No full-text available
To read the full-text of this research,
you can request a copy directly from the authors.
Aerosol bolus dispersion in acinar airways - Influence of gravity and airway asymmetry
Abstract
The aerosol bolus technique can be used to estimate the degree of convective mixing in the lung; however, contributions of different lung compartments to measured dispersion cannot be differentiated unambiguously. To estimate dispersion in the distal lung, we studied the effect of gravity and airway asymmetry on the dispersion of 1 μm-diameter particle boluses in three-dimensional computational models of the lung periphery, ranging from a single alveolar sac to four-generation (g4) structures of bifurcating airways that deformed homogeneously during breathing. Boluses were introduced at the beginning of a 2-s inhalation, immediately followed by a 3-s exhalation. Dispersion was estimated by the half-width of the exhaled bolus. Dispersion was significantly affected by the spatial orientation of the models in normal gravity and was less in zero gravity than in normal gravity. Dispersion was strongly correlated with model volume in both normal and zero gravity. Predicted pulmonary dispersion based on a symmetric g4 acinar model was 391 ml and 238 ml under normal and zero gravity, respectively. These results accounted for a significant amount of dispersion measured experimentally. In zero gravity, predicted dispersion in a highly asymmetric model accounted for ∼20% of that obtained in a symmetric model with comparable volume and number of alveolated branches, whereas normal gravity dispersions were comparable in both models. These results suggest that gravitational sedimentation and not geometrical asymmetry is the dominant factor in aerosol dispersion in the lung periphery.
... An understanding of general transport within the alveolar region has been gained from the analysis of individual alveolus models consisting of a single hemispherical shell or single alveolus attached to a tube (Balashazy et al., 2008;Haber et al., 2000;Haber et al., 2003;Lee & Lee, 2003;Sznitman et al., 2007a;Sznitman et al., 2009). From these individual alveolus approaches, geometric complexity has increased to include channels with multiple attached hemispheres (Tsuda et al., 1992), 3D tubular models (Darquenne & Paiva, 1996;Karl et al., 2004), bifurcating models with rectangular alveoli compartments (Harrington et al., 2006;Ma et al., 2009), tubular bifurcating models with attached hemispheres (Ma & Darquenne, 2012), tubes or bifurcating networks using a honeycomb or polyhedral structure of attached alveoli (Fung, 1988;Kumar et al., 2009;Sznitman et al., 2009), and cast or image-based geometries (Berg et al., 2010;Sznitman et al., 2010). Typical findings from these studies are summarized as follows: ...
... • Bifurcations and complexity of the airway geometry strongly influence aerosol deposition (Berg & Robinson, 2011;Fung, 1988;Harrington et al., 2006;Karl et al., 2004;Ma & Darquenne, 2012). ...
... A number of simplified airway models have demonstrated that factors such as inclusion of alveoli (Haber et al., 2000;Tsuda et al., 1994;Tsuda et al., 2002), wall motion (Balashazy et al., 2008;Sznitman et al., 2009), and alveolar bifurcations (Balashazy & Hofmann, 1995;Hegedus et al., 2004;Ma & Darquenne, 2012) are important for capturing accurate transport patterns and deposition fractions in the alveolar region. Therefore, it is not surprising that the 1-D analytical predictions did not match the CFD predictions in the D3 geometry. ...
Previous studies have demonstrated that factors such as airway wall motion, inhalation waveform, and geometric complexity influence the deposition of aerosols in the alveolar airways. However, deposition fraction correlations are not available that account for these factors in determining alveolar deposition. The objective of this study was to generate a new space-filling model of the pulmonary acinus region and implement this model to develop correlations of aerosol deposition that can be used to predict the alveolar dose of inhaled pharmaceutical products. A series of acinar models was constructed containing different numbers of alveolar duct generations based on space-filling 14-hedron elements. Selected ventilation waveforms were quick-and-deep and slow-and-deep inhalation consistent with the use of most pharmaceutical aerosol inhalers. Computational fluid dynamics simulations were used to predict aerosol transport and deposition in the series of acinar models across various orientations with gravity where ventilation was driven by wall motion. Primary findings indicated that increasing the number of alveolar duct generations beyond 3 had a negligible impact on total acinar deposition, and total acinar deposition was not affected by gravity orientation angle. A characteristic model containing three alveolar duct generations (D3) was then used to develop correlations of aerosol deposition in the alveolar airways as a function of particle size and particle residence time in the geometry. An alveolar deposition parameter was determined in which deposition correlated with d(2)t over the first half of inhalation followed by correlation with dt(2), where d is the aerodynamic diameter of the particles and t is the potential particle residence time in the alveolar model. Optimal breath-hold times to allow 95% deposition of inhaled 1, 2, and 3 μm particles once inside the alveolar region were approximately >10, 2.7, and 1.2 s, respectively. Coupling of the deposition correlations with previous stochastic individual path (SIP) model predictions of tracheobronchial deposition was demonstrated to predict alveolar dose of commercial pharmaceutical products. In conclusion, this study completes an initiative to determine the fate of inhaled pharmaceutical aerosols throughout the respiratory airways using CFD simulations.
... However, the size of the acinar ducts and alveoli in fact varies with increasing generations (Haefeli-Bleuer & Weibel, 1988). These models were used to study the effects of various factors (e.g., model geometry (Harrington et al., 2006;Khajeh-Hosseini-Dalasm & Longest, 2015;Ma & Darquenne, 2012), breathing patterns , lung diseases (Oakes et al., 2010(Oakes et al., , 2015Xi et al., 2021)) on the flow field and aerosol deposition in the human acinar region. To date, aerosol deposition in heterogeneous multigenerational acinar models has rarely been reported in which the size of ducts and alveoli varies with generation. ...
... Researches show that the expansion and contraction of acinar follow approximately a sinusoidal curve (Oakes et al., 2010). Therefore the wall motion in existing studies was primarily assumed as a sinusoidal pattern with several linear patterns (Kolanjiyil & Kleinstreuer, 2019;Ma & Darquenne, 2012). It is widely acknowledged that alveolar models with rigid walls cannot capture the motion of human acinus (Harrington et al., 2006), and there is no convective exchange between alveolar and ductal flow (Sznitman, 2013;Sznitman et al., 2007), which guarantees a pathway for particles with little intrinsic motion into alveolar space. ...
It is critical to accurately estimate the deposition of inhaled particles in the pulmonary acinus to reduce the damage of ambient aerosols or maximize drug particles' efficacy. However, interparticle interactions were always neglected in the simulation of aerosol deposition in human acinus. A four-generation human acinar model with varying sizes of each generation was developed. Two boundary conditions, rigid wall and moving wall were investigated to simulate the effect of wall motion on the flow field and aerosol deposition for the size range of 0.1–5 μm. Results show that wall motion has a net effect on particles' location and deposition, especially for submicron particles. Moreover, interparticle collisions were employed to gain richer aerosol particle dynamics. Results demonstrate that the minimum concentration of particles for coalescence is 8.5 × 10⁴ particles/cm³ in the acinar region. The coalescence of particles is influenced by particle concentration and diameter, and wall motion and has a non-negligible effect on particle deposition. Furthermore, it should be noted that the influence of collision would be more significant during more respiratory cycles. Our findings demonstrate that wall motion and interparticle collisions play a non-negligible role in the aerosol deposition.
... Methodology-wise, this study can be further improved by considering a time series of exhaled aerosol images rather than the cumulative static images used in this study. A dynamic variation of bolus distribution/concentration vs. expiration time will presumably provide more information about airway structures and thus be more accurate in diagnosing/staging airway structural abnormalities [50][51][52][53]. ...
Aerosols exhaled from the lungs have distinctive patterns that can be linked to the abnormalities of the lungs. Yet, due to their intricate nature, it is highly challenging to analyze and distinguish these aerosol patterns. Small airway diseases pose an even greater challenge, as the disturbance signals tend to be weak. The objective of this study was to evaluate the performance of four convolutional neural network (CNN) models (AlexNet, ResNet-50, MobileNet, and EfficientNet) in detecting and staging airway abnormalities in small airways using exhaled aerosol images. Specifically, the model’s capacity to classify images inside and outside the original design space was assessed. In doing so, multi-level testing on images with decreasing similarities was conducted for each model. A total of 2745 images were generated using physiology-based simulations from normal and obstructed lungs of varying stages. Multiple-round training on datasets with increasing images (and new features) was also conducted to evaluate the benefits of continuous learning. Results show reasonably high classification accuracy on inbox images for models but significantly lower accuracy on outbox images (i.e., outside design space). ResNet-50 was the most robust among the four models for both diagnostic (2-class: normal vs. disease) and staging (3-class) purposes, as well as on both inbox and outbox test datasets. Variation in flow rate was observed to play a more important role in classification decisions than particle size and throat variation. Continuous learning/training with appropriate images could substantially enhance classification accuracy, even with a small number (~100) of new images. This study shows that CNN transfer-learning models could detect small airway remodeling (<1 mm) amidst a variety of variants and that ResNet-50 can be a promising model for the future development of obstructive lung diagnostic systems.
... They demonstrated that inherent wall motion is essential to understand natural acinar flow phenomena. Ma and Darquenne (2012) studied the effect of gravity and airway asymmetry on the dispersion of 1 μm particles in a single alveolar sac and four-generation (g4) bifurcating airways that deformed homogeneously during breathing. Their results concluded that aerosol dispersion was strongly correlated with model volume. ...
