Respiratory Physiology & Neurobiology 163 (2008) 128138

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Respiratory Physiology & Neurobiology

journal homepage: www.elsevier.com/locate/resphysiol

Modeling airow and particle transport/deposition

in pulmonary airways
Clement Kleinstreuer a,b, , Zhe Zhang a , Zheng Li a
a
b

Department of Mechanical & Aerospace Engineering, North Carolina State University, Raleigh, NC 27695-7910, USA
Department of Biomedical Engineering, North Carolina State University, Raleigh, NC 27695-7910, USA

a r t i c l e

i n f o

Article history:
Accepted 7 July 2008
Keywords:
Pulmonary airways
Deposition enhancement factor
Tracheobronchial airways

a b s t r a c t
A review of research papers is presented, pertinent to computer modeling of airow as well as nano- and
micron-size particle deposition in pulmonary airway replicas. The key modeling steps are outlined, including construction of suitable airway geometries, mathematical description of the air-particle transport
phenomena and computer simulation of micron and nanoparticle depositions. Specically, diffusiondominated nanomaterial deposits on airway surfaces much more uniformly than micron particles of the
same material. This may imply different toxicity effects. Due to impaction and secondary ows, micron
particles tend to accumulate around the carinal ridges and to form hot spots, i.e., locally high concentrations which may lead to tumor developments. Inhaled particles in the size range of 20 nm dp 3 m
may readily reach the deeper lung region. Concerning inhaled therapeutic particles, optimal parameters
for mechanical drug-aerosol targeting of predetermined lung areas can be computed, given representative
pulmonary airways.
2008 Elsevier B.V. All rights reserved.

1. Introduction and overview

Experimental and computational modeling of biomechanics
of the human respiratory system is quite challenging because of
the complex airway geometries, three-phase ow phenomena,
uidstructure interactions, and species mass transfer. Of basic
concern is the understanding and achievement of O2 CO2 gas
exchange under normal and pathological conditions. Modeling
applications include: (i) dosimetry-and-health effects of inhaled
toxic particulate matter, of interest to toxicologists, health-care
providers and regulators and (ii) optimal drug-aerosol targeting to
predetermined sites to combat lung and systemic diseases. Clearly,
the biomechanics phenomena occurring in a complete set of realistic pulmonary airways cannot yet be simulated let alone for every
patient. However, based on CT-scans and MRI as well as benchmark
experimental data sets, detailed computer simulations can be performed at least for representative airway segments. In addition,
global lung models in terms of simple semi-empirical correla-

The views and conclusions contained herein are those of the authors and should
not be interpreted as necessarily representing the ofcial policies or endorsements,
either expressed or implied, of the Air Force Ofce of Scientic Research.
Corresponding author at: Department of Mechanical & Aerospace Engineering
and Department of Biomedical Engineering, Campus Box 7910, North Carolina State
University, Raleigh, NC 27695-7910, USA. Tel.: +1 919 515 5261; fax: +1 919 515 7968.
E-mail address: ck@eos.ncsu.edu (C. Kleinstreuer).
1569-9048/$ see front matter 2008 Elsevier B.V. All rights reserved.
doi:10.1016/j.resp.2008.07.002

tions have provided surprisingly accurate deposition efciencies

for a wide range of (spherical) particle diameters.
With the advent of petascale (1015 calculations/s) computing,
future simulation results will cover the most important biomechanics phenomena in actual human airways and provide solutions to
the patient-specic drug-aerosol targeting problem.
1.1. Toxic particulate matter inhalation
Toxic material in vapor, liquid droplet and solid particle forms
is being inhaled, as it appears indoors or outdoors in all shapes and
sizes, typically ranging from nanometers (109 m) to micrometers
(106 m). Most severely affected by polluted air may be the children
and the elderly. Given any set of ambient conditions in terms of pollutant concentration, temperature and humidity, it is of interest to
predict how much deposits where in the human respiratory tract
under realistic breathing conditions. Such results, usually obtained
via experimentally validated computer simulations, are of great
interest to toxicologists, epidemiologists, health-care providers,
and regulators of air pollution standards. Toxic material dynamics is
described in two size-dependent categories; because the transport
mechanism for nanomaterial is diffusion dominant while micron
particles are impaction and possibly gravitation dominant. Hence,
nanoparticles, which include some vapors, are modeled with a mass
transfer equation and micron particles with Newtons second law
of motion (Kleinstreuer, 2006).

C. Kleinstreuer et al. / Respiratory Physiology & Neurobiology 163 (2008) 128138

1.1.1. Toxic nanomaterial

Nanotechnology and related manufacture of nano-scale materials are major growth industries (Roco, 2006). Clearly at the stages of
nanomaterial production, handling and use, nanoparticles become
airborne and inhaled (Service, 2003; Theodore and Kunz, 2005;
among others). Hence, the specter of serious health problems arise
from inhalation of such (toxic) metal, metal-oxide, carbon-based
and synthetic nanomaterials (Oberdrster et al., 2005; Kumar,
2006; among others). After nanoparticle inhalation, tissue absorption and transport to extra-pulmonary organs, nanomaterial may
target the central nervous system and immune system (Bang and
Murr, 2002; Oberdrster et al., 2005). It is not just the level of toxicity of some nanomaterials which poses potential respiratory and
other health risks; but, also their size, shape and surface distribution which turns out to be even more toxic than inhaled micron
particles of the same material. Also, other toxins could bind with
nanoparticles and piggyback their way into the body. In summary,
the enhanced toxicity of nanomaterial can be attributed to (i) the
greater surface reactivity of nanoparticles due to high curvatures as
well as the larger surface area relative to the nanoparticle mass; (ii)
the prolonged retention time and decreasing fraction of clearance
for ultrane particles; (iii) an almost uniform coating of the airway surfaces by nanoparticles; (iv) larger deposition fractions (DF)
of nanomaterial in deeper parts of the lung, including the alveolar
region.
So far, there are relatively few investigations of (spherical)
nanoparticle deposition in the human airways, primarily because of
the difculty of nanoparticle generation for experimental measurements and accurate predictions with computational uid-particle
dynamics (CFPD) simulations. In a series of papers, Cheng et al.
(1988, 1995, 1996, 1997a,b) and Smith et al. (2001) published their
measurements of mass transfer and deposition of nanoparticles
(3.6 nm < dp < 150 nm) in casts of human nasal, oral and upper tracheobronchial (TB) airways; Cohen et al. (1990) reported their
experimental work on nanoparticle deposition in an upper tracheobronchial airway cast; (Kelly et al., 2004b) measured the nasal
deposition efciencies of nanoparticles with diameter between 5
and 150 nm; Daigle et al. (2003) and Kim and Jaques (2004) measured total respiratory tract deposition fraction of nanoparticles
(8100 nm) in healthy adults. Examples of numerical simulations
for nanoparticle deposition include Asgharian and Anjilvel (1994),
Balashazy and Hofmann (1993, 1995), Yu et al. (1996, 1998), Moskal
and Gradon (2002), Hofmann et al. (2003), Kelly et al. (2004b),
Zhang and Kleinstreuer (2004), Shi et al. (2006), Zamankhan et al.
(2006), and Longest and Xi (2007b).
Almost all theoretical as well as experimental studies describing the diffusional deposition in the tracheobronchial airways
assumed uniform or parabolic inlet velocity proles and particle
distributions. However, the actual velocity proles and particle
distributions are quite different from those axisymmetric proles and distributions due to ow development, secondary ows,
and non-uniform particle transport in the upstream airway section (Kleinstreuer and Zhang, 2003a). In addition, many published
numerical simulations were lacking detailed model validations.
Recently, the EulerEuler approach has been validated as an accurate and effective modeling technique for spherical nanoparticle
deposition in idealized airway segments (Shi et al., 2004; Zhang
and Kleinstreuer, 2004; Zhang et al., 2005). So far, little information is available about modeling of nanoparticle (<100 nm)
deposition in the alveolar region. In fact, major nanoparticle deposition may occur in the pulmonary region (e.g., about 2035%
of 40100 nm particles, see Kim and Jaques, 2004). The low surface tension produced by a surfactant lm in the deeper parts of
the lung, including the alveolar region, may aid the transfer of
nanoparticles through the liquid wall layer (Geiser et al., 2000)

