Abstract

Body on a Chip: Human Microscale Models for Drug Development

Michael Shuler, Samuel B. Eckert Professor of Engineering, Cornell University; President Hesperos, Inc.

Integrated, multi-organ microphysiological systems (MPS) based on human tissues (also known as “human-on-a-chip”) could be important tools to improve the selection of drug candidates most likely to earn regulatory approval from clinical trials. Such microscale systems combine organized human tissues with the techniques of microfabrication based on PBPK (Physiologically Based Pharmacokinetic) models.  I will describe such systems being constructed at Hesperos and at Cornell. They are “self-contained” in that they can operate independently and do not require external pumps as is the case with many 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). We have achieved unidirectional flow in a pumpless system which is important for mimicking the response of  vascular tissues and constructed blood brain mimics with human in vitro like characteristics. The use of microelectrode arrays to monitor electrically active tissues (cardiac and neuronal) and micro cantilevers (muscle) have been demonstrated. While most systems use 5 or fewer organ modules, we have demonstrated that a 13 “organ” compartment device can be constructed demonstrating the potential to address a wide range of problems in pharmacology and toxicology in a low cost system. Most importantly these technical advances allow prediction of both a drug’s potential efficacy and toxicity (side-effects) in pre-clinical studies and have been applied to circulating immune cells.