Liver Reengineering

该奖项是根据2009年美国复苏和再投资法案（公法111-5）资助的。器官严重短缺，器官等待名单目前有10万份申请，并以每年5%的速度增长。这项研究的重点是肝脏：美国每年有27,000人死于肝脏疾病，其中4,000人主要是因为他们无法接受移植。长期解决供体器官可用性的方法是利用胚胎干细胞产生新的肝细胞用于细胞移植。然而，由于植入率低，直接传递细胞效率低，因此要使细胞移植在临床上发挥作用，必须有一种组织工程载体来确保细胞的长期植入性、生存能力和功能。到目前为止，这种支架很难在体外制造。本研究的长期目标是开发一种天然肝支架，用于干细胞的完全和稳定成熟，最终用于治疗器官功能不全或衰竭。本项目的目的是开发一种用于胚胎干细胞来源肝细胞移植的去细胞化器官生物支架。这项研究的基本原理是，缺血损伤、不可移植器官的数量远远超过目前的需求，它们为干细胞治疗提供了一个理想的平台。因此，本研究有望i)为细胞移植创造一个新的平台，ii)确定天然肝细胞外基质在胚胎干细胞肝分化中的作用。知识的优点。从科学上讲，确定天然细胞外基质在干细胞分化中的作用可能会导致更有效和高效的干细胞分化方案，从而解决组织工程中的另一个瓶颈，即成人细胞的实际来源。再细胞化生物支架也可作为全器官模型用于药物开发和测试以及药物研究。最后，这项工作有望导致复杂的全器官组织工程方法，具有在体外培养整个器官的潜力。在临床上，再细胞化肝生物支架可为肝移植提供急需的替代方案。此外，它可以作为部分肝支持来预防肝功能不全，例如癌症患者的广泛肝切除术和左外侧移植物移植——一种供体安全的替代方案，目前用于儿童，但不足以治疗成人患者。最后，这些移植物可以潜在地用于治疗先天性肝病，作为健康肝细胞移植的血管，导致患者肝脏的再生。更广泛的影响。教育的目标是培养组织工程、干细胞工程、外科技术和定量系统生物学方面的研究生和本科生。此外，基于这项研究，研究团队和合作者将开发化学工程/生物工程本科教育的教学模块，并将其作为本科和研究生课程的项目整合到课程作业中。这些模块包括一个教室去细胞化显示系统和一个自由分发的交互式软件模块。这些教学模式和研究结果也将提交在教育和科学杂志上发表，以加强传播。移植工程方法的发展有望成为组织工程的主要使能技术，并最终通过为成千上万的肝功能衰竭患者提供实用的治疗对社会产生影响。

This award is funded under the American Recovery and Reinvestment Act of 2009 (Public Law 111-5)0853569UygunThere is a critical shortage of organs, with the organ waiting list currently at 100,000 requests and increasing by 5% every year. This study focuses on the liver: 27,000 die in the US annually due to liver disease, 4,000 essentially because they cannot get a transplant. A long-term solution to donor organ availability is to utilize embryonic stem cells to generate new hepatocytes for cell transplantation. However, the delivery of cells directly is inefficient due to low engraftment, and a tissue-engineered vehicle to ensure cell engraftment, viability, and functionality in the long term is a necessity to make cell transplantation work clinically. Such a scaffold has so far proven difficult to manufacture in vitro.The long-term goal of this research is to develop a natural hepatic scaffold for complete and stable maturation of stem-derived liver cells, ultimately for treatment of organ insufficiency or failure. The objective of this project is to develop a decellularized organ bioscaffold for embryonic stem-cell derived hepatocyte transplantation. The rationale of the study is that ischemically damaged, untransplantable organs are available in numbers that far surpass the current demand, and they present an ideal platform of delivery for stem cell-based therapies. As a result this study is expected to i) create a new platform for cell transplantation, and ii) identify the role of native liver extracellular matrix in hepatic differentiation of embryonic stem cells.Intellectual merits. Scientifically, the identification of the role of native extracellular matrix in stem cell differentiation may lead to much more effective and efficient stem cell differentiation protocols, thus addressing the other bottleneck in tissue engineering which is a practical source for adult human cells. The recellularized bioscaffold could also be employed as a whole-organ model for drug development and testing and pharmaceutical studies. Finally, this work is expected to lead to sophisticated whole-organ tissue engineering approaches with potential of developing entire organs in vitro. Clinically, the recellularized liver bioscaffold could provide much needed alternatives to liver transplantation. Further, it could be used as a partial liver support to prevent liver insufficiency, in cases such as extensive hepatic resections in cancer patients and left lateral graft transplantation - a donor-safe alternative which is currently used for children but is not sufficient to treat adult patients. Finally, the grafts could be potentially used to treat inborn liver diseases, as vessel for healthy hepatocyte transplantation, leading to repopulation of the patient liver.Broader Impacts. The goal in Education is to train graduate students and undergraduate students in tissue engineering, stem cell engineering, surgical techniques, and quantitative systems biology. Further, based on this research, teaching modules for undergraduate education in chemical engineering/bioengineering will be developed and integrated to coursework by the research team and collaborators, as projects in undergraduate and graduate courses. These modules include a classroom decellularization display system, and an interactive software module to be freely distributed. These teaching modules and the study results will also be submitted for publication in educational and scientific journals to enhance dissemination. The development of a graft engineering methodology is expected to become a major enabling technology in tissue engineering and ultimately make an impact on society by providing a practical treatment for thousands of patients with liver failure.