Automated bidirectional coupling of multiscale models of aerosol dosimetry: validation with subject-specific deposition data.

Assessing the toxicity of airborne particulate matter or the efficacy of inhaled drug depends upon accurate estimates of deposited fraction of inhaled materials. In silico approaches can provide important insights into site- or airway-specific deposition of inhaled aerosols in the respiratory system. In this study, we improved on our recently developed 3D/1D model that simulate aerosol transport and deposition in the whole lung over multiple breath cycles (J. Aerosol Sci 151:105647). A subject-specific multiscale lung model of a healthy male subject using computational fluid-particle dynamics (CFPD) in a 3D model of the oral cavity through the large bronchial airways entering each lobe was bidirectionally coupled with a recently improved Multiple Path Particle Dosimetry (MPPD) model to predict aerosol deposition over the entire respiratory tract over multiple breaths for four conditions matching experimental aerosol exposures in the same subject from which the model was developed. These include two particle sizes (1 and 2.9 µm) and two subject-specific breathing rates of ~300 ml/s (slow breathing) and ~750 ml/s (fast breathing) at a target tidal volume of 1 L. In silico predictions of retained fraction were 0.31 and 0.29 for 1 µm and 0.66 and 0.62 for 2.9 µm during slow and fast breathing, respectively, and compared well with experimental data (1 µm: 0.31±0.01 (slow) and 0.27±0.01 (fast), 2.9 µm: 0.63±0.03 (slow) and 0.68±0.02 (fast)). These results provide a great deal of confidence in the validity and reliability of our approach.

Influence of alveolar mixing and multiple breaths of aerosol intake on particle deposition in the human lungs.

Predictive dosimetry models play an important role in assessing health effect of inhaled particulate matter and in optimizing delivery of inhaled pharmaceutical aerosols. In this study, the commonly used 1D Multiple-Path Particle Dosimetry model (MPPD) was improved by including a mechanistically based model component for alveolar mixing of particles and by extending the model capabilities to account for multiple breaths of aerosol intake. These modifications increased the retained fraction of particles and consequently particle deposition predictions in the deep lung during tidal breathing. Comparison with an existing dataset (J. Aerosol Sci., 99:27-39, 2016) obtained under two breathing conditions referred to as slow and fast breathing showed significant differences in 1 µm particle deposition between predictions based on subject-specific breathing patterns and lung volume (slow: 30 ± 1%, fast: 21 ± 1%, (average ± standard deviation), N = 7) and measurements (slow: 43 ± 9%, fast: 30 ± 5%) when the prior version of MPPD (single breath and no mixing, J. Aerosol Sci., 151:105647, 2021) was used. Adding a mixing model and multiple breaths moved the predictions (slow: 34 ± 2%, fast:25 ± 2%) closer to the range of deposition measurements. For 2.9 µm particles, predictions from both the original (slow: 70 ± 2%, fast: 57 ± 2%) and the revised MPPD model (slow: 71 ± 2%, fast: 59 ± 3%) compared well with experiments (slow: 67 ± 8%, fast: 58 ± 10%). This was expected as suspended fraction of 2.9 µm particles was small and thus the addition of alveolar mixing and multi breath capability only slightly increased the retained fraction for particles of this size and greater. The revised 1D model improves dose predictions in the deep lung and support human risk assessment from exposure to airborne particles.

Efficient bi-directional coupling of 3D Computational Fluid-Particle Dynamics and 1D Multiple Path Particle Dosimetry lung models for multiscale modeling of aerosol dosimetry.

The development of predictive aerosol dosimetry models has been a major focus of environmental toxicology and pharmaceutical health research for decades. One-dimensional (1D) models successfully predict overall deposition averages but fail to accurately predict local deposition. Computational fluid-particle dynamics (CFPD) models provide site-specific predictions but at a computational cost that prohibits whole lung predictions. Thus, there is a need for developing multiscale strategies to provide a realistic subject-specific picture of the fate of inhaled aerosol in the lungs. CT-based 3D/CFPD models of the large airways were bidirectionally coupled with individualized 1D Navier-Stokes airflow and particle transport based upon the widely used Multiple Path Particle Dosimetry Model (MPPD). Distribution of airflows among lobes was adjusted by measured lobar volume changes observed in CT images between FRC and FRC + 1.5 L. As a test of the effectiveness of the coupling procedures, deposition modeling of previous 1 µm aerosol exposure studies was performed. The complete coupled model was run for 3 breaths, with the computation-intense portion being the 3D CFPD Lagrangian particle tracking calculation. The average deposition per breath was 11% in the combined multiscale model with site-specific doses available in the CFPD portion of the model and airway- or region-specific deposition available for the MPPD portion. In conclusion, the key methods developed in this study enable predictions of ventilation heterogeneities and aerosol deposition across the lungs that are not captured by 3D or 1D models alone. These methods can be used as the foundation for multi-scale modeling of the full respiratory system.

