Liver Reengineering

肝脏再造

• 批准号: 0853569
• 负责人: Korkut Uygun
• 金额: $ 30.57万
• 依托单位: Massachusetts General Hospital
• 依托单位国家: 美国
• 项目类别: Standard Grant
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-10-01 至 2012-09-30
• 项目状态: 已结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=0853569&HistoricalAwards=false
• 关键词: Liver; Reengineering

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.

该奖项是根据2009年美国复苏和再投资法案（公法111-5）0853569 Uygun资助的器官严重短缺，目前器官等待名单上有10万个请求，每年增加5%。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获得移植。供体器官可用性的长期解决方案是利用胚胎干细胞产生用于细胞移植的新肝细胞。然而，由于低植入，直接递送细胞是低效的，并且长期确保细胞植入、存活力和功能性的组织工程化载体是使细胞移植在临床上发挥作用的必要条件。这种支架迄今已被证明很难在体外制造。本研究的长期目标是开发一种天然的肝支架，用于干细胞衍生的肝细胞的完全和稳定成熟，最终用于器官功能不全或衰竭的治疗。本研究的目的是开发一种脱细胞器官生物支架，用于胚胎干细胞源性肝细胞移植。这项研究的基本原理是，缺血性损伤的不可移植器官的数量远远超过目前的需求，它们为基于干细胞的治疗提供了一个理想的平台。因此，本研究有望i）为细胞移植提供一个新的平台，ii）确定天然肝细胞外基质在胚胎干细胞肝分化中的作用。从科学上讲，天然细胞外基质在干细胞分化中的作用的鉴定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，这是成人细胞的实际来源。再细胞化的生物支架也可以用作药物开发和测试以及药学研究的全器官模型。最后，这项工作有望导致复杂的全器官组织工程方法，具有在体外开发整个器官的潜力。在临床上，再细胞化的肝脏生物支架可以提供急需的替代肝移植。此外，它可以用作部分肝脏支持，以防止肝功能不全，例如癌症患者的广泛肝切除术和左外侧移植物移植-目前用于儿童但不足以治疗成人患者的供体安全替代方案。最后，这种移植物有可能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。教育的目标是培养研究生和本科生在组织工程，干细胞工程，外科技术和定量系统生物学。此外，基于这项研究，在化学工程/生物工程本科教育的教学模块将开发和整合到课程的研究团队和合作者，作为项目在本科和研究生课程。这些模块包括一个教室去细胞化显示系统，和一个交互式软件模块，可自由分发。这些教学单元和研究结果也将提交给教育和科学期刊出版，以加强传播。移植物工程方法的发展有望成为组织工程中的一项主要技术，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。