Download Visualization and Quantification of Nasal and Olfactory Deposition in

Visualization and Quantification of Nasal
and Olfactory Deposition in a Sectional
Adult Nasal Airway Cast
Jinxiang Xi, Jiayao Eddie Yuan, Yu
Zhang, Dannielle Nevorski, Zhaoxuan
Wang & Yue Zhou
Pharmaceutical Research
An Official Journal of the American
Association of Pharmaceutical Scientists
ISSN 0724-8741
Volume 33
Number 6
Pharm Res (2016) 33:1527-1541
DOI 10.1007/s11095-016-1896-2
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Author's personal copy
Pharm Res (2016) 33:1527–1541
DOI 10.1007/s11095-016-1896-2
RESEARCH PAPER
Visualization and Quantif ication of Nasal and Olfactory
Deposition in a Sectional Adult Nasal Airway Cast
Jinxiang Xi 1 & Jiayao Eddie Yuan 2 & Yu Zhang 1 & Dannielle Nevorski 1 & Zhaoxuan Wang 1 & Yue Zhou 3
Received: 12 December 2015 / Accepted: 1 March 2016 / Published online: 4 March 2016
# Springer Science+Business Media New York 2016
ABSTRACT
Purpose To compare drug deposition in the nose and olfactory region with different nasal devices and administration
techniques. A Sar-Gel based colorimetry method will be developed to quantify local deposition rates.
Methods A sectional nasal airway cast was developed based
on an MRI-based nasal airway model to visualize deposition
patterns and measure regional dosages. Four nasal spray
pumps and four nebulizers were tested with both standard
and point-release administration techniques. Delivered dosages were measured using a high-precision scale. The colorimetry correlation for deposited mass was developed via image
processing in Matlab and its performance was evaluated
through comparison to experimental measurements.
Results Results show that the majority of nasal spray droplets
deposited in the anterior nose while only a small fraction (less
than 4.6%) reached the olfactory region. For all nebulizers
considered, more droplets went beyond the nasal valve, leading to distinct deposition patterns as a function of both the
nebulizer type (droplet size and initial speed) and inhalation
flow rate. With the point-release administration, up to 9.0%
(±1.9%) of administered drugs were delivered to the olfactory
region and 15.7 (±2.4%) to the upper nose using Pari Sinus.
Conclusions Standard nasal devices are inadequate to deliver
clinically significant olfactory dosages without excess drug
losses in other nasal epitheliums. The Sar-Gel based
* Jinxiang Xi
[email protected]
1
School of Engineering and Technology, Central Michigan University, 1200
South Franklin Street, Mount Pleasant, MI 48858, USA
2
Department of Mechanical Engineering, Columbia University, New
York, New York, USA
3
Aerosol and Respiratory Dosimetry Program, Lovelace Respiratory
Research Institute, Albuquerque, New York, USA
colorimetry method appears to provide a simple and practical
approach to visualize and quantify regional deposition.
KEY WORDS colorimetry . intranasal delivery .
nose-to-brain delivery . olfactory . point-release
INTRODUCTION
Neurological medications delivered to the olfactory mucosa
can enter the brain via olfactory pathways and bypass the
Blood–brain-Barrier (1). However, clinical applications of
the direct nose-to-brain delivery are rare because of the extremely low olfactory doses using conventional nasal devices.
Many challenges exist that prevent effective olfactory drug
delivery. Because the olfactory nerves are located at the uppermost portion of the nose, aerosolized particles need to penetrate high and deep enough within the nose to deposit in this
secluded area (Fig. 1a). Due to the complex structure of the
human nasal cavity, most nasally administered drugs are filtered by the nasal valve and cannot reach the upper nose and
the olfactory region. A fundamental function of the nose is the
filtration of the inhaled particles as the first line of defense to
airborne pollutants; however, this function also precludes effective delivery of drug particles to the superior meatus and
the olfactory region.
Particle deposition in the human nose has been well studied
in human subjects, in vitro nasal replicas, and computational
models. Despite high variabilities between subjects, these studies have consistently revealed that nasal deposition can be
affected by many factors, such as the nasal devices, drug formulations, administration techniques, and patient breathing.
Compared to the extensive reports of total deposition fractions
(DFs) in literature, reports of deposition pattern or regional
dosages were scarce. This is still the case in spite of the wellaccepted fact that local or regional deposition is more
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Xi et al.
Fig. 1 Olfactory region and nasal
airway cast. (a) The olfactory (OL)
mucosa is located at the uppermost
of the nasal cavity and is connected
directly to the brain. A nasal airway
cast with a constant wall thickness
was developed from an MRI-based
nasal airway model. The cast was
separated into different sections for
measurement of regional
depositions. Grooves were
designed at the connections for easy
assembly and good sealing. (b) The
cast was also cut open to visualize
and measure the location
depositions inside the nose. The
olfactory region was also separated
and fabricated with 3D printing to
measure the olfactory delivery
efficiencies.
clinically relevant than total deposition to predict therapeutic
outcomes or assess adverse health effects.
