Article

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Ultratrace Measurement of Acetone from Skin Using Zeolite: Toward

Development of a Wearable Monitor of Fat Metabolism
Yuki Yamada,*,†,‡ Satoshi Hiyama,‡ Tsuguyoshi Toyooka,‡ Shoji Takeuchi,§ Keiji Itabashi,∥
Tatsuya Okubo,∥ and Hitoshi Tabata†
†
Department of Bioengineering, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8656, Japan
‡
Research Laboratories, NTT DOCOMO, Inc., 3-6 Hikarinooka, Yokosuka, Kanagawa 239-8536, Japan
§
Institute of Industrial Science, The University of Tokyo, 4-6-1 Komaba, Meguro-ku, Tokyo 153-8505, Japan
∥
Department of Chemical System Engineering, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8656, Japan
*
S Supporting Information

ABSTRACT: Analysis of gases emitted from human skin and contained

in human breath has received increasing attention in recent years for
noninvasive clinical diagnoses and health checkups. Acetone emitted from
human skin (skin acetone) should be a good indicator of fat metabolism,
which is associated with diet and exercise. However, skin acetone is an
analytically challenging target because it is emitted in very low
concentrations. In the present study, zeolite was investigated for
concentrating skin acetone for subsequent semiconductor-based analysis.
The adsorption and desorption characteristics of five zeolites with
different structures and those hydrophobicities were compared. A
hydrophobic zeolite with relatively large pores (approximately 1.6 times
larger than the acetone molecule diameter) was the best concentrator of
skin acetone among the zeolites tested. The concentrator developed using
zeolite was applied in a semiconductor-based gas sensor in a simulated
mobile environment where the closed space was frequently collapsed to reflect the twisting and elastic movement of skin that
would be encountered in a wearable device. These results could be used to develop a wearable analyzer for skin acetone, which
would be a powerful tool for preventing and alleviating lifestyle-related diseases.

M ore than 200 compounds have been identified in human

breath, and some of these are associated with various
diseases, physiological changes, and physical conditions.
Consequently, breath analysis has received increasing attention
in recent years for noninvasive clinical diagnoses and health
checkups.1,2 Among the many compounds in human breath,
acetone is expected to be a good indicator of fat metabolism,
which is associated with diet,3,4 aerobic exercise,5,6 and
diabetes.7,8 Obesity increases the risk of lifestyle-related
diseases, and enabling patient monitoring of breath acetone
concentrations could play a pivotal role in day-to-day
management of dieting and diabetes control.3,9 However,
with breath analysis, it is difficult to motivate patients to blow
into a measurement device on a daily basis. Therefore, a simpler
method that requires less user input is required.
Many compounds, including acetone, are emitted from
human skin,10−12 and breath and skin acetone concentrations
are correlated.13 Compared with breath acetone, skin acetone is
advantageous for analysis because it is continuously emitted
and analysis requires no active action on the part of the user,
unlike the deep exhalation required for breath analysis. Skin
analysis is also more precise than breath analysis as it excludes
factors such as the flow rate of exhalation. A wearable analyzer
for skin acetone would provide a powerful tool for preventing
and alleviating lifestyle-related diseases. However, development
of such a device is challenging. This is because skin acetone is
typically emitted at concentrations of only several tens of parts
per billion (ppb), which is too low for detection by small
commercially available sensors. For example, semiconductor-
based gas sensors have limits of detection around 200 ppb.4 By
contrast, existing high-sensitivity methods for skin acetone
analysis use large apparatus, such as gas chromatographs (GCs)
or liquid chromatographs combined with skin gas collection
bags,13 cooling concentrators,14 trapping filters,15 or solid-phase
microextraction cartridges,16−18 which are not suitable for
development into a wearable device. To develop a wearable
device, either the size of the high-sensitivity devices or the
sensitivity requirements of the small devices needs to be
reduced.
Here, to reduce the detector sensitivity requirements,
concentration of the acetone emitted from skin was
investigated (Figure 1). Zeolite was selected for concentration
Received: January 23, 2015
Accepted: July 3, 2015

