How multi-organ microdevices can help foster drug development

Abstract

Multi-organ microdevices can mimic tissue-tissue interactions that occur as a result of metabolite travel from one tissue to other tissues in vitro. These systems are capable of simulating human metabolism, including the conversion of a pro-drug to its effective metabolite as well as its subsequent therapeutic actions and toxic side effects. Since tissue-tissue interactions in the human body can play a significant role in determining the success of new pharmaceuticals, the development and use of multi-organ microdevices present an opportunity to improve the drug development process. The devices have the potential to predict potential toxic side effects with higher accuracy before a drug enters the expensive phase of clinical trials as well as to estimate efficacy and dose response. Multi-organ microdevices also have the potential to aid in the development of new therapeutic strategies by providing a platform for testing in the context of human metabolism (as opposed to animal models). Further, when operated with human biopsy samples, the devices could be a gateway for the development of individualized medicine. Here we review studies in which multi-organ microdevices have been developed and used in a ways that demonstrate how the devices' capabilities can present unique opportunities for the study of drug action. We will also discuss challenges that are inherent in the development of multi-organ microdevices. Among these are how to design the devices, and how to create devices that mimic the human metabolism with high authenticity. Since single organ devices are testing platforms for tissues that can later be combined with other tissues within multi-organ devices, we will also mention single organ devices where appropriate in the discussion.

Keywords: Body-on-a-chip; MPS; Micro-cell culture analogs of PBPKs; Microphysiological systems; Multi-organ microdevices; μCCAs.

Figure 1

Illustration of how simplified PBPK models can guide the physiologic design of multi-organ microdevices: Organs that are of interest for a particular study are incorporated as chamber on the device. Organs that are not of interest can be combined within one volume (filled with liquid for well-perfused organs or filled with hydrogel for poorly perfused organs). Fluidic circuitry are the physical equivalent of the equations that express the transport of a drug in a in the PBPK model, and the cells that are cultured within each organ chamber are an equivalent for the equations that express the absorption and metabolism of drugs. The device that is illustrated here was used for the simulation of the first pass metabolism of acetaminophen.