CAREER: Engineering a Liver Sinusoid Functional Unit

Drexel University, Philadelphia PA

Investigators

Abstract

CBET-0747752 Noh A new approach to generate an authentic human liver model is proposed in this project. The liver lobule is composed of operational units termed the liver sinusoid, where most of the liver activities take place. Fundamental liver biology studies predominantly rely on cell culture models. While much progress has been made during the past two decades in prolonging hepatocyte viability and maintaining liver functions in vitro, there are still no authentic liver models that accurately represent the architecture and functions of human liver tissue, thereby limiting advances in liver biology studies and drug development. The goal of this research is to generate an innovative human liver model (bioreactor) that closely mimics the liver sinusoid functional unit. Microfabrication and microfluidics will be combined with cell culture technology to create such an authentic human liver model. The intellectual merits of this project are as follows. First, the relationship between cellular organization and cell-specific functions within the liver will be clarified. In particular, the roles and interactions of liver cells and the effects of the cellular microenvironment (specifically, culture media formulation, bile removal, and oxygen concentration) on maintaining liver-specific functions will be elucidated in the process of optimizing the authentic liver model. Computational and experimental studies will be combined for the optimization process. Second, this project will generate an authentic human liver model which is currently unavailable, and explore its applications. A novel bioreactor system with an authentic liver model will be developed for the study of cellular responses to stimuli. The availability of a liver model (bioreactor) that retains cellular phenotypes of a liver sinusoid functional unit will facilitate the analyses of many aspects of the molecular mechanisms that underlie hepatocyte, or other liver cell activities in a variety of areas such as toxicology, viral infection, cancer research, and drug/gene screening. To demonstrate the utility of the novel human liver model, a focused study that analyzes the effect of Hepatitus B virus (HBV) replication on specific hepatocyte signaling pathways is proposed. This study will unveil how HBV replication affects normal human hepatocyte physiology, which is currently unknown. This research will also have significant technical impacts on the pharmaceutical industry. An authentic human liver model can greatly help them identify targets, design and develop drugs, and test them to predict performance in human clinical trials. Development of human organ models will also be expanded to other internal organs such as the lung and the breast that have unique functional units. The broader impacts of this activity include an educational component to address the national lack of microfludics education in the current engineering and science curricula by developing a set of laboratory modules and kits. This Microfluidics Laboratory Modules and Kits will have significant educational impacts at different levels. Most of all, the novel lab modules and kits will provide engineering and science students (both undergraduate and graduate) opportunities to explore microfluidic phenomena and their biomedical applications through engaging lab classes. The lab modules and kits will be initially tested at Drexel University via two courses and then distributed to more diverse users. Faculty members at Cooper Union, Rowan University, University of Connecticut, Lincoln University*, and Cheyney University* (*historically minority institutions for higher education) are committed to test the lab modules and kits in their current courses and senior design projects. The lab modules and kits will also be used in outreach programs such as NSF-supported Research Experience for Teachers (RET) and NSF GK-12 to allow high school students and teachers to ?see and feel? miniature science, promoting their interests in science and engineering. The success of this project will lead to the commercialization of the Microfluidics Laboratory Kits for broader dissemination.