129

so that the toxicity effect of deposited particles in these regions

is enhanced. Furthermore, the coupling of uid ow and alveolar
wall movement during expansion/contraction (i.e., uidstructure
interactions) and its effects on particle transport/deposition have
rarely been analyzed (Tsuda et al., 1994; Haber et al., 2003; Darquenne and Prisk, 2003; Haber and Tsuda, 2006). Reliable studies
of transport and deposition of non-spherical nanoparticles are even
less available. Non-spherical particle motion, say, of carbon nanotubes, is much more complicated than that of spherical particles
because these particles undergo simultaneous translation, rotation
and re-orientation when traveling in shear ow (Brenner and Condiff, 1972; Bernstein and Shapiro, 1994). Due to the complicated
motion of non-spherical particles, most of the existing models for
non-spherical particles, such as ber deposition in human airways,
focus on deposition of bers with diameters in the micro-size range
in single airway bifurcation models assuming simple shear ow
or simple ber transport (e.g., Cai and Yu, 1988; Asgharian and
Anjilvel, 1995; Zhang et al., 1996; Balashazy et al., 2005).
1.1.2. Toxic micron particles
While the potential health hazards of nanomaterials has only
been very recently acknowledged, inhaled micron-particle depositions for dosimetry-and-health-risk assessments have been studied
for decades (Heyder, 2004). Clearly, the experimental and computational contributions reviewed deal with spherical micron
particles that are completely neutral concerning toxic or therapeutic effects.
For example, Schlesinger et al. (1982), Gurman et al. (1984),
and Kim and Garcia (1991) showed that cyclic inhalation generates higher particle deposition efciencies than steady inhalation
at the mean Reynolds number of the inlet ow waveform. Specically, Gurman et al. (1984) have estimated a 15% increase in inertial
impaction with cyclic ows. Kim and Garcia (1991) calculated that
the deposition efciency (DE) should increase by about 23% with
sine-wave type ows regardless of the cyclic frequency. Cheng and
Wang (1976) measured the deposition of 0.582.05 m aerosols
along the airway walls of a second generation under condition of
constant and cyclic inspiratory ows for a single mean inspiratory ow rate. Overall deposition was found to be greater under
cyclic ow. The maximum increase was 26% above that observed
when constant ow at the mean Reynolds number was assumed.
Schlesinger et al. (1982) and Gurman et al. (1984) measured the
deposition of 3 and 8 m monodispersed aerosols in replicate casts
of the human tracheobronchial tree under conditions of constant
and cyclic inspiratory ows. Their results also showed that the
deposition efciencies within hollowed airway casts under cyclic
ow were greater than those under constant ow assuming the
mean ow rate. For a high ow rate (60 L/min), the deposition
efciencies (DEs) increase by about 100% for 8 m particle and
up to 600% for 3 m particles. However, this marked increase in
DE may be attributed to turbulence effects under cyclic ow conditions in their experiments. Kim and Garcia (1991) measured
the deposition of micron-sized particles in a single bifurcation
model approximately representing generations G3G4 for cyclic
ow at mean Reynolds numbers of 6795547 and Stokes numbers
of 0.0280.25. Their results showed that the DE with cyclic ow
was also higher than that obtained with constant ow. More in
vitro experimental studies of micron-particle deposition in tracheobronchial airways focused on steady inhalation in glass or metal
casts of the TB tree from one to several bifurcations (see Ferron,
1977; Kim and Iglesias, 1989; Oldham et al., 1997, 2000; Kim and
Fisher, 1999; Zhang and Finlay, 2005; among others), or realistic airway replica based on cadavers representing trachea (G0) to
generations G3, G4 or G5 (see Schlesinnger and Lippmann, 1972;
Schlesinger et al., 1977; Zhou and Cheng, 2005; among others).

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The deposition efciencies at each generation were usually measured in these studies for different combinations of particle size and
inspiratory ow rate. However, detailed air/particle transport phenomena as well as local deposition patterns and surface densities
of deposited particle in bifurcating airways are difcult to obtain
experimentally.
Clearly, computational uid dynamics (CFD) simulation is an
effective way to gain such information. Examples of such contributions focusing on tracheobronchial trees, include Comer et
al. (2001), Zhang et al. (2002a,2005), Nowak et al. (2003), van
Ertbruggen et al. (2005), Li et al. (2007a), and Longest and Xi
(2007a). So far, most of these studies concentrated on one to
several bifurcations of the TB tree. Some of these studies lacked
sufcient model validations (e.g., Nowak et al., 2003). Considering the large amount of branches in the lower airways (say, 215
for the 16th generation in Weibels lung model), the direct simulation of particles in the entire tracheononchial airways (say, from
G0 to G16) is still impossible. However, petascale computing may
allow for rather accurate patient-specic lung modeling in the near
future.
1.2. Mechanical drug-aerosol targeting
Inhalation of drug aerosols, typically in the effective diameter
range of 310 m, is a standard procedure for treating respiratory ailments, especially chronic obstructive pulmonary diseases
(COPD) and asthma. The nasal and oral pathways are now also being
used as portals to deliver medicine for pain management and to
combat systemic diseases, respectively, where oral inhalation of
insulin for diabetes patients is one modern example. However, to
be successful and cost-effective, drug-aerosol delivery has to be targeted. Obviously, maximum deposition of suitable therapeutic solid
particles (or droplets or vapor) at predetermined sites, which are
related to specic diseases, minimizes potential side-effects in case
of aggressive drugs and reduces health-care cost with the increased
efcacy. Targeting is here understood as a mechanical goal to
bring drug aerosols from their release points (i.e., the inhaler exit)
to a desired landing area in the respiratory system for maximum
medical effectiveness. In order to achieve that goal, future inhaler
devices have to operate based on a targeting methodology featuring optimal: (i) particle characteristics, (ii) inhalation waveform,
(iii) particle-release positions, and (iv) concentration range. This
mechanistic approach differs from drug targeting via special design
of molecular, carrier and controlled-release properties which cause
selective distribution characteristics and pharmacokinetic behavior
leading to improved therapy.
Several aspects of drug-aerosol delivery have been recently
reviewed in the books edited by Gradon and Marijnissen (2003)
as well as Hickey (2004). The book by Finlay (2001) and the volume
edited by Bissgard et al. (2002) also discuss pertinent elements
of drug delivery to the lungs. Experimentally validated computer
simulations of micron-particle transport and deposition, employing pressurized metered dose inhalers (pMDIs) and a new delivery
methodology for optimal drug-aerosol targeting, are discussed by
Kleinstreuer et al. (2007a).
2. Geometric models of the oral and pulmonary airways
Accurate and realistic airway models are the necessary precursor for experimental or computational airow and particle
transport/deposition analyses. Once a comprehensive, exible and
experimentally validated computer simulation model has been
developed, local and segmentally averaged concentrations of toxic
particles as well as operational parameters for optimal drug-aerosol
targeting can be determined. Ultimately, such tasks can be accom-

plished for individual patients, eliminating the present problem of

inter-subject variability.
In any case, the nasal plus oral airways are labeled the extrathoracic region which forms with the tracheobronchial and alveolar
regions the respiratory system. From a functional viewpoint, the
respiratory tract is divided into the conducting zone (i.e., Generations 016) and the respiratory zone (Generations 1723) where the
O2 CO2 gas exchange takes place. An alternative geometric division
would include the extrathoratic, upper bronchial, lower bronchial,
and alveolar region (see Fig. 1). There are two basic approaches for
generating geometric lung models, i.e., either via algorithms which
specify inhaled-volume-based rules for the relationships between
parent and daughter airways (e.g., Kitaoka et al., 1999 and Tawhai
et al., 2000) or lung replicas digitally reconstructed from CT-scan or
MRI data (e.g., van Ertbruggen et al., 2005). Using the rst approach,
Tebockhorst et al. (2007) also included in their computer model
lung-airway morphogenesis, due to development in children or
triggered by lung diseases.
Finlay (2001) in his Chapter 5 summarized human lung geometric and breathing data, while Hickey and Thompson (2004)
focused more on the structure and function of the human airways. For experimental studies and computational analyses the
respiratory tract has been traditionally segmentized into the nasal
cavities, oral airway (i.e., mouth to trachea), the tracheobronchial
tree (typically Generations 03 or 6) and part of the alveolar region
ranging from single alveolar cells to alveolated ducts. Historically,
Weibel (1963) was the rst to provide idealized geometric data, i.e.,
tube diameter and length, of symmetrically bifurcating lung airways, known world-wide as the Weibel Type A model. In contrast,
Horseld et al. (1971) and Raabe et al. (1976) published geometry information on asymmetric airways obtained from human
lung resin casts, while Hammersley and Olson (1992) focused on
small airway bifurcations. Phalen et al. (1985) published measurements of the right upper lobe airways taken from 20 replica casts
of people aged 11 days to 21 years. Morphometric data of the
human pulmonary acinus, i.e., all the daughter generations of a
single terminal bronchiole, was collected by Haefeli-Bleuer and
Weibel (1988). Modern imaging techniques allow for an even more
detailed mapping of the human respiratory tract. For example, Ley
et al. (2002) obtained from CT-scan data a semi-automatically generated tracheobronchial tree, while Tawhai et al. (2004) as well
as Cebral and Summers (2004) used CT-scans to construct central airways. Others, mainly focusing on the human upper airways
for meshing and subsequently computer simulations, constructed
rigid 3D congurations which somewhat represent actual airways
(see Kleinstreuer and Zhang, 2003a; Matida et al., 2004; Farkas et
al., 2006; Jin et al., 2007; Xi and Longest, 2007; among others).
Dynamic effects of ner geometric aspects of the upper respiratory tract were also investigated, such as local area changes
during inhalation (Ehtezazi et al., 2004; Zhang and Finlay, 2005),
cartilaginous rings in the trachea (Zhang and Finlay, 2005), and
different static glottis openings (Brouns et al., 2007). Rather faithful replicas of the upper respiratory tract for experimental studies
were employed by Cheng et al. (1999) and Grgic et al. (2004),
among others. Transient geometric changes have to be considered
in the throat while speaking, swallowing or switching breathing modes and in the alveolar region during inhalation/exhalation
(Ehtezazi et al., 2004; Haber and Tsuda, 2006). Transport phenomena and certain airway diseases may also be coupled to
temporary changes in local airway geometry and hence should
be considered as well. Examples include mucus-layer ow (Kim
et al., 1987) and clearance (Grotberg, 2001) as well as patients
with asthma, COPD, cystic broses, tumors, etc., as reviewed by
Meyer et al. (2003), Brown and Bennett (2004), and Yang et al.
(2006).

