Abstract

Microfabrication and Cell Culture: Building a “Body-on-a-Chip” to Enhance Drug Development

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

Human microphysiological or “Body-on-a-Chip” systems are powerful tools to assess the potential efficacy and toxicity of drugs in pre-clinical studies.  Having a human based, multiorgan system, that emulates key aspects of human physiology can provide important insights to complement animal studies and in vitro studies using human cells from a single organ in the decision about which drugs to move into clinical trials.  These systems are constructed using a polymeric platform (eg. PMMA) that house interconnected modules with tissue mimics of various organs.  The system design is based on physiologically based pharmacokinetics-pharmacodynamic (PBPK-PD) models. Each module emulates an organ or tissue in the body.  Each module is constructed using techniques of traditional microfabrication combined with cell cultures typically using primary cells, induced pluripotent stem cells, or established cell cultures. Our goal is to construct low cost systems that can be operated robustly for 28 days using a chemically defined medium and a novel pumpless system.  In addition to traditional measurements of circulating biomarkers we measure electrical activity using microelectrode arrays and cellular force generation using silicon cantilevers as functional measures of organ response to drugs or chemicals. Using a system with four or more organs we can predict the exchange of metabolites between organ compartments in response to various drugs and dose levels. We have constructed models incorporating barrier tissues such as GI tract, blood brain barrier, and skin with internal organs such as liver, cardiac, and neuromuscular junctions. With these systems, we can predict both efficacy and toxicity of drugs in humans from preclinical studies.  Further, we can use these systems to investigate temporal concentration relationships of drugs during preclinical development4. We believe that these “Body-on-a-Chip” systems have great potential to increase the efficiency of conversion of drug candidates into successful projects.