Using physiologically-based pharmacokinetic-guided “body-on-a-chip” systems to predict mammalian response to drug and chemical exposure

Abstract

The continued development of in vitro systems that accurately emulate human response to drugs or chemical agents will impact drug development, our understanding of chemical toxicity, and enhance our ability to respond to threats from chemical or biological agents. A promising technology is to build microscale replicas of humans that capture essential elements of physiology, pharmacology and/or toxicology (microphysiological systems). Here, we review progress on systems for microscale models of mammalian systems that include two or more integrated cellular components. These systems are described as a “Body-on-a-Chip.”, and utilize the concept of physiologically-based pharmacokinetic (PBPK) modeling in the design. These microscale systems can also be used as model systems to predict whole-body responses to drugs as well as study the mechanism of action of drugs using PBPK analysis. In this review, we provide examples of various approaches to construct such systems with a focus on their physiological usefulness and various approaches to measure responses (e.g. chemical, electrical, or mechanical force and cellular viability and morphology). While the goal is to predict human response, other mammalian cell types can be utilized with the same principle to predict animal response. These systems will be evaluated on their potential to be physiologically accurate, to provide effective and efficient platform for analytics with accessibility to a wide range of users, for ease of incorporation of analytics, functional for weeks to months, and the ability to replicate previously observed human responses.

Personalized radiotherapy: concepts, biomarkers and trial design

“…A technological approach that has been increasingly commented on recently is human microphysiological systems, which are microscale "on-chip" models of human multiorgan systems; 104 however, the potential of such three dimensional organ platforms in prediction of tissue perturbations to external stimuli needs extensive developmental experimentation. 105,106 It is also argued that the zebrafish embryo system may be a tool for pre-clinical toxicity assessment. 107 Relevant acute and late normal tissue effects of combined-modality therapy have been demonstrated in mice as a model organism.…”

Tissue Engineering and Regenerative Medicine 2015: A Year in Review

“…While the field of tissue engineering remains influenced by the original expectation that ''the more complex the tissue the better,'' this intuition is not necessarily true, particularly for in vitro modeling work. Whether studying responses to a specific environmental factor (such as drug, hypoxia or inflammation) using a single or multi-tissue device, [68][69][70][71] the purpose of a platform should be to make the simplest system that has a desired functional readout. The complexity of an individual tissue type or the necessary combination of multiple tissue types will naturally depend on the factor being studied.…”

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