© XXXX American Chemical Society A DOI: 10.1021/acs.analchem.5b00296

Anal. Chem. XXXX, XXX, XXX−XXX
Analytical Chemistry
Figure 1. Schematic diagram of our proposed method using zeolite to concentrate the very low concentrations of acetone emitted from human skin.
(a) Acetone is continuously emitted from human skin. (b) Emitted acetone is adsorbed into zeolite pores. (c) Adsorbed acetone is desorbed by
heating the zeolite, and then the acetone is detected by a semiconductor-based gas sensor.
of skin acetone, which was then detected using a semi-
conductor-based gas sensor. Zeolites are microporous materials
that adsorb gaseous molecules, and are widely used as
adsorbents, ion exchangers, and catalysts.19 It is commonly
used in automotive exhaust treatment 20 and chemical
industries,21 and has been used to coat a quartz crystal
microbalance for gas sensing.22 More than 200 structure types
of zeolites have been recognized, and it is expected that a
specific zeolite could be targeted to efficient acetone
adsorption/desorption agent by the selection of appropriate
structure type and its hydrophobicity.
The aims of this work were: (1) to investigate and compare
the adsorption/desorption properties of acetone gas with
various zeolites with different structures and those hydro-
phobicities, and to identify the best zeolite for concentration of
skin acetone, (2) to verify whether the concentrated skin
acetones can be measured using a semiconductor-based gas
sensor, and (3) to confirm the feasibility of the developed
method for analysis of acetone emitted from the skin of human
volunteers. To the best of our knowledge, this is the first study
to demonstrate the concentration of skin acetones using zeolite
and their subsequent detection using a semiconductor-based
gas sensor. These results could help us in developing a wearable
analyzer for skin acetone that could be used for self-monitoring
of fat metabolism in daily life.
■
EXPERIMENTAL SECTION
Zeolites Used in This Study. Five representative zeolites
with different structures and hydrophobicities were selected
(Table 1). The zeolite FER-156 was synthesized by a research
group of one of the authors (T. Okubo) according to a
published method.23 This zeolite has a FER structure, and its
pore size is comparable with the acetone molecule diameter
(4.6 Å). The zeolite HISIV3000 was purchased from Union
Table 1. Characteristics of Zeolites Used in This Studya
Structure type Pore size [Å] SiO2/Al2O3 [mol/mol]
FER-156 FER 3.5−5.4 156
HISIV3000 MFI 5.1−5.6 800
390HUA FAU 7.4 500
385HUA FAU 7.4 100
350HUA FAU 7.4 10
a
Codes consisting of three capital letters, such as FER, MFI, and FAU,
indicate a topology of zeolite frameworks and are assigned by the
structure commission of the International Zeolite Association.
B DOI: 10.1021/acs.analchem.5b00296
Article
Showa K.K. (Tokyo, Japan). This zeolite has a MFI structure,
and its pores are slightly larger than those of FER-156. The
zeolites 390HUA, 385HUA, and 350HUA were purchased from
Tosoh Corp. (Tokyo, Japan). These zeolites have FAU
structures and their pores are larger than those of
HISIV3000. The SiO2/Al2O3 ratio of the zeolite was used as
an indicator of the zeolite hydrophobicity, with a high ratio
corresponding to high hydrophobicity. On the basis of this
grading, 390HUA has higher hydrophobicity than 385HUA and
350HUA (see Table 1).
Adsorption/Desorption of Pure Acetone Gas into/
from the Zeolites. An aliquot (5 mg) of zeolite powder was
placed in a 16.9 mL glass vial (CV-140, Osaka Chemical Co.,
Ltd., Osaka, Japan) and the open vial was heated at 200 °C for
20 min on a hot plate to remove any volatile impurities from
the zeolite. The vial was then sealed and pure acetone gas
diluted with nitrogen gas was injected into the vial using a
syringe so that the final concentration of acetone in the vial was
800 ppb. This initial acetone concentration was used as a
reference to evaluate the acetone adsorption/desorption
characteristics of each zeolite, because the concentration in
the vial without zeolite samples will stay the same during the
experiments. After 15 min, the acetone concentration in the vial
was measured by GC (SGEA-P2, FIS Inc., Hyogo, Japan) to
determine the acetone adsorption capacity of each zeolite.
Then, the vial was opened and the gas it contained was
exchanged with clean air. After resealing the vial, the vial was
heated at 200 °C for 5 min on the hot plate. The acetone
concentration in the sealed vial was then measured using the
GC, and this was used to determine how much acetone
desorbed from each zeolite.
Development of the Concentrator Using Zeolite.
Zeolite powder (4.42 g) was mixed with 4.42 g of silica sol
(SNOWTEX N30G, Nissan Chemical Industries, Ltd., Tokyo,
Japan), 0.35 g of carboxymethyl cellulose ammonium salt
(Wako Pure Chemical Industries, Ltd., Osaka, Japan), and 20
mL of distilled water. A platinum coil heater (300 × 300 × 500
μm) was then dipped into the mixture. Any of the mixture that
adhered to the coil was air-dried on the coil surface at room
temperature. This dip and dry process was repeated several
times, and then the coil heater was used to calcine the air-dried
mixture at 500 °C for 1 h. The obtained calcined mixture
weighed 0.6 mg, and was used to concentrate either pure
acetone gas or acetone emitted from the skin of human
volunteers.
Adsorption/Desorption of Pure Acetone Gas into/
from the Concentrator in Repeated Measurements. The
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concentrator was heated at 330 °C for 30 s with the coil heater
to remove any volatile impurities from the concentrator and
then moved into a 6.4 mL glass vial. The vial was sealed and
pure acetone gas diluted with nitrogen gas was injected into the
vial using a syringe so that the final concentration of acetone in
the vial was 800 ppb. After 15 min, the acetone concentration
in the vial was measured using the GC to determine the
