The utility of microscale human liver co-cultures for investigating drug toxicity outcomes

Date: April 14 2016
Presenter(s): Dr. Salman Khetani

You can download the presentation slides here!

Third HepatoPac Webinar was presented on 14 April, 2016 by Dr. Salman Khetani, Associate Professor, Department of Bioengineering, University of Illinois at Chicago, USA.

Summary: Drug-induced liver injury (DILI) remains a leading cause of acute liver failures and the attrition of pharmaceuticals in both preclinical and clinical settings. Due to species-specific differences in drug metabolism pathways, animal models do not always fully predict human DILI. Thus, there is a need for predictive human liver models, which include hepatocarcinoma-derived cell lines, primary hepatocytes and liver slices. However, cancerous cell lines suffer from abnormal levels of liver functions and morphology, while liver slices do not retain phenotypic functions for more than a few days in vitro. Therefore, isolated primary human hepatocytes are widely considered to be the “gold standard” for drug toxicity assessments; however, in culture formats that rely exclusively on extracellular matrix, hepatocytes display a rapid decline in key functions (i.e. drug metabolism enzymes, transporters), which prevents long-term drug dosing. In this webinar, I will describe how micropatterned co-cultures (MPCCs) containing cryopreserved hepatocytes in industry-standard multi-well plates can provide significantly higher sensitivity (while maintaining high specificity) for drug toxicity assessments than traditional sandwich-cultured hepatocyte monolayers. The compatibility of MPCCs with high content imaging readouts for mechanistic studies will also be discussed. Case studies from multiple pharmaceutical companies will be presented to demonstrate the “real-world” utility of the MPCC platform for both rapid binning of compounds by hazard and investigative toxicology. The MPCC platform will be compared against other 2D and 3D engineered liver models. Use of commercially available induced pluripotent stem cell-derived hepatocyte-like cells in MPCCs and their readiness for an early/initial drug toxicity screening will also be discussed. In the future, MPCCs can be used to reduce drug attrition and prevent harm to patients in the clinic.

Dr. Salman Khetani received his BS degrees, summa cum laude, in electrical engineering and biomedical engineering from Marquette University, and MS and PhD degrees in bioengineering from the University of California at San Diego (UCSD). He was a Jacobs fellow and National Science Foundation graduate fellow at UCSD. Dr. Khetani conducted his postdoctoral studies at MIT in the laboratory of Dr. Sangeeta Bhatia, professor in the Harvard-MIT Division of Health Sciences and Technology and a world-renowned leader in multi-scale liver tissue engineering and regenerative medicine. Dr. Khetani’s research has been published in peer-reviewed journals such as Drug Metabolism and Disposition, Toxicological Sciences, Nature Biotechnology and the Proceedings of the National Academy of Sciences. In 2007, Dr. Khetani co-founded Hepregen Corporation and led research there as director of research from 2008 to 2011 in order to bring to market bioengineered models of animal and human livers for pharmaceutical drug development. Dr. Khetani then started his academic faculty career in the department of mechanical engineering and school of biomedical engineering at Colorado State University (2011-2015) and recently transitioned as associate professor of bioengineering to University of Illinois at Chicago where he directs the Microfabricated Tissue Models laboratory. He is the recipient of the NSF CAREER award, and his research (past and current) has been funded by DOD, FDA, NIH, NSF, the State of Colorado, and major pharmaceutical companies.