Materials Today  Volume 18, Number 3  April 2015

RESEARCH: Review

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Breath analysis by nanostructured metal

oxides as chemo-resistive gas sensors
Marco Righettoni1, Anton Amann2,3 and Sotiris E. Pratsinis1,*
1

Particle Technology Laboratory, Department of Mechanical and Process Engineering, ETH Zurich, CH-8092 Zurich, Switzerland
Univ.-Clinic for Anesthesia, Innsbruck Medical University, A-6020 Innsbruck, Austria
3
Breath Research Institute of the University of Innsbruck, A-6850 Dornbirn, Austria
2

Recently breath analysis has attracted a lot of attention for disease monitoring and clinical diagnostics as
spectrometric techniques of high sophistication and novel sensing materials become available. Here
advances in these technologies in connection to breath analysis are critically reviewed. A number of
breath markers or tracer compounds are summarized and related to different diseases, either for
diagnostics or for monitoring. Emphasis is placed on chemo-resistive gas sensors for their low cost and
portability highlighting their potential and challenges for breath analysis as they start to be used in
studies involving humans.
Introduction
The idea using information in breath to determine the physiological state of humans has its origins at the time of Hippocrates (460
370 BC). Much later, in 1782/83, Lavoisier reported the first
quantitative analysis of CO2 in the breath of Guinea pigs and
demonstrated that CO2 is a product of combustion in the body [1].
Modern breath analysis appeared in the late 1960s and early 1970s
together with modern analytical chemistry when Pauling demonstrated by gas liquid partition chromatography that over 200
gaseous compounds appear in human breath [2]. At the time,
these compounds were not identified. Since then several reviews
[36] have shown the importance and potential of breath analysis
as one of the least invasive techniques for clinical diagnostics,
disease state monitoring and environmental exposure assessment.
This review describes the current state of breath analysis focusing on the potential use of inexpensive and portable chemoresistive gas sensors that are already used for explosive detection
[7], air-quality monitoring [8] and as alcohol breath analyzers [9].
Such sensors can complement or serve as an alternative to more
sophisticated spectrometric systems for breath analysis and speciation, especially for clinical diagnostics and monitoring. Here, the
current knowledge in breath components as illness markers is first
summarized, along with a classification of applied techniques.
*Corresponding author: Pratsinis, S.E. (sotiris.pratsinis@ptl.mavt.ethz.ch)

Next, the main focus of this review, metal oxide chemo-resistive

gas sensors, is discussed in detail. Finally the review summarizes
the potential of such sensors for breath analysis and discusses
related challenges in connection to sensors properties and applications to humans.

Breath analysis
The bulk of breath consists of nitrogen, oxygen, CO2, water, inert
gases, and traces of volatile organic compounds (VOCs) at concentrations ranging from parts per trillion (ppt) to parts per
million (ppm) [10]. However, our understanding of the human
breath VOC spectrum is far from complete. A compendium of
1765 VOCs with a chemical abstract number (CAS-number) of
healthy humans has been published recently [11]. Most VOCs are
however, not generated in the body (endogenous), but derive from
food ingestion, exposure to an environmental pollutants (exogenous) or from metabolization of a drug [12]. To monitor metabolic
or pathologic processes in the body, endogenous substances are
particularly attractive.

Breath markers
Some VOCs present in the breath, the so-called breath markers,
correlate to specific diseases [13,14]. Furthermore, few pathologies
are related to a pattern of VOCs rather than a specific marker while
some breath components are related to more than one disease.

1369-7021/ 2014 Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.mattod.2014.08.017

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FIGURE 1

Select breath markers with their average concentrations for healthy and
unhealthy humans: acetone (diabetes) [17,21], ammonia (kidney disease)
[21,22], carbon monoxide (lung inflammation) [27,28], dimethyl sulfide (liver
disease) [34,35], ethane (schizophrenia) [38,39,42], hydrogen cyanide
(bacterial infection) [43,44] and nitric oxide (asthma) [3033].

