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Despite the prevalence of inhalation therapy in the treatment of various respiratory diseases, predicting and optimizing lung deposition fractions of inhaled drugs for maximal efficacy remains challenging due to the complex anatomical structures of the extra-thoracic airways, notably the glottal region. One of the widespread speculations in current insilico simulations lies in assuming a static glottis during inhalation, while in reality inhalation leads to significant glottis cross-sectional area expansion. The present work attempts to explore, insilico, the influence of transient movement of the glottal structures on inhalation therapy outcomes. To this end, we adopted a CT-based realistic human tracheobronchial tree (TB) model and explored transient airflows and deposition outcomes for a broad range of inhaled aerosols (i.e., d p =1-12 μm) under a dry powder inhaler (DPI) maneuver. Three different glottal expansion ratios, spanning static to 40 percent cross-sectional area expansion have been considered for the analysis. Our findings point to the tangible impact of glottal motion on airflow and particle deposition along the respiratory tract for a DPI maneuver, where a static glottis underpredicts the total particle deposition in the TB model for lower sized particles (d p ≤ 3 μm) compared to predictions for all dynamic glottal motions. In contrast, for larger size particles (i.e., 5 ≤d p ≤ 10 μm), a static glottis yields lower total deposition in the TB model compared with dynamic glottal motions. Our study also underlines that regional deposition of smaller micron-sized particles is most affected by glottal deformation in the conducting airways., (Copyright © 2022 The Authors. Published by Elsevier B.V. All rights reserved.)

Background: Mechanistic computer models for calculation of total and regional deposition of aerosols in the lungs are important tools for predicting or understanding clinical studies and for facilitating development of pharmaceutical inhalation products. Validation of such models must be indirect since generational in vivo data are lacking. Planar scintigraphy is probably the most common method addressing regional lung deposition in humans. Scintigraphic regions of interest (ROI) contain mixtures of airway generations and can therefore not be directly compared to model results. We propose a method to translate computed deposition per generation to deposition in scintigraphic ROI to be able to compare computed results with corresponding results obtained in humans. Methods: The total and regional lung deposition computed by the one-dimensional algebraic typical-path software Mimetikos Preludium was compared for 18 study legs in 14 published deposition studies involving 9 dry powder inhaler brands to the activity in planar scintigraphic ROIs (oropharyngeal, central [ C ], intermediate, and peripheral [ P ]) using for the computed regional lung distribution a generic mapping of the contribution of each airway generation to the ROIs. Results: The computed oropharyngeal and total lung deposition correlated with high significance ( p  < 0.0001) to the scintigraphic results with a near one-to-one relationship. For the regional lung distribution, computed C , P , and P / C results correlated with high significance ( p  < 0.01) to the corresponding scintigraphic measures. The computed C ( P ) deposition was on average about 28% lower (8% higher) than the mean scintigraphic results. The computed P / C ratio was on average 29% higher than the mean scintigraphic ratio. Conclusions: The results indicate that both the computational deposition model and the mapping algorithm are valid. The small underprediction of the C region merits further investigations. We believe that this method may prove useful also for the validation of computational fluid particle dynamic lung deposition models.