Elucidating the aerosol dynamics in the pulmonary acinar region is imperative for both health risk assessment and inhalation therapy, especially nowadays with the occurrence of the global COVID-19 pandemic. During respiration, the chest's outward elastic recoil and the lungs' inward elastic recoil lead to a change of transmural pressure, which drives the lungs to expand and contract to inhale and expel airflow and aerosol. In contrast to research using predefined wall motion, we developed a four-generation acinar model and applied an oscillatory pressure on the model outface to generate structure deformation and airflow. With such tools at hand, we performed a computational simulation that addressed both the airflow characteristic, structural mechanics, and aerosol dynamics in the human pulmonary acinar region. Our results showed that there is no recirculating flow in the sac. The structural displacement and stress were found to be positively related to the change of model volume and peaked at the end of inspiration. It was noteworthy that the stress distribution on the acinar wall was significantly heterogeneous, and obvious concentrations of stress were found at the junction of the alveoli and the ducts or the junction of the alveoli and alveoli in the sac. Our result demonstrated the effect of breathing cycles and aerosol diameter on deposition fraction and location of aerosols in the size range of 0.1-5 μm. Multiple respiratory cycles were found necessary for adequate deposition or escape of submicron particles while having a negligible influence on the transport of large particles, which were dominated by gravity. Our study can provide new insights into the further investigation of airflow, structural mechanics, and aerosol dynamics in the acinar depth.
... The particle density is mostly considered to be 1 g/cm 3 , which is about 1000 times the density of air. 19,[37][38][39][40] Based on these assumptions, the electrostatic force and buoyant force of particles in the airflow are usually ignored. 23 As a result, the motion of particles in airflow is mainly affected by gravity (F G ), viscous drag force (F D ), and random force [F(t)]. ...
Understanding the dynamics of airflow in alveoli and its effect on the behavior of particle transport and deposition is important for understanding lung functions and the cause of many lung diseases. The studies on these areas have drawn substantial attention over the last few decades. This Review discusses the recent progress in the investigation of behavior of airflow in alveoli. The information obtained from studies on the structure of the lung airway tree and alveolar topology is provided first. The current research progress on the modeling of alveoli is then reviewed. The alveolar cell parameters at different generation of branches, issues to model real alveolar flow, and the current numerical and experimental approaches are discussed. The findings on flow behavior, in particular, flow patterns and the mechanism of chaotic flow generation in the alveoli are reviewed next. The different flow patterns under different geometrical and flow conditions are discussed. Finally, developments on microfluidic devices such as lung-on-a-chip devices are reviewed. The issues of current devices are discussed.
... Dispersion or convective mixing of particles and gases in the respiratory tract is attributed to several mechanisms: Taylor dispersion due to the shear flow spreading out the concentration distribution in the airways in the direction of the flow, asynchronous and inhomogeneous ventilation as often is observed in diseased lungs, disturbances and secondary motions at airway bifurcations, irreversibility of the airflow in lung airways between inhalation and exhalation, but most notably mixing of the tidal air with the reserve air in the alveoli (Taulbee, Yu, & Heyder, 1978). Alveolar mixing is recognized as one of the major mechanisms for dispersion of inhaled particles with the conducting airways also playing a significant role in the overall mixing process (Brand, Rieger, Schulz, Beinert, & Heyder, 1997;Darquenne & Paiva, 1998;Ma & Darquenne, 2012;Taulbee et al., 1978). A few studies suggest that alveolar mixing may also be due to chaotic advection, which stems from a stretched and folded patterns of streamlines in the alveolus due to alveolus expansion and contraction (Henry, Butler, & Tsuda, 2002;Tsuda, Henry, & Butler, 1995;Tsuda, Otani, & Butler, 1999). ...
... The subsequent work by Sznitman et al. (Sznitman 2013;Sznitman et al. 2007Sznitman et al. , 2009) used the same assumption of constant expansion ratio for all length scales. There are also substantial researches in the area either by numerical simulations (Harding and Robinson 2010;Sznitman 2014, 2015;Kumar et al. 2009;Ma and Darquenne 2012;Oakes et al. 2016;Ostrovski et al. 2016;Sznitman et al. 2007Sznitman et al. , 2009Tsuda et al. 1995) or experimental investigations (Berg et al. 2010;Chhabra and Prasad 2011;Fishler et al. 2013Fishler et al. , 2015Fishler et al. , 2017Ma et al. 2009;Tippe and Tsuda Electronic supplementary material The online version of this article (https ://doi.org/10.1007/s1040 4-020-02377 -9) contains supplementary material, which is available to authorized users. ...
Understanding flow distributions in human lungs has attracted significant attention since the last few decades. However, there are still large discrepancies between different studies in the distribution of air flow into alveoli at different generations of bifurcation. In this study, a new method has been developed to calculate expansion ratio of alveoli and ratio of alveolar to ductal flow rate at different generations for air- and saline-filled lungs. The effects of alveolar number, breathing period, lung tidal volume, and surface tension are examined. It is found that the expansion ratio of alveoli varies significantly at different generations in the saline-filled lungs. For the air-filled lung, the expansion ratio of individual alveolus remains constant for different generations. The current study provides new data on the flow rate ratios which is critical for understanding flow distributions and flow behaviors in alveoli. Surface tension in alveoli and alveolar number has obvious effects on the value of flow ratio. The current study sheds new light into the flow behavior in lungs and lays the foundation for detailed study on flow and particle transport characteristics in human lungs.
... Chaotic mixing was argued to be the outcome of the interaction of axial flow due to expansion/contraction with recirculation due to shear imposed by the airway flow. This idea was subsequently investigated by three-dimensional simulations and experiments , Tsuda, Henry, and Butler 2008, Tsuda, Laine-Pearson, and Hydon 2011Sznitman et al. 2009;Henry et al. 2012), and was more recently enriched by a complementary mixing mechanism (Darquenne and Prisk 2003;Sznitman et al. 2009;Ma and Darquenne 2012;Fishler et al. 2017) based on streamline crossing by the particles in the presence of high velocity gradients. The idea of chaotic mixing was exploited in a simple filtration model that assumed pure convection along airways in combination with perfect mixing inside the alveolar volume of each generation (Georgakakou et al. 2016), and which-despite its simplicity-produced reasonable results (Gourgoulianis et al. 2017). ...
A dynamic, single-path model is developed for dry powder transport in the lungs. The model differentiates between particle behavior in the respiratory bronchioles and alveolar ducts on one hand and inside the alveoli on the other. In particular, it considers the alveolar volume of each generation as a mixing chamber. Air inflow to the alveoli is calculated by accounting for the deformation of airways during breathing. Particle dispersion along the respiratory tract is taken into account and mechanistic deposition rates are developed for the alveoli. Deposition by Brownian diffusion is modeled by a concentration boundary layer, whose thickness varies inversely with the intensity of mixing. The plausibility of the assumption of alveolar mixing is tested indirectly by comparison of model predictions with benchmark data of the exhaled concentration profile and of the pulmonary deposition of continuously inhaled aerosols. The observed agreement lends support to the hypothesis that alveolar mixing represents fundamental physics of the breathing process. It also supports the suggestion that alveolar mixing provides an additional axial dispersion mechanism in the acinus, which is independent of particle size and is active at zero gravity.
Copyright © 2020 American Association for Aerosol Research
... While Sznitman et al. [25] and Haber et al. [22] suggested that the gravity orientation has a strong correlation with deposition efficiencies in the alveolar ducts and space-filling alveolar region, Khajeh-Hosseini-Dalasm and Longest [26] found that the alveolar dosimetry was not sensitive to the gravitational orientation as long as the model contained three generations of alveolar ducts or more. Likewise, several studies [31][32][33] suggested that the alveolar deposition is strongly related to the geometry complexity, Hofemeier et al. [27] observed that the geometry heterogeneity of the acinus has little impact on particle deposition in those regions. The objective of this study is to examine the influences of alveolar geometrical complexities on airflow and particle dynamics in the acinar models that retain a different number of alveoli. ...
Background: The integration of inhalation drug delivery and nanotechnology offers exciting potentials to enhance the targeting, release, diagnostic, and therapeutic outcomes of drugs. Human lungs provide many advantages over other routers such as noninvasive delivery, a large surface area for absorption, avoiding the first-pass metabolism, and quick therapeutic onset. It is crucial to understand nanoparticle dosimetry in the acinar region to reliably evaluate the therapeutic outcomes of nanomedicines. However, an acinus unit comprises up to 10,000 alveoli and to model a complete acinus is still a prohibitive task. Besides, the presence of inter-alveolar septa creates a labyrinth pathway for inhaled airflow and particles.
Methods: The objective of this study is to numerically investigate nanoparticle deposition in three alveolar models with varying physical complexities, which retain 1, 4, and 45 alveoli, respectively. A discrete-phase Lagrangian model was implemented to track nanoparticle trajectories under the influence of rhythmic wall expansion and contraction. Both temporal and spatial dosimetry in the alveoli were computed.
Results: Strikingly different behaviors were observed in the dynamic alveolar model between micron particles and nanoparticles. Minimal deposition rates were predicted for 500–600 nm particles for all the three models considered. Consistently lower deposition rates were found in the 45-alveoli model than the other two simplified models for all particles ranging from 1 nm to 1000 nm. Considering the gravitational orientation effect, nanoparticles smaller than 200 nm appears insensitive to the alveolar orientation and only becomes perceivable around 500 nm. For nanoparticles larger than 500 nm, lower doses were predicted in the horizontal alveoli than in the vertical alveoli, regardless of the model complexity.