Heterogeneity in lobar and near-acini deposition of inhaled aerosol in the mouse lung.

Laboratory animals are often used to derive health risk from environmental exposure or to assess the therapeutic effect of a drug delivered by inhaled therapy. Knowledge of the in-situ distribution of deposited particles on airway and alveolar surfaces is essential in any assessment of these effects. A unique database including both high-resolution lung anatomy and deposition data in four strains of laboratory mice have been recently made publicly available to the research community (https://doi.org/10.25820/9arg-9w56). Using these data, we investigated the effect of particle size on the distribution of deposited particles at the lobar and near-acini level. Analysis was performed on a total of 33 mice where 3, 16 and 14 animals were exposed to 0.5µm, 1µm and 2µm particles, respectively. Ratio of normalized deposition to normalized volume was calculated for each lobe (DV lobe ). At the near-acini level, the skew and standard deviation of the frequency distribution of particle deposition were calculated. Significant deviation above 1 was found for DV ratio in the cranial lobe (DV Cranial ). DV Middle , DV Caudal and DV Accessory were all significantly <1 and lower than DV left (p<0.01). At the near-acini level, skew and standard deviation were positively correlated with particle size and the presence of hot spots (high deposition) were mainly found in the apical region of the lung. These results highlight the uneven distribution of deposited particles in the mouse lung. Thus, depending on the lung sample location, individual analysis to determine overall deposition may either underestimate or overestimate total lung burden, at least for micron-sized particles.

Removal of sedimentation decreases relative deposition of coarse particles in the lung periphery.

Lung deposition of >0.5-µm particles is strongly influenced by gravitational sedimentation, with deposition being reduced in microgravity (µG) compared with normal gravity (1G). Gravity not only affects total deposition, but may also alter regional deposition. Using gamma scintigraphy, we measured the distribution of regional deposition and retention of radiolabeled particles ((99m)Tc-labeled sulfur colloid, 5-µm diameter) in five healthy volunteers. Particles were inhaled in a controlled fashion (0.5 l/s, 15 breaths/min) during multiple periods of µG aboard the National Aeronautics and Space Administration Microgravity Research Aircraft and in 1G. In both cases, deposition scans were obtained immediately postinhalation and at 1 h 30 min, 4 h, and 22 h postinhalation. Regional deposition was characterized by the central-to-peripheral ratio and by the skew of the distribution of deposited particles on scans acquired directly postinhalation. Relative distribution of deposition between the airways and the alveolar region was derived from data acquired at the various time points. Compared with inhalation in 1G, subjects show an increase in central-to-peripheral ratio (P = 0.043), skew (P = 0.043), and tracheobronchial deposition (P < 0.001) when particles were inhaled in µG. The absence of gravity caused fewer particles to deposit in the lung periphery than in the central region where deposition occurred mainly in the airways in µG. Furthermore, the increased skew observed in µG likely illustrates the presence of localized areas of deposition, i.e., "hot spots", resulting from inertial impaction. In conclusion, gravity has a significant effect on deposition patterns of coarse particles, with most of deposition occurring in the alveolar region in 1G but in the large airways in µG.

Convective flow dominates aerosol delivery to the lung segments.

