Abstract

Body on a Chip: Human Microscale Models for Drug Development

James Hickman, Professor, University of Central Florida

The preclinical drug development process is inefficient at selecting drug candidates for human clinical trials, since only 11% of drug candidates selected for clinical trials exit with regulatory approval. Current technology is based on isolated human cells and animal surrogates.  We believe that a “human” multiorgan model based on physiologically based pharmacokinetics-pharmacodynamic (PBPK-PD) models that house interconnected modules with tissue mimics of various organs.  The system captures key aspects of human physiology that would potentially reduce drug attrition in clinical trials and decrease the cost of development. Integrated, multi-organ microphysiological systems (MPS) based on human tissues (also known as “body-on-a-chip”) could be important tools to improve the selection of drug candidates exiting preclinical trials for those drug most likely to earn regulatory approval from clinical trials. This methodology integrates microsystems fabrication technology and surface modifications with protein and cellular components, for initiating and maintaining self-assembly and growth into biologically, mechanically and electronically interactive functional multi-component systems.


I will describe such systems being constructed at Hesperos and at UCF that are guided in their design by a PBPK model. They are “self-contained” in that they can operate independently and do not require external pumps as is the case with man other microphysiological systems. They are “low cost”, in part, because of the simplicity and reliability of operation. They maintain a ratio of fluid (blood surrogate) to cells that is more physiologic than in many other in vitro systems allowing the observation of the effects of not only drugs but their metabolites. While systems can be sampled to measure the concentrations of drugs, metabolites, or biomarkers, they also can be interrogated in situ for functional responses such as electrical activity, force generation, or integrity of barrier function. Operation up to 28 days has been achieved allowing observation of both acute and chronic responses with serum free media. We have worked with various combinations of internal organ modules (liver, fat, neuromuscular junction, skeletal muscle, cardiac, bone marrow, blood vessels and brain) and barrier tissues (eg skin, GI tract, blood brain barrier, lung, and kidney). The use of microelectrode arrays to monitor electrically active tissues (cardiac and neuronal) and micro cantilevers (muscle) have been demonstrated. Most importantly these technical advances allow prediction of both a drug’s potential efficacy and toxicity (side-effects) in pre-clinical studies. This talk will also give results of six workshops held at NIH to explore what is needed for validation and qualification of these new systems.