acetone adsorption capacity of the concentrator. The
concentrator was then moved into another 6.4 mL glass vial
and the vial was sealed. The concentrator was heated at 330 °C
for 30 s and the acetone concentration in the sealed vial was
measured using the GC to determine how much acetone
desorbed from the concentrator. The above experiments were
repeated nine times.
Characterization of the Concentrator Using Acetone
Emitted from Skin. Skin acetone samples were collected from
six healthy male volunteers aged in their 20s and 30s. A capped
glass vial with the bottom removed was attached on the skin of
the left forearm of each volunteer to create a closed space. This
vial contained the concentrator. Acetone samples emitted from
the skin were collected and adsorbed into the concentrator over
3, 6, 9, 12, or 15 min. After sample adsorption, the concentrator
was transferred into a 16.9 mL glass vial, which was then sealed
and heated at 330 °C for 30 s with the coil heater. The acetone
concentration in the vial was measured using the GC.
Accuracy of Our Proposed Method in Skin Acetone
Measurements. Skin acetone samples were collected twice
from six healthy volunteers. A capped 16.9 mL glass vial with
the bottom removed was attached on the skin of the left
forearm of each volunteer to create a closed space (Figure 2).
Figure 2. Photograph of skin acetone collection and measurement
from human skin on the left forearm. A closed space is created using a
glass vial containing the concentrator and acetone sensor. The inset
shows a photograph of the concentrator, which is composed of
390HUA zeolite. The scale bar corresponds to 500 μm.
This vial contained the concentrator and a semiconductor-
based acetone sensor4 made of platinum-doped tungsten oxide
(FIS Inc., Hyogo, Japan). We used a sensor that has high
sensitivity for acetone and low sensitivity for the other gases
emitted from human skin, such as acetaldehyde and ammonia
(Figure S1, Supporting Information). Acetone samples emitted
from the skin were collected and adsorbed into the
concentrator over 10 min. After sample adsorption, the
concentrator was heated at 330 °C for 30 s with the coil
heater equipped inside the concentrator. The volunteers did
not feel heat because the heater and the corresponding heated
C DOI: 10.1021/acs.analchem.5b00296
Article
portion of the concentrator were placed far enough away from
the skin surface. In addition, the heated portions were limited
to the micrometer scale and thus their radiant heat did not
affect the skin surface. The acetone concentration in the vial
was measured using the acetone sensor. For comparison,
acetone samples emitted from the skin were collected over 10
min using the same glass vial without the concentrator and
acetone sensor. The acetone concentration in the vial was
measured using the GC.
Skin Acetone Sensing under Real Conditions. A 6.4 mL
bottomless glass vial containing the concentrator and the
acetone sensor was attached to the skin of the left forearm of a
human volunteer to create a closed space. Skin acetone was
collected over 20 min. The closed space was intentionally
collapsed in a cyclic manner during the collection. This was
performed by manually detaching the vial to open the closed
space, and then attaching it again to close the space. The open/
close process was repeated every 30 s during the 20 min
collection period. This process replicates the conditions that
could occur in a wearable device during daily activities, where
twisting and elastic movement of the skin surface could
temporarily collapse the closed space of the sensor. After the
collection time was complete, the concentrator was heated at
330 °C for 30 s using the coil heater to desorb the adsorbed
skin acetone.
These processes were repeated three times in succession, and
changes in the sensitivity of the acetone sensor were
continuously monitored during the experiments. For compar-
ison, the same experiments were conducted without equipping
the vial with the concentrator.
■ RESULTS AND DISCUSSION
Five representative zeolites were studied to determine how
pore size and hydrophobicity affected the concentration of skin
acetone. The adsorption and desorption characteristics of FER-
156, HISIV3000, and 390HUA zeolites for pure acetone gas
were compared (Figure 3). With an acetone concentration of
880 ppb in a sealed glass vial, more than 800 ppb acetone was
adsorbed by all three zeolites after a 15 min incubation period
(Figure 3a). These results indicate that approximately 92% of
the acetone was adsorbed into the zeolites, and their adsorption
capacities were similar. In contrast, desorption of acetone by
heating was different for the three zeolites. The zeolite
390HUA showed much better desorption performance than
the other zeolites, and approximately 85% of the adsorbed
acetone was desorbed from this zeolite under the present
conditions (Figure 3b). The differences in desorption are
presumably caused by the structural differences of the zeolites.
Acetone would desorb from zeolite 390HUA more easily than
the other zeolites because its pores are approximately 1.6 times
larger than the acetone molecule diameter. If the zeolite pores
are too large, acetone and the zeolite will not strongly interact.
This indicates that there is a trade-off between adsorption
capacity and desorption kinetics, and this could be used to
select a zeolite to act as the best concentrator for a specific
molecule.
To investigate the effect of the differences in zeolite
hydrophobicity, the adsorption and desorption characteristics
of pure acetone gas with the FAU type zeolites (390HUA,
385HUA, and 350HUA) were compared (Figure 4). When an
acetone concentration of 780 ppb was generated in the sealed
glass vial, more than 740 ppb acetone was adsorbed by all three
of the zeolites after a 15 min incubation period (Figure 4a).
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Analytical Chemistry Article