C. Kleinstreuer et al. / Respiratory Physiology & Neurobiology 163 (2008) 128138

131

Fig. 1. Schematics of human respiratory system and image of actual airways (from Kleinstreuer et al., 2008).

3. Computational aspects of airow and particle transport

simulations
As alluded to in Section 1.1, lung aerosol dynamics investigations were historically mainly concerned with toxic particulate
matter deposition and subsequently with the implications of
dosimetry-and-health effects. Especially maturing CFD techniques
allowed for non-invasive, high-resolution, cost-effective and safe
simulations of airow pattern, particle transport and particle deposition as well as particle mass transfer into the lung tissue. Major
simplications made include somewhat idealized rigid airways
with smooth (sticky) surfaces, spherical non-interacting ne or
ultrane particles, and constant inhalation ow rates.
Clearly, the geometry of an actual respiratory system is very
complex, augmented by changing wall boundaries, rough surfaces,
and moving mucus layers. Nevertheless, the goal is patient-specic
modeling, and the generic step-by-step procedure for generating
airway geometry data is as follows:
CT-scan images of a subjects respiratory tract (i.e., DiCom les),
enhanced with a contrasting agent, are obtained from a radiologist or surgeon. It should be noted that the determination of
airway or vessel wall thicknesses is still rather difcult. Magnetic
resonance imaging (MRI) is good for distinguishing different tissues; thus, may help to estimate variable wall thickness. The time
between contrast agent intake and scanning is crucial because the
chemical should only change the apparent blood density before
migrating into the tissue and by then greatly diminishing contrasts between blood and tissue.
The DiCom les are loaded into geometry-le-conversion software, such as Mimics/Geomagic (Materialise, Belgium) or
Simpleware (Simpleware Ltd., Exeter, UK). It enables the modeler
to edit the images, isolate the structures of interest, and generate
3D geometry models.

The CAD-like geometry les are then exported in suitable formats, typically to CFD software, for numerical uid ow and solid
structure analysis (see, for example, Wolters et al., 2005, Li and
Kleinstreuer, 2005, and Shi et al., 2006, among many others).
Alternatively, the 3D nite element computer model can be
exported as an STL-le (stereolithography) to a rapid prototyping machine to build a physical model for laboratory studies (e.g.,
Kratzberg et al., 2005).
The condition of deposition is usually fullled when a particle
is one radius away from the wall, i.e., it touches an airway surface. The assumption of dilute micron-particle suspensions allows
for separate computations of the airow (Eulerian approach
solving the NavierStokes equations) and the particle dynamics
(Lagrangian approach solving Newtons second law of motion).
The same holds for the analysis of submicron particles; however,
in that case an EulerEuler approach is recommended, i.e., the
nanoparticle (or vapor) phase is described with the mass transfer equation containing an appropriate diffusion term (Crowe et
al., 1998; Kleinstreuer, 2003; Zhang et al., 2005). For dense suspension ows, e.g., nasal droplet sprays, both phases are coupled
and hence uidparticle interactions have to be modeled, typically via a momentum source term (Kleinstreuer, 2003; Shi and
Kleinstreuer, 2007). Most naturally occurring and man-made particles, including most drug aerosols, are non-spherical and hence
require special mathematical description for accurate trajectory
and deposition simulations (see, for example, Shenoy and Kleinstreuer, 2008). Droplets as well as thermal and humidity effects
in the respiratory environment require also special considerations (Zhang and Kleinstreuer, 2003b; Zhang et al., 2006). The
assumption of quasi-steady inhalation is justiable for micronparticle deposition modeling, when an equivalent inlet Reynolds
number is selected. Specically, Zhang et al. (2002a) showed that
such an equivalent dimensionless group is the arithmetic mean of

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C. Kleinstreuer et al. / Respiratory Physiology & Neurobiology 163 (2008) 128138

the maximum and mean Reynolds numbers of the given inhalation waveform. For elevated inhalation ow rates, i.e., Qin > 12 L/min
during exercise, transition to turbulent airow after the larynx (see
Fig. 1) may occur with relaminarization further downstream. It was
shown that the low Reynolds number k turbulence model of
Wilcox (1998) adequately describes these changing ow regimes
(Kleinstreuer and Zhang, 2003a; Varghese and Frankel, 2003; Zhang
and Kleinstreuer, 2003a; Ryval et al., 2004).
The rapidly growing interest in using the mouth/nose as portals for the delivery of medicine caused a shift in the application
and interpretation of computational/experimental inhalation studies, i.e., toxic particle deposition results appeared as therapeutic
drug-aerosol targeting outcome. One early example is the determination of a critical tumor radius for which drug-aerosol deposition
was at a maximum for all inlet Reynolds and Stokes number combinations (Kleinstreuer and Zhang, 2003b).
3.1. Inhaled air ow elds
The understanding of airow structures in the human airways
underlies the basis for analyzing particle transport and deposition.
Steady and transient inspired air ows in the human nasal/oral
and bronchial airways have been reviewed by Pedley (1977) and
Grotberg (1994, 2001). Detailed investigations, both experimentally and theoretically, were recently provided by Lieber and Zhao
(1998), Fujioka et al. (2001), Caro et al. (2002), Gemci et al. (2002),
Zhang and Kleinstreuer (2002, 2004), Kleinstreuer and Zhang
(2003a), Liu et al. (2003), Nowak et al. (2003), Horschler et al. (2003,
2006), Johnstone et al. (2004), van Ertbruggen et al. (2005), Shi et al.
(2006), Adler and Brucker (2007), and Grosse et al. (2007), among
others. Effects of geometric airway changes are most pronounced
during inhalation. So far, experimental and computational analyses
focused mainly on isolated sections of the human airways and only

for laminar airows. However, at moderate to high breathing rates

the air ow from the larynx to generation G3 is transitional-toturbulent which may complicate ow structures as well as aerosol
transport and deposition (Kleinstreuer and Zhang, 2003a; Zhang
and Kleinstreuer, 2004). Usually, the turbulent intensity in the oral
airway rises rapidly after the constriction caused by the soft palate,
and then decreases until the disturbance is activated again by the
throat (glottis) (Zhang and Kleinstreuer, 2003a; Lin et al., 2007).
Turbulence levels, in terms of kinetic energy k, seem to increase
quickly through the strong varying diameter-zone after the glottis,
and then decay approaching an asymptotic level of approximately
0.20.3 (k/in 2 ) at six-diameter station from the throat (Corcoran
and Chigier, 2000). The ow instabilities may be induced again at
the bifurcation region due to the great geometric transition from
the parent tube to two daughter tubes, while the strongest turbulence uctuations occur just around the ow dividers due to
the contraction of top and bottom surfaces in the carinal ridges
(Zhang and Kleinstreuer, 2004). Then, turbulence decays rapidly in
the straight segments of the bifurcating tubes. Generally, turbulence which occurs after the throat can propagate to at least a few
generations even at a low local Reynolds number (say, Re = 700)
because of the enhancement of ow instabilities just upstream of
the ow divider (Olson et al., 1973; Zhang and Kleinstreuer, 2004).
Typical inspiratory airow patterns in bifurcating airways are
shown in Fig. 2. The essential ow characteristics includes: (i)
the air stream splits at the ow dividers and new boundary layers are generated at the inner walls of daughter tubes; (ii) the
velocity patterns vary with the development of upstream ows
and the generation of the new boundary layers near the inner
walls at the dividers; (iii) the skewed prole with a maximum
axial velocity near the inner wall may be observed just after the
ow divider so that different tubes may experience different air
ow rates; (iv) strong secondary vortices appear inside the branch

Fig. 2. Velocity proles in the bifurcation airway model at steady inhalation with Qin = 30 L/min. The left panel exhibits mid-plane speed contours. The right panel shows the
axial velocity contours and secondary velocity vectors at different cross sections (see Zhang and Kleinstreuer, 2004).

