Engineering of hepatic grafts with decellularized native matrices

使用脱细胞天然基质进行肝移植工程

基本信息

批准号：
7643685
负责人：
Alejandro Soto-Gutierrez
金额：
$ 5.03万
依托单位：
MASSACHUSETTS GENERAL HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-04-15 至 2009-10-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7643685
关键词：
Acute Adrenal Cortex Hormones Adult Advisory Committees Albumins Ammonia Animal Model Apoptotic Applications Grants Architecture Biomedical Engineering Blood Coagulation Factor Blood Vessels Cardiac Death Cell Maturation Cell Therapy Cell Transplantation Cell-Matrix Junction Cells Cessation of life Characteristics Chronic Commit Cues Cytochrome P450 Cytoskeleton Data Detection Development Development Plans Diazepam Disease Doctor of Medicine Doctor of Philosophy Drug Metabolic Detoxication Employment Engineering Engraftment Ensure Environment Future General Hospitals Goals Graft Survival Hand Hepatic Hepatic Tissue Hepatocyte Human Implant In Vitro Kidney Lead Lidocaine Liver Liver Failure Liver diseases Lobe Lung Massachusetts Medicine Metabolic Methods Modeling Mus Operative Surgical Procedures Organ Organ Culture Techniques Pancreas Patients Perfusion Positioning Attribute Principal Investigator Property Protein C Inhibitor Protocols documentation Public Health Rattus Research Research Personnel Serum Solutions Stem cells Structure System Techniques Technology Testing Time Tissue Engineering Tissues Training Transplantation Vascularization Waiting Lists Work alpha 1-Antitrypsin anti aging base career career development cell motility cell type cellular engineering cytokine design embryonic stem cell extracellular hepatocyte engraftment human embryonic stem cell improved in vivo innovation interest liver function liver transplantation medical schools novel novel strategies prevent professor public health relevance scaffold stem stem cell differentiation success three dimensional structure tool

项目摘要

DESCRIPTION (provided by applicant): This is a career grant application for Dr. Soto-Gutierrez; an M.D.; [sic] Ph.D. who specializes in cell therapies and liver diseases. Dr. Soto-Gutierrez has recently developed novel methods of differentiating stem cells into liver cells, and his interests have shifted to application of such tools to organ engineering. To establish himself as an independent researcher in the field of organ engineering, Dr. Soto-Gutierrez submits this five-year career development plan under the sponsorship of Dr. Martin Yarmush, the Helen Andrus Benedict Professor of Surgery and Bioengineering at Harvard Medical School and the director of the Center for Engineering in Medicine at the Massachusetts General Hospital, which includes i) intensive hand-on training in organ engineering, isolated liver-matrices perfusion and stem cell differentiation, ii) academic courses and seminars, and iii) guidance of a select advisory committee. Our long-term goals are to develop a natural hepatic platform for complete and stable maturation of stem-derived liver cells and to engineer functional liver grafts. The objectives of the proposed study are to develop an extracorporeal perfusion liver-matrix-scaffold system for repopulation and hepatic maturation of stem liver-derived cells, and investigate its employment for the creation of auxiliary liver grafts for transplantation in patients with impaired hepatic function. The central hypothesis to be tested here is that the decellularized natural liver scaffold, obtained from discarded livers, can be extensively repopulated and can provide an adequate maturation environment for stem derived liver cells, and this organ culture system can be employed to engineer metabolic functional liver grafts for transplantation. The rationale of the study is that is chemically damaged, untransplantable organs are available in numbers that far surpass the current demand, and they present an ideal platform for delivery for stem cell-based therapies. The work described here is expected to i) establish a protocol for recellularization and engraftment of hepatocytes [sic] in decellularized matrices, ii) generate a repopulation and maturation system for stem cell-derived hepatocytes, and iii) develop a novel method of liver graft engineering for transplantation as auxiliary liver support in hepatic diseases. The results of this work will also have a positive impact by establishing the basis and platform for future sophisticated organ engineering techniques that incorporates several different cell types, can be applied to other organs and may lead to development of entire organs in vitro. PUBLIC HEALTH RELEVANCE: Liver diseases cause about 27,000 deaths annually in the US, 2,500 of which perish on the waiting list for liver transplant. A major reason of liver related deaths is the limited donor pool. This project aims to improve public health by utilizing currently discarded donor livers as natural scaffolds for stem cell-derived liver cells to constitute livers grafts to be transplantable with success.

描述（由申请人提供）：这是Soto-Gutierrez博士的职业赠款申请； An M.D。; [SIC]博士谁专门从事细胞疗法和肝病。 Soto-Gutierrez博士最近开发了将干细胞区分为肝细胞的新型方法，他的兴趣已转移到将这种工具应用于器官工程上的应用。为了确立器官工程领域的独立研究人员，Soto-Gutierrez博士在马丁·安德鲁斯·本尼迪克特（Helen Andrus Benedict）手术和生物工程学教授马丁·雅尔默什（Martin Yarmush）的赞助下提交了这项为期五年的职业发展计划。和干细胞区分，ii）学术课程和研讨会，以及iii）特定咨询委员会的指导。我们的长期目标是开发一个天然的肝平台，以完全稳定的茎源性肝细胞成熟并设计功能性肝移植。拟议的研究的目标是开发一种体外灌注肝垫 - 马托里克斯软体动物系统，用于重生和肝肝脏衍生细胞的肝成熟，并研究其在肝功能受损的患者中创建辅助肝移植以创建辅助肝脏移植的工作。这里要检验的中心假设是，可以广泛重新填充从废弃的肝脏获得的脱细胞天然肝支架，并可以为茎衍生的肝细胞提供足够的成熟环境，并且该器官培养系统可以用于工程师的代谢功能肝移植物进行移植。这项研究的理由是化学损坏，不可转移的器官的数量远远超过了当前的需求，并且为基于干细胞的疗法提供了理想的平台。 The work described here is expected to i) establish a protocol for recellularization and engraftment of hepatocytes [sic] in decellularized matrices, ii) generate a repopulation and maturation system for stem cell-derived hepatocytes, and iii) develop a novel method of liver graft engineering for transplantation as auxiliary liver support in hepatic diseases.这项工作的结果还将通过建立包含几种不同细胞类型的未来复杂器官工程技术的基础和平台来产生积极的影响，可以应用于其他器官，并可能导致整个体外器官的发展。公共卫生相关性：肝病每年在美国造成约27,000人死亡，其中2500名在肝移植的等待名单上灭亡。肝相关死亡的主要原因是有限的供体池。该项目旨在通过利用目前废弃的供体肝脏作为干细胞衍生的肝细胞的天然脚手架来改善公共卫生，以构成肝脏移植物，可以成功地移植。