Microfabricated Devices for Studying the Metabolism and Cytotoxicity of Drug Candidates.

During drug development, large libraries of new chemical entities (NCEs) are generated and undergo in vitro screens of metabolism and cytotoxicity. These screens are heavily relied upon to select lead compounds with the highest chance of success in pre-clinical studies and clinical trials, but suffer from limited in vivo predictive power despite using human liver-derived components. There is a need for new assays that utilize smaller reagent volumes to reduce the cost of these high-throughput screens; better mimic the liver environment; and ultimately account for toxicities in other major organ systems. Microfabricated devices, in their current state, integrate multiple reaction steps in a single device, decreasing the cost of a single metabolism or cytotoxicity screen by lowering the reagent consumption and increasing throughput. The incorporation of three-dimensional co-cultures in these devices promise increased accuracy of in vitro screens, because cellular phenotype and response of hepatocytes in these cultures are more representative of the liver. In this review, we focus on microfabricated devices developed over the past decade and highlight technologies that we believe have the potential of reaching shorter- and longer-term goals of reducing the cost of bringing new drugs to market and revolutionizing the discovery stage of the drug development pipeline.