C. Kleinstreuer et al. / Respiratory Physiology & Neurobiology 163 (2008) 128138

tubes. The upstream ow elds (i.e., ow history), and realistic airway geometry features (e.g., asymmetric bifurcations, non-planar
branches, cartilaginous rings and local obstructions) will inuence
the specic airow characteristics, including patterns of skewed
axial velocity proles, axial velocity magnitude, as well as locations and intensities of secondary vortices (see Zhang et al., 2002d;
Nowak et al., 2003; Yang et al., 2006; Li et al., 2007b; Lin et al.,
2007).

(5)

DEparticle =

number of deposited particles in a specifc region

number of particles entering this region

(6)

Concerning particle deposition mechanisms, diffusional and

gravitational phenomena are measurable at very low ow rates,
i.e., typically in the lower lung regions, where diffusion is dominant for ultrane particles in areas of high concentration gradients
and gravity effects signicant for relatively large/heavy particles
(Heyder, 2004). Key in diffusional transport of spherical nanomaterial due to the Brownian motion effect is the diffusion coefcient
given by the StokesEinstein equation:
3dp

(2)

where kB is the Boltzmann constant (1.38 1023 J K1 ), T is the

temperature,  is the uid viscosity, and Cslip is the Cunningham
slip correction factor (Clift et al., 1978).
For particle deposition studies the Stokes number (St) is generally being used in the form
St =

p dp2 U
18D

is gravity, and the underlined

tively, FD is the drag force, Fi
force terms (lubrication and interaction forces) are activated near
the airway wall (Longest et al., 2004). For high aerosol loadings,
a particle-particle interaction (or collision) force has to be added.
When non-isothermal effects have to be considered, including particle growth (i.e., hygroscopicity), modeling details are given by
Zhang and Kleinstreuer (2003b) and Broday and Georgopoulos
(2001), among others.
The regional deposition of micron particles in human airways
can be quantied in terms of the deposition fraction or deposition
efciency in a specic region (e.g. oral airway, rst, second and third
bifurcation, etc.). They are dened as:
number of deposited particles in a specic region
number of particles entering the mouth and/or nose

(1)

kB TCslip

(4)

DFparticle =

(dp ) squared, as expressed with the impaction parameter, i.e.,

Dnano =

d
p
gravity
+ Fi,lubrication + Fi,interact
(mp ui ) = FD + Fi
dt
gravity

3.2.1. Micron vs. nano-size particles

In general, both transport and deposition of inhaled particulate matter are denitely size-dependent. Typically, nanomaterial
dispersion is due to diffusion and convection, while micron
particles are transported via convection and/or sedimentation. Specically, micron-particle deposition in the lung occurs
mainly by impaction, including secondary airow convecting
particles to the airway walls, as well as diffusional or gravitational effects. Clearly, inertial impaction (IP) is proportional to
the air ow rate (Q) and the (aerodynamic) particle diameter

IP =

of the large particle-to-air density ratio, dilute particle suspensions and negligible particle rotation, drag is the dominant force
with additional forces relevant near the airway walls. Thus,
Newtons second law of motion can be written for laminar and
turbulent micron-particle transport as:

where uPi and mp are the velocity and mass of the particle, respec-

3.2. Particle deposition

Qdp2

133

(3)

which can be also interpreted as the ratio of particle relaxation and

ow characteristic times. In Eq. (3), p is the particle density. Thus,
the Stokes number, being mainly a function of particle-diameter
squared as well as the characteristic air velocity U and length scale
D, is a measure of the inuence of the inertial effects during a
particles trajectory. However, in the (human) respiratory system
the local airway geometries are rather complex or exhibit sudden changes, while the airow velocities are rapidly changing as
well. Thus, Stokes numbers as well as Reynolds numbers have to be
dened locally to capture more accurately the underlying physics
of micron-particle deposition.
3.2.2. Micron-particle deposition
Assuming non-interacting spherical micron particles, a
Lagrangian frame of reference can be employed and in light

The regional deposition efciency is mainly used to develop the

deposition equation for algebraic (total) lung modeling.
The local deposition patterns of micron particles can be quantied in terms of a deposition enhancement factor (DEF). The particle
deposition enhancement factor is dened as the ratio of local to
average deposition densities, where deposition densities are computed as the number of deposited particles in a surface area divided
by the size of that surface area (Balashazy et al., 1999, 2003; Zhang
et al., 2005). Clearly, if the overall and maximum DEF-values in
one airway region are close to one, the distribution of deposited
particles tends to be uniform. In contrast, the presence of high DEFvalues indicates non-uniform deposition patterns, including hot
spots. Some hot spots of toxic particulate matter are related to
the induction of certain lung diseases, e.g., cancer.
Focusing mainly on the oral and bronchial airways, micronparticle transport and deposition has been extensively investigated
by Stahlhofen et al. (1989), Katz and Martonen (1996), Li et al.
(1998), Balashazy et al. (1999, 2003), Cheng et al. (1999), Katz et
al. (1999), Kim and Fisher (1999), Corcoran and Chigier (2000),
Stapleton et al. (2000), Gemci et al. (2002), Zhang et al. (2002a,b,c,
2005), Kleinstreuer and Zhang (2003a, 2003b), Grgic et al. (2004),
Heyder (2004), Matida et al. (2004), van Ertbruggen et al. (2005),
Zhang and Finlay (2005), Zhou and Cheng (2005), Longest et al.
(2006), Kleinstreuer et al. (2007b), and Xi and Longest (2007),
among others. Recently, micron-particle transport and deposition in the human nasal airways have gained attention due to the
advancements in new nasal drug delivery technologies and computer simulations (Cheng, 2003; Kelly et al., 2004a; Su and Cheng,
2005; Inthavong et al., 2006; Shi et al., 2007). However, very little information is available regarding transport and deposition of
vaporizing droplet in the human nasal airways (Shi et al., 2007).
As shown in Fig. 3, micron-particle deposition during inhalation is mainly due to impaction, secondary ow convection, and
turbulent dispersion (Li et al., 2007a). Thus, they largely deposit at
stagnation points for axial particle motion, such as the tongue portion in the oral cavity, the outer bend of the pharynx/larynx, and
the regions just upstream of the glottis and the straight tracheal
tube. As expected, for micron particles the high DEF-values appear

134

C. Kleinstreuer et al. / Respiratory Physiology & Neurobiology 163 (2008) 128138

Fig. 4. 3D distributions of deposition enhancement factor (DEF) of micron particles

in a bifurcation airway model representing G0G3 under steady inhalation with
Qin = 30 L/min and dp = 10 m (see Zhang et al., 2005).

e.g., asymmetric and non-planar geometries, may result in some

different local deposition rates (Nowak et al., 2003; Li et al., 2007a,c;
Xi and Longest, 2007).
3.3. Nanomaterial transport and deposition
The appropriate modeling approach for ultrane particle transport is the mass transfer equation with the StokesEinstein
equation for the Brownian motion type nanoparticle diffusivity
(Dnano ) (see Eq. (2)); although, a few researchers adopted the
EulerLagrange approach when simulating nanoparticle transport
(Hofmann et al., 2003; Zamankhan et al., 2006; Longest and Xi,
2007b). Thus, the proper convectiondiffusion equation for laminar
and turbulent transport reads:


Y


uj Y =
+
t
xj
xj



Dnano +

T
Y

 Y 

(7)

xj

where Y is the mass fraction and  Y is the turbulence Schmidt

number for Y.
The regional deposition fraction can be determined according
to Ficks law (Zhang and Kleinstreuer, 2004), i.e.,
DFregion =

n
+ (T /Y ))(Y /n)

Ai (D
i=1

Fig. 3. Micron-particle deposition pattern in an oral-tracheobronchial airway model

(Qin = 30 L/min, dp = 5 m) (see Li et al., 2007c).

mainly around the carinal ridges due to inertial impaction, but the
specic distribution of DEFs at each carina is different and varies
with the inhalation ow rate as well. Some micron particles also
land outside the vicinities of the cranial ridges due to secondary
ows and turbulent dispersion.
The local particle deposition patterns can be further quantitatively described by 3D surface distributions of DEF results. As shown
in Fig. 4 (Zhang et al., 2005), the maximum DEF-value is about 1400
for dp = 10 m. This implies that the deposition patterns of micron
particles in the upper airways are highly non-uniform, and hence
a small surface area where the maximum DEF occurs, may receive
hundred times higher dosages when compared to the average value
for the whole airway. Such a site of massive particle deposition is
usually located around the carinal ridges in the bronchial airways.
Recent CFPD studies have also shown that more realistic models,

(8)

Qin Yin

where Ai is the area of the local wall cell (i), and n is the number of
wall cells in one certain airway region, e.g., oral airway, rst airway
bifurcation, etc. The local deposition patterns of nanoparticles can
again be quantied in terms of a deposition enhancement factor
(Balashazy et al., 1999, 2003; Zhang et al., 2005), which is dened
as the ratio of local to average deposition densities, i.e.,

DEF =

n 
i=1

+ (T /Y ))(Y /n)

(D

i
n

+ (T /Y ))(Y /n) /

Ai (D
i

A
i=1 i

(9)

Assuming that the airway wall is a perfect sink for aerosols upon
touch, the boundary condition at the wall is Yw = 0. This assumption is reasonable for fast aerosol-wall reaction kinetics (Fan et al.,
1996) and also suitable for estimating conservatively the maximum
deposition of particles or toxic vapors in airways.
A typical nanoparticle deposition pattern is shown in Fig. 5 in
terms of DEF-distributions in a bifurcation airway model (Zhang
et al., 2005). Again, the enhanced deposition mainly occurs at the
carinal ridges and the inside walls around the carinal ridges due
to the complicated air ows and large particle concentration gradients in these regions. As the particle size increases, wall depositions

C. Kleinstreuer et al. / Respiratory Physiology & Neurobiology 163 (2008) 128138

Fig. 5. 3D distributions of deposition enhancement factor (DEF) of nanoparticles

in a bifurcation airway model representing G0G3 under steady inhalation with
Qin = 30 L/min and dp = 10 nm (see Zhang et al., 2005).