There exist established methods to measure total deposition fractions in hollow replica casts. In contrast, validated
methods to visualize and quantify regional or local deposition
fractions are rare. Computational models can predict deposition patterns; however, their use in clinical practices has largely been hampered due to the lack of model validation and
direct correlation with medical outcomes. Moreover, because
particle deposition is affected by so many factors (i.e., device-,
drug-, patient-, administration-related), no single factor is
commonly accepted as predictive of the deposition pattern
in the nose, rendering experimental testing a necessity in validating targeted drug deliveries. Dye-based methods such as
using methylene blue have been used to evaluate the regional
bioequivalence of administered drugs by visually inspecting
the stain intensity (2). Disadvantages of such methods include
the inability of dosage quantification, solution dripping, and
solution diffusion. Other studies have used gamma scintigraphy with technetium-99 m (99m Tc) labeled particles to visualize the deposition distributions in human noses (3–5) or
in vitro nasal airway casts (6–8). Deposition images of the radioactive aerosols were acquired using a gamma camera and
were subsequently processed to translate the color intensity
into dosages. This method is known to be complicated by
the attenuation of gamma rays on their way out of the body,
with up to half of the photons being scattered or stopped by
the body tissue (9). Photon scattering could also distort the
scintigraphy image and gave a biased dosage. Typically,
30% of photons that reached by the gamma camera were
scattered and caused measurement deviations. Other
compounding factors include pre-study color-dosage, quality
control of aerosol radiolabeling, and radioactivity recovery
(10). In addition, the scintigraphy image is 2D and hence
cannot differentiate depositions in multilayers.
Dalby and associates developed an inexpensive and effective method to visualize and quantify droplet deposition patterns, and demonstrated the utility of this approach. Sar-Gel,
a water-indicating paste (Sartomer Arkema Group, Exton,
PA), changes its color from white to purple upon contact with
water. Even though not very responsive to moisture in the
ambient air, Kundoor and Dalby (11,12) demonstrated that
Sar-Gel was highly sensitive to applied water mass and could
detect water volume as low as 0.5 μL, the smallest water droplet from nasal sprays. Furthermore, color spreading by diffusion was not observed until the single drop volume exceeded
25 μL. Considering other attributes such as ease of use, fast
reaction time, and easy clean up, Sar-Gel appears to be an
ideal candidate to visualize droplet deposition patterns in this
study. Noticing that the color change of Sar-Gel is gradual
and depends on the amount of water mass, it is hypothesized
that a colorimetry-water mass correlation can be established
to quantify inversely the applied water mass from an image of
Sar-Gel color.
Various inhalation devices and administration techniques
have been investigated to improve drug delivery to the
olfactory region. Key factors influencing the deposition site
from nasal sprays or nebulizers are droplet size, exiting
velocity, administration angle, and spray plume angle.
Cheng et al. (13) studied nasal spray pumps and their
deposition patterns in a sectional nasal airway cast and
reported that larger droplets and a wider spray angle
increased the deposition in the front nose. Narrow plume
angles and small droplet sizes provide larger deposition
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Quantification of Olfactory Deposition in an Nasal Airway Cast
beyond the nasal valve. Kundoor and Dalby (12) tested the
administration angle starting from 0° all the way up to 90° in
15° increments. It was found that an angle of 60° or 75°
created the most favorable trajectories in regards to depositing
in the olfactory region of the nasal cavity. Wang et al. (14)
developed a olfactory targeting technique by intubating a nasal spray nozzle into the nasal passage and releasing drugs
underneath the olfactory region. However, this technique
hasn’t gained popularity because of its invasive nature; it’s
hard to insert the nozzle close to the olfactory mucosa without
damaging the wall tissues. A less invasive approach was proposed by Gizurarson (15) that used a nasal pump with a narrow plume angle to transport drugs to the superior meatus
and olfactory region. This method relied on a relative high
pressure for drug particles to penetrate into the confined olfactory region and the enhancements of olfactory delivery
were limited. A similar design termed as the Pressurized
Olfactory Delivery (POD) device was put forward by
Hoekman and Ho (16), which implemented swirling flows to
facilitate drug particles to penetrate into the upper nose.
Enhanced aerosol deposition in the olfactory region has been
demonstrated in rats using this device (17). However, considering the interspecies variability in the nasal anatomy, direct
extrapolation of the rat results to humans is questionable (18).
One apparent anatomical disparity is the ratio of olfactorynasal area, which is about 50% in rats and is only 5.2% in
humans (19). Noticing that particles deposited in the upper
nose were from a certain area in the nostril, Si et al. (20) suggested a point-release technique by releasing drugs from a
selected point instead of the entire area of the nostril.
Significantly improved olfactory delivery efficiency has been
demonstrated using this technique; however, still a substantial
amount of drug particles was lost in the nasal passage, which
would evoke adverse side effects. Furthermore, the delivered
dosage to the disease site must be high enough to elicit therapeutic effects. Any device with an olfactory delivery efficiency
less than 20%, for instance, will lose 80% medications in either
the nose or the lung, and will not be able to induce noticeable
outcomes in the brain without serious drug wastes in other
regions. It is noted that all aforementioned devices depend
solely on aerodynamic forces to transport particles, and there
is no active control over the motion of particles within the
nasal cavity. As a result, most particles will be filtered out in
the complex nasal passages, leaving few particles that could
possibly deposit in the olfactory region.
This study aims to improve the olfactory delivery by testing
four commercially available nasal spray pumps and four different types of nebulizers in an MRI-based nasal airway model. The deposition pattern inside the nose, as well as the total
and subregional deposition fractions, will be visualized and
quantified. There are four specific aims in this study: (1) to
develop a sectional nasal airway cast for the visualization and
quantification of local deposition, (2) to compare nasal and
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olfactory deposition with nasal sprays and nebulizers under
normal administration conditions (entire-nostril release), (3)
to test the point-release technique in nasal and olfactory deposition with four types of nebulizers, and (4) to develop a
colorimetry-deposition correlation that can quantify local
doses and verify its performance using experimental
measurements.
