Engineered Models of Liver Diseases for Drug Development
- Tuesday, Dec 11, 2012
- 2:00pm - 3:00pm
- Wyss Institute, Room 521, 3 Blackfan Circle, Boston, MA 02115
- Salman Khetani, Ph.D.
- Assistant Professor
- Department of Mechanical Engineering
- Colorado State University
Bile canaliculi in a hepatocyte island in culture.
Animal studies ultimately provide a limited view of human-relevant responses due to species-specific differences in liver functions. Human liver cells either isolated from donor organs and/or derived from a patient’s stem cells could potentially address this species gap. However, these cells rapidly lose their liver functions when cultured in conventional models, which disperse tissues into single cells with simple extracellular matrix manipulations or aggregate cells into spheroids while neglecting higher-order processes such as microscale architecture that is essential for modulating liver functions. The application of semiconductor-driven microtechnology in the biomedical arena now allows fabrication of microscale tissue subunits that can be functionally improved and have the dual advantage of miniaturization. We have worked with primary animal and human hepatocytes in microfabricated model systems that allow major liver-specific gene expression and functions (i.e. CYP450s) to be maintained in culture for several weeks in vitro. The main features of our model systems are a precise microscale architecture that optimizes cell-cell interactions, and interactions of hepatocytes with both liver and non-liver-derived stromal cells. These features have culminated in micropatterned co-cultures (MPCCs), also known as HepatoPac commercialized by Hepregen Corporation and currently utilized by several pharmaceutical companies for drug testing. Microfabrication tools have also allowed miniaturization of MPCCs in 24- and 96-well industry-standard plate-based formats that integrate easily into the existing workflow within the pharmaceutical industry and are amenable to high content imaging for assessing cell toxicity. Furthermore, we have utilized MPCCs for several applications in drug development including drug clearance predictions, drug metabolite profiling and prediction of drug-induced liver toxicity with advantages over the current gold standard screening models applied in pharmaceutical practice. More recent work involves modeling of liver diseases such as hepatitis C and type-2 diabetes for potential discovery of novel drugs that provide an optimal balance of efficacy and safety. In the future, continued combination of microtechnology and tissue engineering may enable development of integrated tissue models in the so-called 'human on a chip'.
Biography: Salman R. Khetani received dual Bachelor of Science degrees in Electrical and Biomedical Engineering from Marquette University, and MS and PhD degrees in Bioengineering from the University of California at San Diego as a NSF graduate fellow. He trained under MIT Professor Sangeeta Bhatia, a world-renowned expert in liver tissue engineering. Salman and his colleagues have used microtechnology tools to develop highly stable microscale models of human and rodent livers for applications in drug development and infectious diseases. His work has been published in journals such as Nature Biotechnology and the Proceedings of the National Academy of Sciences. In 2008, Salman co-founded Hepregen Corporation to further develop microscale liver technologies for the broader marketplace. As director of research, Salman led the team conducting research with industrial and government partners and helped launch a suite of liver-based products currently in use by pharmaceutical companies for toxicity testing. At Hepregen, Salman secured almost $1.8M in funding from NSF, NIH and FDA, including a highly competitive NIH Challenge grant. In October of 2011, Salman joined the faculty of CSU as an assistant professor of Mechanical and Biomedical Engineering. His current academic research continues to leverage microtechnology tools to create in vitro models of liver diseases for multiple applications.
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