135

A summary graph of regional particle deposition fraction in

human upper airways is given in Fig. 6 (see Shi et al., 2007 and
Zhang et al., 2005, for details). It shows that inhaled particles in
the diameter range of 0.01 to about 1 m are difcult to be captured by the upper respiratory tract, i.e., they may reach the deeper
lung region if not exhaled (Heyder, 2004). Both inspiratory ow
rate and particle size play a signicant role in the particle deposition process. Specically, with an increasing particle diameter
the DFs decrease for nanoparticles because of the decrease in diffusive capacity while they may increase for micron particles due
to increasing impaction. Similarly, the higher the inhalation ow
rate, the lower the deposition of nanoparticles and the higher the
deposition of micron particles (Zhang et al., 2005). Furthermore,
the location of bifurcation airways and airway geometry features
(e.g., asymmetry, non-planar, obstruction) may inuence inhaled
particle deposition as well, as numerically conrmed by Zhang et
al. (2002d), Nowak et al. (2003), Farkas and Balashazy (2007), Li et
al. (2007c), and Luo et al. (2007).
4. Conclusions and future work

Fig. 6. Experimentally validated computer simulation results of particle deposition

fractions in human upper airways as a function of particle size (see Shi et al., 2007
and Zhang et al., 2005).

decrease and the airparticle mixtures become much more uniform, featuring at similar particle distribution proles and hence
wall gradients, which reduce the differences in local wall deposition rates (Zhang and Kleinstreuer, 2004). Geometric effects may
not signicant for nanoparticle deposition (see Xi and Longest,
2008). Although the enhanced deposition sites (i.e., those with high
DEF-values) in the bifurcating airways are similar for nano- and
micro-size particles, the maximum DEF-values for nanoparticles
are two to three orders of magnitude smaller than for microparticles. Specically, the DEFmax for microparticles is of the order of 102
to 103 , while DEFmax for nanoparticles is of the order of 1 (Zhang et
al., 2005). A more uniform distribution of deposited nanoparticles
may relate to a different toxicity effect when compared to ne particles made of the same materials. Specically, not only the larger
surface areas relative to the particle mass but also, more importantly, the larger surface areas with a near-uniform deposition can
generate a higher probability of interaction with cell membranes.
Hence, it may result in a greater capacity to absorb and transport toxic substances into tissue, blood and the whole body, and
the enhanced possibility of systematic diseases, such as cardiovascular diseases (see Hoet et al., 2004, Oberdrster et al., 2005). In
contrast, the extremely high local DEF-values for micron particles
indicates the possibility of local pathological changes in bronchial
airways, such as the formation of lung tumors (Balashazy et al.,
2003).

A review of research papers is presented, pertinent to computer

modeling of airow as well as nano- and micron-size particle deposition in mainly pulmonary airway replicas. The key modeling steps
are outlined, including construction of suitable airway geometries,
mathematical description of the airparticle transport phenomena
and computer simulation of micron and nano-particle depositions. Specically, diffusion-dominated nanomaterial deposits on
airway surfaces much more uniformly than micron particles of
the same material. This may imply different toxicity effects. Due
to impaction and secondary ows, micron particles tend to accumulate around the carinal ridges and to form hot spots, i.e.,
locally high concentrations which may lead to tumor developments. Inhaled particles in the size range of 20 nm dp 3 m may
readily reach the deeper lung region. Concerning inhaled therapeutic particles, optimal parameters for mechanical drug-aerosol
targeting of predetermined lung areas can be computed, given representative pulmonary airways.
Future computational work will center around simulation
realism and accuracy in order to understand and predict dosimetryand-health-risk effects in case of inhaled toxins and optimal
operational conditions of smart inhaler systems in case of drugaerosol targeting. New hardware and software developments in the
petascale computing environment will allow for patient-specic
solutions to these problems.
Acknowledgements
This effort was sponsored by the Air Force Ofce of Scientic
Research, Air Force Material Command, USAF, under grant number
FA9550-07-1-0461 (Dr. Walt Kozumbo, Program Manager). The U.S.
Government is authorized to reproduce and distribute reprints for
governmental purposes notwithstanding any copyright notation
thereon. The use of both CFX software from ANSYS Inc. (Canonsburg, PA) and IBM Linux Cluster at the High Performance Computing
Center at North Carolina State University (Raleigh, NC) are gratefully
acknowledged as well.
References
Adler, K., Brucker, C., 2007. Dynamic ow in a realistic model of the upper human
lung airways. Experiments in Fluids 43, 411423.
Asgharian, B., Anjilvel, S., 1994. A Monte-Carlo Calculation of the Deposition Efciency of Inhaled Particles in Lower Airways. Journal of Aerosol Science 25,
711721.

