A Geometric Morphometrics Approach for Predicting Olfactory Region Accessibility: Toward Personalized Nose-to-Brain Drug Delivery

<b>Background:</b> The anatomical variability of the nasal cavity affects intranasal drug delivery, especially to the olfactory region for nose-to-brain treatments. While previous studies used average models or 2D measurements to account for inter-individual variability, 3D shape variation of the region crossed by drug particles that target the olfactory area, namely the region of interest (ROI), remains unexplored to our knowledge. <b>Methods:</b> A geometric morphometric analysis was performed on the ROI of 151 unilateral nasal cavities from the CT scans of 78 patients. Ten fixed landmarks and 200 sliding semi-landmarks were digitized, using Viewbox 4.0, and standardized via Generalized Procrustes Analysis. Shape variability was analyzed through Principal Component Analysis. Morphological clusters were identified using Hierarchical Clustering on Principal Components, and characterized with MANOVA, ANOVA, and Tukey tests. <b>Results:</b> Validation tests confirmed the method's reliability. Three morphological clusters were identified. Variations were significant in the X and Y axes, and minimal in Z. Cluster 1 had a broader anterior cavity with shallower turbinate onset, likely improving olfactory accessibility. Cluster 3 was narrower with deeper turbinates, potentially limiting olfactory accessibility. Cluster 2 was intermediate. Notably, 31.5% of patients had at least one cavity in cluster 1. <b>Conclusions:</b> Three distinct morphotypes of the region of the nasal cavity that potentially influence accessibility were identified. These findings will guide future computational fluid dynamics studies for optimizing nasal drug targeting and represent a practical step toward tailoring nose-to-brain drug delivery strategies in alignment with the principles of personalized medicine.