Figure 3. (a) Acetone (pure gas) adsorption characteristics of three

zeolites with different structures. The error bars represent the standard
error from three measurements. (b) Desorption characteristics of the
three zeolites. The error bars represent the standard error from three Figure 4. (a) Acetone (pure gas) adsorption characteristics of three
measurements. zeolites with different hydrophobicities. The error bars represent the
standard error from three measurements. (b) Desorption character-
istics of the three zeolites. The error bars represent the standard error
These results indicate that approximately 95% of the acetone from three measurements.
was adsorbed into the zeolites, and their adsorption capacities
were similar. Desorption of acetone from the three zeolites by
heating was quite different. Zeolite 390HUA showed much
better desorption performance than the other zeolites (Figure
4b). Approximately 81% of the adsorbed acetone desorbed
from zeolite 390HUA, whereas only around 3% of the adsorbed
acetone desorbed from zeolite 350HUA. These results indicate
that hydrophilic zeolites, such as 350HUA, strongly adsorb
polar molecules such as acetone. These results show that a
hydrophobic zeolite with relatively large pores will be most
suitable for use as a concentrator of skin acetone. Among the
five zeolites examined in this study, 390HUA is the best choice
as a concentrator of acetone.
Next, the acetone adsorption capacity and the reproducibility
of acetone adsorption/desorption of the calcined 390HUA
concentrator were investigated (Figure 5). The concentrator
used in this study (0.6 mg) was able to adsorb up to 688 ppb
pure acetone gas in an average incubation time of 15 min for
843 ppb of generated pure acetone gas. This adsorption Figure 5. Adsorption and desorption characteristics of the
capacity is feasible because the skin acetone emission rate per concentrator for pure acetone in repeated measurements.
unit time and area will be 2 to 3 ppb, and it will thus take 3.8 to
5.7 h to reach 688 ppb collected skin acetone gas. Assuming from the concentrator for the nine distinct measurements.
that our proposed method will be implemented in wearable These results indicate that our proposed method has high
devices to monitor fat metabolism, a 15 min to 1 h collection reproducibility.
time will be sufficient for this application and saturation of the We then verified adsorption/desorption of acetone with the
zeolite pores will not occur in such a collection time. We also concentrator made of 390HUA zeolite in human volunteers.
found that 93% ± 3% of the adsorbed pure acetone desorbed Gas samples were collected and adsorbed into 390HUA over 3,
D DOI: 10.1021/acs.analchem.5b00296
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Analytical Chemistry Article

