Implementing organ-on-chip in a next-generation risk assessment of chemicals: a review

Abstract

Organ-on-chip (OoC) technology is full of engineering and biological challenges, but it has the potential to revolutionize the Next-Generation Risk Assessment of novel ingredients for consumer products and chemicals. A successful incorporation of OoC technology into the Next-Generation Risk Assessment toolbox depends on the robustness of the microfluidic devices and the organ tissue models used. Recent advances in standardized device manufacturing, organ tissue cultivation and growth protocols offer the ability to bridge the gaps towards the implementation of organ-on-chip technology. Next-Generation Risk Assessment is an exposure-led and hypothesis-driven tiered approach to risk assessment using detailed human exposure information and the application of appropriate new (non-animal) toxicological testing approaches. Organ-on-chip presents a promising in vitro approach by combining human cell culturing with dynamic microfluidics to improve physiological emulation. Here, we critically review commercial organ-on-chip devices, as well as recent tissue culture model studies of the skin, intestinal barrier and liver as the main metabolic organ to be used on-chip for Next-Generation Risk Assessment. Finally, microfluidically linked tissue combinations such as skin-liver and intestine-liver in organ-on-chip devices are reviewed as they form a relevant aspect for advancing toxicokinetic and toxicodynamic studies. We point to recent achievements and challenges to overcome, to advance non-animal, human-relevant safety studies.

Keywords: Gut-on-chip; Liver-on-chip; Microfluidics; Next-generation risk assessment; Organ-on-chip; Skin-on-chip.

Fig. 1

Examples of commercially available OoC devices for different research applications A OrganoPlate® 3-lane|Mimetas (2020) B Organs-on-Chips Technology|Emulate (2020) C PhysioMimix™|CN BIO Innovations (2020) D HUMIMIC Chip2|TissUse GmbH (2022) E Akura™ Flow: Transforming Drug Discovery and Development with Body-on-a-Chip Technology|InSphero (2020) F Organ-on-a-chip|Micronit (2020) G The QV900|Ideal for high-content experiments and industrial use|Kirkstall Ltd (2020) H Products-Bi/ond (2020) I The ParVivo™ Organ-on-Chip Technology|Nortis Bio (2020) J HuDMOP®|IONTOX (2022). All pictures taken from the websites of manufacturers (see references)

Fig. 2

Summary of selected 3D in vitro skin tissue models, depicted with increasing biological complexity and their research applicability and predictability for NGRA using an open access OoC device for air–liquid culturing

Fig. 3

Summary of 3D intestinal tissue models with increasing complexity and their research applicability and predictability for NGRA. The figure depicts two culture designs: A only one bottom membrane (top: applicable for cultures using open-accessible layout OoC or two channel closed layout OoC) and B three channel closed with perfusion from both sides. (bottom) *only in primary cell cultures

Fig. 4

Summary of 3D liver tissue models with increasing complexity and their application in NGRA. The figure depicts two tissue approaches, A only a bottom membrane (top; applicable for cultures using open-accessible devices) and B three channel closed-accessible designs with perfusion from both sides. (bottom) *only in HepaRG, primary cell cultures and iPSC **does not exist (yet) as spheroid