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 慢性肾脏疾病是一个重大的医疗保健问题，影响了美国人口的15％，耗资数十亿美元 每年用于医疗保健美元。对于大多数进行性疾病的患者而言，移植是最好的选择 与透析相比，预期寿命的显着增加和生活质量的改善。 估计潜在的美国死者捐赠器官供应超过了移植的器官的当前数量 以4至5倍的倍数为倍，主要限制了移植的可接受器官数量 恢复和植入之间存在缺血性损伤。先验的一种冷冻水果或“银行”肾脏的方法 移植将有效地消除器官分布供应链的时间影响。这 将允许新的移植范式，以改善捐助者/收件人匹配，允许更好 患者准备，促进耐受性诱导方案并增加器官利用，同时改善移植物 和患者的生存。克服传统策略局限的一种承诺方法是 玻璃化 - 即冷却器官如此迅速，以至于它们无法从液体转变为实心 冰。在冷冻保护剂（CPA）的帮助下，器官进入稳定的玻璃状状态，其中可行 存储是理论上的。但是，关键的挑战是在没有冰形或破裂的情况下重新加热： 如果重新加热太慢，形成冰晶体，并且重新加热不均匀，则热应力会导致破裂。期间 我们最初的R01资金，我们开发了一种新颖的方法，称为“纳米武装”，该方法实现了这两个目标。 氧化铁纳米颗粒在器官的整个脉管系统中均与CPA溶液一起灌注。这 然后，通过冷却将器官玻璃体玻璃玻璃玻璃玻璃玻璃射频线圈进行玻璃辐射线圈的玻璃辐射线圈，从而 在纳米颗粒中加热，因此从器官内部加热。我们发现纳米武器可能会重新升级 动物模型中的玻璃体器官，包括肾脏。我们最近首次表明了纳米武器 器官在移植后体外和体内功能。此外，我们显示了成功的玻璃化和 人尺寸（猪）肾脏的纳米武器。这些新数据支持我们采用方法的可行性 冷冻水果和纳米臂整个人体器官进行移植。然而，许多问题 保留，包括与对照器官相比，纳米臂肾功能的功能，如果有的话，发生了什么伤害 在纳米武术期间，以及如何扩展到人类大小的器官。在此续签R01中，我们建议：（1） 定量评估大鼠模型中的冷冻保存和纳米臂移植功能，包括长期 术语保存，长期功能，损伤模式以及宿主免疫响应的改变，（2）工程师 并优化纳米武器玻璃化的人尺寸器官的规模，（3）玻璃体和纳米臂大小 肾脏在测量生存能力，结构完整性和器官功能的同时。