Fitting tissue chips and microphysiological systems into the grand scheme of medicine, biology, pharmacology, and toxicology

Abstract

Impact statementMicrophysiological systems (MPS), which include engineered organoids and both individual and coupled organs-on-chips and tissue chips, are a rapidly growing topic of research that addresses the known limitations of conventional cellular monoculture on flat plastic -a wellperfected set of techniques that produces reliable, statistically significant results that may not adequately represent human biology and disease. As reviewed in this article and the others in this thematic issue, MPS research has made notable progress in the past three years in both cell sourcing and characterization. As the field matures, currently identified challenges are being addressed, and new ones are being recognized. Building upon investments by the Defense Advanced Research Projects Agency, National Institutes of Health, Food and Drug Administration, Defense Threat Reduction Agency, and Environmental Protection Agency of more than $200 million since 2012 and sizable corporate spending, academic and commercial players in the MPS community are demonstrating their ability to meet the translational challenges required to apply MPS technologies to accelerate drug development and advance toxicology. AbstractMicrophysiological systems (MPS), which include engineered organoids (EOs), single organ/tissue chips (TCs), and multiple organs interconnected to create miniature in vitro models of human physiological systems, are rapidly becoming effective tools for drug development and the mechanistic understanding of tissue physiology and pathophysiology. The second MPS thematic issue of Experimental Biology and Medicine comprises 15 articles by scientists and engineers from the National Institutes of Health, the IQ Consortium, the Food and Drug Administration, and Environmental Protection Agency, an MPS company, and academia. Topics include the progress, challenges, and future of organs-on-chips, dissemination of TCs into Pharma, children's health protection, liver zonation, liver chips and their coupling to interconnected systems, gastrointestinal MPS, maturation of immature cardiomyocytes in a heart-on-a-chip, coculture of multiple cell types in a human skin construct, use of synthetic hydrogels to create EOs that form neural tissue models, the blood-brain barrier-on-a-chip, MPS models of coupled female reproductive organs, coupling MPS devices to create a body-on-a-chip, and the use of a microformulator to recapitulate endocrine circadian rhythms. While MPS hardware has been relatively stable since the last MPS thematic issue, there have been significant advances in cell sourcing, with increased reliance on human-induced pluripotent stem cells, and in characterization of the genetic and functional cell state in MPS bioreactors. There is growing appreciation of the need to minimize perfusate-to-cell-volume ratios and respect physiological scaling of coupled TCs. Questions asked by drug developers are followed by an analysis of the potential value, costs, and needs of Pharma. Of highest value and lowest switching costs may be the d...

The Microbiome and the Gut‐Liver‐Brain Axis for Central Nervous System Clinical Pharmacology: Challenges in Specifying and Integrating In Vitro and In Silico Models

“…Although there are notable challenges that have yet to be fully overcome for both individual and coupled chips, 3,35,115,116 the future for this technology is promising. In this section, we highlight MPS used for drug discovery and toxicology, briefly review the application of pharmacokinetics (PKs) to MPS studies, discuss an MPS model that recapitulates important aspects of gut-liver-kidney-brain pharmacodynamics (PDs), and speculate on the future.…”

“…117,118 Ultimately, vascularized organoids may supplement or replace tissue chips, but many multi-omic assays require more cell mass or effluent volume than can be obtained from conventional organoid well plates or very small organ chips. 3 There are several different ways to apply OoC technologies to study the M-GLIBA. Figure 4a is a schematic diagram of the key physiological systems involved in the M-GLIBA, including the pancreas and the enteric and autonomic nervous systems.…”

“…The next challenge is to successfully couple multiple chips while maintaining flow rates, concentrations, and sterility. 3,35 Multiple-organ MPS models. Although many of the corporate ventures in OoCs are focusing on single-organ chips for drug screening, there is much interest in using coupled-chip MPS models for ADMET to study situations in which metabolism of a metadrug or drug by one organ creates a drug that treats or toxifies another organ.…”

“…The Microbiome and the Gut-Liver-Brain Axis for Central Nervous System Clinical Pharmacology: Challenges in Specifying and Integrating In Vitro and In Silico Models Kyle G. Hawkins 1 , Caleb Casolaro 2 , Jacquelyn A. Brown 1,3 , David A. Edwards 4 and John P. Wikswo 1,2,3,5, *…”

“…cells, and cellular waste for off-line analysis without damaging the cells; (vi) quantification of drug absorption, distribution, metabolism, excretion, and toxicity (ADMET); and (vii) the ability to visualize host-microbiome interactions. 3,6,[35][36][37] Such systems are being utilized to create disease models and ultimately to enable personalized models for precision medicine. These in vitro models would benefit from and support multi-omics analyses and in silico computational models.…”