This Research Career Award proposal describes a five year training program for the development of an academic career as a physician-scientist and biomedical engineer. The principal investigator (PI), with training as a physician and engineer, completed residency in Internal Medicine at University of Miami/Jackson Memorial Hospital and a research fellowship at Massachusetts General Hospital (MGH)/Harvard Medical School. His career goal is to establish a cutting edge research program focusing on hepatic tissue engineering and bioartificial liver (BAL) development. Through a program of didactic coursework and mentorship, the PI will focus his research efforts on embryonic stem cell biology. Dr. Martin Yarmush, a recognized expert in tissue engineering and metabolic engineering, will serve as the Pl's mentor throughout the course of this project. He is Professor in the Department of Surgery at MGH and the director of the Center for Engineering in Medicine. He has supervised numerous postdoctoral fellows and graduate students in biomedical engineering. Dr. David Scadden, Associate Professor in the Department of Medicine at MGH, and an authority on stem cell biology, will serve as a co-mentor on this project. He has supervised numerous postdoctoral fellows and medical students. A research advisory committee, composed of distinguished physicians, scientists, and engineers, will provide scientific and career guidance to the PI. The research focus in this proposal is to develop techniques to derive adult hepatocytes from embryonic stem (ES) cells in vitro. For the purpose of developing the technology and gaining a better understanding of the underlying basic science, a mouse model will be used. The specific aims are: (1) To develop a microfluidic bioreactor for high throughput characterization of embryonic stem cell differentiation into hepatocytes; (2) To regulate embryonic stem cell differentiation into mature hepatocytes using immobilized and soluble factors; (3) To characterize the differentiated cell populations and optimize their expression of organ specific functions using principles of metabolic engineering. These studies will provide the basic knowledge and technologies enabling the PI to develop a steady source of hepatocytes for BAL devices. The Center for Engineering in Medicine in the Department of Surgery at MGH, and the Harvard Medical School community provide an excellent environment in which to foster the career of the PI. The distinguished faculty, interdisciplinary environment, well equipped core facilities, and extensive collaborative interactions will provide the PI with everything necessary to pursue and launch his career goals.