Conclusions: The magnitude of the airflow velocity (depending on ventilated volume) is an essential factor in determining the deposition of inhaled nanoparticles. Future correlation development for acinar deposition should consider the velocity distribution in different regions of the acinus.
... By contrast, Khajeh-Hosseini-Dalasm and Longest [22] suggested that total acinar deposition rates were insensitive to the gravity orientation when the geometry had more than three alveolar duct generations. While some studies [18,34,35] found that the geometry complexity significantly affected acinar aerosol deposition, Hofemeier et al. [23] recently observed that heterogeneity in acinar geometry had little effect on alveolar deposition. Similarly, while Hofemeier et al. [23] reported that the acinar deposition rate increased for deeper inhalations, Talaat and Xi [15] reported that the deposition was relatively insensitive to the breathing depth in single terminal alveolar models. ...
Unique features exist in acinar units such as multiple alveoli, interalveolar septal walls, and pores of Kohn. However, the effects of such features on airflow and particle deposition remain not well quantified due to their structural complexity. This study aims to numerically investigate particle dynamics in acinar models with interalveolar septal walls and pores of Kohn. A simplified 4-alveoli model with well-defined geometries and a physiologically realistic 45-alveoli model was developed. A well-validated Lagrangian tracking model was used to simulate particle trajectories in the acinar models with rhythmically expanding and contracting wall motions. Both spatial and temporal dosimetries in the acinar models were analyzed. Results show that collateral ventilation exists among alveoli due to pressure imbalance. The size of interalveolar septal aperture significantly alters the spatial deposition pattern, while it has an insignificant effect on the total deposition rate. Surprisingly, the deposition rate in the 45-alveoli model is lower than that in the 4-alveoli model, indicating a stronger particle dispersion in more complex models. The gravity orientation angle has a decreasing effect on acinar deposition rates with an increasing number of alveoli retained in the model; such an effect is nearly negligible in the 45-alveoli model. Breath-holding increased particle deposition in the acinar region, which was most significant in the alveoli proximal to the duct. Increasing inhalation depth only slightly increases the fraction of deposited particles over particles entering the alveolar model but has a large influence on dispensing particles to the peripheral alveoli. Results of this study indicate that an empirical correlation for acinar deposition can be developed based on alveolar models with reduced complexity; however, what level of geometry complexity would be sufficient is yet to be determined.
... 2,46,47 More complex alveolar models that had polyhedral structures and multiple alveoli had been demonstrated to influence aerosol deposition at different levels. 2,10,15,48 However, when the acinar structure had more than three alveolar ducts, increasing model complexity had a negligible effect on total acinar deposition. 2 The alveolar wall motion also exhibits high levels of variability in contrast to an idealized sinusoidal function. 45,49 A one-way momentum exchange was assumed from the rhythmically oscillating wall to airflows and further to inhaled particles. ...
The particle dynamics in an oscillating alveolus under tidal breathing can be dramatically different from those in a static alveolus. Despite its close relevance to pulmonary drug delivery and health risk from airborne exposure, quantifications of alveolar deposition are scarce due to its inaccessibility to in vivo measurement instruments, tiny size to replicate in vitro, and dynamic wall motions to model. The objective of this study is to introduce a numerical method to quantify alveolar deposition with continuous particle release in a rhythmically oscillating alveolus by integrating the deposition curves for bolus aerosols and use this method to develop correlations applicable in assessing alveolar drug delivery efficiency or dosimetry of inhaled toxicants. An idealized blind-end terminal alveolus model was developed with rhythmically moving alveolar boundary conditions in phase with tidal breathing. The dynamic wall expansion mode and magnitude were based on experimentally measured chest wall motions and tidal volumes. A well-validated Lagrangian tracking model was used to simulate the transport and deposition of inhaled micrometer particles. Large differences were observed between dynamic and static alveoli in particle motion, deposition onset, and final alveolar deposition fraction. Alveolar deposition of bolus aerosols is highly sensitive to breath-holding duration, particle release time, and alveolar dimension. For 1 µm particles, there exists a cut-off release time (zero bolus deposition), which decreases with alveolar size (i.e., 1.0 s in a 0.2-mm-diameter alveolus and 0.56 s in a 0.8-mm-diameter alveolus). The cumulative alveolar deposition was predicted to be 39% for a 0.2-mm-diameter alveolus, 22% for a 0.4-mm-diameter alveolus, and 10% for a 0.8-mm-diameter alveolus. A cumulative alveolar deposition correlation was developed for inhalation delivery with a prescribed period of drug release and the second correlation for the time variation of alveolar deposition of ambient aerosols, both of which captured the relative dependence of the particle release time and alveolar dimension.
... 58 application for predicting aerosol bolus dispersion. [77][78][79] Aerosol dispersion (which is different from gas dispersion) has shown promise in lung structure characterisation for healthy and diseased lungs. A cloud of inhaled aerosol bolus disperses through the lung, and when exhaled, the bolus recombines and the resulting dispersion can be correlated with spatial locations within the airways. ...
Respiratory disease is a significant problem worldwide, and it is a problem with increasing prevalence. Pathology in the upper airways and lung is very difficult to diagnose and treat, as response to disease is often heterogeneous across patients. Computational models have long been used to help understand respiratory function, and these models have evolved alongside increases in the resolution of medical imaging and increased capability of functional imaging, advances in biological knowledge, mathematical techniques and computational power. The benefits of increasingly complex and realistic geometric and biophysical models of the respiratory system are that they are able to capture heterogeneity in patient response to disease and predict emergent function across spatial scales from the delicate alveolar structures to the whole organ level. However, with increasing complexity, models become harder to solve and in some cases harder to validate, which can reduce their impact clinically. Here, we review the evolution of complexity in computational models of the respiratory system, including successes in translation of models into the clinical arena. We also highlight major challenges in modelling the respiratory system, while making use of the evolving functional data that are available for model parameterisation and testing.
... To date, respiratory flows in the deep pulmonary acinar regions have been typically investigated in silico using computational fluid dynamics (CFD) or alternatively in vitro with scaled-up experimental models following hydrodynamic similarity matching. In the past few decades, CFD methods have been increasingly applied to study acinar flow phenomena, from single alveolar models 6,7 and alveolated ducts [8][9][10][11][12] to more elaborate in silico models that capture anatomically-realistic acinar tree structures with multiple generations of alveolated ducts and up to several hundreds of individual alveoli [13][14][15] . ...
Quantifying respiratory flow characteristics in the pulmonary acinar depths and how they influence inhaled aerosol transport is critical towards optimizing drug inhalation techniques as well as predicting deposition patterns of potentially toxic airborne particles in the pulmonary alveoli. Here, soft-lithography techniques are used to fabricate complex acinar-like airway structures at the truthful anatomical length-scales that reproduce physiological acinar flow phenomena in an optically accessible system. The microfluidic device features 5 generations of bifurcating alveolated ducts with periodically expanding and contracting walls. Wall actuation is achieved by altering the pressure inside water-filled chambers surrounding the thin PDMS acinar channel walls both from the sides and the top of the device. In contrast to common multilayer microfluidic devices, where the stacking of several PDMS molds is required, a simple method is presented to fabricate the top chamber by embedding the barrel section of a syringe into the PDMS mold. This novel microfluidic setup delivers physiological breathing motions which in turn give rise to characteristic acinar air-flows. In the current study, micro particle image velocimetry (µPIV) with liquid suspended particles was used to quantify such air flows based on hydrodynamic similarity matching. The good agreement between µPIV results and expected acinar flow phenomena suggest that the microfluidic platform may serve in the near future as an attractive in vitro tool to investigate directly airborne representative particle transport and deposition in the acinar regions of the lungs.
... In the absence of versatile experimental tools numerical investigations, including computational fluid dynamics (CFD), have been highly valuable for investigating the dynamics of inhaled aerosols in models of acinar geometries, spanning simple alveolated ducts [16][17][18][19] to more complex bifurcating tree networks [20][21][22] , and more recently using anatomically-reconstructed alveolar geometries [23][24][25] with high-resolution imaging modalities (e.g. micro-computed tomography). ...
Particle transport phenomena in the deep alveolated airways of the lungs (i.e. pulmonary acinus) govern deposition outcomes following inhalation of hazardous or pharmaceutical aerosols. Yet, there is still a dearth of experimental tools for resolving acinar particle dynamics and validating numerical simulations. Here, we present a true-scale experimental model of acinar structures consisting of bifurcating alveolated ducts that capture breathing-like wall motion and ensuing respiratory acinar flows. We study experimentally captured trajectories of inhaled polydispersed smoke particles (0.2 to 1 μm in diameter), demonstrating how intrinsic particle motion, i.e. gravity and diffusion, is crucial in determining dispersion and deposition of aerosols through a streamline crossing mechanism, a phenomenon paramount during flow reversal and locally within alveolar cavities. A simple conceptual framework is constructed for predicting the fate of inhaled particles near an alveolus by identifying capture and escape zones and considering how streamline crossing may shift particles between them. In addition, we examine the effect of particle size on detailed deposition patterns of monodispersed microspheres between 0.1-2 μm. Our experiments underline local modifications in the deposition patterns due to gravity for particles ≥0.5 μm compared to smaller particles, and show good agreement with corresponding numerical simulations.
... In addition, aerosol transport, mixing, and deposition could be strongly affected by CO f , which is particularly relevant for inhaled therapeutics. Ma and Darquenne (18) and Darquenne et al. (8) proposed the existence of cardiogenic mixing to explain differences between measurement and simulations of aerosol dispersion and for the heterogeneity of particle deposition in microgravity, respectively. In a following study to Darquenne et al. (8), they addressed the effect of CO f on the deposition and dispersion of 1 m particles during breath holdings (7). ...
