(1075-D) A breathing lung-on-chip for preclinical in vitro safety and toxicology with physiologically relevant outcomes

Abstract: Classically, thorough safety evaluation involving animal testing is required for the approval of new products in the consumer goods and pharma industries. Thanks to the development of advanced NAM methods, like in silico approaches and in vitro models, in particular organs-on-chip, nowadays regulatory agencies contemplate the possibility of human-relevant testing by passing animal experimentation.
Here, we present an approach for lung modeling including key physiological parameters such as substrate softness and mechanical actuation, the AXLung-on-chip system. The AlveoliX research team established a specific process to qualify technology and biomodels. We explored the relevance of our model through different case studies in the context of toxicology, drug safety and efficacy.
To assess the exposure to environmental hazards, an alveolar model was exposed to nebulized inhalants (Cloudα AX12). Integrating breathing dynamics increased model’s sensitivity to nebulized nanoparticles commonly used in the cosmetic and food industry (ZnO and TiO2), and toxicants such as PHMG. Exposure to these products incited pro-inflammatory responses accompanied by an increased cytotoxicity (>2.5-fold) and barrier breakdown (>3-fold decrease).
Further, we evaluated the safety of oncologic drugs and the efficacy of an antifibrotic compound by using patient-derived immunocompetent models. Our immunocompetent alveolar model reproduced specific signatures associated with increased inflammation and immune cell activation, relevant hallmarks for preclinical safety evaluation. Additionally, we proved the antifibrotic effect of the compound in vitro, which reverted collagen secretion in the efficacy model.
In summary, our results underline the relevance of the AXLung-on-chip system for molecule testing as shown in case studies. Furthermore, we describe the importance of an accurate qualification and validation process of a new organ-on-chip model for its successful application in the pre-clinical phase especially when it comes to first in human applications such as IND studies.