Critical Considerations for the Design of Multi-Organ Microphysiological Systems (MPS).

Mridu Malik,Yang Yang,Gretchen J Mahler,Mandy B Esch,Parinaz Fathi

doi:10.3389/fcell.2021.721338

Abstract

Identification and approval of new drugs for use in patients requires extensive preclinical studies and clinical trials. Preclinical studies rely on in vitro experiments and animal models of human diseases. The transferability of drug toxicity and efficacy estimates to humans from animal models is being called into question. Subsequent clinical studies often reveal lower than expected efficacy and higher drug toxicity in humans than that seen in animal models. Microphysiological systems (MPS), sometimes called organ or human-on-chip models, present a potential alternative to animal-based models used for drug toxicity screening. This review discusses multi-organ MPS that can be used to model diseases and test the efficacy and safety of drug candidates. The translation of an in vivo environment to an in vitro system requires physiologically relevant organ scaling, vascular dimensions, and appropriate flow rates. Even small changes in those parameters can alter the outcome of experiments conducted with MPS. With many MPS devices being developed, we have outlined some established standards for designing MPS devices and described techniques to validate the devices. A physiologically realistic mimic of the human body can help determine the dose response and toxicity effects of a new drug candidate with higher predictive power.

Highlights

The development of new pharmaceuticals is time-intensive and expensive
This study demonstrated that various chemokines, such as those associated with hypoxia and loss of endothelial cell tight junction proteins, may play a role in T cell infiltration into tumors
Tissues that typically only experience low mechanical shear due to interstitial fluidic flow in vivo, are not disturbed by such lowgrade, bidirectional shear (Esch et al, 2015). Another advantage of gravity-driven flow is that Microphysiological systems (MPS) designs can be compact, eliminating long interconnecting channels from the designs as shown with the recently developed body cube (Chen et al, 2020), and thereby lowering the overall liquid volume needed to operate the systems to nearphysiological blood surrogate levels (Chen et al, 2020)

Summary

INTRODUCTION

The development of new pharmaceuticals is time-intensive and expensive. A thorough assessment of a drug’s efficacy and safety must precede clinical testing in patients. The recirculating flow of fluid in the device allowed the tested drugs to reach each tissue within the MPS and display multi-organ toxicity (Oleaga et al, 2016). Tissues that typically only experience low mechanical shear due to interstitial fluidic flow in vivo, are not disturbed by such lowgrade, bidirectional shear (Esch et al, 2015) Another advantage of gravity-driven flow is that MPS designs can be compact, eliminating long interconnecting channels from the designs as shown with the recently developed body cube (Chen et al, 2020), and thereby lowering the overall liquid volume needed to operate the systems to nearphysiological blood surrogate levels (Chen et al, 2020). While current long-term exposure analysis is still primarily performed in animals, the steady development of MPS is moving toward substituting animal-based chronic exposure testing as well

DESIGN PRINCIPLES FOR MPS

Design criteria

CONCLUSION