Organ banking for transplant--kidney cryopreservation by vitrification and novel nanowarming technology

移植器官库——玻璃化肾脏冷冻保存和新型纳米加温技术

• 批准号: 10657291
• 负责人: JOHN C BISCHOF
• 金额: $ 64.06万
• 依托单位: UNIVERSITY OF MINNESOTA
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-04-13 至 2027-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10657291
• 关键词: Affect; Animal Model; Architecture; Benchmarking; Biocompatible Materials; Biological; Blood Vessels; CCR; Chronic Kidney Failure; Compensation; Cryopreservation; Cryoprotective Agents; Crystallization; Data; Dialysis procedure; Endothelium; Engineering; Family suidae; Funding; Glass; Goals; Healthcare; Heart; Heating; Human; Ice; Immune response; In Vitro; Injury; Ischemia; Kidney; Kidney Transplantation; Life Expectancy; Liquid substance; Liver; Measures; Methods; Modeling; Molecular; Nanotechnology; Organ; Organ Donor; Organ Preservation; Organ Size; Organ Transplantation; Oryctolagus cuniculus; PF4 Gene; Patients; Performance; Perfusion; Phase Transition; Population; Preparation; Progressive Disease; Protocols documentation; Quality of life; RF coil; Rattus; Recovery; Renal function; Reperfusion Therapy; Reproducibility; Rewarming; Rodent; Solid; Speed; System; Technology; Temperature; Testing; Time; Tissue Viability; Tissues; Transplantation; Transplantation Tolerance; allotransplant; body system; clinical translation; cold temperature; comparison control; cost; implantation; improved; in vivo; iron oxide nanoparticle; ischemic injury; magnetic field; nanoparticle; nanowarming; new technology; novel; novel strategies; preservation; pressure; radio frequency; response to injury; scale up; success; supply chain; thermal stress; transplant model; vitreous state

ABSTRACT Chronic kidney disease is a significant healthcare issue affecting >15% of the U.S. population and costing billions in healthcare dollars annually. Transplantation is the best option for most patients with progressive disease, resulting in a significant increase in life expectancy and improved quality of life compared to dialysis. The potential U.S. deceased donor organ supply is estimated to exceed the current number of organs transplanted by a factor of 4- to 5-fold, with a major limitation to the number of acceptable organs for transplant being the ischemic injury sustained between recovery and implantation. A method to cryopreserve or “bank” kidneys prior to transplant would effectively remove the influence of time from the supply chain of organ distribution. This would allow a new paradigm for transplantation that would improve donor/recipient matching, allow for better patient preparation, facilitate tolerance induction protocols, and increase organ utilization while improving graft and patient survival. One promising approach that overcomes the limitations of conventional strategies is vitrification—that is, cooling organs so quickly that they cannot undergo the phase transition from liquid to solid ice. With the help of cryoprotective agents (CPAs), the organ enters a stable glass-like state wherein viable storage is theoretically indefinite. The critical challenge, however, is rewarming without ice formation or cracking: if rewarming is too slow, ice crystals form, and if rewarming is not uniform, thermal stress causes cracking. During our initial R01 funding, we developed a novel approach termed “nanowarming” that achieved both objectives. Iron oxide nanoparticles were perfused throughout the vasculature of the organ along with CPA solutions. The organ was then vitrified by cooling and rewarmed on-demand by placing it in a radiofrequency coil that induces heating in the nanoparticles and, therefore, from within the organ. We found that nanowarming could rewarm vitrified organs, including kidneys, in animal models. We have recently shown, for the first time, that nanowarmed organs function in vitro and in vivo following transplantation. Further, we showed successful vitrification and nanowarming of human-sized (porcine) kidneys. These new data support the feasibility of our approach to cryopreserve and nanowarm whole human organs for transplantation. Nevertheless, many questions remain, including how nanowarmed kidneys function compared to control organs, what, if any, injury occurs during nanowarming, and how to scale up to human-sized organs. In this renewal R01, we propose to: (1) Quantitatively assess cryopreserved and nanowarmed kidney transplant function in a rat model, including long- term preservation, long-term function, modes of injury, and alterations of the host immune response, (2) Engineer and optimize scale-up for nanowarming vitrified human-sized organs, and (3) Vitrify and nanowarm human-sized kidneys while measuring viability, structural integrity, and organ function.

抽象的 慢性肾病是一个重大的医疗保健问题，影响超过 15% 的美国人口，造成数十亿美元的损失 每年医疗费用的移植是大多数患有进展性疾病的患者的最佳选择， 与透析相比，可显着延长预期寿命并提高生活质量。 据估计，美国潜在的死者捐献器官供应量将超过目前的移植器官数量 4 至 5 倍，可接受移植器官数量的主要限制是 恢复和植入之间持续的缺血性损伤是一种在肾脏提前冷冻或“储存”的方法。 移植可以有效消除器官分配供应链中时间的影响。 将创造一种新的移植模式，改善供体/受体匹配，实现更好的移植 患者准备，促进耐受诱导方案，提高器官利用率，同时改善移植 一种克服传统策略局限性的有前景的方法是 玻璃化——也就是说，器官冷却得如此之快，以至于它们无法经历从液体到固体的相变 在冷冻保护剂（CPA）的帮助下，器官进入稳定的玻璃状状态，可以存活。 然而，储存在理论上是无限期的，但关键的挑战是在不形成冰或破裂的情况下复温： 如果复温太慢，就会形成冰晶，如果复温不均匀，热应力会导致开裂。 在我们最初的 R01 资金支持下，我们开发了一种名为“纳米变暖”的新颖方法，实现了这两个目标。 氧化铁纳米颗粒与 CPA 溶液一起灌注到器官的整个脉管系统中。 然后通过冷却将器官玻璃化，并根据需要将其放入射频线圈中重新加热，该线圈感应 纳米颗粒中的加热，因此，从器官内部加热我们发现纳米变暖可以重新变暖。 我们最近首次在动物模型中展示了玻璃化器官，包括肾脏。 移植后器官在体外和体内的功能也得到了成功。 人类（猪）肾脏的纳米变暖这些新数据支持了我们方法的可行性。 然而，冷冻保存和纳米加热整个人体器官用于移植仍然存在许多问题。 仍然存在，包括与对照器官相比，纳米加热的肾脏如何发挥作用，发生什么损伤（如果有） 在纳米变暖期间，以及如何扩大到人体大小的器官在这个更新 R01 中，我们建议：（1） 定量评估大鼠模型中冷冻保存和纳米加热的肾移植功能，包括长期肾移植 长期保存、长期功能、损伤模式和宿主免疫反应的改变，(2) 工程师 并优化纳米加热玻璃化人体大小器官的放大，以及（3）玻璃化和纳米加热人体大小器官 肾脏，同时测量活力、结构完整性和器官功能。