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Microfabricated Human Liver Tissues for Drug Development

C.E. Credits: P.A.C.E. CE Florida CE
Speaker
  • Associate Professor, Department of Bioengineering, University of Illinois at Chicago
    Biography
      Dr. Salman Khetani received his dual Bachelor of Science degrees in electrical engineering and biomedical engineering from Marquette University, and Masters and PhD degrees in bioengineering from University of California at San Diego (UCSD). He was a Jacobs fellow and National Science Foundation graduate fellow at UCSD. After postdoctoral research at MIT in the laboratory of Professor Sangeeta Bhatia, Dr. Khetani co-founded and directed research at Hepregen Corporation to commercialize his bioengineered liver inventions for pharmaceutical drug development. In 2011, Dr. Khetani returned to academia, first to Colorado State University and then in 2015 as associate professor of Bioengineering at the University of Illinois at Chicago, where his 'Microfabricated Tissue Models' laboratory (http://mtm.uic.edu/) designs and implements novel engineered tissues for drug screening, investigations of human diseases, and regenerative medicine. Dr. Khetani's 50+ publications in journals such as Hepatology, Nature Biotechnology, and PNAS have been cited more than 4000 times with an h-index of 30. Lastly, Dr. Khetani's research has been funded over the last 12 years via ~$6M in grants from the NIH, NSF, DOD, FDA, and the NSF CAREER award.

    Abstract

    The liver plays a critical role in the metabolism and clearance of more than 70% of marketed drugs. Furthermore, toxicity to the liver is a major reason for preclinical and clinical drug failures. Animals are not always predictive of human liver-drug interactions due to significant species-specific differences in drug metabolism and toxicity pathways. Thus, in vitro models of the human liver are now routinely utilized in pharmaceutical practice to complement animal testing; such models enable faster and cheaper drug testing and hold the promise to prevent harm to living patients. Isolated primary human liver cells are the gold standard for fabricating human liver models, but these cells rapidly lose their liver functions, including drug metabolism capacities, in conventional 2-dimensional monocultures. In contrast, semiconductor-driven microfabrication tools and co-culture with non-parenchymal cells have been used to precisely modulate the microenvironment around hepatocytes towards enhancing and stabilizing phenotypic functions for 4-6 weeks. Such engineered liver co-cultures have significantly improved the sensitivity for the detection of drug clearance, drug metabolite identification, drug-transporter interactions, and drug-induced liver toxicity. This presentation will showcase the development and validation of engineered human liver co-cultures for the above-mentioned applications; it will then discuss emerging trends in further improving the physiological relevance of the platform using liver non-parenchymal cells and determining the role of major liver diseases (e.g., non-alcoholic fatty liver disease) in changing drug outcomes.

    Learning objectives:
    1. The key design features necessary for building robust in vitro human liver models and
    2. The various applications within the drug development pipeline where such models can be effectively utilized.


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