Liver Reengineering

该奖项是根据2009年《美国复苏和再投资法案》(公法111-5)0853569获得资助的。目前器官严重短缺，等待器官的名单上有100,000个请求，而且每年以5%的速度增长。这项研究的重点是肝脏：在美国，每年有27,000人死于肝病，其中4,000人主要是因为无法接受移植。供体器官可获得性的长期解决方案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，直接运送细胞的效率很低，而确保细胞长期植入、存活和功能的组织工程载体是使细胞移植在临床上发挥作用的必要条件。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的肝支架，使干细胞完全和稳定地成熟，最终用于治疗器官功能不全或衰竭。本项目的目标是开发一种用于胚胎干细胞来源的肝细胞移植的脱细胞器官生物支架。这项研究的基本原理是，缺血损伤的、不可移植的器官的数量远远超过了当前的需求，它们为基于干细胞的治疗提供了一个理想的平台。因此，这项研究有望为细胞移植创造一个新的平台，以及ii)鉴定天然肝细胞外基质在胚胎干细胞肝脏分化中的作用。科学地鉴定天然细胞外基质在干细胞分化中的作用可能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，这是成人细胞的实用来源。这种再细胞生物支架还可以作为药物开发和测试以及药学研究的整体器官模型。最后，这项工作有望导致复杂的整体器官组织工程方法，具有在体外开发整个器官的潜力。在临床上，二次细胞化的肝生物支架可以为肝移植提供急需的替代方案。此外，在癌症患者的广泛肝切除和左侧移植物移植等情况下，它可以用作部分肝脏支持，以防止肝功能不全--这是一种供者安全的替代方案，目前用于儿童，但不足以治疗成人患者。最后，移植物可能被用于治疗先天性肝病，作为健康肝细胞移植的血管，导致患者肝脏的重新繁殖。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，在这项研究的基础上，化学工程/生物工程本科教育的教学模块将由研究团队和合作者开发并整合到课程中，作为本科生和研究生课程的项目。这些模块包括教室去细胞显示系统和可自由分发的交互软件模块。这些教学单元和研究结果也将提交在教育和科学期刊上发表，以加强传播。移植工程方法学的开发有望成为组织工程学的主要使能技术，并最终通过为数千名肝功能衰竭患者提供实用治疗而对社会产生影响。

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.