Evaluation of a bioprinted 3D airway tissue model for toxicity testing of nanomaterials; pathway to integration into a tiered testing strategy for hazard assessment to support safety-by-design

There is an urgent need to identify hazards posed by novel nanomaterials (NMs), however, new models are required to streamline testing approaches, increase our understanding of mechanism of toxicity and incorporate Safer-by-Design concepts into NM development. Here, we conducted an evaluation of a sophisticated 3D bioprinted airway model for a first-in-kind hazard assessment of NMs. Exploiting the consistency and reproducibility provided by bioprinting techniques, airway constructs were generated by precisely controlled sequential layering of endothelial cells, fibroblasts embedded in collagen, and bronchial epithelial cells and exposed to ZnO and BaSO₄ NMs case-study materials. Exposure to ZnO resulted in greater temporal and dynamic immunotoxic and histological responses in contrast to BaSO₄, demonstrating the successful differentiation of high and low reactivity NMs. Comparison with simple in vitro toxicity studies and existing in vivo and human data demonstrated the physiological relevance of increasing model complexity. The relative benefits of the 3D bioprinted airway model and potential for inclusion in tiered testing strategies was substantiated by comprehensive review of the current state-of-the-art alternative models. This study supports the wider adoption of a sophisticated in vitro airway model to reduce our reliance on in vivo testing and advance efforts to develop Integrated Approaches to Assessment and Testing to support Safer-by-Design NM innovation.