The morphometry of the large conducting airways is presumed to have a strong effect on the regional deposition of inhaled aerosol particles. Nevertheless, sex-based differences have not been fully quantified and are still largely ignored in designing inhalation therapies. To this end, we retrospectively analyzed high-resolution computed tomography scans for 185 individuals (90 women, 95 men) in the age range of 12-89 yr to determine airway luminal areas, airway lengths, and bifurcation angles. Only subjects free of chronic airway disease were considered. In men, luminal areas of the upper conducting airways were, on average, ∼30%-50% larger when compared with those in women, with the largest differences found in the trachea (289.72 ± 54.25 vs. 193.50 ± 42.37 mm 2 for men and women, respectively). The ratio of the largest luminal area in men to the smallest luminal area in women (in any given segment) ranged between 4.5 and 8.6, the largest differences being found in the lobar bronchi. Sex-based differences were minor in the case of bifurcation angles (e.g., average main bifurcation angle: 93.04 ± 9.58° vs. 91.03 ± 9.81° for men and women, respectively), but large intersubject variability was found irrespective of sex (e.g., range of main bifurcation angle: 65.04°-122.01° vs. 69.46°-113.94° for men and women, respectively). Bronchial segments were shorter by ∼5%-20% in women relative to men, the largest differences being located in the upper lobes. False discovery rate analysis revealed statistically significant associations among morphometric measures of the right lung in women (but not in men), suggesting two phenotypes among women that we attribute to the smaller female thoracic volume. NEW & NOTEWORTHY We found significant sex-based morphometric differences in the central airways of healthy men and women that were only mildly attenuated in subsets matched for lung volume. Lumen areas were significantly larger in men (∼30%-50%). Large variability (∼75%-87%) in airway bifurcation angles (60°-122°) was found irrespective of sex. The branching pattern of the right main and right upper bronchi in women (but not in men) follows two phenotypes modulated by lung volume.

Background: Despite the widespread use of aerosol inhalation as a drug delivery method, targeted delivery to the upper airways remains an ongoing challenge in the quest for improved clinical response in respiratory disease., Methods: Here, we examine in silico flow and particle dynamics when using an oral Inhaled Volume Tracking manoeuvre. A short pulsed aerosol bolus is injected during slow inhalation flow rates followed by clean air, and a breath-hold is initiated once it reaches the desired depth. We explore the fate of a broad particle size range (1-40 μm) for both upright and supine positions., Findings: Our findings illustrate that despite attempts to mitigate dispersion using slower flow rates, the laryngeal jet disperses the aerosol bolus and thus remains a hurdle for efficient targeted delivery. Nevertheless, we show a decrease in extra-thoracic deposition; large aerosols in the range of 10-30 μm potentially outperform existing inhalation methods, showing deposition fractions of up to 80% in an upright orientation., Interpretation: The improved deposition during Inhaled Volume Tracking shows promise for clinical applications and could be leveraged to deliver larger payloads to the upper airways., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Non-spherical particles, and fibers in particular, are potentially attractive airborne carriers for pulmonary drug delivery. Not only do they exhibit a high surface-to-volume ratio relative to spherical aerosols, but their aerodynamic properties also enable them to reach deep into the lungs. Until present, however, our understanding of the deposition characteristics of inhaled aerosols in the distal acinar lung regions has been mostly limited to spheres. To shed light on the fate of elongated aerosols in the pulmonary depths, we explore through in silico numerical simulations the deposition and dispersion characteristics of ellipsoid-shaped fibers in a physiologically-realistic acinar geometry under oscillatory breathing flow conditions mimicking various inhalation maneuvers. The transient translation and rotational movement of micron-sized elongated particles under drag, lift, and gravitational forces are simulated as a function of size (d p ) and aspect ratio (AR). Our findings underscore how acinar deposition characteristics are intimately linked to the geometrical combination of d p and AR under oscillatory flow conditions. Surprisingly, the elongation of the traditionally recommended size range of spherical particles (i.e., 2-3 μm) for acinar deposition may lead to a decrease in deposition efficiency and dispersion. Instead, our findings advocate how elongating particles (i.e., high AR) in the larger size range of 4-6 μm might be leveraged for improved targeted deposition to the acinar regions. Together, these results point to new windows of opportunities in selecting the shape and size of micron-sized fibers for targeted pulmonary deposition. Such in silico efforts represent an essential stepping stone in further exploring aerosol drug carrier designs for inhalation therapy to the deep lungs., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Inhalation therapy is a hallmark of modern respiratory medicine. Over recent years, computational fluid-particle dynamics (CFPD) simulations of respiratory airflows and aerosol deposition in the lungs have rapidly developed into an increasingly mature research field in the biomedical engineering realm, owing, among others, to tremendous advances in computational capabilities and available resources. Despite such progress, the intrinsic anatomical and physiological complexity of the lungs prevents the straightforward implementation of 'brute force' simulation strategies applied across the entire pulmonary tract. Here, we discuss how knowledge gathered from recent in silico studies can be purposefully leveraged to design efficient hybrid multiscale lung models and explore quantitatively via computational fluid-particle dynamics inhalation therapy outcomes. In contrast to the efforts geared toward patient-specific applications, we argue instead that such in silico strategies hold tremendous promise for broad inter-subject variability studies that can help foster the development of clinically efficient inhalation therapies across large human patient populations., Competing Interests: Conflict of interest Statement Nothing declared.