Figure 1 summarizes potential breath markers and their typical

concentrations in healthy humans (green bars) compared to those
during disease (gray bars). Each of these molecules is produced
endogenously (sometimes also by bacteria in the gut or in the oral
cavity) and has potential clinical relevance. Here few markers are
highlighted.
Acetone is one of the most abundant components in the breath
and has been studied in detail and related to metabolic disorders.
The acetone concentration in breath is mainly governed by its
concentration in the blood vessels supplying the upper airways
and by its respective blood:breath partition coefficient of 340
[15,16]. The acetone concentration increases in patients with
uncontrolled diabetes (Fig. 1) [12,17] but also during normal
overnight sleep in healthy individuals [18] and during prolonged
fasting [19]. The acetone contained in the exhaled breath is a
metabolic product of the body fat breakdown and so it is expected
to be a good indicator of fat-burning [20].
Ammonia is present at relatively high concentrations in the
human breath (830 ppb) [21] and its increase might be related to
bacterial production in the oral cavity, to kidney disease (Fig. 1)
[22], hepatic encephalopathy or infection with Helicobacter pylori
[23]. An accurate real-time monitoring of the renal function via
ammonia and trimethylamine [24] could improve the assessment
of treatment response and dialysis efficiency for end-stage renal
disease and acute kidney injury [22].
Exhaled carbon monoxide (CO) and nitric oxide (NO) are breath
markers to pulmonary diseases such as asthma, chronic obstructive pulmonary disease (COPD) and bronchiectasis [25]. Elevated
levels of exhaled CO (56.2 ppm) have been reported in untreated
asthma patients. Upon treatment with inhaled corticosteroids the
breath CO returns close to the healthy levels (1.61.8 ppm) [26].
The difference in exhaled CO between healthy [27] and asthmatic
humans [28], however, is much less than in exhaled NO. Fractional
exhaled nitric oxide (FENO) is the most extensively studied breath
marker as abnormal NO levels in the exhaled breath have
been documented in several lung diseases [25], particularly asthma
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[2931]. Increased levels of exhaled NO have been widely documented in patients with asthma [32,33].
Sulfur-containing compounds like dimethylsulfide are responsible for the characteristic odor in the breath of cirrhotic patients
[34,35]. For healthy people the concentration of sulfur-containing
compounds in the breath is very low (few ppb) while for sick it is
slightly increased. For example, the dimethyl sulfide concentration increased from about 10 to 60 ppb in the breath of liver
disease patients [34]. Dimethylsulfide is also produced by bacteria
and fungi which are related to lung infection (e.g. Streptococcus
pneumoniae, Haemophilus influenzae) [36].
Many studies have demonstrated that breath ethane [37,38] is
related to lipid peroxidation [39] and oxidative stress [40]. Elevated
ethane levels have been noted also in other diseases [41] such as
breast cancer, heart-transplant rejection, rheumatoid disease,
acute myocardial infarction and schizophrenia [42].
Hydrogen cyanide (HCN) is a common metabolite in human
breath and an increase in its concentration might be attributed to
cystic fibrosis [43]. HCN may originate from endogenous production, bacteria (e.g. Pseudomonas aeruginosa) [44], foods containing
cyanogenic glycosides, smoking and intoxication via inhalation
[43].
In addition to exhaled breath, volatile compounds can be
measured directly in the headspace of cell cultures [45]. Around
50 volatile compounds released or consumed by human cells have
been identified by spectral library match and retention time. Most
of these compounds have also been observed in exhaled breath,
skin emanations, urine headspace or in feces. In investigations of
lung cancer patients it turned out that there is no single volatile
biomarker, but much more a panel of compounds which differentiates lung cancer from healthy volunteers [46].
As shown in Fig. 1 most breath markers show ranges of concentrations and may still vary considerably in the group of healthy
persons or even in one particular volunteer when observed longitudinally. There are indeed variations between individuals that
depend on multiple factors, such as inter-individual physiological
differences, dietary dependencies, as well as sampling method and
measurement technique. Nevertheless, identifying the concentration ranges for each specific breath marker is a requirement for the
development of analytical tools (e.g. sensors).

