Inhaled Aerosol Distribution in Human Airways:A Scintigraphy-Guided Study in a 3D Printed Model

Sylvia Verbanck, PhD,1 Ghader Ghorbaniasl, PhD,2 Martyn F. Biddiscombe, PhD,3,4

Dusica Dragojlovic, MSc,2 Nathan Ricks, MSc,2 Chris Lacor, PhD,2 Bart Ilsen, MD,5

Johan de Mey, MD, PhD,5 Daniel Schuermans, MSc,1 S. Richard Underwood, MD,4

Peter J. Barnes, MD, PhD,3 Walter Vincken, MD, PhD,1 and Omar S. Usmani, MD, PhD3

Abstract

Background: While it is generally accepted that inertial impaction will lead to particle loss as aerosol is beingcarried into the pulmonary airways, most predictive aerosol deposition models adopt the hypothesis that the inhaledparticles that remain airborne will distribute according to the gas flow distribution between airways downstream.Methods: Using a 3D printed cast of human airways, we quantified particle deposition and distribution andvisualized their inhaled trajectory in the human lung. The human airway cast was exposed to 6 lm monodis-perse, radiolabeled aerosol particles at distinct inhaled flow rates and imaged by scintigraphy in two perpen-dicular planes. In addition, we also imaged the distribution of aerosol beyond the airways into the five lunglobes. The experimental aerosol deposition patterns could be mimicked by computational fluid dynamic (CFD)simulation in the same 3D airway geometry.Results: It was shown that for particles with a diameter of 6 lm inhaled at flows up to 60 L/min, the aerosoldistribution over both lungs and the individual five lung lobes roughly followed the corresponding distributions ofgas flow. While aerosol deposition was greater in the main bronchi of the left versus right lung, distribution ofdeposited and suspended particles toward the right lung exceeded that of the left lung. The CFD simulations alsopredict that for both 3 and 6 lm particles, aerosol distribution between lung units subtending from airways ingeneration 5 did not match gas distribution between these units and that this effect was driven by inertial impaction.Conclusions: We showed combined imaging experiments and CFD simulations to systematically study aerosoldeposition patterns in human airways down to generation 5, where particle deposition could be spatially linkedto the airway geometry. As particles are negotiating an increasing number of airways in subsequent branchinggenerations, CFD predicts marked deviations of aerosol distribution with respect to ventilation distribution,even in the normal human lung.

Key words: 3D printed airway model, computational fluid dynamics, radio-labeled monodisperse aerosols

Introduction

The air we breathe constantly challenges our exposedrespiratory tract, and on an average day, 10,000–15,000 Lof inhaled air traverses the airways, carrying potentially nox-ious respirable particles such as cigarette smoke, air pollutants,

allergens, and microbes that can injure the lungs and lead torespiratory disease. Globally, respiratory diseases are in-creasing in prevalence and present a considerable burden onhealthcare.(1) Mucosal inflammation and airway narrowingassociated with respiratory disease are often patchily distrib-uted within the intrapulmonary bronchial tree, sometimes

1Respiratory Division, University Hospital UZ Brussel, Vrije Universiteit Brussel, Brussels, Belgium.2Research Group Fluid Mechanics and Thermodynamics, Department of Mechanical Engineering, Vrije Universiteit Brussel, Brussels,

Belgium.3Airway Disease Section, National Heart and Lung Institute, Imperial College London and Royal Brompton Hospital, London, United

Kingdom.4Nuclear Medicine Department, Royal Brompton Hospital, London, United Kingdom.5Radiology Department, University Hospital UZ Brussel, Vrije Universiteit Brussel, Brussels, Belgium.