Recently, dynamic MR imaging of hyperpolarized (3)He during inhalation revealed an alternation of the image intensity between left and right lungs with a cardiac origin (Respiratory Physiology & Neurobiology: 185, 468-471,2013). This effect is investigated further using dynamic and phase contrast flow MR imaging with inhaled (3)He during slow inhalations (flow rate ~ 100 mL s(-1)) to elucidate air-flow dynamics in the main lobes in six healthy subjects. The ventilation MR signal and gas inflow in the left lower part of the lungs was found to oscillate clearly at the cardiac frequency in all subjects, whereas the MR signals in the other parts of the lungs had a similar oscillatory behavior but were smaller in magnitude and in anti-phase to the signal in the left lower lung. The airflow in the main bronchi showed periodic oscillations at the frequency of the cardiac cycle. In four of the subjects, backflows were observed for a short period of time of the cardiac cycle, demonstrating a pendelluft effect at the carina bifurcation between the left and right lungs. Additional (1)H structural MR images of the lung volume and synchronized ECG recording revealed that maximum inspiratory flow rates in the left lower part of the lungs occurred during systole when the corresponding left lung volume increased whereas the opposite effect was observed during diastole with gas flow being redirected to the other parts of the lung. In conclusion, cardiogenic flow oscillations have a significant effect on regional gas flow and distribution within the lungs.
Copyright © 2014, Journal of Applied Physiology.
... In particular, under rhythmic wall motion 1 mm particles display intricate trajectories that can span over the entire acinar network; such kinematics cannot be captured by models of isolated cavities or single alveolated ducts, revealing the importance of aerosol transport studies in multibranched acinar trees. Recently, an algorithm to design multigeneration acinar networks with spherical alveoli was developed (Ma and Darquenne, 2011), confirming the need for tracking cumulative breathing cycles to obtain accurate deposition data across an entire tree (Ma and Darquenne, 2012), where tree asymmetry plays an important role for sedimentation. However, all the aforementioned multibranch networks represent at most 0.1% of the average volume of an entire pulmonary acinus-187 mm 3 (Haefeli-Bleuer and Weibel, 1988), ultimately limiting the translation of deposition results to entire acini. ...
Large amounts of net electrical charge are known to accumulate on inhaled aerosols during their generation using commonly-available inhalers. This effect often leads to superfluous deposition in the extra-thoracic airways at the cost of more efficient inhalation therapy. Since the electrostatic force is inversely proportional to the square of the distance between an aerosol and the airway wall, its role has long been recognized as potentially significant in the deep lungs. Yet, with the complexity of exploring such phenomenon directly at the acinar scales, in vitro experiments have been largely limited to upper airways models. Here, we devise a microfluidic alveolated airway channel coated with conductive material to quantify in vitro the significance of electrostatic effects on inhaled aerosol deposition. Specifically, our aerosol exposure assays showcase inhaled spherical particles of 0.2, 0.5, and 1.1 μm that are recognized to reach the acinar regions, whereby deposition is typically attributed to the leading roles of diffusion and sedimentation. In our experiments, electrostatic effects are observed to largely prevent aerosols from depositing inside alveolar cavities. Rather, deposition is overwhelmingly biased along the inter-alveolar septal spaces, even when aerosols are charged with only a few elementary charges. Our observations give new insight into the role of electrostatics at the acinar scales and emphasize how charged particles under 2 µm may rapidly overshadow the traditionally accepted dominance of diffusion or sedimentation when considering aerosol deposition phenomena in the deep lungs.
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.
With the expectation of human landing on Mars in the near future, it is critical to understand how the Martian particles deposit in the human terminal alveoli to prevent the astronauts from health damage by the Martian toxic particles. Therefore, this study has numerically investigated the micro-particle behaviours in an alveolar model under Martian gravity using an Euler-Lagrangian method considering several physical and physiological factors. The important findings are as following: 1) Martian particle deposition is sensitive to the alveolar direction and respiratory depth significantly, but not sensitive to the wall motion pattern; 2) both the particle size and density affect the deposition starting time and duration; 3) compared with the earth gravity, the total deposition efficiency decreases and the total deposition time is much extended under the Martian gravity. It concludes that the particle deposition under Martian gravity environment are obviously different from the one under the earth gravity environment.
Respiratory tract dosimetry predictions for inhalation of tobacco product smoke and aerosols are sensitive to the values of the physicochemical properties of constituents that make up the puff. Physicochemical property values may change significantly with temperature, particularly in the oral cavity and upper airways of the lung, where the puff undergoes adjustments from high temperatures in the tobacco product to reach body temperature. The assumption of fixed property values may introduce uncertainties in the predicted doses in these and other airways of the lung. To obtain a bound for the uncertainties and improve dose predictions, we studied temperature evolution of the inhaled puff in the human respiratory tract during different puff inhalation events. Energy equations were developed for the transport of the puff in the respiratory tract and were solved to find air and droplet temperatures throughout the respiratory tract during two puffing scenarios: 1. direct inhalation of the puff into the lung with no pause in the oral cavity, and 2. puff withdrawal, mouth hold, and puff delivery to the lung via inhalation of dilution air. These puffing scenarios correspond to the majority of smoking scenarios. Model predictions showed that temperature effects were most significant during puff withdrawal. Otherwise, the puff reached thermal equilibrium with the body. Findings from this study will improve predictions of deposition and uptake of puff constituents, and therefore inform inhalation risk assessment from use of electronic nicotine delivery systems (ENDS) and combusted cigarettes.
Significant differences in alveolar size exist in humans of different ages, gender, health, and among different species. The effects of alveolar sizes, as well as the accompanying breathing frequencies, on regional and local dosimetry of inhaled nanoparticles have not been sufficiently studied. Despite a well-accepted qualitative understanding of the advection-diffusion-sedimentation mechanism in the acinar region, a quantitative picture of the interactions among these factors remains inchoate. The objective of this study is to quantify the effects of alveolar size on the regional and local deposition of inhaled nanoparticles in alveolar models of varying complexities and to understand the dynamic interactions among different deposition mechanisms. Three different models were considered that retained 1, 4, and 45 alveoli, respectively. For each model, the baseline geometry was scaled by ¼, ½, 2, 4, and 8 times by volume. Temporal evolution and spatial distribution of particle deposition were tracked using a discrete-phase Lagrangian model. Lower retentions of inhaled nanoparticles were observed in the larger alveoli under the same respiration frequency, while similar retentions were found among different geometrical scales if breathing frequencies allometrically matched the alveolar size. Dimensional analysis reveals a manifold deposition mechanism with tantamount contributions from advection, diffusion, and gravitational sedimentation, each of which can become dominant depending on the location in the alveoli. Results of this study indicate that empirical correlations obtained from one sub-population cannot be directly applied to others, nor can they be simply scaled as a function of the alveolar size or respiration frequency due to the regime-transiting deposition mechanism that is both localized and dynamic.
Computational Fluid Dynamics (CFD) have offered an attractive gateway to investigate in silico respiratory flows and aerosol transport in the depths of the lungs. Yet, not only do existing models lack sufficient anatomical realism in capturing the heterogeneity and morphometry of the acinar environment, numerical simulations have been widely restricted to domains capturing a mere few percent of a single acinus. Here, we present to the best of our knowledge the most detailed and comprehensive in silico simulations to date on the fate of aerosols in the acinar depths. Our heterogeneous acinar domains represent complete sub-acinar models (i.e. 1/8th of a full acinus) based on the recent algorithm of Koshiyama & Wada (2015), capturing statistics of human acinar morphometry (Ochs et al. 2004). Our simulations deliver high-resolution, 3D spatial-temporal data on aerosol transport and deposition, emphasizing how variances in acinar heterogeneity only play a minor role in determining general deposition outcomes. With such tools at hand, we revisit whole-lung deposition predictions (i.e. ICRP) based on past 1D lung models. While our findings under quiet breathing substantiate general deposition trends obtained with past predictions in the alveolar regions, we underscore how deposition fractions are anticipated to increase, in particular during deep inhalation. For such inhalation maneuver, our simulations support the notion of significantly augmented deposition for all aerosol sizes (0.005-5.0μm). Overall, our efforts not only help consolidate our mechanistic understanding of inhaled aerosol transport in the acinar depths but also continue to bridge the gap between "bottom-up" in silico models and regional deposition predictions from whole-lung models. Such quantifications provide what is deemed more accurate deposition predictions in morphometrically-faithful models and are particularly useful in assessing inhalation strategies for deep airway deposition (e.g. systemic delivery).