Most previous computational studies on aerosol transport in models of the central airways of the human lung have focused on deposition, rather than transport of particles through these airways to the subtended lung regions. Using a model of the bronchial tree extending from the trachea to the segmental bronchi (J Appl Physiol 98: 970-980, 2005), we predicted aerosol delivery to the lung segments. Transport of 0.5- to 10-µm-diameter particles was computed at various gravity levels (0-1.6 G) during steady inspiration (100-500 ml/s). For each condition, the normalized aerosol distribution among the lung segments was compared with the normalized flow distribution by calculating the ratio (R(i)) of the number of particles exiting each segmental bronchus i to the flow. When R(i) = 1, particle transport was directly proportional to segmental flow. Flow and particle characteristics were represented by the Stokes number (Stk) in the trachea. For Stk < 0.01, R(i) values were close to 1 and were unaffected by gravity. For Stk > 0.01, R(i) varied greatly among the different outlets (R(i) = 0.30-1.93 in normal gravity for 10-µm particles at 500 ml/s) and was affected by gravity and inertia. These data suggest that, for Stk < 0.01, ventilation defines the delivery of aerosol to lung segments and that the use of aerosol tracers is a valid technique to visualize ventilation in different parts of the lung. At higher Stokes numbers, inertia, but not gravitational sedimentation, is the second major factor affecting the transport of large particles in the lung.

Alveolar duct expansion greatly enhances aerosol deposition: a three-dimensional computational fluid dynamics study.

Obtaining in vivo data of particle transport in the human lung is often difficult, if not impossible. Computational fluid dynamics (CFD) can provide detailed information on aerosol transport in realistic airway geometries. This paper provides a review of the key CFD studies of aerosol transport in the acinar region of the human lung. It also describes the first ever three-dimensional model of a single fully alveolated duct with moving boundaries allowing for the cyclic expansion and contraction that occurs during breathing. Studies of intra-acinar aerosol transport performed in models with stationary walls (SWs) showed that flow patterns were influenced by the geometric characteristics of the alveolar aperture, the presence of the alveolar septa contributed to the penetration of the particles into the lung periphery and there were large inhomogeneities in deposition patterns within the acinar structure. Recent studies have now used acinar models with moving walls. In these cases, particles penetrate the alveolar cavities not only as a result of sedimentation and diffusion but also as a result of convective transport, resulting in a much higher deposition prediction than that in SW models. Thus, models that fail to incorporate alveolar wall motions probably underestimate aerosol deposition in the acinar region of the lung.

Validation of CFD predictions of flow in a 3D alveolated bend with experimental data.

Verifying numerical predictions with experimental data is an important aspect of any modeling studies. In the case of the lung, the absence of direct in vivo flow measurements makes such verification almost impossible. We performed computational fluid dynamics (CFD) simulations in a 3D scaled-up model of an alveolated bend with rigid walls that incorporated essential geometrical characteristics of human alveolar structures and compared numerical predictions with experimental flow measurements made in the same model by particle image velocimetry (PIV). Flow in both models was representative of acinar flow during normal breathing (0.82ml/s). The experimental model was built in silicone and silicone oil was used as the carrier fluid. Flow measurements were obtained by an ensemble averaging procedure. CFD simulation was performed with STAR-CCM+ (CD-Adapco) using a polyhedral unstructured mesh. Velocity profiles in the central duct were parabolic and no bulk convection existed between the central duct and the alveoli. Velocities inside the alveoli were approximately 2 orders of magnitude smaller than the mean velocity in the central duct. CFD data agreed well with those obtained by PIV. In the central duct, data agreed within 1%. The maximum simulated velocity along the centerline of the model was 0.5% larger than measured experimentally. In the alveolar cavities, data agreed within 15% on average. This suggests that CFD techniques can satisfactorily predict acinar-type flow. Such a validation ensure a great degree of confidence in the accuracy of predictions made in more complex models of the alveolar region of the lung using similar CFD techniques.

Effect of gravity on aerosol dispersion and deposition in the human lung after periods of breath holding.

To determine the extent of the role that gravity plays in dispersion and deposition during breath holds, we performed aerosol bolus inhalations of 1-microm-diameter particles followed by breath holds of various lengths on four subjects on the ground (1G) and during short periods of microgravity (microG). Boluses of approximately 70 ml were inhaled to penetration volumes (V(p)) of 150 and 500 ml, at a constant flow rate of approximately 0.45 l/s. Aerosol concentration and flow rate were continuously measured at the mouth. Aerosol deposition and dispersion were calculated from these data. Deposition was independent of breath-hold time at both V(p) in microG, whereas, in 1G, deposition increased with increasing breath hold time. At V(p) = 150 ml, dispersion was similar at both gravity levels and increased with breath hold time. At V(p) = 500 ml, dispersion in 1G was always significantly higher than in microG. The data provide direct evidence that gravitational sedimentation is the main mechanism of deposition and dispersion during breath holds. The data also suggest that cardiogenic mixing and turbulent mixing contribute to deposition and dispersion at shallow V(p).