JOURNAL OF AEROSOL MEDICINE AND PULMONARY DRUG DELIVERYVolume 29, Number 0, 2016ª Mary Ann Liebert, Inc.Pp. 1–9DOI: 10.1089/jamp.2016.1291

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occurring in specific airway regions.(2,3) It has been reportedthat lung carcinomas develop more in the right lung and morefrequently in the upper lobes.(4–6) This supports the notion ofan association between sites of pathology and the topograph-ical deposition of inhaled noxious particles.(7,8)

In contrast, in the therapeutic management of respiratorydiseases, the inhaled airstream is utilized to carry aerosol-ized drug particles into the lungs. However, the narroweddiseased airways can redirect the airstream, dramaticallyaffecting intrapulmonary gas flow distribution patterns,(9)

and alter the distribution of inhaled therapeutic particleswithin the lungs.(10) Therefore, it is important to determinethe extent to which aerosolized particles actually move withthe ventilation gas flow that carries them through the re-spiratory tract to advance our understanding of the deposi-tion mechanisms of toxic and therapeutic particulate matter.

In vivo studies evaluating inhaled particle transport anddeposition in the diseased human lung that have controlledpertinent aerodynamic parameters such as particle size andventilatory flow are scarce.(10–12) An experimental scinti-graphic study in asthmatics indicated the importance of bothflow and particle size in determining the regional topo-graphical airways deposition of inhaled particles and alsoshowed dramatic reductions in the delivered lung dosewithout loss of therapeutic efficacy by utilizing uniform-sizedaerosols.(10) However, scintigraphy poses a radiation burdento patients, hampering systematic investigations.(12) Alter-native approaches using computational fluid dynamic (CFD)simulations suggest that aerosol particle distribution may notentirely match gas ventilation distribution across the seg-mental bronchi, even in healthy lungs.(13) Yet, the clinicalapplicability of CFD approaches is limited due to the lack ofexperimental data within a realistic airway geometry.

In this study, we developed an integrated theoretical andexperimental lung model to address the central question ofwhether aerosols follow ventilatory gas flow distribution inman. To this end, we undertook 3D printing of a thin-walledhollow airway structure based on computed-tomographicimaging of the bronchial tree down to generation five. Byembedding this physical cast in a tubing network leading tothe five lung lobes, we aimed to deliver radiolabeled particlesof uniform size (monodisperse) to assess the trajectory of theparticles through these airways and beyond into the five an-atomical lung lobes. Exacting control of particle aerodynamicsize and breathing flow during the aerosol exposure experi-ments, and a detailed analysis of the scintigraphic imagesbased on geometrical reference points, enabled a directquantitative comparison with state-of-the-art large eddy CFDsimulations in exactly the same 3D lung geometry.

Finally, the CFD simulations were also used to predictaerosol distribution patterns for a smaller particle size(3 lm) and to simulate gas versus aerosol distribution be-tween lung units subtending from generation 5 airways.

Methods

Details of the airway model, the CFD model simulationparameters and scintigraphic image acquisition, and post-processing are provided in the Supplementary Data. Thedigital airway contours of the 3D model, segmented from aCT of the bronchial tree from a young healthy female,merged with an average upper airway model(14) and its 2D

projections are depicted in Figure 1. The terminal airways ofthe physical airway cast (Fig. 2) were each snugly fitted withsilicone tubes of 1m length with a low-resistance bacterialfilter (Microgard�II, Carefusion, SanDiego, CA; Niox�,Aerocrine, Morrisville, NC) sited halfway in the tube. Alltubes led into individual entrance ports in a custom-builtflow collector (EM Technik, Maxdorf, Germany) with onecommon exit port through which air was drawn using asuction pump (Andersen Samplers, Atlanta, GA).

To measure airflow through each of the terminal pathways, aflow meter (TSI4040, St. Paul, MN) was fitted between thedownstream end of the low-resistance particle filter and the tubethat connected it to the flow collector. On the flow collector,entrance ports were organized according to the lobar unit that thecorresponding terminal airway belonged to (Fig. 2B). This fa-cilitated grouping of tubes and filters for imaging of aerosoldeposition per lung lobe after aerosol exposure of the cast.

