High subzero preservation of liver for transplantation

移植用肝脏的高度低温保存

• 批准号: 9898358
• 负责人: Mehmet Toner
• 金额: $ 38.48万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-07-17 至 2021-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9898358
• 关键词: Animals; Bioinformatics; Biomedical Engineering; Biomimetics; Blood Vessels; Blood capillaries; Body Water; Breathing; Cell Survival; Cells; Clinical; Clinical Pathways; Crystallization; Data; Dehydration; Development; Discontinuous Capillary; Encapsulated; Endothelial Cells; Energy Metabolism; Engineering; Ensure; Evaluation; Extracellular Space; Freezing; Glycocalyx; Hepatocyte; Hour; Human; Ice; Infiltration; Infrastructure; Length; Liquid substance; Literature; Liver; Metabolic; Methods; Microfluidics; Modeling; Molecular; Molecular Profiling; Names; Nature; Operative Surgical Procedures; Organ; Organ Donor; Organ Preservation; Organ Transplantation; Outcome; Pathway interactions; Patients; Pharmacology; Phenotype; Play; Process; Property; Protocols documentation; Public Health; Rana; Rattus; Regulatory Pathway; Reperfusion Therapy; Research; Role; Screening procedure; Spatial Distribution; Technology; Temperature; Testing; Time; Tissues; Translating; Transplantation; United States; Waiting Lists; Work; animation; base; body system; cell injury; cost; extracellular; improved; interdisciplinary approach; liver preservation; liver transplantation; novel strategies; organ injury; phase change; preservation; prevent; programs; scale up; stress tolerance; success; tissue/organ preservation; visual tracking; wasting

PROJECT SUMMARY With more than five times the number of patients on the wait list than will receive a donor organ in the United States, the field of transplantation is facing a serious donor shortage crisis. Overcoming the organ shortage will require integrated strategies, including a particular focus on overcoming ineffective bio-preservation and stabilization protocols. Longer storage durations will provide the infrastructure required to enable global matching programs, eliminate the need to scramble and conduct unplanned surgeries, and reduce unnecessary waste of quality organs. We believe the method for preserving mammalian organs should employ hibernating and freeze-tolerant strategies in nature that are then further augmented using bioengineering principles. Consequently, we seek to develop a protocol for human organ preservation which will achieve high subzero storage temperatures (ranging from -10 to -20 °C) in the presence of extracellular ice, and storage durations of weeks to months, using inspiration from in nature. Our approach is unique in organ/tissue preservation literature since we aim to actively initiate ice propagation in the vasculature and extracellular spaces, rather than extreme means of inhibiting ice crystallization as is the current standard. The presence of non-injurious ice will be essential in achieving longer storage durations, while also playing an important role in the scale-up to human livers. While this program targets the banking of human liver, our discoveries and solutions will be translatable to other tissues and organ systems. In Specific Aim 1, we will adapt endothelial cell-coated microvascular networks already developed by our group3 in order to model and develop strategies to overcome challenges associated with ice propagation. Since endothelial cells in the vasculature will be the most vulnerable to ice propagation, SA#1 will be an essential proof of concept of our novel strategy and we already have promising data. In Specific Aim 2, we will engineer an ice nucleating agent which will promote non-injurious propagation of ice in extracellular spaces. Ice nucleating agents are essential for restricting ice formation to extracellular spaces and have been identified as critical strategies for freezing survival. In Specific Aim 3, we will reprogram cells to descend into a state of `suspended animation' with enhanced stress tolerance, as inspired by nature. We will achieve this using both passive temperature effects as well as using pharmacological agents. We will perform in-depth characterization of the molecular impact of our cellular reprogramming efforts. In each specific aim, we scale up rapidly to rat whole liver while also validating in human livers in order to maximize impact.

项目概要 等待名单上的患者数量是美国接受捐赠器官的患者数量的五倍多 各国移植领域正面临着严重的供体短缺危机，克服器官短缺将成为可能。 需要综合战略，包括特别注重克服无效的生物保护和 更长的存储时间将提供实现全球性所需的基础设施。 匹配方案，省去手忙脚乱、计划外的手术，减少不必要的手术 优质器官的浪费。 我们认为保存哺乳动物器官的方法应该采用冬眠和耐冻的方法 我们寻求利用生物工程原理进一步增强自然界中的策略。 制定人体器官保存协议，以实现高低温保存 存在细胞外冰的情况下的温度（范围从 -10 至 -20 °C），以及储存时间 几周到几个月，我们的方法在器官/组织保存方面是独一无二的。 文献，因为我们的目标是主动启动冰在脉管系统和细胞外空间的传播，而不是 比目前标准的抑制冰结晶的极端方法无害。 冰对于实现更长的储存时间至关重要，同时在扩大规模方面也发挥着重要作用 虽然该计划的目标是人类肝脏的储存，但我们的发现和解决方案将是 可转化为其他组织和器官系统。 在具体目标 1 中，我们将采用我们已经开发的内皮细胞涂层微血管网络。 第三组，以建模和制定策略来克服与冰传播相关的挑战。 由于脉管系统中的内皮细胞最容易受到冰传播的影响，因此 SA#1 将是 我们的新策略的概念的重要证明，并且我们已经在具体目标 2 中获得了有希望的数据。 设计一种冰成核剂，促进冰在细胞外空间的无害传播。 冰成核剂对于限制细胞外空间的冰形成至关重要，并且已被鉴定 作为冻结生存的关键策略，在特定目标 3 中，我们将重新编程细胞，使其进入一种状态。 受到大自然的启发，我们将利用两者来实现这一目标。 我们将深入研究被动温度效应以及使用药物。 我们的细胞重编程工作的分子影响的表征在每个具体目标中，我们都进行了扩展。 迅速在大鼠整个肝脏中进行验证，同时也在人类肝脏中进行验证，以最大限度地发挥影响。