136

C. Kleinstreuer et al. / Respiratory Physiology & Neurobiology 163 (2008) 128138

Asgharian, B., Anjilvel, S., 1995. The effect of ber inertia on its orientation in a shear
ow with application to lung dosimetry. Aerosol Science and Technology 23,
282290.
Balashazy, I., Hofmann, W., 1993. Particle deposition in airway bifurcations. 1. Inspiratory ow. Journal of Aerosol Science 24, 745772.
Balashazy, I., Hofmann, W., 1995. Deposition of aerosols in asymmetric airway bifurcations. Journal of Aerosol Science 26, 273292.
Balashazy, I., Hofmann, W., Heistracher, T., 1999. Computation of local enhancement factors for the quantication of particle deposition patterns in airway
bifurcations. Journal of Aerosol Science 30, 185203.
Balashazy, I., Hofmann, W., Heistracher, T., 2003. Local particle deposition patterns
may play a key role in the development of lung cancer. Journal of Applied Physiology 94, 17191725.
Balashazy, I., Moustafa, M., Hofmann, W., Szoke, R., El-Hussein, A., Ahmed, A.R., 2005.
Simulation of ber deposition in bronchial airways. Inhalation Toxicology 17,
717727.
Bang, J.J., Murr, L.E., 2002. Atmospheric nanoparticles: preliminary studies and
potential respiratory health risks for emerging nanotechnologies. Journal of
Materials Science Letters 21, 361366.
Bernstein, O., Shapiro, M., 1994. Direct determination of the orientation distribution
function of cylindrical particles immersed in laminar and turbulent shear ows.
Journal of Aerosol Science 25, 113136.
Bissgard, H., OCallaghan, C., Smaldone, G., 2002. Drug Delivery to the Lungs. Marcel
Dekker, New York.
Brenner, H., Condiff, D.W., 1972. Transport mechanics in systems of orientable
particles. III. Arbitrary particles. Journal of Colloid Interface Science 41,
228274.
Broday, D.M., Georgopoulos, P.G., 2001. Growth and deposition of hygroscopic particulate matter in the human lungs. Aerosol Science and Technology 34, 144159.
Brouns, M., Verbanck, S., Lacor, C., 2007. Inuence of glottic aperture on the tracheal
ow. Journal of Biomechanics 40, 165172.
Brown, J.S., Bennett, W.D., 2004. Deposition of coarse particles in cystic brosis:
model predictions versus experimental results. Journal of Aerosol MedicineDeposition Clearance and Effects in the Lung 17, 239248.
Cai, F.S., Yu, C.P., 1988. Inertial and interceptional deposition of spherical particles
and bers in a bifurcating airway. Journal of Aerosol Science 6, 679688.
Caro, C.G., Schroter, R.C., Watkins, N., Sherwin, S.J., Sauret, V., 2002. Steady inspiratory ow in planar and non-planar models of human bronchial airways. In:
Proceedings of the Royal Society of London Series a-Mathematical Physical and
Engineering Sciences 458, pp. 791809.
Cebral, J.R., Summers, R.M., 2004. Tracheal and central bronchial aerodynamics using
virtual bronchoscopy and computational uid dynamics. IEEE Transactions on
Medical Imaging 23, 10211033.
Cheng, J., Wang, C., 1976. Particle deposition from simulated respiratory ows in
a bronchial tree model. In: Proceedings of the American Industrial Hygiene
Conference, Atlanta, Georgia.
Cheng, K.H., Cheng, Y.S., Yeh, H.C., Guilmette, R.A., Simpson, S.Q., Yang, Y.H., Swift,
D.L., 1996. In vivo measurements of nasal airway dimensions and ultrane
aerosol deposition in the human nasal and oral airways. Journal of Aerosol
Science 27, 785801.
Cheng, K.H., Cheng, Y.S., Yeh, H.C., Swift, D.L., 1995. Deposition of ultrane aerosols in
the head airways during natural breathing and during simulated breath-holding
using replicate human upper airway casts. Aerosol Science and Technology 23,
465474.
Cheng, K.H., Cheng, Y.S., Yeh, H.C., Swift, D.L., 1997a. An experimental method for
measuring aerosol deposition efciency in the human oral airway. American
Industrial Hygiene Association Journal 58, 207213.
Cheng, K.H., Cheng, Y.S., Yeh, H.C., Swift, D.L., 1997b. Measurements of airway
dimensions and calculation of mass transfer characteristics of the human oral
passage. Journal of Biomechanical Engineering-Transactions of the ASME 119,
476482.
Cheng, Y.S., 2003. Aerosol deposition in the extrathoracic region. Aerosol Science
and Technology 37, 659671.
Cheng, Y.S., Yamada, Y., Yeh, H.C., Swift, D.L., 1988. Diffusional deposition of ultrane
aerosols in a human nasal cast. Journal of Aerosol Science 19, 741751.
Cheng, Y.S., Zhou, Y., Chen, B.T., 1999. Particle deposition in a cast of human oral
airways. Aerosol Science and Technology 31, 286300.
Clift, R., Grace, J.R., Weber, M.E., 1978. Bubbles, Drops and Particles. Academic Press,
NY.
Cohen, B.S., Sussman, R.G., Lippmann, M., 1990. Ultrane particle deposition in a
human tracheobronchial cast. Aerosol Science and Technology 12, 10821091.
Comer, J.K., Kleinstreuer, C., Zhang, Z., 2001. Flow structures and particle deposition
patterns in double-bifurcation airway models. Part 1. Air ow elds. Journal of
Fluid Mechanics 435, 2554.
Corcoran, T.E., Chigier, N., 2000. Characterization of the laryngeal jet using phase
Doppler interferometry. Journal of Aerosol Medicine-Deposition Clearance and
Effects in the Lung 13, 125137.
Crowe, C., Sommerfeld, M., Tsuji, Y., 1998. Multiphase Flows With Droplets And
Particles. CRC Press, New York.
Daigle, C.C., Chalupa, D.C., Gibb, F.R., Morrow, P.E., Oberdorster, G., Utell, M.J., Frampton, M.W., 2003. Ultrane particle deposition in humans during rest and exercise.
Inhalation Toxicology 15, 539552.
Darquenne, C., Prisk, G.K., 2003. Effect of gravitational sedimentation on simulated aerosol dispersion in the human acinus. Journal of Aerosol Science 34,
405418.

Ehtezazi, T., Horseld, M.A., Barry, P.W., OCallaghan, C., 2004. Dynamic change of the
upper airway during inhalation via aerosol delivery devices. Journal of Aerosol
Medicine-Deposition Clearance and Effects in the Lung 17, 325334.
Fan, B.J., Cheng, Y.S., Yeh, H.C., 1996. Gas collection efciency and entrance ow
effect of an annular diffusion denuder. Aerosol Science and Technology 25,
113120.
Farkas, A., Balashazy, I., 2007. Simulation of the effect of local obstructions and
blockage on airow and aerosol deposition in central human airways. Journal of
Aerosol Science 38, 865884.
Farkas, A., Balashazy, I., Szocs, K., 2006. Characterization of regional and local deposition of inhaled aerosol drugs in the respiratory system by computational uid
and particle dynamics methods. Journal of Aerosol Medicine 19, 329343.
Ferron, G.A., 1977. Deposition of polydisperse aerosols in two glass models representing the upper human airway. Journal of Aerosol Science 8, 409427.
Finlay, W.H., 2001. The Mechanics of Inhaled Pharmaceutical Aerosols: An Introduction. Academic Press, London, UK.
Fujioka, H., Oka, K., Tanishita, K., 2001. Oscillatory ow and gas transport through a
symmetrical bifurcation. Journal of Biomechanical Engineering-Transactions of
the ASME 123, 145153.
Geiser, M., Schurch, S., Im Hof, V., Gehr, P., 2000. Retention of particles: structural
and interfacial aspects. In: Gehr, P., Heyder, J. (Eds.), Particle-Lung Interaction.
Marcel Dekker, New York.
Gemci, T., Corcoran, T.E., Chigier, N., 2002. A numerical and experimental study of
spray dynamics in a simple throat model. Aerosol Science and Technology 36,
1838.
Gradon, L., Marijnissen, J., 2003. Optimization of Aerosol Drug Delivery. Kluwer
Academic Publishers, Norwell, MA.
Grgic, B., Finlay, W.H., Burnell, P.K.P., Heenan, A.F., 2004. In vitro intersubject and
intrasubject deposition measurements in realistic mouth-throat geometries.
Journal of Aerosol Science 35, 10251040.
Grosse, S., Schroder, W., Klaas, M., Klockner, A., Roggenkamp, J., 2007. Time resolved
analysis of steady and oscillating ow in the upper human airways. Experiments
in Fluids 42, 955970.
Grotberg, J.B., 1994. Pulmonary ow and transport phenomena. Annual Review of
Fluid Mechanics 26, 529571.
Grotberg, J.B., 2001. Respiratory uid mechanics and transport processes. Annual
Review of Biomedical Engineering 3, 421457.
Gurman, J.L., Lippmann, M., Schlesinger, R.B., 1984. Particle deposition in replicate
casts of the human upper tracheobronchial tree under constant and cyclic inspiratory ow. 1. Experimental. Aerosol Science and Technology 3, 245252.
Haber, S., Tsuda, A., 2006. A cyclic model for particle motion in the pulmonary acinus.
Journal of Fluid Mechanics 567, 157184.
Haber, S., Yitzhak, D., Tsuda, A., 2003. Gravitational deposition in a rhythmically
expanding and contracting alveolus. Journal of Applied Physiology 95, 657671.
Haefeli-Bleuer, B., Weibel, E.R., 1988. Morphometry of the human pulmonary acinus.
Anatomical Record 220, 401414.
Hammersley, J.R., Olson, D.E., 1992. Physical models of the smaller pulmonary airways. Journal of Applied Physiology 72, 24022414.
Heyder, J., 2004. Deposition of inhaled particles in the human respiratory tract and
consequences for regional targeting in respiratory drug delivery. In: Proceedings
of the American Thoracic Society, vol. 1, pp. 315320.
Hickey, A.J., 2004. Pharmaceutical Inhalation Aerosol Technology. Marcel Dekker,
New York.
Hickey, A.J., Thompson, D.C., 2004. Physiology of the airways. In: Hickey, A.J. (Ed.),
Pharmaceutical Inhalation Aerosol Technology. Marcel Dekker, New York, pp.
129.
Hoet, P., Brueske-Hohlfeld, I., Salata, O., 2004. Nanoparticlesknown and unknown
health risks. Journal of Nanobiotechnology 2, 12.
Hofmann, W., Golser, R., Balashazy, I., 2003. Inspiratory deposition efciency of
ultrane particles in a human airway bifurcation model. Aerosol Science and
Technology 37, 988994.
Horschler, I., Brucker, C., Schroder, W., Meinke, M., 2006. Investigation of the impact
of the geometry on the nose ow. European Journal of Mechanics B-Fluids 25,
471490.
Horschler, I., Meinke, M., Schroder, W., 2003. Numerical simulation of the ow eld
in a model of the nasal cavity. Computers and Fluids 32, 3945.
Horseld, K., Dart, G., Olson, D.E., Filley, G.F., Cumming, G., 1971. Models of the human
bronchial tree. Journal of Applied Physiology 31, 207217.
Inthavong, K., Tian, Z.F., Li, H.F., Tu, J.Y., Yang, W., Xue, C.L., Li, C.G., 2006. A numerical
study of spray particle deposition in a human nasal cavity. Aerosol Science and
Technology 40, U1033U1034.
Jin, H.H., Fan, J.R., Zeng, M.J., Cen, K.F., 2007. Large eddy simulation of inhaled particle
deposition within the human upper respiratory tract. Journal of Aerosol Science
38, 257268.
Johnstone, A., Uddin, M., Pollard, A., Heenan, A., Finlay, W.H., 2004. The ow inside
an idealised form of the human extra-thoracic airway. Experiments in Fluids 37,
673689.
Katz, I.M., Davis, B.M., Martonen, T.B., 1999. A numerical study of particle motion
within the human larynx and trachea. Journal of Aerosol Science 30, 173183.
Katz, I.M., Martonen, T.B., 1996. Three-dimensional uid particle trajectories in the
human larynx and trachea. Journal of Aerosol Medicine-Deposition Clearance
and Effects in the Lung 9, 513520.
Kelly, J.T., Asgharian, B., Kimbell, J.S., Wong, B.A., 2004a. Particle deposition in human
nasal airway replicas manufactured by different methods. Part I. Inertial regime
particles. Aerosol Science and Technology 38, 10631071.

