Chantal Darquenne

Aerosol Deposition in Health and Disease

The success of inhalation therapy is not only dependent upon the pharmacology of the drugs being inhaled but also upon the site and extent of deposition in the respiratory tract. This article reviews the main mechanisms affecting the transport and deposition of inhaled aerosol in the human lung. Aerosol deposition in both the healthy and diseased lung is described mainly based on the results of human studies using nonimaging techniques. This is followed by a discussion of the effect of flow regime on aerosol deposition. Finally, the link between therapeutic effects of inhaled drugs and their deposition pattern is briefly addressed. Data show that total lung deposition is a poor predictor of clinical outcome, and that regional deposition needs to be assessed to predict therapeutic effectiveness. Indeed, spatial distribution of deposited particles and, as a consequence, drug efficiency is strongly affected by particle size. Large particles (>6 μm) tend to mainly deposit in the upper airway, limiting the amount of drugs that can be delivered to the lung. Small particles (<2 μm) deposit mainly in the alveolar region and are probably the most apt to act systemically, whereas the particle in the size range 2-6 μm are be best suited to treat the central and small airways.

A realistic two-dimensional model of aerosol transport and deposition in the alveolar zone of the human lung

Abstract A realistic two-dimensional model of aerosol transport and deposition in the alveolar zone of the human lung was developed, using the FIDAP software package (Fluent, Inc). Gas flow corresponding to a mouth flow rate of 500 ml s −1 was computed in a symmetric 6-generation structure of alveolated ducts located in a vertical plane. A bolus of 2 μm -diameter particles was introduced in the model at the beginning of inspiration. Particle trajectories were predicted for one breath cycle ( 2 s inspiration, 2 s expiration). There were large non-uniformities in deposition between generations, between ducts of a given generation and within each alveolated duct, suggesting that local aerosol concentrations can be much larger than the mean acinar concentration. A significant number of particles failed to exit the structure during expiration. Most of these particles were located deep in the structure (distal to the 3rd generation), leaving them in a position to penetrate deeper in the lung during the subsequent inspiration and eventually deposit.

Aerosol deposition in the human lung periphery is increased by reduced-density gas breathing.

Aerosol mixing resulting from turbulent flows is thought to be a major mechanism of deposition in the upper respiratory tract (URT). Because turbulence levels are a function of gas density, the use of a low-density carrier gas should reduce deposition in the URT allowing the aerosol to reach more peripheral airways of the lung. We performed aerosol bolus tests on 11 healthy subjects to investigate the effect of reduced gas density on regional aerosol deposition in the human lung. Using both air and heliox (80% helium, 20% oxygen) as carrier gas, boluses of 1 and 2 microm-diameter particles were inhaled to five volumetric lung depths (V(p)) between 150 and 1200 mL during an inspiration from residual volume (RV) to 1 liter above functional residual capacity at a constant flow rate of approximately 0.50 L/sec, which was immediately followed by an expiration to RV at the same flow rate. Aerosol deposition and axial dispersion were calculated from aerosol concentration and flow rate measured at the mouth. For 1 microm-diameter particles, deposition was significantly reduced by 29 +/- 28% (mean +/- SD, p < 0.05) when breathing heliox instead of air at shallow V(p) (150 mL) and significantly increased by 11 +/- 9% at deep V(p) (1200 mL). For 2 microm-diameter particles, deposition was significantly higher at V(p) = 500 mL by 6 +/- 7% and the predicted V(p) to achieve 100% deposition was significantly lower with heliox (834 +/- 146 mL) compared to air (912 +/- 128 mL) (p < 0.05). Despite a decrease in deposition at shallow V(p), there was no change in axial dispersion, suggesting that other factors such as radial turbulent mixing result in decreased aerosol deposition. Our results suggested that heliox reduces upper airway deposition of 1 and 2 microm-diameter particles allowing more particles to penetrate and subsequently deposit in the peripheral 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.

Aerosol deposition characteristics in distal acinar airways under cyclic breathing conditions

Although the major mechanisms of aerosol deposition in the lung are known, detailed quantitative data in anatomically realistic models are still lacking, especially in the acinar airways. In this study, an algorithm was developed to build multigenerational three-dimensional models of alveolated airways with arbitrary bifurcation angles and spherical alveolar shape. Using computational fluid dynamics, the deposition of 1- and 3-μm aerosol particles was predicted in models of human alveolar sac and terminal acinar bifurcation under rhythmic wall motion for two breathing conditions (functional residual capacity = 3 liter, tidal volume = 0.5 and 0.9 liter, breathing period = 4 s). Particles entering the model during one inspiration period were tracked for multiple breathing cycles until all particles deposited or escaped from the model. Flow recirculation inside alveoli occurred only during transition between inspiration and expiration and accounted for no more than 1% of the whole cycle. Weak flow irreversibility and convective transport were observed in both models. The average deposition efficiency was similar for both breathing conditions and for both models. Under normal gravity, total deposition was ~33 and 75%, of which ~67 and 96% occurred during the first cycle, for 1- and 3-μm particles, respectively. Under zero gravity, total deposition was ~2-5% for both particle sizes. These results support previous findings that gravitational sedimentation is the dominant deposition mechanism for micrometer-sized aerosols in acinar airways. The results also showed that moving walls and multiple breathing cycles are needed for accurate estimation of aerosol deposition in acinar airways.

