CAREER: Towards a stem cell-derived 3D human liver array for high-throughput screening

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1351909 Khetani, Salman R.Drug-induced liver injury (DILI) is a leading cause of acute liver failures and liver transplants in humans that can lead to restrictions on drug use, black-box warnings on drugs, and the pre-launch and post-market attrition of pharmaceuticals. In addition to its impact on the well-being of patients, the economic impact of DILI is significant (~$1B and 12-15 years to bring 1 successful drug to market). Animal testing that is required by the Food and Drug Administration (FDA) is not fully representative of the human condition due to significant and evolutionary differences between animals and humans in liver functions. Therefore, preclinical screening of compounds for potential toxicity using human cells now constitutes a critical part of the drug development pipeline. Induced pluripotent stem cell-derived human liver cells, called hepatocytes (iHeps), can not only provide a near unlimited source of cells for screening millions of compounds, but also enable personalized (patient-specific) drug screening and therapeutic applications in the future. However, iHeps created to date are not as functionally mature as adult primary hepatocytes (isolated from donor livers) which is required to adequately predict clinical outcomes before the drugs are tested on live patients in clinical trials. To address this technology gap, the investigator will utilize microfabrication tools adapted from the semiconductor (microchip) industry to engineer a miniaturized 3D human liver mimic using iHeps and other liver supportive cell types that displays functional maturity and stability for several weeks in vitro (outside the body). This liver mimic will be characterized using several important markers for its functional maturity relative to adult primary hepatocytes. Additionally, the liver mimic will be probed for its ability to provide clinically meaningful information on DILI due to single drug and multiple drug treatments in attempts to model clinical drug dosing regimens. The investigator will integrate his research with educational programs designed to build a continuum of mentorship and scientific community in the nascent biomedical engineering (BME) undergraduate program at Colorado State University (CSU) and in the Northern Colorado region. In particular, the investigator will design and implement: a) a new course that exposes CSU BME college students to mentored research experiences in a formal research laboratory setting; b) a step-wise program that exposes high school students to career options in BME and culminates in hands-on summer research experiences in CSU BME laboratories; and, c) recurrent learning modules that expose K-6 students in an after-school program to advances in science and engineering. The iHep-based 3D human liver mimic that will be developed could ultimately lead to the development of efficacious and safe therapeutics earlier in drug development towards increasing the likelihood of clinical success and limiting patient exposure to unsafe drugs. This platform may also be applicable for evaluating the injury potential of industrial chemicals that contaminate the environment, in promoting a better cellular/molecular understanding of diseases of the liver, and in helping to design and implement personalized medicine strategies. More broadly, the engineered device could ultimately be integrated with other tissue models into a single integrated system that provides a multi-organ (i.e. 'whole body') level of understanding of various exogenous insults. The aforementioned educational efforts will develop a robust mechanism to get students of different age groups interested in science and engineering education and to get each other involved in teaching and implementing programs for younger students.Due to the interdisciplinary nature of the project, this CAREER award by the Biotechnology, Biochemical, and Biomass Engineering Program of the CBET Division is co-funded by the Instrument Development for Biological Research Program of the Division of Biological Infrastructure.