The development and implementation of personalized medicine is paramount to improving the efficiency and efficacy of patient care. In the respiratory system, function is largely dictated by the choreographed movement of air and blood to the gas exchange surface. The passage of air begins in the upper airways, either via the mouth or nose, and terminates at the alveolar interface, while blood flows from the heart to the alveoli and back again. Computational fluid dynamics ( CFD ) is a well‐established tool for predicting fluid flows and pressure distributions within complex systems. Traditionally CFD has been used to aid in the effective or improved design of a system or device; however, it has become increasingly exploited in biological and medical‐based applications further broadening the scope of this computational technique. In this review, we discuss the advancement in application of CFD to the respiratory system and the contributions CFD is currently making toward improving precision medicine. The key areas CFD has been applied to in the pulmonary system are in predicting fluid transport and aerosol distribution within the airways. Here we focus our discussion on fluid flows and in particular on image‐based clinically focused CFD in the ventilatory system. We discuss studies spanning from the paranasal sinuses through the conducting airways down to the level of the alveolar airways. The combination of imaging and CFD is enabling improved device design in aerosol transport, improved biomarkers of lung function in clinical trials, and improved predictions and assessment of surgical interventions in the nasal sinuses. WIREs Syst Biol Med 2017, 9:e1392. doi: 10.1002/wsbm.1392
This article is categorized under: Analytical and Computational Methods > Computational Methods
Models of Systems Properties and Processes > Mechanistic Models
Models of Systems Properties and Processes > Organ, Tissue, and Physiological Models
The dispersion of inhaled microparticles in the pulmonary acinus of the lungs is often attributed to the complex interplay between convective mixing, due to irreversible flows, and intrinsic particle motion (i.e. gravity and diffusion). However, the role of each mechanism, the exact nature of such interplay between them and their relative importance still remain unclear. To gain insight into these dispersive mechanisms, we track liquid-suspended microparticles and extract their effective diffusivities inside an anatomically-inspired microfluidic acinar model. Such results are then compared to experiments and numerical simulations in a straight channel. While alveoli of the proximal acinar generations exhibit convective mixing characteristics that lead to irreversible particle trajectories, this local effect is overshadowed by a more dominant dispersion mechanism across the ductal branching network that arises from small but significant streamline crossing due to intrinsic diffusional motion in the presence of high velocity gradients. We anticipate that for true airborne particles, which exhibit much higher intrinsic motion, streamline crossing would be even more significant.
Purified (111) Ag was used as a radiotracer to investigate silver loading and release, pharmacokinetics, and biodistribution of polyphosphoester-based degradable shell crosslinked knedel-like (SCK) nanoparticles as a comparison to the previously reported small molecule, N-heterocyclic silver carbene complex analog (SCC1) for the delivery of therapeutic silver ions in mouse models. Biodistribution studies were conducted by aerosol administration of (111) Ag acetate, [(111) Ag]SCC1, and [(111) Ag]SCK doses directly into the lungs of C57BL/6 mice. Nebulization of the (111) Ag antimicrobials resulted in an average uptake of 1.07 ± 0.12% of the total aerosolized dose given per mouse. The average dose taken into the lungs of mice was estimated to be 2.6 ± 0.3% of the dose inhaled per mouse for [(111) Ag]SCC1 and twice as much dose was observed for the [(111) Ag]SCKs (5.0 ± 0.3% and 5.9 ± 0.8% for [(111) Ag]aSCK and [(111) Ag]zSCK, respectively) at 1 h post administration (p.a.). [(111) Ag]SCKs also exhibited higher dose retention in the lungs; 62-68% for [(111) Ag]SCKs and 43% for [(111) Ag]SCC1 of the initial 1 h dose were observed in the lungs at 24 h p.a.. This study demonstrates the utility of (111) Ag as a useful tool for monitoring the pharmacokinetics of silver-loaded antimicrobials in vivo.
Copyright © 2015 John Wiley & Sons, Ltd.
It is largely acknowledged that inhaled particles ranging from 0.001 to 10 μm are able to reach and deposit in the alveolated regions of the lungs. To date, however, the bulk of numerical studies have focused mainly on micron-sized particles whose transport kinematics are governed by convection and sedimentation, thereby capturing only a small fraction of the wider range of aerosols leading to acinar deposition. Too little is still known about the local acinar transport dynamics of inhaled (ultra)fine particles affected by diffusion and convection. Our study aims to fill this gap by numerically simulating the transport characteristics of particle sizes spanning three orders of magnitude (0.01 - 5 μm) covering diffusive, convective and gravitational aerosol motion across a multi-generational acinar network. By characterizing the deposition patterns as a function of particle size, we find that submicron particles (Ο(0.1 μm)) reach deep into the acinar structure and are prone to deposit near alveolar openings; meanwhile, other particle sizes are restricted to accessing alveolar cavities in proximal generations. Our findings underline that a precise understanding of acinar aerosol transport, and ultrafine particles in particular, is contingent upon resolving the complex convective-diffusive interplay in determining their irreversible kinematics and local deposition sites.
Copyright © 2014, Journal of Applied Physiology.
Fine aerosol transport in the alveolated regions of the lungs is intrinsically coupled to alveolar flow patterns driven by lung breathing motions. Hence, understanding acinar flow characteristics is critical in determining local aerosol deposition sites. To date, inhaled aerosol dynamics have been mainly investigated using self-similar expanding lung models, although it is known that anisotropic lung motions exist and thus, potentially alter flow characteristics and enhance convective mixing. Using both experimental and numerical approaches, we assess here the influence of respiratory flow asynchrony on convective mixing by investigating alveolar flow patterns and massless particle transport for increasing phase lags between local wall motion and acinar ductal flows. Experimental results using a microfluidic platform, as well as numerical simulations, suggest that alveolar flow patterns are time-dependent in contrast to quasi-steady phenomena that pertain under synchronous conditions. To capture statistics of convective mixing, we numerically track massless tracers over multiple breathing cycles using anatomically inspired models of alveolated airways. By systemically probing various degrees of phase lag, our results underline the strong correlation between the magnitude of particle dispersion and flow asynchrony. In particular, we find that the dispersion of massless particles in acinar ducts is dramatically increased under flow asynchrony, relative to local, isolated alveolar cavity mixing. Despite the simplicity of the present models, our work highlights the critical role of respiratory flow asynchrony in governing the fate of fine inhaled particles in the pulmonary acinus.
Due to experimental challenges, computational simulations are often sought to quantify inhaled aerosol transport in the pulmonary acinus. Commonly, these are performed using generic alveolar topologies, including spheres, toroids and polyhedra, to mimic the complex acinar morphology. Yet, local acinar flows and ensuing particle transport are anticipated to be influenced by the specific morphological structures. We have assessed a range of acinar models under self-similar breathing conditions with respect to alveolar flow patterns, convective flow mixing and deposition of fine particles. By tracking passive tracers over cumulative breathing cycles, we find that irreversible flow mixing correlates with the location and strength of the recirculating vortex inside the cavity. Such effects are strongest in proximal acinar generations where the ratio of alveolar to ductal flow rates is low and inter-alveolar disparities are most apparent. Our results for multi-alveolated acinar ducts highlight that fine inhaled particles subject to alveolar flows are sensitive to the alveolar topology, underlining inter-alveolar disparities in particle deposition patterns. Despite the simplicity of the acinar models investigated, our findings suggest that alveolar topologies influence more significantly local flow patterns and deposition sites of fine particles for upper generations emphasizing the importance of the selected acinar model. In distal acinar generations, however, the alveolar geometry primarily needs to mimic the space-filling alveolar arrangement dictated by lung morphology.
Convective respiratory flows in the pulmonary acinus and their influence on the fate of inhaled particles are typically studied using computational fluid dynamics (CFD) or scaled-up experimental models. However, experiments that replicate several generations of the acinar tree while featuring cyclic wall motion have not yet been realized. Moreover, current experiments generally capture only flow dynamics, without inhaled particle dynamics, due to difficulties in simultaneously matching flow and particle dynamics. In an effort to overcome these limitations, we introduce a novel microfluidic device mimicking acinar flow characteristics directly at the alveolar scale. The model features an anatomically-inspired geometry that expands and contracts periodically with five dichotomously branching airway generations lined with alveolar-like cavities. We use micro-particle image velocimetry with a glycerol solution as the carrying fluid to quantitatively characterize detailed flow patterns within the device and reveal experimentally for the first time a gradual transition of alveolar flow patterns along the acinar tree from recirculating to radial streamlines, in support of hypothesized predictions from past CFD simulations. The current measurements show that our microfluidic system captures the underlying characteristics of the acinar flow environment, including Reynolds and Womersley numbers as well as cyclic wall displacements and alveolar flow patterns at a realistic length scale. With the use of air as the carrying fluid, our miniaturized platform is anticipated to capture both particle and flow dynamics and serve in the near future as a promising in vitro tool for investigating the mechanisms of particle deposition deep in the lung.
Axial dispersion in alveolated channels was studied experimentally. Our motivation was to improve understanding of the physics of gas mixing in the pulmonary acinus. The apparatus consisted of a quasi-two-dimensional central convective channel surrounded top and bottom by dead-end cells (alveoli). Quasi-steady oscillatory bulk flow and a small steady-flow of tracer gas (He, SF6) were introduced upstream of the apparatus. The steady-state axial concentration distribution was measured by mass spectrometry, and its gradient was used to calculate an axial dispersion coefficient (D*) from a generalized Fick's law. We found that for small Peclet (Pe) numbers D* was appreciably smaller than molecular diffusivity of the tracer gas, while for large Pe, D* was substantially greater than the Taylor—Aris result for flow enhanced dispersion in non-alveolated parallel plates. D* was sensitive to the ratio of alveolar volume to central channel volume, which was varied from 0.75 to 4.64. These results are consistent with theoretical predictions. We conclude that the structure of the alveolated channel alters the interaction between lateral diffusion and axial convection, and as a result, conditions axial dispersion phenomena.