C. Kleinstreuer et al. / Respiratory Physiology & Neurobiology 163 (2008) 128138

Kelly, J.T., Asgharian, B., Kimbell, J.S., Wong, B.A., 2004b. Particle deposition in human
nasal airway replicas manufactured by different methods. Part II: Ultrane particles. Aerosol Science and Technology 38, 10721079.
Kim, C.S., Fisher, D.M., 1999. Deposition characteristics of aerosol particles in sequentially bifurcating airway models. Aerosol Science and Technology 31, 198220.
Kim, C.S., Garcia, L., 1991. Particle deposition in cyclic bifurcating tube ow. Aerosol
Science and Technology 14, 302315.
Kim, C.S., Iglesias, A.J., 1989. Deposition of inhaled particles in bifurcation airway
models. I. Inspiratory deposition. Journal of Aerosol Medicine 2, 114.
Kim, C.S., Iglesias, A.J., Sackner, M.A., 1987. Mucus clearance by 2-phase gas-liquid
ow mechanismasymmetric periodic-ow model. Journal of Applied Physiology 62, 959971.
Kim, C.S., Jaques, P.A., 2004. Analysis of total respiratory deposition of inhaled ultrane particles in adult subjects at various breathing patterns. Aerosol Science and
Technology 38, 525540.
Kitaoka, H., Takaki, R., Suki, B., 1999. A three-dimensional model of the human airway
tree. Journal of Applied Physiology 87, 22072217.
Kleinstreuer, C., 2003. Two-Phase Flow: Theory and Applications. Taylor & Francis,
New York.
Kleinstreuer, C., 2006. Biouid Dynamics: Principles and Selected Applications. CRC
Press, Boca Raton, FL.
Kleinstreuer, C., Shi, H.W., Zhang, Z., 2007a. Computational analyses of a pressurized
metered dose inhaler and a new drug-aerosol targeting methodology. Journal of
Aerosol Medicine-Deposition Clearance and Effects in the Lung 20, 294309.
Kleinstreuer, C., Zhang, Z., 2003a. Laminar-to-turbulent uid-particle ows in a
human airway model. International Journal of Multiphase Flow 29, 271289.
Kleinstreuer, C., Zhang, Z., 2003b. Targeted drug aerosol deposition analysis for
a four-generation lung airway model with hemispherical tumors. Journal of
Biomechanical Engineering-Transactions of the ASME 125, 197206.
Kleinstreuer, C., Zhang, Z., Donohue, J.F., 2008. Targeted drug-aerosol delivery in
the human respiratory system. Annual Review of Biomedical Engineering 10,
195220.
Kleinstreuer, C., Zhang, Z., Kim, C.S., 2007b. Combined inertial and gravitational
deposition of microparticles in small model airways of human respiratory system. Journal of Aerosol Science 38, 10471061.
Kratzberg, J., Dittman, J., Keller, M., Larson, K., MeCormick, M., Greifzu, S., Raghavan, M.L., 2005. Fabrication of a patient-specic replica of abdominal aortic
aneurysm with realistic compliance and translucency. International Journal of
Cardiovascular Medicine and Science 5, 3338.
Kumar, C., 2006. NanomaterialsToxicity Health and Environmental Issues.
WileyVCH Verlag GmbH & Co. KGaA, Weinheim.
Ley, S., Mayer, D., Brook, B.S., van Beek, E.J.R., Heussel, C.P., Rinck, D., Hose, R., Markstaller, K., Kauczor, H.U., 2002. Radiological imaging as the basis for a simulation
software of ventilation in the tracheo-bronchial tree. European Radiology 12,
22182228.
Li, W.I., Perzl, M., Ferron, G.A., Batycky, R., Heyder, J., Edwards, D.A., 1998. The macrotransport properties of aerosol particles in the human oral-pharyngeal region.
Journal of Aerosol Science 29, 9951010.
Li, Z., Kleinstreuer, C., 2005. Fluidstructure interaction effects on sac-blood pressure
and wall stress in a stented aneurysm. Journal of Biomechanical EngineeringTransactions of the ASME 127, 662671.
Li, Z., Kleinstreuer, C., Zhang, Z., 2007a. Particle deposition in the human tracheobronchial airways due to transient inspiratory ow patterns. Journal of Aerosol
Science 38, 625644.
Li, Z., Kleinstreuer, C., Zhang, Z., 2007b. Simulation of airow elds and microparticle deposition in realistic human lung airway models Part I: Airow patterns.
European Journal of Mechanics B-Fluids 26, 632649.
Li, Z., Kleinstreuer, C., Zhang, Z., 2007c. Simulation of airow elds and microparticle
deposition in realistic human lung airway models. Part II. Particle transport and
deposition. European Journal of Mechanics B-Fluids 26, 650668.
Lieber, B.B., Zhao, Y., 1998. Oscillatory ow in a symmetric bifurcation airway model.
Annals of Biomedical Engineering 26, 821830.
Lin, C.L., Tawhai, M.H., McLennan, G., Hoffman, E.A., 2007. Characteristics of the turbulent laryngeal jet and its effect on airow in the human intra-thoracic airways.
Respiratory Physiology and Neurobiology 157, 295309.
Liu, Y., So, R.M.C., Zhang, C.H., 2003. Modeling the bifurcating ow in an asymmetric
human lung airway. Journal of Biomechanics 36, 951959.
Longest, P.W., Kleinstreuer, C., Buchanan, J.R., 2004. Efcient computation of microparticle dynamics including wall effects. Computers and Fluids 33, 577601.
Longest, P.W., Vinchurkar, S., Martonen, T., 2006. Transport and deposition of respiratory aerosols in models of childhood asthma. Journal of Aerosol Science 37,
12341257.
Longest, P.W., Xi, J.X., 2007a. Computational investigation of particle inertia effects
on submicron aerosol deposition in the respiratory tract. Journal of Aerosol
Science 38, 111130.
Longest, P.W., Xi, J.X., 2007b. Effectiveness of direct Lagrangian tracking models for
simulating nanoparticle deposition in the upper airways. Aerosol Science and
Technology 41, 380397.
Luo, H.Y., Liu, Y., Yang, X.L., 2007. Particle deposition in obstructed airways. Journal
of Biomechanics 40, 30963104.
Matida, E.A., Finlay, W.H., Lange, C.F., Grgic, B., 2004. Improved numerical simulation
of aerosol deposition in an idealized mouth-throat. Journal of Aerosol Science
35, 119.
Meyer, T., Mullinger, B., Sommerer, K., Scheuch, G., Brand, P., Beckmann, H.,
Haussinger, K., Weber, N., Siekmeier, R., 2003. Pulmonary deposition of

137

monodisperse aerosols in patients with chronic obstructive pulmonary disease.

