Abstract

Human-on-a-chip Systems For Use in Efficacy and Toxicological Investigations in Pre-clinical Drug Discovery Utilizing Stem Cell-derived Disease Models

James Hickman, Professor, University of Central Florida

The utilization of multi-organ human-on-a-chip or body-on-a-chip systems for toxicology and efficacy, which ultimately should lead to personalized medicine applications, is a topic that has received much attention recently for drug discovery and subsequent regulatory approval. The considerable attrition-rate of drug candidates at all stages of development to a significant extent arises from the poor predictive nature of preclinical models for efficacy and toxicity, especially the inability to translate efficacy between preclinical and clinical situations. Systems capable of directly measuring organ function, biomarker release, and most importantly the synergistic interactions between organs, especially the generation of liver metabolites would be ideal. Our human-on-a-chip systems utilize function based cell models that accurately capture and predict multi organ complexity in response to administered compound within correctly scaled and physiologically relevant platforms. Our group, in collaboration with Dr. Michael Shuler from Cornell University, has been constructing these systems with up to 6 organs and have demonstrated long-term (>28 days) evaluation of drugs and compounds, that have shown similar response to results seen from clinical data or reports in the literature. Application of these systems for stem cell derived disease models of ALS and Alzheimer’s will be presented.  Cardiac and skeletal muscle mechanistic toxicity and PDPK modeling will also be addressed. Additionally, this talk will give results of six workshops held at NIH to explore what is needed for validation and qualification of these new systems.