There is a surprisingly substantial amount of aerosol mixing and deposition deep in the lung, which cannot be explained by classic transport mechanisms such as streamline crossing, inertial impaction, or gravitational sedimentation with reversible acinar flow. Mixing associated with "stretch and fold" convective flow patterns can, however, be a potent source of transport. We show such patterns in experimental preparations using rat lungs and in the theoretical Baker Transform. In both cases, mixing is associated with the temporal evolution of two length scales. The first is the slowly increasing diffusive length scale. The second is the rapidly decreasing lateral length scale, due to "stretching and folding," over which diffusion must take place. This interaction leads to aerosol mixing in much shorter times than previously appreciated. Finally, we propose a new method by which to quantify the state of mixing, using an approximation to the entropy of the aerosol concentration distribution. The results of the analysis suggest that stretching and folding may be a key feature underlying peripheral aerosol transport.
Current theories describe aerosol transport in the lung as a dispersive (diffusion-like) process, characterized by an effective diffusion coefficient in the context of reversible alveolar flow. Our recent experimental data, however, question the validity of these basic assumptions. In this study, we describe the behavior of fluid particles (or bolus) in a realistic, numerical, alveolated duct model with rhythmically expanding walls. We found acinar flow exhibiting multiple saddle points, characteristic of chaotic flow, resulting in substantial flow irreversibility. Computations of axial variance of bolus spreading indicate that the growth of the variance with respect to time is faster than linear, a finding inconsistent with dispersion theory. Lateral behavior of the bolus shows fine-scale, stretch-and-fold striations, exhibiting fractal-like patterns with a fractal dimension of 1.2, which compares well with the fractal dimension of 1.1 observed in our experimental studies performed with rat lungs. We conclude that kinematic irreversibility of acinar flow due to chaotic flow may be the dominant mechanism of aerosol transport deep in the lungs.
Our current understanding of the transport and deposition of aerosols (viruses, bacteria, air pollutants, aerosolized drugs) deep in the lung has been grounded in dispersive theories based on untested assumptions about the nature of acinar airflow fields. Traditionally, these have been taken to be simple and kinematically reversible. In this article, we apply the recently discovered fluid mechanical phenomenon of irreversible low-Reynolds number flow to the lung. We demonstrate, through flow visualization studies in rhythmically ventilated rat lungs, that such a foundation is false, and that chaotic mixing may be key to aerosol transport. We found substantial alveolar flow irreversibility with stretched and folded fractal patterns, which lead to a sudden increase in mixing. These findings support our theory that chaotic alveolar flow--characterized by stagnation saddle points associated with alveolar vortices--governs gas kinematics in the lung periphery, and hence the transport, mixing, and ultimately the deposition of fine aerosols. This mechanism calls for a rethinking of the relationship of exposure and deposition of fine inhaled particles.
This review is concerned with mixing and transport in the human pulmonary acinus. We first examine the current understanding of the anatomy of the acinus and introduce elements of fluid mechanics used to characterize the transport of momentum, gas and aerosol particles. We then review gas transport in more detail and highlight some areas of current research. Next we turn our attention to aerosol transport and in particular to mixing within the alveoli. We examine the factors influencing the level of mixing, review the concept of chaotic convective mixing, and make some brief comments on how mixing affects particle deposition. We end with a few comments on some issues unique to the neonatal and developing lung.
This review discusses the potential utility of two methods using inhaled aerosol to detect and diagnose lung disease. Part 1, published earlier,(1) focused upon aerosol bolus dispersion, which measures convective gas mixing. Here, Part 2 focuses upon aerosol-derived airway morphometry (ADAM), which assesses the diameters of airways and acini. This method is discussed in terms of its validity, ability to detect known interventions and diseases, and reproducibility (administering and performing this procedure were already discussed(1)). With ADAM, airway and acinar diameters are expressed in terms of the effective airway diameter (EAD), which can be measured as a function of volumetric depth in the lungs. Evidence that ADAM is valid is provided by studies showing EAD agrees well with morphometric indices of airway and acinar size, especially once the distribution of aerosol is accounted for, and changes appropriately in response to known interventions and several diseases. Of particular note is the ability of ADAM to detect and quantify emphysema. One limitation of using ADAM to compare airway dimensions among people is that EADs in this region are sensitive to variability in airway volume, which can confound these comparisons. In contrast, EADs measured in the peripheral lung are relatively insensitive to variations in airway volume, thus acinar EADs can be readily compared. Other attractive features of ADAM are that it is simple to administer, can be successfully performed by patients, and is reproducible. Thus, ADAM is a promising method to characterize the dimensions of peripheral lung structures; it may be particularly useful to diagnose emphysema and to follow this disease's progression and response to treatment.
To investigate the potential use of aerosol dispersion (AD) and the skewness (SK) of expired aerosol boluses in detecting and characterizing lung injury, AD and SK were computed in a model of inhomogeneous ventilation. The lung was represented as two parallel compartments with volumes V1 and V2 and ventilatory time constants τ1 and τ2. Within a compartment, inspired aerosol was assumed to disperse as a Gaussian function of inspired volume. Expired aerosol concentration was computed by the complete mixing of expirate from the compartments. AD was defined as the square root of the difference of the variances of inspired and expired boluses with the coefficient of dispersion (CD) = AD/VP. For V1 = V2 and τ2 > τ1, CD and SK increased with (τ2 - τ1) and flow rate and decreased with VP. For V2 < V1, SK was maximum with V2 = 0.33V1 but was still increased up to 59% over baseline (τ1 = τ2) values with V2 = 0.01V1. The results suggest that: 1) CD and SK are markers of parallel inhomogeneity in lung ventilation, 2) CD and SK may be more sensitive to lung injury when measured at higher flow, and 3) SK may be particularly sensitive to a small region of injured lung.
We developed two new three-dimensional models of aerosol transport and deposition representative of two generations in the alveolar zone of the human lung, one with the bifurcation area, and one without. The models were used to simulate particle trajectories of 1–5μm particles in generations 18–22 of the human lung in different orientations with respect to gravity. Orientation had a significant effect on the overall deposition predicted, which varied by a factor of approximately 3 between the orientations with highest and lowest deposition. Total deposition was a function of orientation and the ratio of terminal settling velocity to mean lumen flow velocity. Predicted deposition was significantly greater in the model without the bifurcation than in the model with the bifurcation. We conclude that modeling the bifurcation is important due to the complex relationship between aerodynamic drag and gravitational sedimentation within the bifurcation zone.
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.
Accurate modeling of air flow and aerosol transport in the alveolated airways is essential for quantitative predictions of pulmonary aerosol deposition. However, experimental validation of such modeling studies has been scarce. The objective of this study is to validate CFD predictions of flow field and particle trajectory with experiments within a scaled-up model of alveolated airways. Steady flow (Re = 0.13) of silicone oil was captured by particle image velocimetry (PIV), and the trajectories of 0.5 mm and 1.2 mm spherical iron beads (representing 0.7 to 14.6 mum aerosol in vivo) were obtained by particle tracking velocimetry (PTV). At twelve selected cross sections, the velocity profiles obtained by CFD matched well with those by PIV (within 1.7% on average). The CFD predicted trajectories also matched well with PTV experiments. These results showed that air flow and aerosol transport in models of human alveolated airways can be simulated by CFD techniques with reasonable accuracy.
Quantitative data on aerosol deposition in the human respiratory tract are useful for understanding the causes of certain lung diseases and for designing efficient drug delivery systems via inhalation. In this study, aerosol deposition in a 3D anatomically based human large-medium airway model was simulated using computational fluid dynamics (CFD). The model extended from mouth to generation 10 and included two-thirds of the airways obtained by multi-detector row computed tomography (MDCT) imaging on normal healthy human subjects. Steady oral inhalation (15, 30, and 60 L/min) and aerosol (1-30 micrometer) deposition were computed by CFD using the realizable k-epsilon turbulence model. Based on the mean turbulence flow field, the computed extrathoracic deposition, ratio of left to right lung deposition, and deposition efficiency at each generation compared favorably with existing in vivo and in vitro experiments. The significant deposition in the large-medium airway model showed that the total tracheobronchial deposition is dominated by the large-medium airways for micrometer-sized aerosol particles. These quantitative data and the methods developed in this study provided valuable means toward subject-specific modeling of aerosol deposition in the human lung based on realistic lung geometry.
We investigated the axial dispersive effect of the upper airway structure (comprising mouth cavity, oropharynx, and trachea) on a traversing aerosol bolus. This was done by means of aerosol bolus experiments on a hollow cast of a realistic upper airway model (UAM) and three-dimensional computational fluid dynamics (CFD) simulations in the same UAM geometry. The experiments showed that 50-ml boluses injected into the UAM dispersed to boluses with a half-width ranging from 80 to 90 ml at the UAM exit, across both flow rates (250, 500 ml/s) and both flow directions (inspiration, expiration). These experimental results imply that the net half-width induced by the UAM typically was 69 ml. Comparison of experimental bolus traces with a one-dimensional Gaussian-derived analytical solution resulted in an axial dispersion coefficient of 200-250 cm(2)/s, depending on whether the bolus peak and its half-width or the bolus tail needed to be fully accounted for. CFD simulations agreed well with experimental results for inspiratory boluses and were compatible with an axial dispersion of 200 cm(2)/s. However, for expiratory boluses the CFD simulations showed a very tight bolus peak followed by an elongated tail, in sharp contrast to the expiratory bolus experiments. This indicates that CFD methods that are widely used to predict the fate of aerosols in the human upper airway, where flow is transitional, need to be critically assessed, possibly via aerosol bolus simulations. We conclude that, with all its geometric complexity, the upper airway introduces a relatively mild dispersion on a traversing aerosol bolus for normal breathing flow rates in inspiratory and expiratory flow directions.