METHODS AND MATERIALS
Nasal Airway Cast
To reliably test inhalation drug delivery, anatomically accurate airway models are necessary. A nasal airway model that
had been reconstructed from MRI scans of a 53-year-old male
(21) was used to prepare in vitro nose replicas (Fig. 1a). This
MRI dataset was initially reported in 1989 (22) and had been
used since then in multiple particle deposition simulations and
experiments (23–28). Magics (Materialise, Ann Arbor, MI)
was used to generate the wall with a finite thickness. The nasal
airway cast had a uniform wall thickness of 4 mm and a detailsize of 0.1 mm, which is the level of geometrical detail retained
in the hollow cast. An in-house 3D printer (Stratasys Objet30
Pro, Northville, MI) was used to build the nose replicas. The
material is polypropylene (Veroclear, Northville, MI), which is
transparent and rigid, and the printing layer thickness is
16 μm (0.0006 in), leading to a smooth surface of the replicas.
In order to measure regional deposition fractions, the nasal
airway cast was divided into several parts that corresponded to
different nose regions, such as nasal vestibule and valve, turbinate, nasopharynx, etc. (Fig. 1a). Only aerosols deposited in
the vestibule-turbinate region were measured in this study. A
step groove was designed at the end of each cast part for easy
assembly and good sealing (Fig. 1a). The groove has a height
of 2.5 mm, a width of 2.0 mm (half the wall thickness), and a
clearance of 0.2 mm so that the cast parts can easily slide into
each other. To visualize the deposition patterns inside the
nose, the vestibule-turbinate was further divided into two
parts along the top ridge of the right nasal septum to show
the internal structures of the right nasal passage. From Fig. 1a,
the inferior, middle, and superior turbinates can be clearly
seen in the cut replica. The advantage of a cut model is that
particle deposition patterns can be directly visualized. To
quantitatively measure the drug dosages in the olfactory region, a region that approximates the olfactory region was cut
out from the turbinate region, as shown in Fig. 1b.
Nasal Spray Pumps and Nebulizers
Four nasal spray products that are commonly prescribed for
rhinosinusitis patients were tested in this study: Apotex,
Astelin, Miaoling, and Nasonex. The spray plume angle was
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Xi et al.
measured from snapshots of the spray video-recording. Each
nasal pump will be tested five times. The exit speeds were not
measured in this study due to the lack of required equipment
(particle image velocimetry). The output per press was quantified by measuring the weight difference of the device before
and after the drug administration using an electronic balance.
The dose output measurement was repeated five times for
each device for later statistical analysis. The output per press
was also quantified by releasing drugs into a container and
measuring the container’s weight difference before and after
the drug administration. Compared to quantification of spray
pump output by measuring its weight loss per press, this method takes evaporation into account, which could otherwise lead
to an overestimation of the device output.
Four nebulizers that represent four different types of aerosol generation techniques were tested in this study: Drive
Voyager Pro, Respironics Ultrasonic, Pari Sinus, and Philips
Respironics 1100312 InnoSpire Essence. Drive Voyager Pro
is a vibrating mesh nebulizer and will be referred to as the
“mesh” nebulizer in the rest of the text. Similarly, the
Respironics Ultrasonic nebulizer will be simply referred to as
“ultrasonic”. Even though both techniques use ultrasonic frequencies, their aerosol generation mechanisms are different.
The mesh nebulizers use ultrasonic waves to vibrate the mesh,
which generates monodisperse micrometer droplets as the solution passes through it. By contrast, ultrasonic nebulizers
produce aerosols by applying ultrasonic waves at the liquid
surface. Philips Respironics Essence is a typical jet nebulizer
with a high droplet velocity, and will be referred as “Philips”
or “Jet nebulizer”. Pari Sinus is also based on the jet-flow
technique, but gives a much slower output velocity. In addition, Paris Sinus has a secondary pulsating flow of 45 Hz frequency with an amplitude of 24 mbar, and was designed specifically to deliver drugs to paranasal sinuses. The operating
parameters, such as aerosol size, flow output, and nebulization
rate, were summarized from the device manuals and listed in
Table I. The dose output of each nebulizer was measured by
operating the nebulizer for a prescribed period of time and
measuring the weight difference of the nebulizer before and
after the operation. Each measurement was repeated five
times for statistical analysis.
