Computational analysis of a 3D mucociliary clearance model predicting nasal drug uptake

Accurate and realistic predictions of the fate of nasally inhaled drugs help to understand the complex fluid-particle dynamics in the nasal cavity. Key elements of such a comprehensive numerical analysis include: (i) inhaled drug-aerosol transport and deposition with air-particlemucus interactions; and (ii) mucociliary clearance (MCC) dynamics, including drug transport, dissolution and absorption for different nasal inlet conditions. The open-source computational fluid dynamics (CFD) toolbox, OpenFOAM, has been employed for the development of the computer simulation model. As part of the design, a novel 3D meshing technique allows for the smooth capture of both the relatively large flow domain as well as the micron-size mucus layer. This efficient meshing strategy drastically reduces the overall meshing time from hours to a matter of minutes. The effect of pharmacokinetic characteristics of drugs on dissolution, subsequent uptake and clearance were analyzed. A method to impose a boundarydriven flow velocity was introduced in order to mimic the beating of the cilia. Several drug specific parameters, such as solubility, partition coefficient and particle size, were considered. The effects of particle distribution on MCC and uptake were simulated as well. The CFD predictions show that drugs with a high partition coefficient are absorbed rapidly. Similarly, drugs with higher solubility show an appreciable increase in cumulative uptake in the epithelium. Particle size, however, plays a more nuanced role in drug uptake. Specifically, smaller particles with their relatively large surface areas, tend to dissolve quicker and are absorbed more rapidly when compared to larger particles. However, after the initial steeper increase in cumulative uptake of the smaller particles, the difference in the uptake values for the two cases is negligible. Furthermore, the initial deposition locations in the nasal cavity play an important role in overall drug uptake. Particles deposited closer to the ciliated portion of the nasal cavity (i.e. the posterior region) were more readily absorbed when compared to particles deposited closer to the unciliated nasal vestibule.