Organ-on-a-chip engineering: Toward bridging the gap between lab and industry

Abstract

Organ-on-a-chip (OOC) is a very ambitious emerging technology with a high potential to revolutionize many medical and industrial sectors, particularly in preclinical-to-clinical translation in the pharmaceutical arena. In vivo, the function of the organ(s) is orchestrated by a complex cellular structure and physiochemical factors within the extracellular matrix and secreted by various types of cells. The trend in in vitro modeling is to simplify the complex anatomy of the human organ(s) to the minimal essential cellular structure “micro-anatomy” instead of recapitulating the full cellular milieu that enables studying the absorption, metabolism, as well as the mechanistic investigation of drug compounds in a “systemic manner.” However, in order to reflect the human physiology in vitro and hence to be able to bridge the gap between the in vivo and in vitro data, simplification should not compromise the physiological relevance. Engineering principles have long been applied to solve medical challenges, and at this stage of organ-on-a-chip technology development, the work of biomedical engineers, focusing on device engineering, is more important than ever to accelerate the technology transfer from the academic lab bench to specialized product development institutions and to the increasingly demanding market. In this paper, instead of presenting a narrative review of the literature, we systemically present a synthesis of the best available organ-on-a-chip technology from what is found, what has been achieved, and what yet needs to be done. We emphasized mainly on the requirements of a “good in vitro model that meets the industrial need” in terms of the structure (micro-anatomy), functions (micro-physiology), and characteristics of the device that hosts the biological model. Finally, we discuss the biological model–device integration supported by an example and the major challenges that delay the OOC technology transfer to the industry and recommended possible options to realize a functional organ-on-a-chip system.

Advances in Engineering Human Tissue Models

“…One of the most promising technologies for bridging the gap between in vitro and in vivo systems is organs-on-chips (OOCs), alternatively called microphysiological in vitro models. OOCs technology has emerged from the combination of recent advances in microengineering and fluidic physics with trends in growing cells in 3D, allowing for the development of models that more faithfully recapitulate key features of specific human tissues and their interactions (Ramadan and Zourob, 2020 ). The design of the vast majority of OOC models are based on (micro-)fluidic devices, fabricated by soft-lithographic techniques, with continuously perfused chambers inhabited by living cells arranged in a biomimetic manner, while facilitating precise control over delivery of nutrients and spatiotemporal tuning of oxygen and pH gradients (Bein et al, 2018 ; Ronaldson-Bouchard and Vunjak-Novakovic, 2018 ).…”

“…Among the added benefits of using such systems are the continuous supply of nutrients and removal of waste, the unparalleled, independent control over multiple key factors of the cell system, the possibility for in situ , high precision and automated monitoring and sample analysis, as well as the ability to interface different cellular compartments for enhanced cell cross-talk and exchange of signaling molecules and growth factors. But, what creates an enormous potential for enhancing the physiological relevance of the in vitro cell systems, spurring new, unforeseeable applications of this technology, is the combination of a biomimetic niche with accurate, precise, and coupled delivery of more complex biochemical and biophysical cues (Bein et al, 2018 ; Ramadan and Zourob, 2020 ). Even though most of the attention OOCs have gained is focused on pharmacology and pre-clinical drug screening applications, as low-cost and animal-free alternative tool (Ramadan and Zourob, 2020 ), it is clear that the principle behind this technology lines perfectly with the TE paradigm and scope: convergence of cells with the advanced chip technology-biomaterials and delivery of physiologically relevant cues toward more robust tissue equivalents.…”

“…But, what creates an enormous potential for enhancing the physiological relevance of the in vitro cell systems, spurring new, unforeseeable applications of this technology, is the combination of a biomimetic niche with accurate, precise, and coupled delivery of more complex biochemical and biophysical cues (Bein et al, 2018 ; Ramadan and Zourob, 2020 ). Even though most of the attention OOCs have gained is focused on pharmacology and pre-clinical drug screening applications, as low-cost and animal-free alternative tool (Ramadan and Zourob, 2020 ), it is clear that the principle behind this technology lines perfectly with the TE paradigm and scope: convergence of cells with the advanced chip technology-biomaterials and delivery of physiologically relevant cues toward more robust tissue equivalents. As a result, various research groups around the world, both in the academic and industrial sectors, have developed a broad range of OOCs, mimicking the human gut (Ramadan and Jing, 2016 ; Kasendra et al, 2018 ; Shin et al, 2019 ), liver (Delalat et al, 2018 ; Jang et al, 2019 ), kidney (Jang et al, 2013 ; Chang et al, 2017 ; Yin et al, 2020 ), lung (Huh et al, 2012 ; Stucki et al, 2018 ; Felder et al, 2019 ), blood-brain barrier (Kilic et al, 2016 ; Wevers et al, 2018 ), bone (Marturano-Kruik et al, 2018 ), and vasculature (Schimek et al, 2013 ; Jeon et al, 2015 ) in both healthy and pathophysiological conditions, such as infection (Villenave et al, 2017 ; Ortega-Prieto et al, 2018 ) and cancer (Ayuso et al, 2016 ; Hassell et al, 2017 ; Hao et al, 2018 ; Carvalho et al, 2019 ), as well as for the interaction of multiple organs, as first showcased by Shuler et al and more recently by others, toward multi-organ and whole-body microsystems (Miller and Shuler, 2016 ; Vernetti et al, 2017 ; Edington et al, 2018 ; Herland et al, 2020 ), to study collective responses to drugs or disease inducing agents and inter-organ communication.…”

“…Also, 3D tissue equivalents and OOCs, as more sophisticated and multi-parametric models, require close control and synchronism of these different parameters to achieve the necessary functionality, particularly when long-term viability is the case (Sontheimer-Phelps et al, 2019 ). Moreover, in multi-organ systems, besides in-vivo- like sequential coupling of each counterpart, scaling must also be taken into account, to match flow volume and rate with cultured tissue mass in order to mimic the native conditions and to achieve the required level to support functionality (Wikswo et al, 2013 ; Bhatia and Ingber, 2014 ; Ronaldson-Bouchard and Vunjak-Novakovic, 2018 ; Ramadan and Zourob, 2020 ). Finally, for this technology to live up to its potential and to be successfully implemented in the drug development process, it is necessary to move from the proof-of-concept laboratory models toward more widely available prototypes to facilitate high-throughput screening and further validation that the models effectively mimic in vivo drug responses.…”

Advances in modelling the human microbiome–gut–brain axis in vitro

“…In parallel with advances in 3D cell biology and organotypic cultures, organs-on-chips (OOCs), alternatively called microphysiological systems (MPS), have also been used for modelling aspects of the microbiota-gut-brain axis. Combining principles of microengineering and fluidics with trends in growing cells in 3D, such models allow for cultivating human tissues in a more biomimetic microenvironment, where cells are exposed to tissue-relevant biochemical and biophysical cues (e.g., fluid shear stress, peristalsis) [ 70 , 71 ]. In addition, OOCs offer unparalleled, independent spatiotemporal tuning and control over multiple key factors of the cell system (e.g., O 2 , pH), in situ , automated monitoring and sample analysis along with downstream analysis, as well as the potential to study cell-cell and cell-niche interactions [ 71 ].…”