Table I Operating Parameters of
the Four Nebulizers
Techniques
Referred as
MMDa (μm)
Flow output (LPM)
Nebulizing (ml/min)
Intranasal Deposition Test
The Schematic diagram of the intranasal deposition test is
shown in Fig. 2. There are three steps: drug delivery testing,
deposition rate and deposition pattern analysis, and cast
cleaning dehumidification. A vacuum (Robinair 3 CFM,
Warren, MI) was connected to the nasopharynx to simulate
inhalations. The volumetric flow rate was monitored by an inline flow meter (Omega, FL-510, Stamford, CT). Before testing, Sar-Gel was applied to the inner surface of the nasal
airway cast with a gloved finger tip in an attempt to provide
an even coating. When spreading the Sar-Gel, it was important to ensure that there was a thin layer of the coating across
the model and that excess Sar-Gel was wiped away. It is possible that the application method of the Sar-Gel could result in
minor variations of coating thickness on the cast surface,
which might lead to slightly different shades of color when
applied the same water mass. However, based on our observations, such color variation was insignificant.. Photos were
taken in an evenly lighted area before the nasal casts were
put together and fastened with a clamp. The weight of the
nasal cast (W0) was then measured using an electronic scale
(Sartorious, 0.01 mg precision, Elk Grove, IL). Drug aerosols
were administered into the right nostril for a specified period
of time at an orientation 60° from the horizontal direction
(12). The new weight of the cast was measured immediately
after the drug administration (W1). The difference (ΔW = W1W2) gave the weight of deposited aerosols, and deposition rate
was calculated as the ratio of ΔW to the spray/nebulizer output. The nasal airway cast was subsequently disassembled,
and photos of the Sar-Gel color on the cast surfaces were
taken. These images were later processed to quantify aerosol
deposition rates. After each test, the Sar-Gel coating on the
inner surface of the cast was washed away using a power
washer (Karcher, 1600 psi, West Allis, WI). A compressed
gas dryer (Craftsman 150 psi) was used to blow the residual
water and moisture inside the nasal passages. The air-dried
cast was then put into an oven (Thermolyne Furnatrol 18200,
Dubuque, IA) set at 55°C for 60 min to remove all remaining
moistures. The cast was then removed from the oven and left
for another one hour to let the temperature and relative
Drive voyage pro
Respironics ultrasonic
Pari sinus
Philips respironics
Innospire essence
Vibrating mesh
Mesh
1.0–5.0
Ultrasonic waves
Ultrasonic
3.0–4.0
2.0
0.5
Jet + pulsating flow
Pari Sinus
3.2, (71% < 5 μm)
NA
0.22
High-velocity jet
Philips or Jet
5.0
7 (max: 9.4)
0.2
MMD mass median diameter
a
A pulsating flow of 45 Hz with an amplitude of 20 mbar is added as a supplemental flow in Pari Sinus
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Fig. 2 Schematic diagram of
intranasal deposition test. There are
three steps: (a) drug delivery
testing, (b) deposition rate and
deposition pattern analysis, and (c)
cast cleaning dehumidification.
humidity of the cast become fully equivalent to the environment. The above procedures were found to be essential to
avoid the complication of water evaporation (wet surface) or
hygroscopic effect (dry surface) in the deposition measurement. Large fluctuations of the electronic scale reading had
been observed otherwise.
Colorimetry
To develop the deposition-colorimetry correlation, eight
circular plates of 4 cm diameter were manufactured
with the 3D printer from the same material as the nose
cast. A layer of Sar-Gel was uniformly coated on the
plate surface and a water mass was applied to the surface to quantify the relationship between the color
depth and applied water mass for different periods of
time. The resulting images were subsequently processed
in Adobe Photoshop (San Jose, CA) to remove the
background and analyzed in Matlab to quantify the color intensity. The test was repeated three times for each
plate. A correlation was developed that can be used for
deposition quantification on a regional or local basis.
Statistical Analysis
Minitab 17 analysis software (State College, PA) was
used to analyze deposition results to determine the importance of different factors. One-Way Analysis of
Variance (ANOVA) and Tukey’s method with stacked
data were used to evaluate the sample variability.
Results were presented as mean ± standard deviation. A
difference was considered statistically significant if the pvalue was smaller than 0.05.
RESULTS
Deposition Using Four Nasal Spray Pumps
The Sar-Gel visualization of the deposition patterns in the
nasal airway cast is shown in Fig. 3 for the four nasal spray
products (Miaoling, Astelin, Apotex, and Nasonex). The spray
plume angles were measured as 19° ± 0.6°, 35° ± 0.8°,
33° ± 0.8°, 20° ± 0.5° for Miaoling, Astelin, Apotex, and
Nasonex, respectively. Most sprays deposited in the nasal
valve region. As expected, the surface deposition patterns
are closely associated with the spray properties. The first product (Miaoling) has a narrow spray angle, a high exit speed, and
large droplet sizes. These properties resulted in a significant
portion of particles depositing in the nasal valve region. Some
of the droplets that escaped the nasal valve filtration penetrated into the superior meatus and deposited in the olfactory
region. For the other three spray products (Astelin, Apotex,
and Nasonex), nearly all droplets were deposited in the nasal
valve region, leaving no droplets to deposit in the superior
meatus. The predominant nasal valve deposition of the nasal
sprays was mainly due to the large droplet sizes (70–90 μm)
and high droplet speeds. Dripping was observed in Miaoling
and Nasonex, both of which had a narrow plume, while dripping was absent in the other two (Astelin, Apotex), which had
a much wider spray plume (Figs. 3a, d vs. b, c). Particle deposition for Apotex appeared to be more dispersed than the
other three sprays pumps; the “pink hue” observed in
Fig. 3c for Apotex was due to particle deposition on the convex surface of the inferior and middle conchae. The unit output (per stroke) is shown in Fig. 3e. Nearly all nasal sprays
discharged into the nostril were filtered out by the nasal cavity
(Fig. 3f).
The dosage delivered to olfactory region, as well as the
ratio of the olfactory-to-nasal deposition, is shown in
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Fig. 3 Deposition pattern and quantification in the nose with four nasal spray products: (a) Miaoling, (b) Astelin, (c) Apotex, and (d) Nasonex. The drug output
and the deposition fraction of each press are shown in (d) and (e), respectively.
Table II. The maximum deposition rate to the olfactory region was 4.6% among the four nasal spray pumps considered.
Deposition Using Four Types of Nebulizers
Four nebulizers that represent four different types of aerosol generation techniques were tested in this study. Slowmoving soft mists were observed in all nebulizers except
the Philips, which exhibits a high-speed jet plume
(Fig. 4a). For the ultrasonic nebulizer, a downward motion
of droplets was observed after releasing, possibly driven by
both gravity and large concentrations of the droplets. The
dose outputs were qualified and compared in Fig. 4b.
