Use of Discarded Organs for Preparation of Liver Grafts

使用废弃器官制备肝移植物

基本信息

批准号：
8778730
负责人：
Basak Elif Uygun
金额：
$ 24.9万
依托单位：
MASSACHUSETTS GENERAL HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-12-17 至 2016-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8778730
关键词：
Accidents Address Adult Affect Albumins Animal Model Architecture Award Biocompatible Materials Biological Preservation Biological Process Biology Cardiac Death Cell Culture Techniques Cell Therapy Cell Transplantation Cell physiology Cell-Matrix Junction Cells Clinical Cytochrome P450 Detergents Development Disease Drug Metabolic Detoxication Engineering Extracellular Matrix Family suidae Future Glycoproteins Goals Graft Survival Health Hepatic Hepatic Tissue Hepatocyte Hospitals Human Image Analysis Implant In Vitro Injury Ionic Strengths Ischemia Lead Liver Liver diseases Marketing Mentors Methodology Methods Modality Modeling New England Organ Organ Donor Organ Model Organ Transplantation Organ failure PECAM1 gene Pancreas Perfusion Pharmacologic Substance Phase Population Preparation Proteoglycan Protocols documentation Rattus Recovery Replacement Therapy Research Role Slice Solutions Source Spatial Distribution Staining method Stains Stem cells Supporting Cell System Techniques Technology Testing Tissue Engineering Tissues Translating Transplantation Urea Waiting Lists Warm Ischemia Work age related base cell type driving force drug testing end-stage organ failure in vitro Model in vivo innovation liver transplantation novel scaffold scale up tool

项目摘要

PROJECT SUMMARY/ABSTRACT Treatment for end-stage organ failure is restricted by the critical shortage of donor organs with the organ waiting list currently at 100,000 requests and it is increasing by 5% every year. The problem is not different for liver, which this study focuses on - about 4,000 people die in the US due to lack of a transplantable organ, and the lack of donor organs is considered a major health crisis. In addition, since transplantation can often be the solution to many aging related diseases, the hidden demand is estimated to be far beyond the current levels. This situation has been a major driving force behind the rise of tissue engineering, with the market for organ failure treatments estimated at about $80 billion. However, over two decades of work aimed at building tissues from the ground up has not succeeded in creating large-scale tissues that can be clinically implanted to address the void in organ replacement therapies. Further, despite intense efforts on the stem cell front, including those from our group, the lack of a reliable cell source for primary adult hepatocytes for use in cell therapies persists and is unlikely to be resolved in the near future. Interestingly enough, there are many potential organ donors that are not considered for transplantation because the organs are damaged. For example, accident victims who arrive at the hospital after cardiac death are not eligible donors because of excessive ischemic damage; even a slight ischemic damage (>30min warm ischemia or >16hrs cold ischemia) is known to lead to complications in the long term with significantly reduced graft survival at 6 months. By some estimates, potential number of Donors after Cardiac Death (DCD) is over 200,000 per year in the US, and about 6,000 are considered to be only marginally damaged. Our long-term goal is to engineer transplantable liver grafts for curing or treating relevant liver diseases. The objective of the proposed study is to develop humanized reengineered liver grafts as a viable in vitro liver model. During the mentored phase (K99) of the award, two essential tools will be developed to reach this goal: 1) a liver perfusion system, which will enable recovery of healthy hepatocytes from marginal donor livers. This technology is expected to lead to establishment of a currently untapped source of adult human hepatocytes that will fill the need for human cells until stem cell approaches mature and become safe and efficient for clinical use. 2) a whole organ perfusion- decellularization and recellularization methodology. The objective here is to develop a novel scaffold for tissue engineering, which supports cell attachment and function and is vascularizable. During the independent phase (R00) of the award, the primary goal is the scaling of the methods developed in K99 phase to large animal models and ultimately human organs. The work proposed in this project is expected to i) establish marginal livers as a reliable source of primary hepatocytes, ii) establish decellularized liver slices as novel 3D cell culture platform to study the role of ECM, iii) develop humanized rat liver grafts as a three dimensional liver model for pharmaceutical studies, and iv) lead to the development of reengineered liver grafts to treat liver diseases. While this work utilizes liver as the model organ, the results of this work will also have a positive impact by establishing the basis of future sophisticated organ engineering techniques that incorporate multiple different cell types and can be translated to other organs (such as pancreas to create vascularized patches for pancreatic ¿-cell transplantation), and may ultimately lead to development of entire organs in vitro.

项目摘要/摘要终端器官故障的治疗受到器官的严重短缺的限制目前以100,000个请求的候补名单增加了5％。由于缺乏可移植器官，本研究重点是在美国死亡的4000人死亡。缺乏捐赠者器官被认为是主要的健康危机。解决许多与衰老相关的探索的方法，估计隐藏的需求远远超出了当前水平。这种情况一直是组织工程兴起的主要推动力，风琴市场但是，失败治疗估计为800亿美元。从头开始，没有在创建临床植入到的大规模组织中尽管在干细胞方面有强烈的影响包括我们小组的那些，缺乏用于细胞的原发性成人肝细胞的可靠细胞来源疗法持续存在，不可能在不久的将来解决。潜在的器官供体因器官被损坏而被考虑进行移植例如，心脏死亡后到达医院的事故受害者不是符合条件的捐助者过度的缺血损害；已知长期导致并发症，有些人在6个月时显着降低了移植物估计，在美国，心脏死亡后的潜在捐助者人数超过200,000，并且大约有6,000个Ansided仅损坏了我们的长期目标。用于治疗或治疗肝脏疾病的肝移植物。人源化的renginered肝移植物作为可行的体外肝模型。奖励，将开发两个基本工具以实现此目标：1）肝脏灌注系统，这将使从边际供体肝脏中恢复健康的肝细胞。建立目前未开发的成年人类肝细胞thell的来源满足了人类细胞的需求直到干细胞接近成熟并变得安全有效地用于临床。脱落和卷积方法。工程，支持细胞的附着和功能，并且在独立阶段是可血管的。（R00）奖项，主要目标是在K99阶段开发的大型动物的方法模型和最终人工器官。肝脏作为原发性肝细胞的可观来源，ii）建立减速肝切片作为新型3D细胞研究ECM的作用的培养平台，iii）发展为三维肝脏的人性化大鼠肝移植药物研究模型，iv）导致肝脏移植物的发展治疗肝脏疾病。通过建立未来复杂的器官工程技术的基础，该技术结合了乘数不同的单元格类型，可以翻译成其他器官胰 - 细胞移植），并可能导致整个器官在体外的发展。