Particle Image Velocimetry (PIV) measurements with the aim of providing experimental data for the SimInhale benchmark case are presented within this work. We, therefore, present a refractive index matched, transparent model of the benchmark geometry, in which the velocity and turbulent kinetic energy fields are examined at flow rates comparable to 15, 30 and 60 L/min (Re ≈ 1000-4500) in air. Furthermore, these results are compared with Large Eddy Simulations (LES). The results reveal a Reynolds number independence of the qualitative velocity field in the range covered within this work. Good agreement is found between the PIV and LES data, with a slight over-prediction of turbulent kinetic energies by the simulations. The obtained experimental data will be part of a common, publicly accessible ERCOFTAC database along with additional results published recently., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Despite the prevalence of inhalation therapy in the treatment of pediatric respiratory disorders, most prominently asthma, the fraction of inhaled drugs reaching the lungs for maximal efficacy remains adversely low. By and large drug delivery devices and their inhalation guidelines are typically derived from adult studies with child dosages adapted according to body weight. While it has long been recognized that physiological (e.g. airway sizes, breathing maneuvers) and physical transport (e.g. aerosol dynamics) characteristics are critical in governing deposition outcomes, such knowledge has yet to be extensively adapted to younger populations. Motivated by such shortcomings, the present work leverages in a first step in silico computational fluid dynamics (CFD) to explore opportunities for augmenting aerosol deposition in children based on respiratory physiological and physical transport determinants. Using an idealized, anatomically-faithful upper airway geometry, airflow and aerosol motion are simulated as a function of age, spanning a five year old to an adult. Breathing conditions mimic realistic age-specific inhalation maneuvers representative of Dry Powder Inhalers (DPI) and nebulizer inhalation. Our findings point to the existence of a single dimensionless curve governing deposition in the conductive airways via the dimensionless Stokes number (Stk). Most significantly, we uncover the existence of a distinct deposition peak irrespective of age. For the DPI simulations, this peak (∼ 80%) occurs at Stk ≈ 0.06 whereas for nebulizer simulations, the corresponding peak (∼ 45%) occurs in the range of Stk between 0.03-0.04. Such dimensionless findings hence translate to an optimal window of micron-sized aerosols that evolves with age and varies with inhalation device. The existence of such deposition optima advocates revisiting design guidelines for optimizing deposition outcomes in pediatric inhalation therapy., Competing Interests: The authors have declared that no competing interests exist.

Regional deposition effects are important in the pulmonary delivery of drugs intended for the topical treatment of respiratory ailments. They also play a critical role in the systemic delivery of drugs with limited lung bioavailability. In recent years, significant improvements in the quality of pulmonary imaging have taken place, however the resolution of current imaging modalities remains inadequate for quantifying regional deposition. Computational Fluid-Particle Dynamics (CFPD) can fill this gap by providing detailed information about regional deposition in the extrathoracic and conducting airways. It is therefore not surprising that the last 15years have seen an exponential growth in the application of CFPD methods in this area. Survey of the recent literature however, reveals a wide variability in the range of modelling approaches used and in the assumptions made about important physical processes taking place during aerosol inhalation. The purpose of this work is to provide a concise critical review of the computational approaches used to date, and to present a benchmark case for validation of future studies in the upper airways. In the spirit of providing the wider community with a reference for quality assurance of CFPD studies, in vitro deposition measurements have been conducted in a human-based model of the upper airways, and several groups within MP1404 SimInhale have computed the same case using a variety of simulation and discretization approaches. Here, we report the results of this collaborative effort and provide a critical discussion of the performance of the various simulation methods. The benchmark case, in vitro deposition data and in silico results will be published online and made available to the wider community. Particle image velocimetry measurements of the flow, as well as additional numerical results from the community, will be appended to the online database as they become available in the future., (Copyright © 2017 Elsevier B.V. All rights reserved.)