Linear relations and small deviations of the time-output
profiles were observed for each nebulizer, indicating consistent performances. However, significant differences in
the dose output were measured among the four nebulizers. For a given period of time, the ultrasonic nebulizer
generated the largest amount of aerosol drugs, followed by
the mesh nebulizer. The Philips and Pari Sinus generate
similar amounts of aerosols, but both are much smaller in
comparison to the ultrasonic or mesh nebulizers (Fig. 4b).
There is almost no difference in Pari Sinus outputs with
and without the vibration (pulsating flow).
The development of dose-colorimetry correlation is shown
in Fig. 5. The color on the plate deepens with the exposure
duration time to the spray (Fig. 5a). The variation of the color
intensity was (colorimetry) quantified using Matlab as a function of the exposure time, and was shown in both linear and
logarithm plots (Fig. 5b). Fig. 5c displays the correlation
Table II Deposition in the Nose and Olfactory Region Using Four
Different Nasal Sprays
Deposition (mg)
Miaoling
Astelin
Apotex
Nasonex
Nasal cavity
Olfactory (OL)
OL-nose dose ratio
108.3
4.97
4.59%
127.7
2.27
1.78%
94.5
0.67
0.71%
93.1
0.71
0.76%
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Fig. 4 Dose outputs of various
nebulizers as a function of the
release duration. (a) Aerosol
patterns from different nebulizers,
and (b) output quantification. Two
adaptors (a cone-shaped adaptor
and a plug) that were designed for
nasal drug delivery are also shown
in (a).
between the color intensity and the applied aerosol mass,
which can be expressed as:
m ¼
1:79−logðx Þ−0:677
Fig. 5 Quantification of Sar-Gel
color variation using a standard
nebulizer (Philips): (a) color map vs.
exposure time, (b) color
quantification (colorimetry), and (c)
mass-colorimetry correlation.
ð1Þ
Figure 6a shows the total deposition fractions of the four
nebulizers under three breathing conditions. The standard
deviation (SD) was calculated from five trials for each nebulizer. Pari Sinus was tested in two modes: with vibration and
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Fig. 6 Total deposition fraction
(DF) for different nebulizers: (a)
measured DF with the mass
weighing approach at three
inhalation flow rates, (b)
comparison of DF obtained
between the mass weighing and
colorimetry methods at 10 L/min.
without vibration. Compared to nasal sprays, the deposition
fractions were much lower for nebulizers. The highest deposition fraction was 46% for the mesh nebulizer at an inhalation rate of 18 L/min. The lowest nasal deposition fraction
was only 15% for the ultrasonic nebulizer during breath holding. In this study, the nebulized drug mass that was not deposited in the nasal cavity passed through the nasal cavity and
exited via the nasopharynx. Interestingly, different trends were
observed in light of how the deposition fraction varied with
inhalation flow rate. For the mesh and ultrasonic nebulizers,
the deposition fraction increased with the flow rate. In contrast, for Pari Sinus (without vibrartion) and Philips, both of
which are jet nebulizers, the deposition fraction was observed
to decrease with increasing flow rates. No apparent trend was
observed for the Pari Sinus with vibration, indicating a more
complex interaction between the airflow and pulsating
aerosols.
The DF was also quantified using the newly developed
colorimetry method and was compared with those obtained
using the mass-weigh method for the four nebulizers at 10 L/
min (Fig. 6b). It was noted that the colorimetry method persistently underestimated the direct mass weighing, but exhibited a similar trend of DF variation, indicating a qualitative
match between the color- and mass-based approaches. The
underestimation might partially be ascribed to the fact that
some droplets deposited underneath the conchae and couldn’t
be detected in the deposition images.
The deposition patterns on the inner surface (turbinate
side) of the right nasal passage are shown in Fig. 7 for various
nebulizers and inhalation flow rates. Very different deposition
patterns were observed among nebulizers, which range from
highly diffusive (jet-type) to very focused (mesh nebulizer).
What are the mechanisms underlying these differences? For
the mesh nebulizer during breath holding, aerosol droplets are
driven by inertia from the nebulizer and yield a relatively
diffusive deposition pattern. Under 10 L/min, an airflow field
is established within the nasal passage which entrains and
transports the slow-moving aerosol droplets. The strip of deposition shown on the middle turbinate (blue arrow) is coincident with the main flow of the inhaled air. With a higher
inhalation flow rate (18 L/min), more aerosol droplets were
entrained into the main flow in the median passage (blue
dashed ellipse). The main deposition mechanism is convection
in this case as opposed to diffusion in the breath holding case.
Similar patterns are observed for the ultrasonic nebulizer under 10 and 18 L/min. The absence of focused deposition in
the ultrasonic nebulizer may be attributed to a lower exiting
velocity and larger amount of aerosol droplets.
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Quantification of Olfactory Deposition in an Nasal Airway Cast
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Fig. 7 Deposition pattern on the
inner surface of the right nasal
passage for varying nebulizers and
inhalation flow rates.
