Engineering a Functional Liver Graft for Treatment of End Stage Liver Disease

设计功能性肝移植来治疗终末期肝病

• 批准号: 8312934
• 负责人: Denver Michael Faulk
• 金额: $ 3.95万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-05-01 至 2014-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8312934
• 关键词: 3-Dimensional; Address; Autologous; Bile fluid; Biomedical Engineering; Blood Circulation; Blood Vessels; Bolus Infusion; Cell Adhesion; Cell Count; Cell Survival; Cell Transplantation; Cell-Matrix Junction; Cells; Cessation of life; Chronic; Cicatrix; Clinical; Comb animal structure; Complex; Cues; Development; Drainage procedure; Engineering; Engraftment; Extracellular Matrix; Foundations; Future; Goals; Hepatic; Hepatic Cord; Hepatic Tissue; Hepatocyte; Honey; Immune response; Immunosuppressive Agents; Implant; In Situ; Inflammatory; Investigation; Label; Liver; Liver Failure; Liver Regeneration; Liver diseases; Location; Methods; Modeling; Morbidity - disease rate; Nutrient; Organ; Organ Donor; Organ Transplantation; Patients; Perfusion; Phenotype; Physiological; Portal vein structure; Public Health; Rattus; Regenerative Medicine; Regimen; Research; Risk; Shapes; Signal Transduction; Spatial Distribution; Staging; Structure; System; Techniques; Testing; Therapeutic; Tissues; Translations; Transplantation; United States; Work; aging population; base; cell type; drug discovery; hepatic vein; implantation; in vivo; liver transplantation; macrophage; older patient; reconstitution; research study; scaffold; success

DESCRIPTION (provided by applicant): Approximately 27,000 deaths occur annually in the United States alone from patients with end-stage liver disease. With an aging population, this number is only expected to increase. The current definitive treatment is orthotropic transplantation. However, due to high demand there exists a critical shortage of donor livers. Those patients fortunate enough to receive a transplant are burdened with the risk of chronic rejection and the morbidity associated with a lifelong regimen of immunosuppressant therapy. This treatment is especially difficult for elderly patients. This application addresses a regenerative medicine strategy for engineering an implantable liver graft for patients with end-stage liver failure. It is based upon three fundamental concepts: 1) the native ECM of the liver, including the three dimensional untrastructure and composition, represents an ideal and required substrate for liver regeneration, 2) whole liver ECM scaffolds retain the three-dimensional macrostructure, the native microvascular network, and the bile drainage system; allowing for complete recellularization of all native cell types, and 3) liver regeneration can be promoted when reseeded whole liver ECM grafts are placed in the appropriate three dimensional microenvironment; specifically, in-situ in patients with liver failure. The objectives f the proposed research are to (1) establish an effective method for reseeding a three- dimensional liver scaffold, with a focus on systematically seeding both parenchymal and non parenchymal cells in their native location and to (2) evaluate the host response to the implantation of a reseeded three- dimensional liver scaffold. Additionally, the methods and techniques developed in this study present an important step towards the establishment of decellularization and recellularization criteria necessary to successful produce the first fully functional bioengineered livers for organ transplantation and drug discovery. PUBLIC HEALTH RELEVANCE: This project directly addresses the public health issue of a severe shortage of donor organs for patients awaiting transplantation. The methods and techniques developed in this study present a critical step towards the development of a fully functional liver graft. The findings of this project will serve as the foundation for future avenue of investigation that will aim to create functional liver tissue for patients with end-stage liver disease, eliminating the need for liver transplantation and paving the way for whole organ engineering.

描述（由申请人提供）：仅在美国，每年就有大约27，000例终末期肝病患者死亡。随着人口老龄化，这个数字预计只会增加。目前确定的治疗方法是正交各向异性移植。然而，由于需求量大，供体肝脏严重短缺。那些有幸接受移植的患者承受着慢性排斥反应的风险和与终身免疫抑制剂治疗方案相关的发病率。这种治疗对老年患者来说尤其困难。该应用提出了一种再生医学策略，用于为终末期肝衰竭患者设计植入式肝脏移植物。它基于三个基本概念：1）肝脏的天然ECM，包括三维亚结构和组成，代表了肝脏再生的理想和必需的基质，2）整个肝脏ECM支架保留了三维宏观结构、天然微血管网络和胆汁引流系统;允许所有天然细胞类型的完全再细胞化，和3）当将再生的全肝ECM移植物置于适当的三维微环境中时，可以促进肝再生;特别是肝衰竭患者的原位治疗。所提出的研究的目的是（1）建立一种用于重新接种三维肝脏支架的有效方法，重点是在其天然位置系统地接种实质和非实质细胞，以及（2）评估宿主对植入重新接种的三维肝脏支架的反应。此外，本研究中开发的方法和技术为建立成功生产用于器官移植和药物发现的第一个全功能生物工程肝脏所必需的脱细胞化和再细胞化标准迈出了重要一步。 公共卫生相关性：该项目直接解决了等待移植的病人严重缺乏捐赠器官的公共卫生问题。在这项研究中开发的方法和技术提出了一个关键的一步，发展一个功能齐全的肝移植。该项目的研究结果将作为未来研究途径的基础，旨在为终末期肝病患者创造功能性肝组织，消除肝移植的需要，并为整个器官工程铺平道路。