A novel approach for modelling the human nose-brain axis in vitro

Olfactory neurons allow circumventing the blood-brain barrier making this route particularly interesting for the non-invasive intranasal treatment of brain diseases (Alzheimer’s Disease). Moreover, commensal nasal microbes present in the respiratory region, the major surface of the nasal cavity, are assumed to induce health-promoting effects via metabolites as the gut or skin microbiome does. These complex nasal host-microbiome interactions are emphasized when considering that olfactory neurons sense bacterial metabolites like odorants and that a loss of smell is associated with an early stage of brain diseases. Demonstrating the importance of the human nose nose-brain axis its mechanisms are incompletely understood due to the use of currently available over-simplified 2D in vitro as well as animal in vivo models. Animal models provide highly valuable insights into cause-effect relationships, but translation to humans is challenging. Thus, within the Micro-SENSE project, we are proposing to build an advanced bioelectronic 3D model of the human nose-brain axis urgently needed for a better understanding of healthy nose physiology. This 3D bioelectronic platform will connect the recently developed (1) e-Transmembrane device hosting a respiratory nasal organoid and nasal microbes, (2) Microelectrode Arrays with affixed intact olfactory tissue and (3) patch-clamp set-ups for specific olfactory neuron studies. Integrated biocompatible PEDOT:PSS electrodes enable non-invasive monitoring and recording of nasal host-microbiome interactions by measuring epithelial barrier integrity and olfactory neuron firing in real time. PEDOT:PSS scaffolds compartmentalize the e-Transmembrane device for connecting with MEAs and patch-clamp set-ups enabling to study drug and metabolite uptake along the brain axis. Genetic and metabolic profiling of the gender-specific nose model will pave the way for optimized intranasal drug delivery targeting olfactory neurons and the nasal microbiome.