Body-On-A-Chip: Towards In Vitro Evaluation of Drugs
Michael L. Shuler
James M. and Marsha McCormick Chair of Biomedical Engineering
Samuel B. Eckert Professor of Chemical Engineering
School of Chemical and Biomolecular Engineering
Cornell University
Tuesday, October 26, 2010
Refreshments at 9:15 AM
Lecture at 9:30 AM
Room 1610 Engineering Hall
We seek to understand the response of the human body to various pharmaceuticals. Our platform technology is an in vitro system that combines microfabrication and cell cultures and is guided by a computer model of the body. We call this in vitro system a micro cell culture analog (microCCA) or a "Body-on-a-Chip". A microCCA device contains mammalian cells cultured in interconnected micro-chambers to represent key body organs linked
through the circulatory system and is a physical representation of a physiologically based pharma-cokinetic model. MicroCCAs can reveal toxic effects that result from interactions between organs as well as provide realistic, inexpensive, accurate, rapid throughput toxicological studies that do not require animals. The advantages of operating on a microscale include the ability to mimic physiological relationships more accurately as the natural length scale is order of 10 to 100 microns.
We have done proof-of-concept experiments to evaluate combination therapy for cancer. Multidrug resistant (MDR) cancer often occurs after initial success with a chemotherapeutic drug. MDR cancer cannot be treated with the original drug as well as many other drugs. A form of MDR is overexpression of P-glycoprotein at levels 50 to100 fold over normal. P-glycoprotein is a pump protein that intercepts drugs and pumps them back out of the cell. We test a possible combination treatment using a chemotherapeutic drug, doxorubicin, and two MDR suppressors. The microCCA shows an unexpected synergistic response to certain drug combinations not observable in traditional assay systems. The toxic response is selective to the MDR resistant cancer cells; the MDR suppressors do not alter toxicity in the "bone marrow" compartment. We have also used a microCCA to test potential combination therapies for colon cancer. Simple microwell plates cannot probe this system, but the microCCA predicts the types of responses observed experimentally. We have coupled these body modules with a micro model of the GI tract to examine the response to oral exposure of drugs, chemicals, or nanoparticles.
Overall, we believe that in vitro, microfabricated devices with cell cultures provide a viable alternative to animal models to predict toxicity and efficacy in response to pharmaceuticals.
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Michael L. Shuler is the James and Marsha McCormick Chair of the Department of Biomedical Engineering as well as the Samuel Eckert Professor of Chemical Engineering in the School of Chemical and Biomolecular Engineering at Cornell University. He is also the Director of the Center on the Microenvironment and Metastasis, a Physical Sciences–Oncology Center funded by the National Cancer Institute. Shuler received his degrees in chemical engineering (B.S., University of Notre Dame, 1969 and Ph.D., University of Minnesota, 1973) and has been a faculty member at Cornell University since January 1974. His research is focused on biomolecular engineering and nanobiotechnology and includes development of an "artificial" animal (in vitro) for testing pharmaceuticals, models of the vasculature to identify interactions of circulating tumor cells with the endothelium, controlled drug delivery to treat brain tumors, production systems for useful compounds, such as paclitaxel from plant cell cultures, and computer models of cells relating physiological function to genomic structure. Shuler's research has led to commercial processes for production of the anticancer agent, Taxol, to tools to produce proteins from recombinant DNA (the "High Five" cell line), to software to support systems biology, and to devices for drug development (HuRel system).
He has received numerous awards for his research. He has an honorary doctorate from the University of Notre Dame. He has received the Amgen Award in Biochemical Engineering, the Professional Progress and Warren K. Lewis Awards from the American Institute of Chemical Engineers. He was the inaugural awardee for the J.E. Bailey Award from the Society for Biological Engineering. Shuler has been elected to membership in the National Academy of Engineering and the American Academy of Arts and Science.