High-fidelity simulations of the complete airway tree are still largely beyond current computational capabilities. Towards large-scale simulations of the human lung, the current study introduces a numerical methodology to predict particle deposition in a simplified approximation of the deep lung during a full breathing cycle. The geometrical model employed consists of an idealised bronchial tree that represents generations 10 to 19 of the conducting zone and a heterogeneous acinar model created using a space-filling algorithm. The computational cost of the coupled simulation is reduced by taking advantage of the flow similarity across the central conducting regions in order to decompose the bronchial tree into representative subunits. Topological information is used to account for the correct gravitational force on the particles in the representative bifurcations, emulating their transport characteristics in the actual bronchial tree. Eventually, airflow and particle transport are simulated in a single representative bifurcation and a single acinar model, resulting in great savings in computational cost. An Eulerian-Lagrangian approach has been used for solving the flow and particle equations during sinusoidal breathing in the decomposed domain. The resulting deposition estimates agree rather well with the known deposition trends reported in the literature, while offering additional insights. For 1-5μm particles, deposition during exhalation is comparable to deposition upon inhalation, suggesting the use of breath-hold maneuvers to further increase sedimentation of these particles. Airway orientation relative to gravity was found to have a significant impact on deposition rates, especially for particles above 2μm and to be higher in the more distal generations, due to the wider range of angles relative to the direction of gravity. In the acinus, particles in the 2-5μm range have a quite high average deposition efficiency that reaches approximately 75% and shows considerable variation (12.4%) due to airway orientation. Finally, a simplified semi-analytical approach is introduced that can lead to even further reduction in computational costs, while incurring only a small loss in accuracy., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Understanding the multitude of factors that control pulmonary deposition is important in assessing the therapeutic or toxic effects of inhaled particles. The use of increasingly sophisticated in silico models has improved our overall understanding, but model realism remains elusive. In this work, we use Large Eddy Simulations (LES) to investigate the deposition of inhaled aerosol particles with diameters of dp=0.1,0.5,1,2.5,5 and 10μm (particle density of 1200kg/m(3)). We use a reconstructed geometry of the human airways obtained via computed tomography and assess the effects of inlet flow conditions, particle size, electrostatic charge, and flowrate. While most computer simulations assume a uniform velocity at the mouth inlet, we found that using a more realistic inlet profile based on Laser Doppler Anemometry measurements resulted in enhanced deposition, mostly on the tongue. Nevertheless, flow field differences due to the inlet conditions are largely smoothed out just a short distance downstream of the mouth inlet as a result of the complex geometry. Increasing the inhalation flowrate from sedentary to activity conditions left the mean flowfield structures largely unaffected. Nevertheless, at the higher flowrates turbulent intensities persisted further downstream in the main bronchi. For dp>2.5μm, the overall Deposition Fractions (DF) increased with flowrate due to greater inertial impaction in the oropharynx. Below dp=1.0μm, the DF was largely independent of particle size; it also increased with flowrate, but remained significantly lower. Electrostatic charge increased the overall DF of smaller particles by as much as sevenfold, with most of the increase located in the mouth-throat. Moreover, significant enhancement in deposition was found in the left and right lung sub-regions of our reconstructed geometry. Although there was a relatively small impact of inhalation flowrate on the deposition of charged particles for sizes dp<2.5μm, impaction prevailed over electrostatic deposition for larger particles as the flowrate was increased. Overall, we report a significant interplay between particle size, electrostatic charge, and flowrate. Our results suggest that in silico models should be customized for specific applications, ensuring all relevant physical effects are accounted for in a self-consistent fashion., (Copyright © 2015 The Authors. Published by Elsevier Ltd.. All rights reserved.)