The deposition patterns between Pari Sinus with and without vibration look generally similar, where both exhibit more
diffusive distributions than the mesh and ultrasonic nebulizers
(Fig. 7c vs. d). Perceivable differences were also noted between
Pari Sinus with and without vibration during breath holding
and low inhalation rate (10 L/min), which was presumably
attributed to the pulsating flow and a higher average velocity
when the vibration is on. At 18 L/min, more droplets were
deposited in the upper nose when the vibration mode was on
(Fig. 7c vs. d, lower panel). Considering the Pari Sinus in
Fig. 7c, the change of deposition pattern (from more diffusive
during breath holding, to less diffusive at 10 L/min, to more
diffusive at 18 L/min) was consistent with the variation of
deposition fraction in Fig. 6a. The more diffusive deposition
pattern with vibration during breath holding was caused by
the larger aerosol dispersion, which was in turn induced by the
flow vibrations.
Considering the Philips jet nebulizer, diffusive deposition
patterns were observed in Philips for all inhalation rates considered. A majority of aerosols were filtered out in the nasal
vestibule and valve region under breath holding conditions
(Fig. 7e). There was also appreciable deposition in the upper
nose and the olfactory region. An increase in the inhalation
rate, however, resulted in less deposition in the upper nose.
This is because the main flow, which is at the median and
lower nasal passages, entrains the inhaled particles that otherwise go to the upper part of nose. It is recalled that the drug
release angle at the nostril is 30° from the vertical direction.
The deposition rates in the three zones (front, upper, lower)
were quantified using the colorimetry correlation (Fig. 8). The
front zone represents the nasal vestibule and valve and has a
one-side projected area (not the convoluted surface area) of
9.02 cm2 (Fig. 8a). The upper zone has a one-side projected
area of 9.14 cm2 and depicts the middle and superior turbinate, which includes the olfactory region. The lower zone
(10.42 cm2) denotes the inferior turbinate and nasal floor.
The aim of this study was to enhance deposition to the upper
region, in hope that more drugs can reach the olfactory
region. Accordingly, the smaller the deposition fraction in
the front and lower zones, the better the olfactory deposition
will be. In this regard, the vibrating mesh gives the optimal
results among the four nebulizers. The high deposition rates in
the lower zone were presumably caused by the main flow field
and/or gravity, which results in the major part of the inferior
turbinate deposition.
Point Release
From our previous numerical studies (20,29,30), releasing
aerosols to a selective point in the nostril, instead of the entire
nostril, could significantly improve deposition to the superior
meatus and olfactory region. Four points were tested in this
study at the inhalation flow rate of 10 L/min, as illustrated in
Fig. 9a. The surface deposition pattern and the sub-regional
deposition fractions are shown in Fig. 9b and c, respectively.
From Fig. 9b, releasing aerosols from different points gives rise
to dramatically different deposition patterns, with the overall
deposition shifting from the upper nose to the lower nose as
the release point changes from Point 1 to Point 4. As expected,
the front point release (point 1) provides the optimal deposition pattern among the points considered, with significantly
reduced deposition in the front and lower nose.
Figure 10 shows particle deposition with the front pointrelease for the other three nebulizers. Both sides of the right
nasal passage (turbinate and septum) were shown here. No
perceivable deposition in the upper nose and olfactory region
was obtained using the ultrasonic nebulizer (Fig. 10a). This is
because of the slow aerosol speed exiting the ultrasonic nebulizer adaptor (Fig. 10b). Instead, considerable deposition in
the upper nose was obtained with both Pari Sinus and
Philips jet nebulizers. The deposition in the lower nose was
also greatly reduced. As the upper nose has a much larger area
than the olfactory region, using the upper nose deposition
fraction as the olfactory deposition will lead to a remarkable
overestimation. The olfactory region was denoted by the red
line (Fig. 10b, upper panel). The deposition in this region was
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Xi et al.
Fig. 8 Sub-regional deposition rates quantified with the colorimetry method: (a) areas of the sub-regions (front, upper, lower) of the nasal airway cast; (b) mesh,
(b) ultrasonic, (c) Pari Sinus (with vibration), (d) Pari Sinus (without vibration), and (e) Philips (jet). There is negligible aerosol deposition in the olfactory region.
quantified using the colorimetry measured by weighing the
increased mass in the olfactory cast (Fig. 10b, middle panel).
Pari Sinus (with vibration) gave about up to 9.0% (±1.7%)
olfactory deposition fraction, while Philips gave about 6.7%
(±1.2%). The olfactory deposition appeared to be insensitive
Fig. 9 Point release with the mesh
nebulizer: (a) four locations of the
point release, (b) surface deposition
patterns, (c) sub-regional deposition
fractions quantified with the
colorimetry method. The inhalation
flow rate is 10 L/min.
to the inhalation rate in both nebulizers, even though increasing the inhalation rate persistently reduced the olfactory deposition. The olfactory dosages at 10 L/min were also quantified using the colorimetry method and the results were validated against those from mass weighing, as shown in the lower
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Quantification of Olfactory Deposition in an Nasal Airway Cast
1537
Fig. 10 Olfactory depositions
utilizing point release approach: (a)
deposition pattern and (b) olfactory
deposition fraction quantified with
the colorimetry method. The
comparison of olfactory depositions
between the colorimetry and the
direct mass weighing method is
shown in the lower panel of (b).
panel of Fig. 10b. Good agreement was achieved between
these two approaches for both Pari Sinus and Philips, even
though the colorimetry approach slightly underestimated the
direct measurements.
DISCUSSIONS AND CONCLUSION
For the four nasal sprays considered in this study, the majority of
aerosol deposition occurred in the nasal vestibule-valve region.