Experimental Lung Research 29, 475484.
Moskal, A., Gradon, L., 2002. Temporary and spatial deposition of aerosol particles
in the upper human airways during breathing cycle. Journal of Aerosol Science
33, 15251539.
Nowak, N., Kakade, P.P., Annapragada, A.V., 2003. Computational uid dynamics simulation of airow and aerosol deposition in human lungs. Annals of Biomedical
Engineering 31, 374390.
Oberdrster, G., Oberdrster, E., Oberdrster, J., 2005. Nanotoxicology: an emerging discipline evolving from studies of ultrane particles. Environmental Health
Perspectives 113, 823839.
Oldham, M.J., Mannix, R.C., Phalen, R.F., 1997. Deposition of monodisperse particles
in hollow models representing adult and child-size tracheobronchial airways.
Health Physics 72, 827834.
Oldham, M.J., Phalen, R.F., Heistracher, T., 2000. Computational uid dynamic predictions and experimental results for particle deposition in an airway model.
Aerosol Science and Technology 32, 6171.
Olson, D.E., Sudlow, M.F., Horsel, K., Filley, G.F., 1973. Convective patterns of ow
during inspiration. Archives of Internal Medicine 131, 5157.
Pedley, T.J., 1977. Pulmonary uid dynamics. Annual Review Fluid Mechanics 9,
229274.
Phalen, R.F., Oldham, M.J., Beaucage, C.B., Crocker, T.T., Mortensen, J.D., 1985. Postnatal enlargement of human tracheo-bronchial airways and implications for
particle deposition. Anatomical Record 212, 368380.
Raabe, O.G., Yeh, H.C., Schum, G.M., Phalen, R.F., 1976. Tracheobronchial Geometry: Human, Dog, Rat, Hamster LF-53. Lovelace Foundation Report, Albuquerque,
New Mexico.
Roco, M., 2006. Nanotechnologys future. Scientic American.
Ryval, J., Straatman, A.G., Steinman, D.A., 2004. Two-equation turbulence modeling
of pulsatile ow in a stenosed tube. Journal of Biomechanical EngineeringTransactions of the ASME 126, 625635.
Schlesinger, R.B., Bohning, D.E., Chan, T.L., Lippmann, M., 1977. Particle deposition
in a hollow cast of human tracheobronchial tree. Journal of Aerosol Science 8,
429445.
Schlesinnger, R.B., Gurman, J.L., Lippmann, M., 1982. Particle deposition within
bronchial airwayscomparisons using constant and cyclic inspiratory ows.
Annals of Occupational Hygiene 26, 4764.
Schlesinnger, R.B., Lippmann, M., 1972. Particle deposition in casts of human upper
tracheobronchial tree. American Industrial Hygiene Association Journal 33,
237251.
Service, R.F., 2003. Nanomaterials show signs of toxicity. Science 300, 243.
Shenoy, A., Kleinstreuer, C., 2008. Flow over a thin circular disk at low-to-moderate
Reynolds numbers. Journal of Fluid Mechanics.
Shi, H., Kleinstreuer, C., 2007. Simulation and analysis of high-speed droplet spray
dynamics. Journal of Fluids Engineering 129, 621633.
Shi, H., Kleinstreuer, C., Zhang, Z., 2006. Laminar airow and nanoparticle or
vapor deposition in a human nasal cavity model. Journal of Biomechanical
Engineering-Transactions of the ASME 128, 697706.
Shi, H., Kleinstreuer, C., Zhang, Z., 2007. Modeling of inertial particle transport and
deposition in human nasal cavities with wall roughness. Journal of Aerosol Science 38, 398419.
Shi, H., Kleinstreuer, C., Zhang, Z., Kim, C.S., 2004. Nanoparticle transport and deposition in bifurcating tubes with different inlet conditions. Physics of Fluids 16,
21992213.
Smith, S., Cheng, U.S., Yeh, H.C., 2001. Deposition of ultrane particles in human
tracheobronchial airways of adults and children. Aerosol Science and Technology
35, 697709.
Stahlhofen, W., Rudolf, G., James, A.C., 1989. Intercomparison of experimental
regional aerosol deposition data. Journal of Aerosol Medicine 2, 285308.
Stapleton, K.W., Guentsch, E., Hoskinson, M.K., Finlay, W.H., 2000. On the suitability
of k-epsilon turbulence modeling for aerosol deposition in the mouth and throat:
a comparison with experiment. Journal of Aerosol Science 31, 739749.
Su, W.C., Cheng, Y.S., 2005. Deposition of ber in the human nasal airway. Aerosol
Science and Technology 39, 888901.
Tawhai, M.H., Hunter, P., Tschirren, J., Reinhardt, J., McLennan, G., Hoffman, E.A., 2004.
CT-based geometry analysis and nite element models of the human and ovine
bronchial tree. Journal of Applied Physiology 97, 23102321.
Tawhai, M.H., Pullan, A.J., Hunter, P.J., 2000. Generation of an anatomically based
three-dimensional model of the conducting airways. Annals of Biomedical Engineering 28, 793802.
Tebockhorst, S., Lee, D., Wexler, A.S., Oldham, M.J., 2007. Interaction of epithelium
with mesenchyme affects global features of lung architecture: a computer model
of development. Journal of Applied Physiology 102, 294305.
Theodore, L., Kunz, R.G., 2005. Nanotechnology: Environmental Implications and
Solutions. Wiley-Interscience, New York, NY.
Tsuda, A., Butler, J.P., Fredberg, J.J., 1994. Effects of alveolated duct structure on
aerosol kinetics. 2. Gravitational sedimentation and inertial impaction. Journal
of Applied Physiology 76, 25102516.
van Ertbruggen, C., Hirsch, C., Paiva, M., 2005. Anatomically based three-dimensional
model of airways to simulate ow and particle transport using computational
uid dynamics. Journal of Applied Physiology 98, 970980.
Varghese, S.S., Frankel, S.H., 2003. Numerical modeling of pulsatile turbulent ow
in stenotic vessels. Journal of Biomechanical Engineering-Transactions of the
ASME 125, 445460.
Weibel, E.R., 1963. Morphometry of the Human Lung. Academic Press, New York.

138

C. Kleinstreuer et al. / Respiratory Physiology & Neurobiology 163 (2008) 128138

Wilcox, D.C., 1998. Turbulence Modeling for CFD. DCW Industries, Inc., La Canada,
CA.
Wolters, B., Rutten, M.C.M., Schurink, G.W.H., Kose, U., de Hart, J., van de Vosse, F.N.,
2005. A patient-specic computational model of uidstructure interaction in
abdominal aortic aneurysms. Medical Engineering and Physics 27, 871883.
Xi, J.X., Longest, P.W., 2007. Transport and deposition of micro-aerosols in realistic
and simplied models of the oral airway. Annals of Biomedical Engineering 35,
560581.
Xi, J.X., Longest, P.W., 2008. Effects of Oral airway geometry characteristics on the
diffusional deposition of inhaled nanoparticles. Journal of Biomechanical Engineering: Transactions of the ASME 130, 011008.
Yang, X.L., Liu, Y., Luo, H.Y., 2006. Respiratory ow in obstructed airways. Journal of
Biomechanics 39, 27432751.
Yu, G., Zhang, Z., Lessmann, R., 1996. Computer simulation of the ow eld and particle deposition by diffusion in a 3D human airway bifurcation. Aerosol Science
and Technology 25, 338352.
Yu, G., Zhang, Z., Lessmann, R., 1998. Fluid ow and particle diffusion in the human
upper respiratory system. Aerosol Science and Technology 28, 146158.
Zamankhan, P., Ahmadi, G., Wang, Z.C., Hopke, P.K., Cheng, Y.S., Su, W.C., Leonard, D.,
2006. Airow and deposition of nano-particles in a human nasal cavity. Aerosol
Science and Technology 40, 463476.
Zhang, L., Asgharian, B., Anjilvel, S., 1996. Inertial and interceptional deposition of
bers in a bifurcating airway. Journal of Aerosol Medicine-Deposition Clearance
and Effects in the Lung 9, 419430.
Zhang, Y., Finlay, W.H., 2005. Measurement of the effect of cartilaginous rings on
particle deposition in a proximal lung bifurcation model. Aerosol Science and
Technology 39, 394399.

Zhang, Z., Kleinstreuer, C., 2002. Transient airow structures and particle transport
in a sequentially branching lung airway model. Physics of Fluids 14, 862880.
Zhang, Z., Kleinstreuer, C., 2003a. Low-Reynolds-number turbulent ows in locally
constricted conduits: a comparison study. AIAA Journal 41, 831840.
Zhang, Z., Kleinstreuer, C., 2003b. Species heat and mass transfer in a human upper
airway model. International Journal of Heat and Mass Transfer 46, 47554768.
Zhang, Z., Kleinstreuer, C., 2004. Airow structures and nano-particle deposition in
a human upper airway model. Journal of Computational Physics 198, 178210.
Zhang, Z., Kleinstreuer, C., Donohue, J.F., Kim, C.S., 2005. Comparison of microand nano-size particle depositions in a human upper airway model. Journal of
Aerosol Science 36, 211233.
Zhang, Z., Kleinstreuer, C., Kim, C.S., 2002a. Cyclic micron-size particle inhalation and
deposition in a triple bifurcation lung airway model. Journal of Aerosol Science
33, 257281.
Zhang, Z., Kleinstreuer, C., Kim, C.S., 2002b. Gas-solid two-phase ow in a triple
bifurcation lung airway model. International Journal of Multiphase Flow 28,
10211046.
Zhang, Z., Kleinstreuer, C., Kim, C.S., 2002c. Micro-particle transport and deposition
in a human oral airway model. Journal of Aerosol Science 33, 16351652.
Zhang, Z., Kleinstreuer, C., Kim, C.S., Hickey, A.J., 2002d. Aerosol transport and deposition in a triple bifurcation bronchial airway model with local tumors. Inhalation
Toxicology 14, 11111133.
Zhang, Z., Kleinstreuer, C., Kim, C.S., 2006. Water vapor transport and its effects on
the deposition of hygroscopic droplets in a human upper airway model. Aerosol
Science and Technology 40, 116.
Zhou, Y., Cheng, Y.S., 2005. Particle deposition in a cast of human tracheobronchial
airways. Aerosol Science and Technology 39, 492500.