For the aerosol exposure experiments, the tracheobron-chial physical cast was attached to the reservoir of thespinning-top aerosol generator (STAG2000; BGI Instru-ments, Waltham, MA) through a 2-m straight tube. Mono-disperse (geometric standard deviation

FIG. 1. The digital air space contours of the airway model. (A) Complete 3D represen-tation and (B) lateral projection and (C) frontal projection. The model structure includes theairspaces from an existing mouth–throat–trachea model(15) linked with the CT-based airwaystructure down to generation 5. Also indicated on the 3D view (with the gravity vectorperpendicular to the mouth inlet) are the cross sections where the transit of CFD-simulatedaerosols can be tracked, and a schematic indication (gray dashed lines) of the five lunglobes, left upper lobe (LUL), left lower lobe (LLL), right upper lobe (RUL), right middlelobe (RML), and right lower lobe (RLL). Also shown on the projections are the regions ofinterest (ROI1–5; thick white lines) drawn with a fixed margin around the model’s outerboundaries (thin gray lines) in each of its two planar views; this enables accurate super-position with the scintigraphic images. CFD, computational fluid dynamic.

FIG. 2. The airway model integration in the experimental setup. (A) Photograph of thehollow physical cast with a 1-mm-thin wall enveloping the digital air spaces of Figure 1A,with its extensions fitted to silicon tubes, each one leading to a filter. On the other side ofeach filter, another silicon tube connects to one of the ports on a custom-built flow collector,from where a common flow could be aspired to represent inhalation by a person. On the flowcollector, tubes are grouped according to the lobe that each particular airway belongs to(green contours of the schematic in B), (B) the five lobar groups are annotated as follows:LUL, LLL, RUL, RML, and RLL. The mouth opening of the cast was to be connected to thespinning-top aerosol generator through a 2-m tube to ensure a predictable input conditionsuch that the radiolabeled monodisperse 6 lm aerosols could be drawn through our exper-imental design for exactly 5 minutes using a suction pump at 30 or 60 L/min.

AEROSOL DEPOSITION AND DISTRIBUTION IN A HUMAN AIRWAY MODEL 3

scintigraphy and simulated by CFD as follows. Particlesdeposited on the walls of the 3D model as computed byCFD were first projected on the two perpendicular planescorresponding to scintigraphic imaging. Then, particlecount in each planar location was dispersed according to adispersion function obtained by scintigraphic measurementof point sources inside the physical cast (SupplementaryFig. S4; Supplementary Data are available online at www.liebertpub.com/jamp).

Results

Figure 3 illustrates the resolution obtained with thescintigraphic maps of aerosol deposition in the physical cast;all experimental data are in the Supplementary Data (Sup-plementary Figs. S1 and S2). The five regions of interestbased on the model contours (Fig. 1) were superimposedonto the frontal and lateral scintigraphic aerosol depositionimages as a reference so that aerosol deposition at the glottisand in the airways could be clearly distinguished. Thegreater relative aerosol deposition in the oropharynx versusthe airways in the case of inhalation flow at 60 L/min(Fig. 3B) versus 30 L/min (Fig. 3A) was also readily ap-preciated. The aerosolized particles that exited beyond theairway endings of the physical cast were collected in silicontubes and filters. The tube and filters were grouped, ac-cording to the lung lobes that the airway endings belongedto, to quantify the particle mass distribution between the fivelung lobes (five lower panels in Fig. 3).

The CFD simulations provided a flow field of the gas(represented in Fig. 4A,B for 30 L/min) and the corre-sponding predicted deposition pattern of the 6 lm particleson the walls of the model (Fig. 4C). Projecting all the de-posited particles of Figure 4C onto the frontal and lateralplanes, and applying experimental point dispersion byscintigraphy, resulted in Figure 4D; Figure 4E provides thesame representation for 60 L/min. This allows a visual ap-preciation of the level of agreement between experimental(Fig. 3A, B) and simulated (Fig. 4D, E) particle depositionpatterns in the airway model. However, a quantitative com-parison between all three experiments and each correspond-ing simulation for both flows can be inferred from the profilesin Figure 5. These profiles were obtained by summing allexperimental or simulated counts at each linear distance be-tween the top and bottom of the TB cast by scanning theimage from the leftmost outline of ROI4 to the rightmostoutline of ROI5 and dividing the counts at each linear dis-tance by the total counts in the TB cast.

Figure 5 also shows the profiles for 3 lm derived from theCFD-based images in Supplementary Figure S3. From therepresentation in Figure 5, it can be appreciated that irre-spective of absolute deposition, a greater proportion ofparticles passes the oropharynx to deposit in the lowerportion of the TB cast when comparing 3 versus 6 lm par-ticles. This holds true for both flow rates.

