SBIR-STTR Award

This Small Business Technology Transfer Phase I project optimizes an in vitro model of human liver tissue and assess its utility for evaluating liver toxicity following chronic drug exposure. While primary human hepatocytes isolated from the liver are utilized by pharmaceutical and biotech industries to evaluate drug metabolism and toxicity, these cells under conventional culture rapidly lose liver-specific functions, which does not allow for chronic effects of drugs to be tested earlier in drug development. Recently, a miniaturized, multiwell human liver tissue model with defined microscale architecture has been developed that maintains phenotypic functions for several weeks. This project will utilize microtechnology tools to functionally optimize the microscale liver tissue for enhanced longevity (months), and assess utility of the system for evaluating clinically-relevant chronic (weeks) drug toxicity using high content imaging readouts and gene expression signatures. The broader impacts of this research are to provide an improved understanding of protein/gene expression changes in primary human hepatocytes following chronic drug exposure, and development of a novel chronic toxicity assay for use in industry. In the future, chronic toxicity screening with microscale liver tissues may be used to eliminate toxic compounds much earlier in the drug development pipeline towards reducing the $1 billion per drug development costs, increasing likelihood of clinical success, and limiting human exposure to unsafe drugs. More broadly, microscale human liver tissues may enable the investigation of mechanisms of toxicant action, allow identification of new biomarkers, and enable studies to assess the risk associated with exposure to mixtures of drugs

This Small Business Innovation Research (SBIR) Phase II project is aimed towards development of a human micro-liver platform and assay technologies for cost-effective, high-throughput, and quantitative screening of drug-induced liver injury (DILI) and drug-drug interactions (DDI) following chronic exposure to pharmaceuticals. While primary human hepatocytes isolated from the liver are widely utilized in the pharmaceutical industry for drug screening, these cells rapidly (hours) lose phenotypic functions under conventional culture conditions. Recently, a human liver tissue model with defined microscale architecture has been developed that maintains phenotypic functions of primary hepatocytes for several weeks in vitro (micro-livers). This project proposes to develop assay technologies (gene expression, reporter-based, and high content imaging) with micro-livers in a high-throughput multi-well format for DILI and DDI screening in early drug discovery. The broader impacts of this research are novel approaches for the development of high-throughput, physiologically-relevant platforms for assessing the potential of compounds to cause adverse effects on organs. The liver platforms developed here may enable the elimination of drugs with problematic toxicity profiles much earlier in the drug development pipeline towards substantially reducing the cost to develop a successful drug ($1 billon per drug), increasing the likelihood of clinical success, and limiting human exposure to unsafe drugs. In the future, these platforms may be useful for evaluating the injury potential of environmental toxicants, in fundamental investigations of liver physiology and disease, and for personalized medicine