Dispersion of 0.5- to 2-micron aerosol in microG and hypergravity as a probe of convective inhomogeneity in the lung.

We used aerosol boluses to study convective gas mixing in the lung of four healthy subjects on the ground (1 G) and during short periods of microgravity (microG) and hypergravity ( approximately 1. 6 G). Boluses of 0.5-, 1-, and 2-micron-diameter particles were inhaled at different points in an inspiration from residual volume to 1 liter above functional residual capacity. The volume of air inhaled after the bolus [the penetration volume (Vp)] ranged from 150 to 1,500 ml. Aerosol concentration and flow rate were continuously measured at the mouth. The dispersion, deposition, and position of the bolus in the expired gas were calculated from these data. For each particle size, both bolus dispersion and deposition increased with Vp and were gravity dependent, with the largest dispersion and deposition occurring for the largest G level. Whereas intrinsic particle motions (diffusion, sedimentation, inertia) did not influence dispersion at shallow depths, we found that sedimentation significantly affected dispersion in the distal part of the lung (Vp >500 ml). For 0.5-micron-diameter particles for which sedimentation velocity is low, the differences between dispersion in microG and 1 G likely reflect the differences in gravitational convective inhomogeneity of ventilation between microG and 1 G.

A source of experimental underestimation of aerosol bolus deposition.

We examined the measurement error in inhaled and exhaled aerosol concentration resulting from the bolus delivery system when small volumes of monodisperse aerosols are inspired to different lung depths. A laser photometer that illuminated approximately 75% of the breathing path cross section recorded low inhaled bolus half-widths (42 ml) and negative deposition values for shallow bolus inhalation when the inhalation path of a 60-ml aerosol was straight and unobstructed. We attributed these results to incomplete mixing of the inhaled aerosol bolus over the breathing path cross section, on the basis of simultaneous recordings of the photometer with a particle-counter sampling from either the center or the edge of the breathing path. Inserting a 90 degrees bend into the inhaled bolus path increased the photometer measurement of inhaled bolus half-width to 57 ml and yielded positive deposition values. Dispersion, which is predominantly affected by exhaled bolus half-width, was not significantly altered by the 90 degrees bend. We conclude that aerosol bolus-delivery systems should ensure adequate mixing of the inhaled bolus to avoid error in measurement of bolus deposition.

Deposition and dispersion of 1-micrometer aerosol boluses in the human lung: effect of micro- and hypergravity.

We performed bolus inhalations of 1-micrometer particles in four subjects on the ground (1 G) and during parabolic flights both in microgravity (microG) and in approximately 1.6 G. Boluses of approximately 70 ml were inhaled at different points in an inspiration from residual volume to 1 liter above functional residual capacity. The volume of air inhaled after the bolus [the penetration volume (Vp)] ranged from 200 to 1,500 ml. Aerosol concentration and flow rate were continuously measured at the mouth. The deposition, dispersion, and position of the bolus in the expired gas were calculated from these data. For Vp >/=400 ml, both deposition and dispersion increased with Vp and were strongly gravity dependent, with the greatest deposition and dispersion occurring for the largest G level. At Vp = 800 ml, deposition and dispersion increased from 33.9% and 319 ml in microG to 56.9% and 573 ml at approximately 1.6 G, respectively (P < 0.05). At each G level, the bolus was expired at a smaller volume than Vp, and this volume became smaller with increasing Vp. Although dispersion was lower in microG than in 1 G and approximately 1.6 G, it still increased steadily with increasing Vp, showing that nongravitational ventilatory inhomogeneity is partly responsible for dispersion in the human lung.

Aerosol dispersion in human lung: comparison between numerical simulations and experiments for bolus tests.

