Body-On-A-Chip: A Tool for Predictive Pharmacology/Toxicology

We seek to understand the response of the human body to various pharmaceutical and environmental chemicals as well as to oral ingestion of nanoparticles. 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 called this in vitro system a micro cell culture analog (microCCA). 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 pharmacokinetic (PBPK}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. The basic concept has been described in the context of microdevices to study toxicity (Sin, et al., Biotechnol. Prog. 20:385, 2004; Khamsi, Nature 435:12, 2005).

We have done "proof-of-concept" experiments as a basis 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 common form of MDR is overexpression of P-glycoprotein which can be expressed in MDR cells at 50 to 100 fold over normal levels. P-glycoprotein is a pump protein that intercepts drugs and pumps them back out of the cell. Here we test a possible combination treatment using a chemotherapeutic drug, doxorubicin, and two MDR suppressors (cyclosporine and nicardipine). The microCCA (with "liver", "bone marrow", "uterine cancer", "slowly perfused" and "rapidly perfused" compartments) shows an unexpected synergistic response to certain drug combinations not observable in traditional assay systems. We have also used a microCCA to test potential combination therapies (Tegafur and uracil) for colon cancer. Tegafur is a prodrug for 5-FU and uracil an inhibitor of DPD, an enzyme which deactivates 5-FU. 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. These coupled GI tract/body modules have been used to mimic human response to acetaminophen plus ethanol and have shown that nanoparticles can interfere with normal physiological responses such as iron uptake and nutrition.

Overall, we believe that in vitro, microfabricated devices with cell cultures provides a viable alternative to animal models to predict toxicity and response to pharmaceuticals.

Bigraphy:
Michael L. Shuler is the James and Marsha McCormick Chair of the Department of Biomedical Engineering as well as the Samuel B. Eckert Professor of Chemical Engineering in the School of Chemical and Biomolecular Engineering at Cornell University, Ithaca, New York. He was also a NYSTAR Distinguished Professor (2001-2006). Shuler received both of his degrees in chemical engineering (BS, University of Notre Dame, 1969 and PhD., University of Minnesota, 1973) and has been a faculty member at Cornell University since January 1974. Shuler's research is focused on biomolecular engineering and includes development of an "artificial" animal (in vitro) for testing pharmaceuticals and chemicals for toxicity, bioprocess production systems for useful compounds, such as paclitaxel from plant cell cultures, production of foreign proteins using a wide variety of genetically engineered hosts, and computer models of cells relating physiological function to genomic structure. Shuler has co-authored a popular textbook in bioprocess engineering (selected by AIChE as among 30 authors of groundbreaking chemical engineering texts). Shuler has been elected to the National Academy of Engineering and American Academy of Arts and Sciences. He has received numerous awards for research, teaching, and advising of students.