There were indeed small fractions of aerosols that penetrated
into the superior meatus and deposited in the olfactory region
for nasal sprays with a narrow plume. The underlying
mechanism that drove aerosols to the olfactory region is the
high inertia from the spray pumps, which, on the other hand,
would inevitably lose most droplets to the walls of the complex
nasal passages due to inertial impaction. Considering that
neurological medications, such as steroids and peptides, are
typically costly and can have adverse side effects on the
respiratory epitheliums, the nasal spray pump does not seem
to be an appropriate device for targeted olfactory drug delivery.
Results from the nasal nebulizers showed substantial enhanced deposition beyond the nasal valve in comparison to
the nasal spray pumps, which is consistent with the scintigraphy studies of Suman et al. (6) and Kundoor et al. (11). Among
the four nebulizers, the mesh nebulizer gave the lowest deposition in the front nose and the highest in the upper nose,
presumably due to the small, monodisperse droplet size and
low droplet speed. On the other hand, the ultrasonic nebulizer
gave the worst performance. As discussed before, even though
both techniques use ultrasound, the former applies the vibration to a fine-pore mesh to drive the liquid through, whereas
the latter applies the vibration to the liquid solution itself to
excite droplets from the liquid interface. As a result, the sizes
and distributions of the generated droplets are different
(Table I). In addition, the vibrating mesh technique does not
require carrier flows, and with suspending small droplets, is
more controllable be means of breathing maneuvers and device adaptions. The second most optimal performances were
found in Pari Sinus. This device generates somewhat similar
patterns of aerosols (Fig. 4 and Table I) and has a supplemental pulsating airflow (45 Hz, 24 mbar in amplitude).
Surprisingly, no substantial difference was observed in deposition rates in the upper nose using Pari Sinus with and without the pulsating flow, indicating negligible impact from the
superimposed pulsating airflow in this study. Upper nose deposition using the Philips (jet) nebulizer exhibited little dependence on the inhalation flow rate, a characteristic similar to
the nasal spray pump. Despite different performances among
the four nebulizers, overall very low deposition rates (2.2
− 8.0%) were measured in the upper nose for all nebulizers.
Negligible deposition was found in the olfactory region, which
was delineated in Fig. 1b. It is acknowledged that each device
has its specific recommended usage and purpose. This study
was not intended to compare which device is superior when
operated as recommended, but rather to test these devices as
candidates with new delivery protocols for a new purpose, i.e.,
to deliver aerosols to the olfactory region.
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The point-release administration technique leverages the
interplay between the air flow and particle motion in the nose,
and selectively releases particles that are most likely to penetrate into the olfactory region. With the optimized releasing
position, flow condition, and particle properties, much enhanced olfactory deposition is expected, which further improves therapeutic outcomes and minimizes adverse systematic side effects. With the point-release technique, up to 9.0%
(±1.7%) of administered aerosols were deposited in the olfactory region, leading to an order of magnitude increase relative
to the standard (entire-nostril) administration. Considering
that a treatment will be effective only if sufficient drug is delivered directly to the required site, it is anticipated that a
clinically relevant olfactory dosage is possible only with excessive drug loss by using standard devices such as nebulizers.
Olfactory dosage is not only sensitive to the nose architecture and to delivery devices, but also to the definition of the
olfactory region. It is generally accepted that the olfactory
mucosa is located on top of the superior meatus, but there is
no consensus on the exact location and the area where drug
molecules can be effectively absorbed into the brain. This lack
of consensus makes it difficult to compare results between
different studies. The reported area of the olfactory region
varied dramatically, ranging from 5.0 cm2 (31), 6.8 cm2 (19),
10 cm2 (32), to 35 cm2 (33). There are also biopsy studies
suggesting that olfactory nerves extend 1–2 cm beyond the
olfactory cleft (34). The area available for the nose-to-brain
transport may be larger than the often cited 3–8% of the nasal
mucosa from cadaver studies (35). Previous studies have defined the extent and location of the olfactory region in different ways. A crescent-shaped olfactory region was defined in Si
et al. (20) and Shi et al. (36) at the very top of the superior
meatus. In contrast, gamma scintigraphy studies often prescribed the upper nose to be equivalent to the olfactory region
(37–40). Recently, Schroeter et al. (33) measured particle deposition in a nose model and reported a maximum olfactory
deposition rate of 5% at a particle size of 10.3 μm. The olfactory region was defined as the dorsal posterior region of the
upper nose, as depicted in Fig. 11. In contrast, Wang et al. (14)
reported an astounding 73.5% deposition rate in the olfactory
region in a nose model that was divided into three portions
(i.e., lower, middle, top), with the top purported as the olfactory region. However, the model realism and the quantification method of regional deposition in an enclosed cavity were
not provided in the above study. The seemingly unrealistic
olfactory deposition rate from a nasal pump highlights the
importance of the anatomical accuracy of the nose model in
olfactory dosimetry studies. To demonstrate the influence of
the olfactory extent and area, we quantified the olfactory dosages based on four different olfactory definitions using the
colorimetry approach, as illustrated in Fig. 11. Significant discrepancies were obtained, with a factor of 6.5 between the
maximum and minimum olfactory dosages (15.7% vs. 2.4%).
Xi et al.
Furthermore, the olfactory dosages differ at a factor of 2.9 for
case B and C (7.7% vs. 2.7%), which have a similar area but
different locations. The deposition is extremely low or zero at
the very top of nose and increases as it is moving away from
the top. This deposition increase makes the olfactory doses
highly dependent on the increased areas. A slight over delineation of the olfactory boundary may cause a disproportional
increase in olfactory dosage. As a result, a guideline for the
olfactory position and extent is needed for future olfactory
dosimetry studies in general, and for the outcome report of
newly developed olfactory delivery devices in particular. It is
also noted that the nerve filaments are not evenly distributed
in the olfactory region, presumably having more nerves (and
quicker absorption) in the top olfactory cleft and less in the
peripheral regions. It is arguably assumed that the rate of
nose-to-brain transport of drug molecules is heterogeneous
across the olfactory region.