Impulse response data were obtained tor the injection of helium and sulfur hexafluoride into air flowing through symmetric tube networks of uniform branch radii, having branch angles varying from 35 to 70 and branch aspect (length-to-radius) ratios varying from 3.6 to 7.0. These data were reduced in terms of the time variance in order to quantify the extent of longitudinal mixing. Over an inspiratory-like flowrate range of 1 to 400 ml/sec, a change in the branch angle alone did not affect axial mixing, while halving the aspect ratio caused a small increase of the time variance. Moreover, the variances obtained during inspiratory-like flow were found to be quite similar to the corresponding values determined during expiratory-like flow.The results of' these experiments as well as those previously reported by Scherer et al. (1975) were compared to the predictions of a compartmental dispersion analysis. The current data were bounded by two theories which hypothesized that the tracer concentration profile either develops continuously as gas flows along a particular transport path or, alternatively, must redevelop beginning at each branch point that is encountered. In both cases, it was essential to include an ‘unfulfilled dispersion’ correction factor in order to account for the incompletely developed concentration profile.The data of Scherer et al. obtained in a 5-generation network analog of the pulmonary airways, was well fit by assuming a continuously developing concentration profile during inspiratory-like flow and a redeveloping profile during expiratory-like flow. In fact. the linear correlation between the average mixing coefficient and tracheal velocity that was observed by Scherer could be predicted by the theory to an unexpectedly high degree of accuracy.
Values for the effective axial diffusivity D for laminar flow of a gas species in the bronchial airways have been obtained as a function of the mean axial gas velocity u by experiment measurements of benzene vapor dispersion in a five generation glass tube model of the bronchial tree. For both inspiration and expiration D is seen to be approximately a linear function of u over the range of Reynolds' numbers 30-2,000 corresponding to peak flows in bronchial generations 0-13 under resting breathing conditions. The diffusivity for expiration is seen to be approximately one-third that for inspiration due presumably to increased radial mixing at bifurcations during expiration. The effective diffusivities relative to the molecular diffusivity can be expressed by the formulas D/Dmol = 1 + 1.08 NPe for inspiration and D/Dmol = 1 + .37 N-Pe for expiration. These velocity dependent diffusivities help to explain the short transit times of gas boluses from mouth to alveoli and will aid in the analysis of airway gas mixing by mathematical transport equations.
The dispersion of aerosol boluses in the lung is a probe for convective mixing and has been proposed as a marker for abnormal lung function. To better understand the factors underlying this phenomenon, aerosol dispersion was compared in human subjects, dogs, and various physical models. In all systems, dispersion increased with the volumetric penetration of the aerosol bolus. The rate of this increase was 83% greater in humans compared with dogs. Dispersion in dogs was close to that in a packed bed with beads of 2.5 mm. Aerosol dispersion decreased with increasing flow rate in human subjects. An artificial larynx inserted into the straight tube caused a 33% increase in dispersion. In humans, aerosol dispersion was significantly correlated with forced expired flow between 25 and 75% of vital capacity. A 2-s pause between inspiration and expiration increased dispersion 23-58% in three isolated dog lungs but did not affect dispersion in the packed bed. The data suggest that lung geometry, flow rate, particle mobility, and the larynx all significantly affect aerosol dispersion by influencing the reversibility of aerosol transport between inspiration and expiration.
The significance of convective and diffusive gas transport in the respiratory system was assessed from the response of combined inert gas and particle boluses inhaled into the conducting airways. Particles, considered as "nondiffusing gas," served as tracers for convection and two inert gases with widely different diffusive characteristics (He and SF6) as tracers for convection and diffusion. Six-milliliter boluses labeled with monodisperse di-2-ethylhexyl sebacate droplets of 0.86-microns aerodynamic diameter, 2% He, and 2% SF6 were inspired by three anesthetized mechanically ventilated beagle dogs to volumetric lung depths up to 170 ml. Mixing between inspired and residual air caused dispersion of the inspired bolus, which was quantified in terms of the bolus half-width. Dispersion of particles increased with increasing lung depth to which the boluses were inhaled. The increase followed a power law with exponents less than 0.5 (mean 0.39), indicating that the effect of convective mixing per unit volume was reduced with depth. Within the pulmonary dead space, the behavior of the inert gases He and SF6 was similar to that of the particles, suggesting that gas transport was almost solely due to convection. Beyond the dead space, dispersion of He and SF6 increased more rapidly than dispersion of particles, indicating that diffusion became significant. The gas and particle bolus technique offers a suitable approach to differential analysis of gas transport in intrapulmonary airways of lungs.
We have measured the longitudinal dispersion of boluses of helium, acetylene and sulphur hexafluoride in a plastic model of the human airways--generations zero through six--during high frequency ventilation (HFV). HFV was maintained by a piston pump. Frequency f and tidal volume VT ranged from 2.5 to 25 Hz and from 5 to 20 ml, respectively. Boluses were injected near the entrance of the zeroth generation (trachea), and the dispersion curves were measured by mass spectrometry at the end of the sixth airway generation. The shapes of the bolus dispersion curves could be well described with Gaussian distribution functions. With the exception of the HFV-conditions with VT = 5 ml, the effective dispersion coefficient DDISP appeared to be independent of the molecular diffusion coefficient. This independency was also found by other investigators in studies with dogs and human subjects. The measured results for DDISP for different f and VT could be satisfactorily described with the empirical equation DDISP = 0.0617 f0.8VT1.38 [cm2S-1]. Application of this equation to f and VT values normally applied in man resulted in DDISP values which should be considered to be too small for maintaining eucapnic ventilation in vivo. On the basis of this result we believe that during HFV in intubated subjects gas transport by longitudinal dispersion will be limited to the instrumental dead space--the endotracheal tube inclusive--and a few generations of large bronchi.
Convective gas mixing in the respiratory tract of 17 healthy male subjects was studied by an aerosol bolus technique. The monodisperse 1 micron di(2-ethylhexyl)sebacate droplets we used behaved as a nondiffusing gas. As the bolus was inspired to different depths and then expired, we measured the extent to which the bolus spread. We found that the deeper the bolus penetrated into the lungs, the more it became dispersed. The half-width of the expired bolus was a linear function of the volume to which the bolus penetrated at volumetric penetrations of 100-800 cm3. This suggests that convective mixing is not confined to central airways but can also occur in the lung periphery.
The geometry and morphometry of intraacinar airways in human lungs were studied on silicone rubber casts from two adult lungs. We defined acini as the complex of alveolated airways distal to the terminal bronchioles--that is, beginning with the first-order respiratory or transitional bronchiole. The morphological properties of pulmonary acini are described. The acinar volume averages 187 mm3 (SD +/- 79 mm3). Intraacinar airways branch dichotomously over about 9 generations (range 6-12). The internal airway diameter falls from 500 micron to 270 micron between acinar generations 0 and 10, whereas the outer diameter (including the sleeve of alveoli) remains constant at 700 micron. Towards the periphery the size of alveoli increases and clusters of alveoli become more numerous. The longitudinal path length of acinar airways (defined as the distance along the ducts from the transitional bronchiole to the alveolar sacs) averages 8.8 mm (+/- 1.4 mm). The morphometric data collected in this study are used to construct an idealized model of human acinar airways that can be related to existing models of the human bronchial tree.
We investigated the longitudinal dispersion of helium (He), methane, acetylene, butane, sulfur hexafluoride, and octafluorocyclobutane (C4F8) in a clear plastic model of the human bronchial airways. The dimensions of the seven airway generations (0-6) of the model were chosen to be equal to those given by Weibel's model A (Morphometry of the Human Lung; New York: Academic, 1963). Total volume of the model amounts to 52 ml. A small bolus of each of the tracer gases was injected within 1 ms into a constant airflow at the inlet of the model, and the bolus dispersion curve was measured at the outlet by means of a mass spectrometer. Both inspirations and expirations were simulated; the four selected values of the flow rate (V) for each simulation were 0.25, 0.5, 1, and 2 1/s, respectively. The measured bolus dispersion curves were corrected for the response characteristics of the mass spectrometer. In this way, the basal shape of the dispersion curve could be shown to be Gaussian. No significant changes in the standard deviation (sigma v) (Ultman et al., J. Appl. Physiol. 44: 297-303, 1978) of each tracer gas are found for the V values applied. sigma v increases significantly (approximately 50%), however, between the lightest (He) and the heaviest (C4F8) tracer gas used. The mean sigma v values of the 24 results (4 V values and 6 tracer gases) obtained for inspirations and expirations are 15.3 and 13.6 ml, respectively.
To investigate mechanisms of intrapulmonary convective gas transport, aerosol bolus dispersion was measured in 16 healthy children aged 7-11 years. Subjects inhaled 50-mL aerosol boluses consisting of 0.4-micron droplets of di(2-ethylhexyl) sebacate suspended in air into volumetric lung depths between 95 and 540 mL. Bolus dispersion was quantified by volumetric bolus half-width and by volumetric standard deviation of particle concentrations. Bolus half-width increased from a mean of 160 mL to 360 mL with increasing lung depth, the regression being a power law with an average exponent of 0.48. Standard deviation increased from 68 to 136 mL with the 0.42th power of volumetric penetration. There was no correlation of bolus dispersion with age, body height, or lung function parameters, except for boluses penetrating very deep into the lung where dispersion was weakly related to lung volume. The results obtained in children did not differ from those found in an adult population in an earlier study. It was concluded that airway size per se does not have a strong influence on bolus dispersion. Rather, parameters of airway geometry may be among the dominating factors influencing the fate of inhaled particles.
