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Review
. 2021 Feb;42(2):119-133.
doi: 10.1016/j.tips.2020.11.009. Epub 2020 Dec 16.

Organ-on-a-Chip: A New Paradigm for Drug Development

Chao Ma  1 , Yansong Peng  2 , Hongtong Li  3 , Weiqiang Chen  4
Affiliations
Review

Organ-on-a-Chip: A New Paradigm for Drug Development

Chao Ma et al. Trends Pharmacol Sci. 2021 Feb.

Abstract

The pharmaceutical industry has been desperately searching for efficient drug discovery methods. Organ-on-a-Chip, a cutting-edge technology that can emulate the physiological environment and functionality of human organs on a chip for disease modeling and drug testing, shows great potential for revolutionizing the drug development pipeline. However, successful translation of this novel engineering platform into routine pharmacological and medical scenarios remains to be realized. In this review, we discuss how the Organ-on-a-Chip technology can have critical roles in different preclinical stages of drug development and highlight the current challenges in translation and commercialization of this technology for the pharmacological and medical end-users. Moreover, this review sheds light on the future developmental trends and need for a next-generation Organ-on-a-Chip platform to bridge the gap between animal studies and clinical trials for the pharmaceutical industry.

Keywords: Organ-on-a-Chip; drug development; microfluidics; microphysiological system; precision medicine.

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Conflict of interest statement

Disclaimer Statement

The authors declare no competing financial interests.

Figures

Figure 1.
Figure 1.. Microfluidic Organ-on-a-Chip platform.
Preclinical studies rely on major tools, i.e. 2D or 3D in vitro cell cultures, and in vivo animal models, for drug development. 2D in vitro culture offers a rapid and reproducible way to analyze drug response; however, they lack the 3D physiological tissue environment. Conventional 3D cell culture in the hydrogel matrix though can provide a 3D culture environment, it still falls short to controllably recapitulate the in vivo physiology and pathology in the human body. Animal models enable in vivo analysis, yet the species of differences between animal and human physiological mechanisms and complexity of the in vivo physiology weakens the accuracy and reproducibility of experimental results. Microfluidic Organ-on-Chip platform that enables controllable cell culture within an organotypic microarchitectural environment provides a simple yet more physiologically relevant platform to controllably and systematically interrogate human biology. Figure generated in BioRender (BioRender.com).
Figure 2.
Figure 2.. Organ-on-a-Chip platforms in preclinical drug development.
Preclinical drug development includes three main stages: early drug discovery, preclinical screening and testing, and preclinical trial and translation. (a) A PDAC-on-a-Chip (left) with a biomimetic vascular network (right) (HUVECs, red) and pancreatic cancer duct (PD7591 cells, green) revealed the Activin-ALK7 pathway as a hypovascularity mechanism for PDAC. Figure adapted with permission from ref. [41], AAAS. (b) A bioengineered glioblastoma brain tumor model with biomimetic tumor-immune-vascular interactions demonstrated that blockade of immunosuppression contributed by tumor-associated macrophage improved anti-PD-1 immunotherapy. Figure adapted with permission from ref. [48], eLife. (c) An NSCLC microenvironment model study found that the mechanical forces during lung breath (vacuum-driven in two side channels) may promote dormancy and drug resistance of NSCLC cells. Figure adapted with permission from ref. [43], Elsevier. (d) A first-pass multi-organ system was applied to predict the PK parameters of nicotine with a linked gut-liver-kidney chip. Figure adapted with permission from ref. [58], Springer Nature. (e) A liver lobule-on-a-chip consisted of a liver cord (green) and a liver sinusoid (red) was applied to analyze adverse drug reactions induced by unexpected drug-drug interactions. Figure adapted with permission from ref. [16], ACS. (f) A multi-organ platform integrated with a multiplex biomarker analysis module was developed to noninvasively monitor liver toxicity, as well as cardiotoxicity mediated by inter-organ metabolism. Figure adapted with permission from ref. [67], PNAS. Abbreviations: NSCLC, non-small-cell lung cancer; PDAC, pancreatic ductal adenocarcinoma. Figure generated in BioRender (BioRender.com).
Figure I.
Figure I.. Drug development pipeline.
The whole drug development process starts from early drug discovery through basic biological research, disease modeling, and target discovery to search for potential drugs. These drug candidates identified during early stage are then screened and tested with various preclinical studies by in vitro, ex vivo, and in vivo models before being approved for subsequent human trials, such as phase I, II, and III trials, during clinical development. Finally, the developed drug that is determined both effective and safe in human is submitted to FDA for regulatory review and commercial approval, after which post-market measures will be implemented for monitoring potential adverse drug reactions. Figure generated in BioRender (BioRender.com).
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