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The Nose as a Pathway to the Brain and Body: Experimental and Computational Models of the Nasal Cavity

par Rigaut, Clément
Président du jury Parente, Alessandro
Promoteur Lambert, Pierre
Co-Promoteur Haut, Benoît
Publication Non publié, 2024-12-17

Thèse de doctorat

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Résumé :

The first part of the present thesis is the nose-to-brain drug delivery. This administration method uses the crossing of the cranium by the olfactory nerve for the therapeutic molecules to diffuse from the nose to the central nervous system. These chapters aim to maximise the powder reaching the olfactory region, the first step of nose-to-brain administration. To map the deposition of the powder in the nasal cavity, we created nasal replicas from the CT scans of a set of patients and printed them using stereolithography.Then, those nasal casts served to quantify the proportion of injected powder that reaches the olfactory region. Subsequent deposition tests varied the instillation device, the administration angle, the inspiratory flow, and the nostril for each anatomy. These experiments highlighted the correlations between anatomical measures and deposition characteristics. First, the surface area of the olfactory region is proportional to the fraction of powder reaching this region when using the optimised delivery parameters for the corresponding anatomy. Second, the asymmetry in the nasal valves determines if the instillation side influences the deposition and, if so, to what extent. So, with only these two measures, anatomies can be classified to estimate of the expected deposition in the olfactory region (and the success likelihood of nose-to-brain drug delivery) and the predicted asymmetry in this deposition.A second aspect of the part is the permeation of the active pharmaceutical ingredient to the olfactory mucosa, which is the next step in the nose-to-brain pathway. For this, we developed an analytical model of the permeation of a pharmaceutical powder through the mucosa. This model includes the dissolution, diffusion, and enzymatic degradation of the active ingredient and the location of the powder deposition. So, we can predict quantity of powder absorbed by the olfactory cells along with the parameters that heavily influence the permeation. Consequently, this model could guide the choices in the formulation or delivery device.The second part of this thesis is the inspired air conditioning by the nose. The air heating air in the nose is essential to avoid damage to the lower respiratory tract. This study used computational fluid dynamics simulations that determined the temperature of the air entering the pharynx for various ambient temperatures and efforts. These simulations included a wide range of terrestrial mammals, leading to an allometric law, including humans of different sizes and ages. It arises that the air conditioning capacity of a mammal depends not only on its body mass but also on its maximal running speed; the mammals that run faster, compared to their mass, have an improved air conditioning capacity.