Determinants of olfactory cleft targeting in intranasal aerosol delivery: a combined computational and experimental...

Efficient targeting of the olfactory cleft remains a key barrier to olfactory-targeted intranasal therapy and emerging nose-to-brain (N2B) delivery strategies. However, the upstream aerodynamic mechanisms governing aerosol access to the olfactory cleft during natural inhalation remain insufficiently characterized.

A standardized representative sinonasal model reconstructed from high-resolution CT data of 32 healthy adults was used to evaluate the effects of administration plane, aerosol particle size, and administration angle on olfactory cleft deposition. Airflow and particle transport were simulated using a lattice Boltzmann-discrete particle method (LBM-DPM) framework across 108 parameterized conditions under natural inhalation. A geometry-consistent 3D-printed nasal model combined with radiotracer-based SPECT/CT imaging was used to experimentally validate deposition trends across administration planes.

Under nebulized delivery during natural inhalation, administration plane and aerosol particle size were the primary determinants of olfactory deposition efficiency, whereas administration angle exerted minimal influence. Shallow insertion facilitated upstream aerosol transport toward the olfactory cleft, with particles of approximately 7 μm achieving the highest and stable deposition efficiency across conditions. A modest interaction between insertion depth and particle size was observed without altering the optimal delivery configuration. In vitro radiotracer experiments demonstrated consistent deposition trends across administration planes compared with numerical simulations, supporting the model predictions.

Under physiological inhalation, shallow nozzle positioning combined with intermediate-sized aerosol particles represents an optimal parameter configuration for olfactory-targeted intranasal aerosol delivery. These findings provide quantitative guidance for optimizing intranasal administration parameters and may support the development of nebulized delivery systems for olfactory-targeted therapies.