Extended Storage of Tissues and Organs in Subzero Environments

组织和器官在零度以下环境中的长期储存

• 批准号: 7891332
• 负责人: Martin L Yarmush
• 金额: $ 63.67万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-07-15 至 2013-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7891332
• 关键词: Address; Adverse effects; Antifreeze; Artificial Organs; Bile fluid; Bioartificial Organs; Biological Preservation; Cells; Cryopreservation; Depressed mood; Desiccation; Development; Effectiveness; Endothelial Cells; Engineering; Ensure; Environment; Enzymes; Freezing; Glucose; Goals; Gold; Hepatic Tissue; Hepatocyte; Hour; Ice; In Vitro; Individual; Investigation; Ischemia; Laboratories; Liver; Measures; Metabolic; Metabolism; Methodology; Methods; Monitor; Organ; Organ Donor; Organ Preservation; Organ Transplantation; Organ Viability; Oxygen; Patients; Perfusion; Population; Process; Production; Protocols documentation; Public Health; Reperfusion Injury; Research; Rewarming; Solutions; System; Techniques; Technology; Temperature; Testing; Time; Tissue Engineering; Tissue Preservation; Tissue Viability; Tissues; Toxic effect; Transplantation; Waiting Lists; Work; analog; base; data mining; improved; innovation; liver function; liver preservation; liver transplantation; public health relevance; scaffold; scale up; success; tissue/organ preservation; uptake

DESCRIPTION (provided by applicant): There are currently ~100,000 patients on the organ transplant waiting list in the US, a number that far exceeds the supply of available organs, and that continues to grow ~5% each year. The most promising solutions, bioartificial tissue and organ construction and donor organ reengineering methodologies, are both ultimately limited by biopreservation technologies, as any tissue engineered products prepared in a laboratory will have to be stored for a period of time until utilization. The current gold standard for whole organ preservation is cold storage on ice for up to 72 hours, during which time the organ continuously deteriorates. A superior biopreservation method that extends the tissue storage time beyond current limitations is yet to be developed. Such a method would provide a crucial enabling technology for tissue and organ preservation, tissue and organ transport, and tissue and organ transplantation. The objective of this study is to extend the viable preservation time of hepatic tissues by sub-zero non- freezing (SZNF) storage in a supercooled preservation medium. The central hypothesis of this study relies on two phenomena: 1) that 3-O-methyl-glucose (3OMG) lowers achievable stable SZNF temperature without major toxic side effects, and that 2) rewarming by normothermic perfusion reduces reperfusion damage. Our hypothesis has been formulated based on our preliminary findings establishing 3OMG as a minimally toxic cryoprotectant for hepatocytes, and establishing that normothermic perfusion can significantly reverse the damaging effects of ischemia. The rationale of the study is that if supercooled preservation can be achieved while avoiding antifreeze toxicity, then organ metabolism can be further slowed thereby reducing anoxic/ischemic damage to minimal levels. Establishment of a sub-zero nonfreezing preservation technology will be a welcome innovation to the field. The work described herein will help develop this enabling technology of supercooled storage, and also establish quantitative standards for evaluating the liver and bioartificial organ viability following preservation. While we focus on the liver, we expect that the protocols established here will also serve as the basis for subzero nonfreezing preservation of other tissue engineered products, such as artificial organ substitutes and seeded scaffold constructs. Public Health Relevance Statement (provided by applicant): There are currently 97,000 patients on the transplant waiting list, and the number increases by ~5% every year. A critical bottleneck in making more donor organs as well tissue engineering alternatives available to the public is the limited preservation duration. The objective of this study is to extend the viable preservation time of organs and bioartificial alternatives by enabling extended storage at sub-freezing temperatures without ice formation. The results of this study are expected to directly improve public health by increasing donor organ availability and making more transplantations possible.

描述（由申请人提供）： 目前，美国器官移植等候名单上约有 10 万名患者，这个数字远远超过可用器官的供应量，并且每年继续增长约 5%。最有前途的解决方案，生物人工组织和器官构建以及供体器官再造方法，最终都受到生物保存技术的限制，因为实验室制备的任何组织工程产品都必须储存一段时间才能使用。目前整个器官保存的黄金标准是在冰上冷藏长达72小时，在此期间器官会不断恶化。目前尚未开发出一种能够将组织储存时间延长到超出当前限制的卓越生物保存方法。这种方法将为组织和器官保存、组织和器官运输以及组织和器官移植提供关键的使能技术。 本研究的目的是通过在过冷保存介质中进行零下非冷冻（SZNF）保存来延长肝组织的存活保存时间。本研究的中心假设依赖于两个现象：1) 3-O-甲基葡萄糖 (3OMG) 降低可达到的稳定 SZNF 温度，且没有重大毒副作用；2) 通过常温灌注复温可减少再灌注损伤。我们的假设是基于我们的初步发现，确定 3OMG 作为肝细胞毒性最低的冷冻保护剂，并确定常温灌注可以显着逆转缺血的破坏作用。该研究的基本原理是，如果可以实现过冷保存，同时避免抗冻剂毒性，则可以进一步减慢器官代谢，从而将缺氧/缺血损伤降至最低水平。 零度以下非冷冻保鲜技术的建立将是该领域受欢迎的创新。本文描述的工作将有助于开发这种过冷储存技术，并建立评估保存后肝脏和生物人工器官活力的定量标准。虽然我们关注肝脏，但我们预计这里建立的方案也将作为其他组织工程产品（例如人造器官替代品和种子支架结构）的零下非冷冻保存的基础。 公共卫生相关性声明（由申请人提供）：目前有 97,000 名患者在移植等待名单上，并且该数字每年增加约 5%。向公众提供更多供体器官以及组织工程替代品的一个关键瓶颈是有限的保存期限。这项研究的目的是通过在低于冰点的温度下延长储存而不形成冰来延长器官和生物人工替代品的可行保存时间。这项研究的结果预计将通过增加供体器官的可用性并使更多的移植成为可能来直接改善公众健康。