inspired by the hibernating and freeze-tolerant animals in nature. We aim to embrace and control the ice formation to achieve high subzero storage temperatures in the presence of extracellular ice, and storage durations of weeks to ultimately months. It is our hypothesis that the presence of ice in a non-injurious frozen state enables storage at lower temperatures (down to -30°C) and consequently a deeper metabolic stasis for weeks, while also enabling scale-up to human organs. In the previous funding period, we developed a new method to use ice nucleating bacteria to tightly control ice formation temperature and developed a partial freezing protocol down to -15°C that can store rat livers up to 5 days with ex vivo function, and also established a proof-of-concept in human livers. In this competing renewal application, we propose to build on our success and reach preservation temperatures down to -30°C, thus achieving suspended animation for weeks. We propose (i) to control ice formation in liver, which our prior studies demonstrated to be a key barrier; (ii) to develop targeted approaches to improve preservation of endothelium, which are at the interface of tissue and ice and are the first point of injury, and (iii) to develop a choreographed metabolic protocol to maximize ATP recovery and improve viability of the grafts for transplant.

抽象的 等待名单上的患者人数超过五倍，超过将在美国接收捐赠器官的人数 移植场正面临严重的捐助者短缺危机。尽管进行了数十年的研究，但主要的关键瓶颈是 整个器官的当前保存时间仅限于几个小时的存储时间。需要更长的保存时间 启用全球匹配计划，消除不必要的浪费器官，并降低与计划外的成本 手术，并为需要供体器官的基于混合性的耐受性诱导方案启用 保持几天的可行性，以便可以安全地进行接收者预处理。因此，此应用程序的重点是 通过延长时间器官的长度可以保存在“悬浮”中，以解决移植的主要需求 动画” ex vivo。我们的方法灵感来自自然界中的冬眠和冻结的动物。我们的目标是拥抱 并控制冰层以在存在细胞外冰的情况下实现高零储存温度和储存 几周到几个月的时间。我们的假设是，冰的存在在非妇女的冷冻状态下 在较低的温度下（降至-30°C），因此可以储存更深的代谢暂停数周，同时也是 使人体器官扩大规模。在上一个资金期间，我们开发了一种使用冰核的新方法 细菌以紧密控制冰形成温度，并制定了部分冷冻方案，向下降至-15°C 商店老鼠最多可以通过体内功能居住5天，并在人类生活中建立了概念验证。在这个 竞争性续订应用程序，我们建议以我们的成功为基础，并达到降至-30°C的准备温度， 这就是我们建议控制肝脏中冰形成的（i），我们先前的研究 被证明是关键障碍； （ii）开发有针对性的方法来改善内皮的保存， 组织和冰的界面是损伤的第一个点，（iii）开发编排的代谢方案 最大化ATP恢复并提高移植物的生存能力。