Extended preservation of human livers: a nature inspired, high subzero controlled, limited freezing approach

人类肝脏的长期保存：一种受自然启发、高度零下控制、有限冷冻的方法

• 批准号: 9910008
• 负责人: YOED RABIN
• 金额: $ 29.97万
• 依托单位: SYLVATICA BIOTECH, INC.
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-13 至 2022-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9910008
• 关键词: Achievement; Acute Liver Failure; Affect; Animals; Area; Arizona; Back; Biological Assay; Biomedical Engineering; Biomedical Research; Businesses; Cells; Clinical; Cryopreservation; Custom; Data; Devices; Dialysis procedure; Economics; Emergency Situation; Equilibrium; Equipment and supply inventories; Evaluation; Freezing; Future; Goals; Graft Rejection; Growth; Heart failure; Helicopter; Hepatocyte; Hour; Human; Ice; Immune Tolerance; Immunologics; In Vitro; Injury; Kidney; Kidney Failure; Kidney Transplantation; Learning; Length; Letters; Life; Liver; Liver Failure; Lobe; Longevity; Modeling; Nature; Operative Surgical Procedures; Organ; Organ Donations; Organ Preservation; Organ Procurements; Organ Transplantation; Outcome; Patients; Perfusion; Phase; Procedures; Protocols documentation; Quality of life; Rattus; Recovery; Resort; Resuscitation; Savings; Schedule; Slice; Stretching; System; Technology; Temperature; Thermodynamics; Time; Tissue Engineering; Tissues; Translating; Transplant Surgeon; Transplantation; Universities; Validation; Waiting Lists; Whole Blood; Work; animation; base; biomaterial compatibility; combinatorial; cost; design; experience; flexibility; high throughput screening; human model; improved; laboratory equipment; liver preservation; liver transplantation; metabolic depression; mortality; novel strategies; preconditioning; preservation; prototype; repaired; stress tolerance; success; transplant model; trauma care; ventricular assist device

ABSTRACT 1 in 5 liver waitlist patients do not receive a new liver in time, while many more patients are never listed but could benefit from liver replacement. While “bridge-to-transplant” technologies (ventricular assist devices and dialysis) have transformed the outlook for heart failure and kidney failure, no such treatment exists for patients with liver failure. Current liver sharing limits (approx. 500 miles) are based on limited preservation durations (6-10 hours). By extending preservation to just a few days we can enable nationwide (theoretically global) donor-recipient matching, allowing many livers that go untransplanted today (e.g. subsets of extended criteria donor livers that have been shown to offer substantial survival benefits) to be offered to the patients who most need them. Transplant surgeons have expressed excitement about this possibility, and it is thought that this achievement would have a profound impact on liver waitlist mortality. Among other benefits, this can also increase graft lifespan and reduce immunological rejection, eliminate the need for costly jet and helicopter transport, transform the practice of liver transplantation from emergency surgery to a flexibly scheduled procedure, and mitigate the severe disparities in liver transplantation. It will also allow immune tolerance induction protocols that have now achieved success in living donation to be adapted to the deceased donor context. To meet these needs, we will develop a comprehensive system for banking human livers for transplantation for periods of 5-7 days with a stretch goal of 10+ days or longer. We have created an integrated two-pronged approach to develop new stasis cocktails optimized for the critical phases of liver preservation: preconditioning and protection (prior to storage), preservation (during storage) and revival- resuscitation-repair (after storage). In parallel, we are creating devices for advanced perfusion, storage, and organ assessment before transplant decision. Our approach adapts the best strategies of freeze-tolerant and hibernating species, augmenting them with recent scientific and bioengineering advances. Importantly, we do not seek to solve all the problems of classical cryopreservation, but rather to be the first to develop preservation in thermodynamic equilibrium at high subzero (HSZ) temperatures (-10°C to -30°C), combined with programmed metabolic depression and enhanced stress tolerance. Feasibility of this approach has already been demonstrated; we have banked rat livers for 5 days at HSZ temperatures, and successfully preserved the first whole human liver lobe at -15°C. For this fast-track proposal, the Phase 1 goal will be to further refine our protocols and validate our initial unprecedented storage duration by banking rat livers for 5-7 days and using comprehensive post-preservation normothermic machine perfusion with functional assessment. We will also scale to whole human liver lobes, with subsequent hepatocyte isolation. Phase 2 will focus on optimizing key parameters that affect preservation outcomes in rat and human livers. Our goal is 6-10+ days of storage via (i) optimal modulation of ice growth, (ii) nature-inspired de-toxify/reenergize perfusion phase and (iii) precise control of thermodynamics using a prototype Bio-Thermodulator device.

抽象的 五分之一的肝脏等候名单患者没有及时接受新的肝脏，而更多的患者从未被列入名单，但可以 受益于肝脏替代技术（心室辅助装置和透析）。 改变了心力衰竭和肾衰竭的前景，但对于肝病患者尚无此类治疗方法 目前的肝脏共享限制（约 500 英里）基于有限的保存时间（6-10 小时）。 通过将保存时间延长到几天，我们可以在全国范围内（理论上是全球）捐助者-接受者 匹配，允许今天许多未移植的肝脏（例如，扩展标准供体肝脏的子集 已被证明可以提供实质性的生存益处）提供给最需要它们的患者。 移植外科医生对这种可能性表示兴奋，并且认为这一成就 将对肝脏候补死亡率产生深远影响，除了其他好处外，这还可以增加移植物。 延长寿命并减少免疫排斥，消除昂贵的喷气式飞机和直升机运输的需要，改造 肝移植实践从急诊手术转向灵活安排手术，减轻 它还将允许目前已有的免疫耐受诱导方案。 为了满足这些需求，我们在活体捐赠方面取得了成功，以适应已故捐赠者的情况。 将开发一个综合系统，用于储存人类肝脏以供移植，为期 5-7 年 天的延伸目标为 10 天以上或更长 我们创建了一个综合的双管齐下的方法。 开发针对肝脏保存关键阶段优化的新型停滞鸡尾酒：预处理和保护 （储存前）、保存（储存期间）和复活-复苏-修复（储存后）。 我们正在创建用于在做出移植决定之前进行高级灌注、储存和器官评估的设备。 该方法采用了耐冻和冬眠物种的最佳策略，并用最新的技术增强了它们 重要的是，我们并不寻求解决所有经典问题。 低温保存，而是第一个开发在零度以下热力学平衡下的保存 (HSZ) 温度（-10°C 至 -30°C），加上程序性代谢抑制和压力增强 这种方法的可行性已得到证实；我们已将大鼠肝脏保存了 5 天。 在 HSZ 温度下，并成功在 -15°C 下保存了第一个完整的人类肝叶。 根据提案，第一阶段的目标将是进一步完善我们的协议并验证我们最初的前所未有的存储 大鼠肝脏保存5-7天并使用综合后保存常温机的持续时间 我们还将通过功能评估扩展到整个人类肝叶，以及随后的肝细胞。 第二阶段将重点优化影响大鼠和人类肝脏保存结果的关键参数。 我们的目标是通过 (i) 冰生长的最佳调节，(ii) 受自然启发的解毒/重新注入能量，储存 6-10 天以上 灌注阶段和 (iii) 使用原型生物热调节器装置精确控制热力学。