The experiments and simulations were in agreement toshow that the total aerosol deposition in the 3D model increasedwith increasing airflow from 30 to 60 L/min (experiment:

FIG. 3. Scintigraphic images of 6 lm particle deposition in the airways. Frontal and lateral views withthe cast positioned as in Figure 1B, C, and five smaller images of the tubings and filters capturing allparticles escaping the cast toward the LUL, LLL, RUL, RML, and RLL. The color scales of all panels inthis figure relate to a logarithmic color scale with maximum value corresponding to the highest count ratein the image. (A) 30 L/min; (B) 60 L/min.

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28% – 0.2% [SD] to 69% – 7% [SD]; simulation: 24% to 74%).In absolute values, particle deposition in the airways beyond thetrachea (generation 1 to 5) was relatively low and very similarfor both airflows (experimental values ranging 3.0%–3.5%;simulation data 5%–6%). However, since the number of parti-cles remaining in suspension beyond the trachea also depends onflow, the resulting deposition efficiency of this airway com-partment (generation 1 to 5) increased with increasing airflowsfrom 30 to 60 L/min (by a factor 2.6 in experiments; a factor 3.1in CFD simulations), as expected for particle transport domi-nated by inertial impaction.

Interestingly, at low airflows (30 L/min) through themodel, aerosol deposition favored the airways of the left

lung, resulting in a left-to-right (L/R) ratio of airway de-position above unity (experiment L/R: 1.35 – 0.04 [SD];simulation L/R: 1.30). Increasing airflow to 60 L/min led toa decrease in the L/R airway deposition ratio (experiment L/R: 1.16 – 0.10 [SD]; simulation L/R: 1.20). Despite an L/Rairway deposition ratio >1, the left lung received a smallerproportion of total aerosol mass (which includes particles insuspension and deposited) compared with the right lung.This is entirely consistent with the smaller portion of gasventilation into the left lung. Indeed, both experimentsand simulations were in agreement to show an L/R ratio ofgas ventilation of 0.88 and a near identical L/R ratio ofaerosol mass of 0.89 – 0.02 (SD) (experimental) and 0.91

FIG. 4. Illustration of simulated flow fields and particle distribution over the airway model at 30 L/minand simulated projections at 30 and 60 L/min. (A, B) CFD-computed velocity fields and streamlines intwo selected perpendicular planes intersecting with the airway model as shown in the insets, (C) aerosolparticle distribution over the airway model in a 3D rendering, (D, E) frontal and lateral projections ofaerosol particle distribution over the airway model for 30 L/min (D) and 60 L/min (E) for comparison withexperimental projections in Figure 3.

AEROSOL DEPOSITION AND DISTRIBUTION IN A HUMAN AIRWAY MODEL 5

(simulation) at an airflow of 30 L/min. We also comparedgas and aerosol distribution over the five lobes (Fig. 6),showing that between the lobes aerosol distribution is moreor less in proportion to gas distribution, both in experimentsand CFD simulations.

Using only CFD and including also 3 lm particle size, wealso investigated to what extent aerosol mass distributiondiverged from gas ventilation distribution as it spreads overmore airways in subsequent bronchial generations. This wasquantified by considering the ratio of gas flow (as a per-centage of total gas flow) to aerosol flow (as a percentage oftotal aerosol flow), Raer/gas, as suggested by Darquenneet al.(13); Raer/gas = 1 in a given airway represents a perfectmatch between aerosol mass flow distribution and gasventilation distribution toward the lung units subtended bythese airways. The individual Raer/gas values computed ineach airway of subsequent bronchial generations between 2and 5 are depicted in Figure 7, showing a progressive in-crease of Raer/gas variability with particle size and flow.

Switching off gravity in the CFD model did not affect anyof the deposition or distribution parameters by more than

3%, consistent with the fact that under the experimentalconditions of the study, the main contributing factor to theobserved aerosol behavior was particle impaction and notsedimentation.

