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。本申请提出了一种再生医学策略，用于为终末期肝衰竭患者设计可植入肝移植物。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。

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.