6, 9, 12, or 15 min. Figure 6 shows that three representative

patterns of the emission flux of skin acetone observed from

Figure 7. Scatter plots of skin acetone concentrations in 10 min

collection time detected by our proposed system (concentrator and
acetone sensor) and by GC.
Figure 6. Relationship between acetone collection time and
concentration of skin acetone desorbed from the concentrator. The proposed method tended to be slightly lower than those
experiments were conducted in the order of decreasing collection time, obtained from the GC. This is presumably because some of the
and thus each of the lapse times from the start of the experiment adsorbed skin acetone molecules remain in the concentrator, as
corresponds to the sum of the collection times. shown in Figure 5.
To investigate the feasibility of our proposed method, skin
acetone was measured using the semiconductor-based acetone
three volunteers among the six. Results obtained from the rest sensor with and without the concentrator (390HUA zeolite)
of three volunteers were similar to either Subject A or Subject under simulated real life conditions. To achieve this, the closed
C, and thus these results were not shown in this figure for space was intentionally collapsed in a cyclic manner during the
clarity. Assuming that the emission rate of skin acetone per unit 20 min gas collection (Figure 8). The sensitivity of the acetone
time and area is constant, the relationship between desorbed
acetone and collection time should theoretically be linear. The
emission rate, however, fluctuates over time according to the
lifestyle behavior, such as the diet and exercise of each subject.
Considering that the experiments were conducted in the order
of decreasing collection time, the emission rates for the longer
collection times (e.g., 12 and 15 min, which correspond to 30
and 45 min in lapse time from the start of the experiment) may
have changed from the rate at the start of the experiment. Thus,
we assumed that the emission rate was constant during the first
9 min in lapse time from the start of the experiment, and found
that the skin acetone concentration desorbed from the
390HUA zeolite linearly increased with increasing collection
time. These results show that 390HUA zeolite can adsorb/
desorb skin acetone as well as pure acetone gas. The obtained
results that the skin acetone concentration desorbed from the
390HUA zeolite did not linearly increase after the first 9 min in
lapse time indicate that the emission rates significantly
Figure 8. Continuous monitoring of the sensitivities of the
increased in Subject B and decreased in Subject C. The slopes
semiconductor-based acetone sensor with and without the concen-
of the curves in Figure 6 show the differences in skin acetone trator under simulated real conditions. The closed space was
emission among the volunteers. Among the six volunteers, intentionally collapsed in a cyclic manner during each 20 min
Subject B emitted acetone at the highest rate per unit time and collection time. Acetone detection is possible when the sensitivity is
area during the experiments. less than 0.8.
To investigate the accuracy of our proposed method, the
concentrations of skin acetone in 10 min collection time
detected by our proposed system (with the concentrator and sensor without the concentrator drastically decreased from 1.00
acetone sensor) and those determined by GC were compared to 0.83 within the first 5 min from the start of the measurement
(Figure 7). The plots show that there is a strong correlation because of the increased concentration of skin acetone in the
between the concentrations of skin acetone obtained from our closed space. It then plateaued at around 0.83 because of the
proposed method and those obtained by the GC (R2 = 0.90, P intentional and cyclic collapsing of the closed space. Such
< 0.001), confirming that our proposed method is practical with collapsing is very likely in daily life, where some activities are
a reasonable range of measurement deviation. It should be accompanied by twisting and elastic movement of the skin
noted that the skin acetone concentrations obtained from our surface. According to the results of the six volunteers in Figure
E DOI: 10.1021/acs.analchem.5b00296
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Analytical Chemistry