A new colorimetry-based method to quantify regional or
local deposition rate was proposed and calibrated with complementary in vitro measurements in this study. The working
principle of this method is that a quantitative correlation exists
between the color change of Sar-Gel and the mass of applied
aerosol droplets. Compared to the mass weighing method, the
colorimetry method consistently under-predicted the deposition rates by 32% (±4%) (Fig. 6b). As a result, adding a correction factor (for instance, 1.52) to Eq. 1 can be used in the
colorimetry correlation to account for the systematic underestimation, such as,
m ¼
2:72−1:52⋅logðx Þ−0:677
ð2Þ
Compared to gamma scintigraphy, the Sar-Gel based
method has the following advantages: a constant formulation
may be used, no radiolabeling is required, and it is simple,
direct, and less expensive. It is acknowledged that the colorimetry method proposed in this study necessitates the usage of
the same material for deposition-colorimetry correlation development and deposition quantification. The lighting environment should also be the same to avoid image color distortion. Another limitation of this color-based method is that it
only quantifies visible aerosols. Aerosols that are deposited
under the nasal conchae or occluded by other structures have
been neglected.
The multi-sectional nasal casting, in combination with the
Sar-Gel colorimetry approach, was demonstrated to provide a
practical approach to visualize and quantify local depositions
in the nasal airway. Advances of imaging and manufacturing
technologies provide more control on cast preparation. An
anatomically accurate nasal airway model that was
previously reconstructed from MRI scans (21,41,42) was used
to develop the hollow cast of the nasal airway by the means of
stereolithographic and 3D rapid prototyping. To characterize
the deposition patterns, the right nasal passage was incised
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Quantification of Olfactory Deposition in an Nasal Airway Cast
1539
Fig. 11 Comparison of the
olfactory deposition fractions based
on different regions that had been
referred to as the olfactory region:
(a) upper nose, (b) superior
meatus, (c) superior-posterior
meatus, and (d) superior meatus
(apex). The colorimetry-quantified
deposition fractions in the four
regions are compared in (e).
into two parts (septum and turbinate) along the top ridge,
which clearly unveiled the complex structure of the nasal turbinate (Fig. 1b). This cut-open nose cast had a unique advantage in the visualization and quantification of local depositions
within the nose, whose small size and labyrinthine passage
make it inaccessible to most measuring instruments. By separating the nasal septum from the turbinate, aerosol deposition
patterns inside the nose can be directly displayed using colorchanging gels or fluorescent particles. To directly measure the
delivery efficiency to the olfactory region, this region was separated from the main nasal cavity and was fabricated separately into two parts via 3D printing (Fig. 1b, right panel). The
projected area (not the surface area) of the olfactory region is
approximately 5.4 mm2. In comparison, Gamma scintigraphy
has also been implemented to visualize and quantify the
deposition pattern inside the nose. However, it generates a
2D image of varying brightness depending on the particle
concentrations in the camera direction. As a result, it cannot
differentiate depositions on different walls that overlap in that
direction. Another setback of the gamma scintigraphy is that
the perceptiveness of the radioactive particles can be
influenced by the distance from the camera and by the
physical properties of the nasal tissues/bones. Furthermore,
radioactive substances are used. Even through proven to be
nearly harmless, they are not readily available, need
professional handling, and are generally costly.
Assumptions that may limit the realism of this study include
the usage of steady flows, a rigid nasal airway cast, and cast
replicas based on one subject. Previous studies have emphasized
the effect upon the airflow and aerosol dynamics from
tidal breathing (43) and compliant walls (44). The nose
replicas were developed from one subject only and did not
account for discrepancies due to age, gender, race, weight,
or height. Considering the potential effect of droplet inertia
on nasal deposition, it was desirable to know the magnitude of
the spray exit velocities from each pump. However, these
velocities were not quantified in this study due to the lack of
required equipment. Inthavong et al. (45,46) measured spray
velocities in different spray regions using particle image
velocimetry and reported an average spray velocity of 15 m/s.
Kimbell et al. (47) reported average spray velocities ranging
from 1.5 to 14.7 m/s that were measured using laser diffraction,
high-speed video, and high-speed spark photography.
Complementary numerical studies with more extensive and
physiologically realistic test conditions are needed to gain further
insights into the observations in this study, and to improve
the drug delivery system for targeted olfactory drug delivery.
In conclusion, four nasal spray pumps and four nebulizers
based on different aerosol-generation techniques were tested
with various delivery protocols to improve aerosol deposition
in the olfactory region. Results show that standard nasal devices
appear to be inadequate to achieve clinically significant deposition rate with the protocols tested in this study. It is anticipated
that protocols relying on aerodynamic forces and aerosol inertia
will fail due to the complete lack of control of the droplet motions and due to the convoluted paths leading from the nostril to
the olfactory region concealed in the uppermost nasal cavity.
New delivery techniques are needed that can help aerosol drugs
to maneuver through the labyrinthine nasal passages with minimum loss to the anterior and turbinate epitheliums.
ACKNOWLEDGMENTS AND DISCLOSURES
The authors report no conflicts of interest in this work.
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