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: 8463800
• 负责人: Denver Michael Faulk
• 金额: $ 1.61万
• 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 2013-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8463800
• 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; Health; 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.

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。目前最终的治疗方法是正交异性移植。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的风险以及与终生免疫抑制剂治疗方案相关的发病率。这种治疗对于老年患者来说尤其困难。该申请提出了一种再生医学策略，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）肝脏的原生ECM，包括三维非结构和成分，代表了肝脏再生理想且必需的基质；2）全肝ECM支架保留了三维宏观结构、原生微血管网络和胆汁引流系统；允许所有天然细胞类型完全再细胞化，3) 当重新接种的全肝 ECM 移植物放置在适当的三维微环境中时，可以促进肝再生；具体来说，是对肝功能衰竭患者进行原位治疗。拟议研究的目标是（1）建立一种重新种植三维肝脏支架的有效方法，重点是在其天然位置系统地种植实质和非实质细胞，以及（2）评估宿主对重新种植的三维肝脏支架植入的反应。此外，本研究开发的方法和技术朝着建立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去细胞化和再细胞化标准迈出了重要一步。

项目成果

The effect of detergents on the basement membrane complex of a biologic scaffold material.

• DOI: 10.1016/j.actbio.2013.09.006
• 发表时间: 2014-01
• 期刊: ACTA BIOMATERIALIA
• 影响因子: 9.7
• 作者: Faulk, D. M.;Carruthers, C. A.;Warner, H. J.;Kramer, C. R.;Reing, J. E.;Zhang, L.;D'Amore, A.;Badylak, S. F.
• 通讯作者: Badylak, S. F.