Computer-aided Development of a Liver Organ Culture System

这是Uygan博士的职业资助申请；他是一名训练有素的化学工程师，专门从事 复杂系统的数学建模和优化。乌伊贡博士最近开发了一部小说 建立肝细胞模型的方法，他的兴趣已经转移到这些工具在生物医学中的应用上 工程学。致。在生物医学系统领域确立自己的独立研究员地位 工程师，Uygan博士在Martin博士的赞助下提交了这份五年职业发展计划 Yarmush，哈佛医学院外科和生物工程教授海伦·安德鲁斯·本尼迪克特 马萨诸塞州总医院医学工程中心主任 包括一)生物医学工程和隔离肝脏灌流方面的强化实践培训，二)学术 课程和研讨会，以及iii)一个特别咨询委员会的指导。 项目概述：这项研究的长期目标是开发肝脏代谢工程 治愈或治疗相关疾病的方法，包括脂肪变性和纤维化，并减少死亡 一般都是因为肝功能衰竭。这项拟议的研究的目标是在硅胶和体外培养配对 灌流肝脏模型，并将其用于边缘肝脏的代谢工程以增加供体 游泳池。这里要检验的中心假设是，肝脏在体外可以保持功能 通过优化代谢调节来延长周期，这种器官培养系统可以用于 复苏缺血肝脏和脱脂供移植。其基本原理是 开发一种将代谢活动和生存能力相关联的硅肝模型将使模拟 大量高效的代谢调节策略，识别出数量有限的候选 补充能量水平的脱脂解决方案，从而实现肝脏灌流的新陈代谢优化 在项目期内实际操作。这里描述的工作有望：1)建立常温 体外灌流作为一种可行的功能性肝脏存储手段，ii)产生一个在计算机上的模型 分离的灌流大鼠肝脏，将代谢功能、肝脏损伤和移植成功联系起来，以及 建立新的方法，使边缘肝移植成为可能，从而减少与肝功能衰竭相关的 死亡。这项工作的结果也将对肝脏器官规模的研究产生积极影响，例如 脂肪变性、纤维化和再生，通过提供一个稳定和完善的系统作为基础。

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.