Computer-aided Development of a Liver Organ Culture System

这是Uygun博士的职业资助申请;一位经过培训的化学工程师，专门从事 复杂系统的数学建模和优化。Uygun博士最近开发了一种新的 他的兴趣已经转移到将这些工具应用于生物医学领域， 工程.到.使自己成为生物医学系统领域的独立研究人员 在马丁博士的赞助下，Uygun博士提交了这份五年职业发展计划。 Yarmush是哈佛医学院外科和生物工程的Helen Andrus Benedict教授 和马萨诸塞州总医院医学工程中心主任， 包括i）生物医学工程和隔离肝脏灌注方面的强化实践培训，ii）学术 课程和研讨会，以及iii）由一个特定咨询委员会提供指导。 项目概述：本研究的长期目标是发展肝脏代谢工程 用于治愈或治疗相关疾病（包括脂肪变性和纤维化）和减少死亡的方法 因为肝功能衰竭拟定研究的目的是在计算机模拟和体外开发配对 灌注肝脏模型，并利用它们进行边缘肝脏的代谢工程，以增加供体 池这里要检验的中心假设是，肝脏可以在离体条件下保持功能性， 通过最佳的代谢调节延长时间，并且该器官培养系统可以用于 复苏缺血的肝脏和脱脂脂肪肝用于移植。其理由是， 开发一种与代谢活性和生存力相关的计算机肝脏模型将能够模拟 大量的代谢调节策略，有效地识别有限数量的候选 用于补充能量水平的脱脂的解决方案，从而实现灌注肝脏的代谢优化 在项目实施期间。这里描述的工作预计i）建立正常体温 体外灌注作为功能性肝脏储存的可行手段，ii）生成体外灌注的计算机模型， 与代谢功能、肝损伤和移植成功相关的分离的灌注大鼠肝，和iii） 建立新的方法，使边缘肝移植，从而减少肝衰竭相关的 死亡这项工作的结果也将对肝脏的器官规模研究产生积极影响，例如 脂肪变性、纤维化和再生，通过提供稳定和良好表征的系统作为其基础。

This is a career grant application for Dr. Uygun; a chemical engineer by training who specializes in mathematical modeling and optimization of complex systems. Dr. Uygun has recently developed novel methods of modeling hepatocytes, and his interests have shifted to application of such tools to biomedical engineering. To. establish himself as an independent researcher in the field of biomedical systems engineering, Dr. Uygun submits this five-year career development plan under the sponsorship of Dr. Martin Yarmush, the Helen Andrus Benedict Professor of Surgery and Bioengineering at Harvard Medical School and the director of the Center for Engineering in Medicine at the Massachusetts General Hospital, which includes i) intensive hand-on training in biomedical engineering and isolated liver perfusion, ii)academic courses and seminars, and iii) guidance of a select advisory committee. Project Summary: The long-term goals of this research are to develop liver metabolic engineering methodologies for curing or treating relevant diseases including steatosis and fibrosis, and reducing deaths due to liver failure in general. The objectives of the proposed study are to develop paired in silico and ex vivo perfused liver models, and utilize them for metabolic engineering of marginal livers to increase the donor pool. The central hypothesis to be tested here is that the liver can be maintained functionally ex vivo for extended periods by optimal metabolic modulation, and this organ culture system can be employed for resuscitating ischemic livers and defatting steatotic livers for transplantation. The rationale is that the development of an in silico liver model that correlates metabolic activity and viability will enable simulating a large number of metabolic modulation strategies efficiently, identifying a limited number of candidate solutions for defatting of repleting energy levels, hence rendering metabolic optimization of perfused livers practical within the project period. The work described here is expected to i) establish normothermic extracorporeal perfusion as a feasible means of functional liver storage, ii) generate an in silico model of the isolated perfused rat liver that correlates metabolic functioning, liver damage and transplant success, and iii) establish novel methods to enable transplantation of marginal livers, thereby reducing liver failure related deaths. The results of this work will also have a positive impact on organ scale research of the liver, such as steatosis, fibrosis and regeneration, by providing a stable and well-characterized system as their basis.