Discussion

We systematically investigated particle transport in thelungs using monodisperse aerosols of 6 lm since this particlesize is common to the size range of aerosol drug formulationsto treat the lungs and to that of the PM10 fraction; that is, thefraction of particulates in air smaller than 10 lm, employedwhen referring to adverse environmental particles consideredinjurious to the lung.(16) Our combined CFD and experi-mental data in a human airway structure show that thoseinhaled particles that are able to negotiate the oropharynxhave an aerosol mass distribution between the five lung lobesroughly corresponding to their gas ventilation distribution(Fig. 6). Therefore, at the lobar level, inhaled aerosols es-sentially get carried away in proportion to the air flow as theybecome distributed between the different lung lobes.

In our normal human airway cast, experimental andsimulated gas ventilation distribution (Fig. 6) was deter-mined by the airway geometry since the only boundarycondition (for experiments and simulations) was that pres-sure at all airway outlets was the same. This gas ventilationdistribution is slightly different from that in two previousCFD models (Fig. 6), where mass flow imposed on thesegmental bronchi was considered proportional to subtendedsegment volume from an anatomical study (left upper lobe

FIG. 5. Experimental and simulated normalized countprofiles in the TB cast. Relative deposition is obtained byconsidering all counts at a linear distance between top andbottom of cast and dividing these by all counts in the model.Three experimental curves for 6 lm (three solid lines) andone simulated curve for 6 lm (dashed line) and for 3 lm(dotted line). (A) 30 L/min and (B) 60 L/min.

FIG. 6. Experimental and simulated gas and aerosol dis-tribution over the five lobes. Gas and aerosol distributionover LUL, LLL, RUL, RML, and RLL. Aerosol distributionalso includes particles that got deposited in the airwaysleading to the corresponding lobe. (A) experiments (mean –SD); (B) simulations.

6 VERBANCK ET AL.

[LUL]: 20%, left lower lobe [LLL]: 25%, right upper lobe[RUL]: 20%, right middle lobe [RML]: 9%, right lower lobe[RLL]: 26%)(13) or where the imposed mass flow distribu-tion was based on CT-derived lobar volumes in one supinehuman subject (LUL: 15%, LLL: 35%, RUL: 13%, RML:5%, RLL: 32%).(17) Despite these differences (Fig. 6), thesmallest lobe (RML) generally receives the smallest portionof the inhaled air, and of the larger lobes, the lower lobes(LLL, RLL) tend to receive a greater portion of inhaled airversus the upper lobes (LUL, RUL), depending also on theorientation in the line of gravity.

In patients with chronic respiratory disease such as asth-ma, cystic fibrosis, or chronic obstructive pulmonary disease(COPD), clusters of diseased airways or parenchymal tissuecan impair normal expansion of selected lobes. The sameholds true for COPD patients undergoing lung volume re-duction interventions,(18) where a lung lobe is either re-moved or deliberately blocked from the rest of the lung. Inall the above pathologies, aerosolized drug therapy is uti-lized for treatment, and we suggest that redistribution ofdrug particles will follow the redistribution of gas ventila-

tion over the lung lobes. A confounding factor in lung dis-ease, which can be studied with the same methodologydescribed here, is how local airway obstruction modifiesflow fields, potentially causing additional turbulent eddiesaffecting local aerosol transport and deposition.

The question of whether inhaled aerosol particles distributeover the lung units in proportion to the airflow distributionover these same units is difficult to study directly in vivo sincethis requires both computed tomographic imaging to accu-rately define the anatomical contours of ventilated lung unitsand single-photon emission to image gas and aerosol distri-bution between these units.(19) At the lobar level, no such gasor aerosol distribution data are currently available in healthysubjects or patients with respiratory disease. In vivo imagingdata of gas ventilation and aerosol mass distribution betweenthe left and right lungs do exist,(20–23) showing that thepreferential particle transport toward the right lung tracks thepreferential gas transport toward the right lung.