We examined the effects of rhythmic expansion of alveolar walls on fluid mechanics in the pulmonary acinus. We generated a realistic geometric model of an alveolated duct that expanded and contracted in a geometrically similar fashion to simulate tidal breathing. Time-dependent volumetric flow was generated by adjusting the proximal and distal boundary conditions. The low Reynolds number velocity field was solved numerically over the physiological range. We found that for a given geometry, the ratio of the alveolar flow (QA) to the ductal flow (QD) played a major role in determining the flow pattern. For larger QA/QD (as in the distal region in the acinus), the flow in the alveolus was largely radial. For small QA/QD (as in the proximal region in the acinus), the flow in the alveolus was slowly rotating and the velocity field near the alveolar opening was complex with a stagnation saddle point typical of chaotic flow structures. Performing Lagrangian fluid particle tracking, we demonstrated that in such a flow structure the motion of fluid could be highly complex, irreversible, and unpredictable even though it was governed by simple deterministic equations. These are the characteristics of chaotic flow behavior. We conclude that because of the unique geometry of alveolated duct and its time-dependent motion associated with tidal breathing, chaotic flow and chaotic mixing can occur in the lung periphery. Based on these novel observations, we suggest a new approach for studying acinar fluid mechanics and aerosol kinetics.
The dispersion of aerosol boluses in the human lungs has been studied in health and disease, usually as a means of investigating convective mixing. However, there are limited data on the roles of critical factors, such as the volume of inhaled boluses, lung inflation, and gender on dispersion. To examine these factors, we measured the difference in volume variance between exhaled and inhaled boluses (sigma 2V) of a 0.5-micron aerosol in 11 healthy male and 12 healthy female subjects as a function of tidal volume (VT = 1,000 and 1,500 ml in females and 1,000 and 2,000 ml in males), bolus penetration volume (Vi at 250-ml increments over each VT), and bolus volume (target VBol = 75, 150, and 300 ml). Analysis of variance showed marginally significant gender effects (P = 0.073) on sigma 2V, with sigma 2V greater in males than in females. There was also a significant effect of VBol on sigma 2V (P < 0.001). A Vi-dependent mean volume shift between inhaled and exhaled boluses (delta V) was observed at all Vi except 500 ml. The observation of gender and VBol effects and the existence of a nonzero delta V suggest that convective mixing mechanisms other than longitudinal dispersion alone occur in the healthy lung. The lack of VT dependence suggests a minimal role of lung inflation above functional residual capacity on dispersion. The dependence of sigma 2V on Vi2 up to 1,750 ml and minimal VBol effects demonstrates that convective mixing processes continue far into the gas exchange regions of the lung and support a significant role for axial streaming.
Aerosol bolus dispersion is a physiological test of lungs, which uses monodisperse submicron particles to measure intrapulmonary convective gas mixing. In this study, aerosol bolus dispersion was measured in healthy subjects in order to assess reference values for possible clinical applications, to assess the reproducibility of these values, and to identify physical and physiological factors influencing aerosol bolus dispersion. Aerosol bolus dispersion was measured in 79 healthy subjects using 20 cm3 aerosol boluses consisting of monodisperse di-2-ethylhexyl sebacate (DEHS) particles. The reproducibility of parameters characterizing the width of the exhaled bolus was of the same order as that of parameters of the flow-volume curve (10%). Aerosol bolus dispersion was independent of the level of lung inflation, and the slope of the relationship between flow rate and dispersion was on average not significantly different from zero (range 100-700 cm3.s-1). Multiple linear regression showed that aerosol bolus dispersion increased with increasing total lung capacity of the subject. We conclude that differences in total lung capacity between individuals should be taken into account when using measures of aerosol bolus dispersion for possible clinical applications.
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.
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.
review discusses the potential utility of two methods using inhaled aerosols to detect and diagnose lung disease and to evaluate the efficacy of therapy. Aerosol bolus dispersion measures convective gas mixing; aerosol-derived airway morphometry assesses the calibers of airway and airspaces. These two methods are discussed in terms of their ease of use (simplicity and acceptability) and current data regarding their validity, reproducibility, specificity, sensitivity, and detection of lung improvement with therapy. Part 1 of this review focuses upon aerosol bolus dispersion; Part 2(1) focuses upon aerosol-derived airway morphometry. Aerosol bolus dispersion has many features that make it clinically attractive. It is simple to administer and patients can successfully perform the maneuvers. It detects known alterations in the lungs. It is reproducible and has high specificity and sensitivity. However, every lung disease or condition known to be detected by aerosol bolus dispersion is also detected by spirometery, maximal expiratory flow-volume curves, or another conventional lung function test. This, aerosol bolus dispersion appears best reserved as a specialized method to supplement conventional lung function tests and to characterize convective gas transport.
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.
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).
In a companion study (Verbanck S, Schuermans D, Vincken W, and Paiva M, J Appl Physiol 90: 1754-1762, 2001), we investigated whether saline aerosol bolus tests could also be used to detect proximal, as opposed to peripheral, airway alterations. We studied 10 never-smokers before and after histamine challenge, obtaining, for various volumetric lung depths (VLD), saline bolus-derived indexes computed by discarding aerosol concentrations below either 50% of the exhaled bolus maximum (half-width, H) or below cutoffs ranging from 5 to 25% (standard deviation, sigma(5%)-sigma(25%)) and skew (sk(5)-sk(25%)). Multiple-breath N(2) washout-derived indexes of conductive (S(cond)) and acinar (S(acin)) ventilation inhomogeneity were also determined. After histamine, S(cond) significantly increased (P = 0.008) whereas S(acin) remained unaffected, indicating purely conductive airway alteration. Consistent with this observation, sk(5%) (or sk(25%)) was increased to the same extent at all VLD, and sigma(5%) was increased preferentially at low VLD. By contrast, H and sigma(25%) displayed preferential increases at high VLD, a pattern similar to that induced by peripheral alterations. The present work shows that proximal airway alteration can be reliably identified by saline bolus tests only if these include measurements at low and high VLD and if bolus dispersion is quantified as a standard deviation with a low cutoff.
We explored the possibility of using a saline aerosol for bolus dispersion measurements to detect peripheral airway alterations in smokers. Indexes of ventilation inhomogeneity in conductive (S(cond)) and acinar (S(acin)) lung zones, as derived from the multiple-breath N(2) washout (Verbanck S, Schuermans D, Van Muylem A, Noppen M, Paiva M, and Vincken W, J Appl Physiol 83: 1807-1816, 1997), were also measured. The saline bolus test consisted of inhaling 60-ml saline aerosol boluses to different volumetric lung depths (VLD) in the 1.1 liter volume above functional residual capacity. In the never-smoker group (n = 12), saline boluses showed bolus dispersion values consistent with normal values reported in the literature for 0.5- to 1-microm aerosols. In the smoker group (n = 12; 28 +/- 9 pack years, mean +/- SD), significant increases were seen on dispersion and skew of the most peripherally inhaled saline boluses (VLD = 800 ml; P < 0.05) as well as on S(acin) (P = 0.007) with respect to never-smokers. Shallow inhaled boluses (VLD = 200 ml) and S(cond) did not reveal any significant differences between smokers and never-smokers. This study shows the consistent response of two conceptually independent tests, in which both saline aerosol and gas-derived indexes point to a heterogeneous distribution of smoking-induced structural alterations in the lung periphery.
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.
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.
Lunar dust presents a potential toxic challenge to future explorers of the moon. The extent of the inflammatory response to lunar dust will in part depend on where in the lung particles deposit. To determine the effect of lowered gravity, we measured deposition of 0.5 and 1 μm diameter particles in six subjects on the ground (1G) and during short periods of lunar gravity (1/6G) aboard the NASA Microgravity Research Aircraft. Total deposition was measured during continuous aerosol breathing, and regional deposition by aerosol bolus inhalations at penetration volumes (V
p) of 200, 500 and 1,200 ml. For both particle sizes (d
p), deposition was gravity-dependent with the lowest deposition occurring at the lower G-level. Total deposition decreased by 25 and 32% from 1G to 1/6G for 0.5 and 1 μm diameter particles, respectively. In the bolus tests, deposition increased with increasing V
p. However, the penetration volume required to achieve a given deposition level was larger in 1/6G than in 1G. For example, for d
p = 1 μm (0.5 μm), a level of 25% deposition was reached at V
p = 260 ml (370 ml) in 1G but not until V
p = 730 ml (835 ml) in 1/6G. Thus in 1G, deposition in more central airways reduces the transport of fine particles to the lung periphery. In the fractional gravity environment of a lunar outpost, while inhaled fine particle deposition may be lower than on earth, those particles that are deposited will do so in more peripheral regions of the lung.
Convective and diffusive gas transport in canine intrapulmonary airways Axial-dispersion of inert species in alveolated channels
- H Schulz
- P Heilmann
- A Hillebrecht
- J Gebhart
- M Meyer
- J Piiper
- J Heyder
- Wj Federspiel
- Pa Grant
- Jj Fredberg
Schulz H, Heilmann P, Hillebrecht A, Gebhart J, Meyer M, Piiper J,
Heyder J. Convective and diffusive gas transport in canine intrapulmonary airways. J Appl Physiol 72: 1557–1562, 1992.
24. Tsuda A, Federspiel WJ, Grant PA, Fredberg JJ. Axial-dispersion
of inert species in alveolated channels. Chem Eng Sci 46: 1419 –1426,
1991.
Aerosol Bolus Dispersion in Acinar Airways
- B Ma
Aerosol Bolus Dispersion in Acinar Airways • Ma B et al.