Stochastic asymmetric bronchial tree models for population-scale variability in dosimetry

Abstract

Pulmonary drug delivery has emerged as a preferred mode of drug administration due to its high effectiveness and reduced side effects compared to other methods. Drugs delivered in this manner can be classified into two classes. Some drugs target the lung tissue and are absorbed in the upper airways. Others aim to reach the deep lung, where they are absorbed into the bloodstream to produce systemic effects elsewhere in the body. The efficacy of drug delivery for both would depend on the regional deposition fraction. Various factors such as particle size, inhalation rate, etc. influence the deposition outcomes. More importantly, the trajectories of inhaled particles depend on the unique geometry of each person’s respiratory tract. Variation in lung anatomy is one of the main reasons why different people respond to inhaled medications differently. In addition, several diseases modify the geometry of the airways, leading to altered particle deposition patterns. Therefore, understanding and predicting regional deposition patterns of inhaled drugs becomes crucial for optimizing drug delivery strategies. To that end, we have developed a stochastic asymmetric multi-path model of the human airways. The tracheobronchial airways were generated based on Hess-Murray’s law and stochastic asymmetric branching. Symmetric and alveolated acinar sub-trees were attached to the terminal bronchioles. Through Monte-Carlo simulations, we report the extent, distribution and inter-subject variability in inhaled particle deposition as a function of several key parameters - branching asymmetry, particle size, breathing rate and bronchoconstriction. We show how particle size influences the deposition of particles, how asymmetry generally reduces deposition (barring certain exceptions) and how bronchoconstriction reduces deposition in the deep lung while increasing it in the upper airways. These insights will prove useful in determining drug dosages as well as design and choice of delivery devices such as inhalers and nebulizers.