Bolus inhalations of 0.87-micron-diameter particles were administered to 10 healthy subjects, and data were compared with numerical simulations based on a one-dimensional model of aerosol transport and deposition in the human lung (J. Appl. Physiol. 77: 2889-2898, 1994). Aerosol boluses were inhaled at a constant flow rate into various volumetric lung depths up to 1,500 ml. Parameters such as bolus half-width, mode shift, skewness, and deposition were used to characterize the bolus and to display convective mixing. The simulations described the experimental results reasonably well. The sensitivity of the simulations to different parameters was tested. Simulated half-width appeared to be insensitive to altered values of the deposition term, whereas it was greatly affected by modified values of the apparent diffusion in the alveolar zone of the lung. Finally, further simulations were compared in experiments with a fixed penetration volume and various flow rates. Comparison showed good agreement, which may be explained by the fact that half-width, mode shift, and skewness were little affected by the flow rate.

Effect of microgravity and hypergravity on deposition of 0.5- to 3-micron-diameter aerosol in the human lung.

We measured intrapulmonary deposition of 0. 5-, 1-, 2-, and 3-micron-diameter particles in four subjects on the ground (1 G) and during parabolic flights both in microgravity (microG) and at approximately 1.6 G. Subjects breathed aerosols at a constant flow rate (0.4 l/s) and tidal volume (0.75 liter). At 1 G and approximately 1.6 G, deposition increased with increasing particle size. In microG, differences in deposition as a function of particle size were almost abolished. Deposition was a nearly linear function of the G level for 2- and 3-micron-diameter particles, whereas for 0.5- and 1.0-micron-diameter particles, deposition increased less between microG and 1 G than between 1 G and approximately 1.6 G. Comparison with numerical predictions showed good agreement for 1-, 2-, and 3-micron-diameter particles at 1 and approximately 1.6 G, whereas the model consistently underestimated deposition in microG. The higher deposition observed in microG compared with model predictions might be explained by a larger deposition by diffusion because of a higher alveolar concentration of aerosol in microG and to the nonreversibility of the flow, causing additional mixing of the aerosols.

Two- and three-dimensional simulations of aerosol transport and deposition in alveolar zone of human lung.

We simulate two- and three-dimensional (2D and 3D) aerosol transport for different particle diameters within alveolated ducts. In agreement with previous studies (W. J. Federspiel and J. J. Fredberg. J. Appl. Physiol. 64: 2614-2621, 1988; A. Tsuda, J. P. Butler, and J. J. Fredberg. J. Appl. Physiol. 76: 2497-2509, 1994), the 2D-computed velocity field shows that the flow inside the alveoli is negligible compared with that in the central channel of the ducts and that a recirculation zone is set up in each alveolus. The calculated particle trajectories indicate that in the 2D and 3D simulations the particles do not deposit uniformly on the alveolar walls. For <0.5-microns-diameter particles, simulations show that particles are mainly located near the entrance of alveoli. This suggests that local and mean aerosol concentrations may be substantially different. For large particles we show that the gravity field significantly affects deposition. Aerosol dispersion is also computed, and the simulations are compared with the classical one-dimensional (1D) approach with use of the trumpet model, with additional terms for deposition. The 3D model simulates total deposition that is intermediate between 1D and 2D models. The differences between 2D and 3D data are attributed to the inclusion of azimuthal alveolar walls in the 3D duct and the change from 2D- to 3D-particle motions. Finally, our work suggests that the 1D model may introduce large errors in the location of deposited particles.

One-dimensional simulation of aerosol transport and deposition in the human lung.

One-dimensional transport models (trumpet model and multibranch-point model) derived from those developed to study gas transport and mixing in the lung are used to simulate aerosol deposition as a function of particle diameter and aerosol dispersion of inhaled bolus in human lungs. In agreement with previous studies, aerosol deposition is satisfactorily simulated by the different models. However, the differences between simulations and experiments of aerosol bolus dispersion suggest that current models are not realistic. This is probably due to the intrinsic limitations of the one-dimensional models to describe aerosol transport in the lung periphery. We show that future model analyses can probably use a symmetric acinar structure like the classic Weibel model of the lung but that multidimensional particle transport equations are required. Furthermore, a rigorous description of aerosol dispersion in the oral-laryngeal path is also needed.