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

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，这一数字预计只会增加。目前的最终治疗方法是正交异性移植。然而，由于需求量很大，供体肝脏严重短缺。那些幸运地接受移植的患者面临着慢性排斥反应的风险，以及与终身免疫抑制疗法相关的发病率。这种治疗对老年患者来说尤其困难。这项申请提出了一种再生医学策略，用于为终末期肝功能衰竭患者设计植入性肝移植。它基于三个基本概念：1)天然的肝脏ECM，包括其三维超微结构和组成，是肝脏再生的理想和必需的基质；2)全肝ECM支架保留了三维宏观结构、天然的微血管网络和胆汁引流系统；3)所有天然细胞类型的完全再细胞化；3)当种植的全肝ECM移植物置于适当的三维微环境中，可促进肝再生；尤其是在肝功能衰竭患者的原位移植。本研究的目的是(1)建立一种有效的三维肝支架移植方法，重点是系统地在其原位种植实质细胞和非实质细胞，以及(2)评估宿主对再次种植的三维肝支架的反应。此外，本研究中开发的方法和技术是朝着建立脱细胞和再细胞标准迈出的重要一步，这些标准是成功生产第一个用于器官移植和药物发现的全功能生物工程肝脏所必需的。 公共卫生相关性：该项目直接解决等待移植的患者的捐赠器官严重短缺的公共卫生问题。这项研究中开发的方法和技术是开发全功能肝移植的关键一步。该项目的发现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肝组织，消除对肝移植的需要，并为整体器官工程铺平道路。

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.