Advancing liver and lung in vitro models to realistically assess human health hazards of engineered nanomaterials

Abstract:

Due to the constant increase in their production, exposure to engineered nanomaterials (ENM) poses an inevitable health risk to both humans and the environment through long-term, repetitive, low-dose exposures. The majority of the literature however, focuses on short-term, high-dose exposures. Hazard assessment of ENM, when applying alternative testing strategies to in vivo research, has previously engaged 2D test systems. Such standard model systems have their limitations, and it is widely accepted that they do not adequately represent the biological matrix in vivo. Advanced, 3D models in this sense have received heightened attention and pose a potential valid alternative to invasive in vivo approaches.

Physiologically Anchored Tools for Realistic nanOmaterial hazard aSsessment (PATROLS) (EU Grant Agreement #:760813; https://www.patrols-h2020.eu) is an EU Horizon2020 funded research and innovation project involving 24 partners across 13 countries throughout Europe, as well as including Canada, Japan, Korea and the US. The aim of the project is to establish, characterise and implement a plethora of innovative, physiologically realistic 3D in vitro models that can be applied as dynamic tools in deducing the potential ENM hazard posed to humans and the environment.

Within PATROLS, amongst other models for the gastro-intestinal tract and the eco-system, specific focus has been given towards advancing 3D liver and lung co-cultures models using both primary cells (human small airway epithelial cells (SAECs) at air-liquid interface)  and cell lines (Hep G2 and HepaRG cells in spheroid formations (around 0.8mm in diameter) and A549 cells at an air-liquid interface). Specifically, systems are being developed to allow key long-term studies to be achieved in vitro. This characterisation will continue throughout ENM exposure to ensure responses seen are reflective of in vivo and epidemiology studies. Once the models have been developed and characterised there will be further consideration of  specific organ dynamics, including movement (i.e. breathing motion in the lung) and flow dynamics (i.e. blood-flow in both the lung and liver) via the use of 3D printing to allow for temperature, dynamic flow and cyclic movement to be monitored, changed and recorded. It is intended that following the successful development of such models, they can be used to establish advanced testing methods that will contribute towards the reduction of in vivo testing approaches across toxicology and drug discovery research.

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