Microphysiological systems in early stage drug development: Perspectives on current applications and future impact

Abstract

Microphysiological systems (MPS) are making advances to provide more standardized and predictive physiologically relevant responses to test articles in living tissues and organ systems. The excitement surrounding the potential of MPS to better predict human responses to medicines and improving clinical translation is overshadowed by their relatively slow adoption by the pharmaceutical industry and regulators. Collaboration between multiorganizational consortia and regulators is necessary to build an understanding of the strengths and limitations of MPS models and closing the current gaps. Here, we review some of the advances in MPS research, focusing on liver, intestine, vascular system, kidney and lung and present examples highlighting the context of use for these systems. For MPS to gain a foothold in drug development, they must have added value over existing approaches. Ideally, the application of MPS will augment in vivo studies and reduce the use of animals via tiered screening with less reliance on exploratory toxicology studies to screen compounds. Because MPS support multiple cell types (e.g. primary or stem-cell derived cells) and organ systems, identifying when MPS are more appropriate than simple 2D in vitro models for understanding physiological responses to test articles is necessary. Once identified, MPS models require qualification for that specific context of use and must be reproducible to allow future validation. Ultimately, the challenges of balancing complexity with reproducibility will inform the promise of advancing the MPS field and are critical for realization of the goal to reduce, refine and replace (3Rs) the use of animals in nonclinical research.

Effect of Replicative Senescence on the Expression and Function of Transporters in Human Proximal Renal Tubular Epithelial Cells

“…Lately, complex systems such as co-culture models, 3D models, or microfluidic organ-on-a-chip using cultured cells derived from normal tissues or embryonic stem (ES)/iPS cells are generating valuable data on the cutting edge of animal alternative technology. 4,19,34) Using normal kidney tissues or kidney organoids derived from ES/iPS cells may bring in vitro models closer to ideal models that accurately reflect the biological system, but the effect of cellular senescence on outputs should be closely monitored. The effects of cellular senescence on cellular function and morphogenesis in RPTECs are still not completely understood.…”

A guide to the organ-on-a-chip

“…This shift is largely based on the results of in vitro studies using these platforms becoming increasingly predictive of clinical data for integrated human physiology. Not surprisingly, numerous OoC start-ups launched from academic laboratories are starting to fill the commercial space for drug testing in the pharmaceutical industry 45 , including GSK 283 , Roche and Pfizer 284 . Nonetheless, there are some important challenges that still need to be overcome 269 , and so we foresee that future developments for OoC technology will likely focus on making the platform (1) more standardized, (2) compatible with imaging, analytical instruments, robotics and mass production, and (3) user-friendly so that it can be widely adopted by non-specialist end users.…”

Establishing Rationale for the Clinical Development of Cell Therapy Products: Consensus between Risk and Benefit

“…This is a major problem that reduces the accuracy of human PK–PD prediction using the results of the study. Recently, the development and use of humanized animal models or in vitro -based human-simulating systems (e.g., microphysiological systems) is increasing ( 39 , 40 ).…”