6, the skin acetone emission rate per unit time and area was 2
to 3 ppb in average, and it will thus take 7 to 10 min to reach 20
ppb of collected gas. This indicates that it will be difficult to
measure skin acetone using only a sensor even if state-of-the-art
acetone sensors that can measure 20 ppb of breath acetone24
are used, because such collapsing will take place in real life
during the gas collection time of 7 to 10 min.
After the 20 min collection time, the sensitivity increased
back to 1.00 because the closed space was opened and the
enclosed gas was completely exchanged with clean air. The
sensitivity is indicated by the ratio of the electrical resistance of
the gas sensor in air (Rair) to the electrical resistance of the gas
sensor in the target gas (R). Thus, it will be difficult to clearly
distinguish the signal from the noise as R/Rair → 1. We set the
limit of detection to R/Rair = 0.8 to avoid false detection and to
conduct reliable gas sensing. Considering that the sensitivities
of the acetone sensor without the concentrator were always R/
Rair > 0.8, we concluded that the acetone sensor alone would
not be able to detect skin acetone under the simulated
conditions. In comparison, the sensitivities of the acetone
sensor with the concentrator were all much less than 0.8 when
the adsorbed skin acetone was desorbed every 20 min.
Therefore, skin acetone could be easily detected under the
simulated conditions with the concentrator made from zeolite.
We also found that almost the same peak sensitivities of the
acetone sensor with the concentrator (0.53 ± 0.01) were
obtained from the three measurements. These results indicate
that our proposed method has high reproducibility even if the
closed space for skin acetone collection is in high humidity
because of the water vapor emitted from the skin surface.
It should be noted that the sensitivities of the acetone sensor
with the concentrator also plateaued after the first 5 min, and
were higher than those of the acetone sensor without the
concentrator. This is because skin-emitted acetone adsorbed
into the concentrator and the adsorbed acetone was retained
until the concentrator was heated for desorption.
The ratio of skin acetone measured by the acetone sensor
with the concentrator to skin acetone measured by the acetone
sensor without the concentrator was 7.5. This magnitude of
concentrated skin acetone could help to reduce the detector
sensitivity requirement.
These results indicate that our proposed method is feasible
and shows potential for implementation in wearable devices.
■
CONCLUSIONS
A skin acetone measurement method was developed using
zeolite to concentrate the acetone gas before analysis with a
semiconductor-based gas sensor. Among the five zeolites tested,
390HUA zeolite, a hydrophobic zeolite with relatively large
pores, was the best for concentration of skin acetone.
Concentration of the acetone by the zeolite and subsequent
semiconductor-based gas sensor analysis was achieved in a
simulated mobile environment, where the closed space was
frequently collapsed to simulate the twisting and elastic
movement of the skin surface that could occur with a wearable
device.
These results could be used to develop a wearable analyzer
for skin acetone that could be used for self-monitoring of fat
metabolism in daily life. In the future, we will further investigate
the characteristics of our proposed system under different
environmental conditions, such as temperature, humidity, and
gas composition. The next major step will be miniaturization
and implementation in a wearable device, such as a wristwatch.
F DOI: 10.1021/acs.analchem.5b00296
Article
■
*
ASSOCIATED CONTENT
S Supporting Information
Additional information as noted in the text. The Supporting
Information is available free of charge on the ACS Publications
website at DOI: 10.1021/acs.analchem.5b00296.
■
AUTHOR INFORMATION
Corresponding Author
*Y. Yamada. E-mail: yuuki.yamada.vt@nttdocomo.com.
Notes
The authors declare no competing financial interest.
■
ACKNOWLEDGMENTS
The authors thank Mariko Hanada, Kazuo Onaga, Junko
Yanagitani, Aki Uesaka, Hitoshi Katayama, Dr. Katsuyuki
Tanaka, and Takeo Tsunemi of FIS Inc. for their help in
developing the concentrators.
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G DOI: 10.1021/acs.analchem.5b00296
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