(394e) “Body-on-a-Chip” Technology for Predicting Human Response to Various Drug Therapies

We seek to understand the response of the human body to various pharmaceutical and environmental chemicals. In effect, to do in vitro ADMET (Adsorption-Distribution-Metabolism-Elimination-Toxicity) studies by combining microtechnology and cell culture to form a micro cell culture analog (microCCA). A CCA uses mammalian cells cultured in interconnected chambers to physically represent a physiologically based pharmacokinetic model (PBPK) or a whole body model. When a CCA system is used in conjunction with a PBPK model, it can estimate human response to chemicals and link molecular mechanism to system response. We will discuss the advantages and limitations of this technology and illustrate its use in evaluating ?cocktail? treatments of multidrug resistant (MDR) cancer. Preliminary studies demonstrate a synergistic interaction between cyclosporin and nicardipine as MDR suppressors when used with the chemotherapeutic doxorubicin to treat MDR uterine cancer. In a microCCA system with liver-bone marrow-MDR uterine cancer-sensitive uterine cancer-remaining slowly and rapidly perfused tissue compartments, the proliferation of MDR resistant cancer is suppressed with only modest impact in cells in the other compartments. A primary limitation of these experiments is the use of 2-D cell cultures; approaches to development of a system with 3-D tissues will be discussed.