Heterogeneity of aerosol deposition in a two-dimensional model of human alveolated ducts

Abstract Transport of 0.5– 5 μm diameter particles was simulated within a symmetric two-dimensional (2D) six-generation structure representative of the human acinus. Aerosol boluses were introduced at the beginning of a breathing cycle (2-s inspiration, 2-s expiration). Airflow corresponded to a flow rate at the mouth of 500 ml/s . Deposition increased from 1% to 100% for 0.5– 5 μm diameter particles. Deposition agreed with the upper limit of alveolar deposition predicted by the one-dimensional (1D) ICRP66 model but only after accounting for multibreath. The 2D model showed that, for each particle size and structure orientation, there was a large heterogeneity in deposition among ducts. Differences of more than one order of magnitude were found between deposition in a single duct of a given generation and the average deposition in that generation. The presence of “hot spots” may have important implications in human health as several studies suggest a strong correlation between airborne pollutants and the onset of pulmonary or cardiovascular diseases.

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.

Effect of gravitational sedimentation on simulated aerosol dispersion in the human acinus

We studied the effect of gravitational sedimentation on the dispersion of 0.5 and 1 micrometer-diameter particle boluses within a two-dimensional symmetric six-generation model of the human acinus. Boluses were introduced at the beginning of a 2-s inspiration immediately followed by a 4-s expiration, in normal gravity (1 G) and in the absence of gravity (0 G). The flow corresponded to a flow rate at the mouth of 500 ml/s. In 0 G, simulated dispersion (Hsim) was 16 ml for both particle sizes. In 1 G, Hsim was 71 and 242 ml for 0.5 and 1 micrometer-diameter particles, respectively, showing the effect of gravitational sedimentation. The difference between experimental data (J. Appl. Physiol. 86 (1999) 1402) and simulations was independent of particle size. This suggests that the residual dispersion was independent of the intrinsic properties of the particles and was more likely due to other mechanisms such as ventilation inhomogeneities, cardiogenic oscillations and alveolar wall motion.

Validating the distribution of specific ventilation in healthy humans measured using proton MR imaging

Specific ventilation imaging (SVI) uses proton MRI to quantitatively map the distribution of specific ventilation (SV) in the human lung, using inhaled oxygen as a contrast agent. To validate this recent technique, we compared the quantitative measures of heterogeneity of the SV distribution in a 15-mm sagittal slice of lung obtained in 10 healthy supine subjects, (age 37 ± 10 yr, forced expiratory volume in 1 s 97 ± 7% predicted) using SVI to those obtained in the whole lung from multiple-breath nitrogen washout (MBW). Using the analysis of Lewis et al. (Lewis SM, Evans JW, Jalowayski AA. J App Physiol 44: 416-423, 1978), the most likely distribution of SV from the MBW data was computed and compared with the distribution of SV obtained from SVI, after normalizing for the difference in tidal volume. The average SV was 0.30 ± 0.10 MBW, compared with 0.36 ± 0.10 SVI (P = 0.01). The width of the distribution, a measure of the heterogeneity, obtained using both methods was comparable: 0.51 ± 0.06 and 0.47 ± 0.08 in MBW and SVI, respectively (P = 0.15). The MBW estimated width of the SV distribution was 0.05 (10.7%) higher than that estimated using SVI, and smaller than the intertest variability of the MBW estimation [inter-MBW (SD) for the width of the SV distribution was 0.08 (15.8)%]. To assess reliability, SVI was performed twice on 13 subjects showing small differences between measurements of SV heterogeneity (typical error 0.05, 12%). In conclusion, quantitative estimations of SV heterogeneity from SVI are reliable and similar to those obtained using MBW, with SVI providing spatial information that is absent in MBW.

Distribution of aerosolized particles in healthy and emphysematous rat lungs: Comparison between experimental and numerical studies

In silico models of airflow and particle deposition in the lungs are increasingly used to determine the therapeutic or toxic effects of inhaled aerosols. While computational methods have advanced significantly, relatively few studies have directly compared model predictions to experimental data. Furthermore, few prior studies have examined the influence of emphysema on particle deposition. In this work we performed airflow and particle simulations to compare numerical predictions to data from our previous aerosol exposure experiments. Employing an image-based 3D rat airway geometry, we first compared steady flow simulations to coupled 3D-0D unsteady simulations in the healthy rat lung. Then, in 3D-0D simulations, the influence of emphysema was investigated by matching disease location to the experimental study. In both the healthy unsteady and steady simulations, good agreement was found between numerical predictions of aerosol delivery and experimental deposition data. However, deposition patterns in the 3D geometry differed between the unsteady and steady cases. On the contrary, satisfactory agreement was not found between the numerical predictions and experimental data for the emphysematous lungs. This indicates that the deposition rate downstream of the 3D geometry is likely proportional to airflow delivery in the healthy lungs, but not in the emphysematous lungs. Including small airway collapse, variations in downstream airway size and tissue properties, and tracking particles throughout expiration may result in a more favorable agreement in future studies.