However, not all CFD simulations agree to reproduce thisexperimental result. For instance, a recent CFD simulationstudy of particles greater than 2.5 lm predicted an L/R ratioof lung aerosol distribution greater than 1, despite a gasventilation L/R ratio of less than 1.(17) The authors referredto specific glottal vortices in their particular model geometryto interpret their CFD result,(17) and possibly the cross-sectional left main bronchus/right main bronchus (LMB/RMB) ratio of the model (which was only 55% vs. 70%–85% used by us and others) could also have contributed tothis paradoxical L/R result. Another CFD simulation studyin a bronchial airway model without oropharynx(13) did notreport particle deposition in the airways, but observed thataerosols roughly followed gas flow, implying an L/R ratio ofaerosol distribution smaller than 1.

Our CFD could be confirmed with experimental data inexactly the same geometry, also obtaining an aerosol dis-tribution L/R

as is usually assumed in empirical prediction models.(26) Inthis scenario, a novel personalized treatment approach(27)

based on mapping of the obstructed airways coupled with areliable CFD simulation method could be employed to cir-cumvent a localized aerosol supply problem in such pa-tients. Ideally, this would incorporate data on the patient’sgas ventilation distribution either assessed by a ventilationimaging modality(28) or estimated from noninvasive tests.(29)

Our model allows flexibility, where downstream resistancescan be introduced on selected airway tubes in our physicalcast to replicate patchy gas ventilation distribution in pa-tients and thereby allow the resulting aerosol redistributionto be studied in a variety of airway diseases.

Limitations of the study

Before initiating this study, we accepted two limitations tokeep radiation exposure (dose and duration) during experi-mental handling to a minimum: we did not image each tubeand filter attached to each generation 5 airway separately, andwe chose to image by planar imaging in two perpendicularplanes instead of full SPECT. Despite these limitations, theprinciples of the present study could inform similar studieswith alternative imaging techniques such as magnetic reso-nance or fluorescence imaging where this limitation can beavoided. If only the distribution beyond the cast is relevant,chemical assays on tubes and filters may even suffice.

We did not attempt to coat the TB cast inner walls, whichmay have led to some aerosol particles bouncing off the wallin experiments, whereas the CFD simulations assume a trapboundary condition. In this sense, the comparison of abso-lute deposition values (that were expected to be low any-way) should be interpreted with caution. However, the mainaim of the present study was relative aerosol deposition anddistribution in and beyond the cast, which should have beenaffected less by this limitation. Another intrinsic limitationof the study design is the lengthening of the terminal air-ways to allow steady boundary conditions for CFD; sincethese were also incorporated in the physical cast, simulatedand experimental deposition efficiency of generation 1–5may not correspond to that which would be obtained if anadditional branching generation were added.

Finally, we only considered a constant inhalation flow ina model with a fixed-orifice glottis, which may not entirelyreflect the situation in a normal breathing human subject.However, it did meet our main study goal to render theexperimental and CFD simulation condition as similar aspossible. Once validated in this way, CFD simulations canbe made to include conditions that are almost impossible toobtain experimentally.

In conclusion, we show here that particle distribution overthe lung lobes roughly follows the corresponding gas ven-tilation distribution in a normal human airway structure. Bycombining aerosol imaging experiments and CFDs in a re-alistic 3D printed hollow cast, the scintigraphic images ofaerosol deposition also revealed loci of disproportionatelyhigh particle deposition in distinct geometrical locationsunder different flow conditions. The CFD model was alsoused to explore to what extent aerosol distribution deviatedfrom gas distribution across an increasing number of smallerairways in branching generations up to 5.

Acknowledgments

This project was supported by the Fund for ScientificResearch-Flanders (FWO-Vlaanderen, Belgium), a VUBConcerted Research Action grant, and the National Institutefor Health Research (NIHR) Respiratory Disease Biomedi-cal Research Unit at the Royal Brompton and HarefieldNHS Foundation Trust and Imperial College London. DrOmar S Usmani is a recipient of a UK NIHR Career De-velopment Fellowship.

Author Disclosure Statement

No competing financial interests exist.

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Received on January 15, 2016in final form, April 18, 2016

Reviewed by:Winfried Möller

Gordon Prisk

Address correspondence to:Sylvia Verbanck, PhD

Respiratory DivisionUniversity Hospital UZ Brussel

Laarbeeklaan 101Brussels 1090

Belgium

E-mail: sylvia.verbanck@uzbrussel.be

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