Methods for breath analysis

Before addressing techniques for breath analysis it is important to
briefly address breath sampling and collection. This is important as
breath collection has not reached standardization yet and this
contributes to the variability of analytical results among different
studies [47]. Therefore, optimized procedures are a key step toward
optimization of breath analysis and standardized sampling methods should be implemented [48], such as for the determination of
the amount of NO in exhaled breath, for which standardized
procedures are already available (American Thoracic Society Documents 2005).
There are several techniques for breath component detection
and measurement that are categorized mostly into three groups:
methods based on gas chromatography or mass spectrometry (1),
laser-absorption spectroscopic techniques (2) and chemical sensors (including arrays or electronic noses) (3). Gas chromatography
(GC) is the most common method. Various detection methods can

be coupled to GC [49] to identify breath components, such as mass

spectrometry (MS) [10], flame ionization detector (FID) [40] and
ion mobility spectrometry (IMS) [50].
In addition, more sophisticated analytical methods have been
developed recently for real-time quantification of several trace
gases in both air and breath such as proton transfer reaction mass
spectrometry (PTR-MS) [51] and selected ion flow tube mass spectrometry (SIFT-MS) [52]. Furthermore chemical sensors based on
nanomaterials have shown promising results for clinical diagnostics by breath analysis [53]. Most notably, electronic noses (enoses) consisting of sensor arrays offer a cheaper and simpler
alternative to GC and MS based techniques [54,55]. The most
common type of sensor arrays is based on conductive inorganic
nanomaterials such as metal nanoparticles [56], single wall nanotubes [57] and polymers [58]. E-noses are already widely deployed
in food processing, perfumes, chemical industry and environmental monitoring [59]. Furthermore, the use of sensor arrays in
medical diagnosis [60] has already shown promising results for
detection or monitoring of kidney disease (62 volunteers) [61],
diabetes (three diabetics) [58], Alzheimer (15 patients) [62], Parkinson (30 patients) [62] and lung cancer (62 patients) [56].
The numbers of papers published related to breath analysis had
an exponential increase recently (Fig. 2), with most of them
coming in the last decade. The number of publications on breath
analysis (including reviews and medical reports, Fig. 2: blue) has
more than doubled since 2000. Breath analysis has become increasingly significant due to its potential applications in clinical
diagnostics and technological progress in gas chromatography and
mass spectrometry (yellow), spectroscopy (red) and sensors
(green). It is a non-invasive technique and is particularly attractive
for patients requiring monitoring of daily parameters such as
glycaemia and urea. Nevertheless, other than the most common
breath ethanol test for blood ethanol (law enforcement), only a
few types of breath tests have been used successfully as clinical

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diagnostics, such as the 13/14C urea breath test in the diagnosis of

H. pylori infection [63], the CO2 detection by capnography [64] and
NO breath test in the diagnosis of airway inflammations [65].
Therefore, the blood assay remains the gold standard for diagnostic decisions [47]. According to the American Diabetes Association, for instance, the glycemic control for diabetic patients is
performed primarily by two techniques: daily self-monitoring of
blood glucose (SMBG) and interstitial glucose, and of HbA1c (every
three months) [66]. However, a non-invasive measurement technique such as breath analysis would provide a major relief, especially for diabetic patients who have to give blood samples thrice a
day.

Metal oxide chemo-resistive gas sensors

As described in the previous section, numerous emerging technologies are developed for use in non-invasive gas diagnostics. Chemo-resistive gas sensors based on metal oxides have been used
already quite extensively for several applications. In comparison to
other methods (e.g. GC and MS based techniques) such sensors
offer several advantages such as simplicity, high miniaturization
potential [67], low power and low cost production [68,69] that
make them attractive for routine clinical tests though they do not
provide the speciation of GC/MS. These sensors are based on the
electrical properties of metal oxide semiconductors. Such chemoresistive gas sensor films can be produced by a variety of techniques [70] that may affect their sensing performance with respect to
sensitivity to ppb (Fig. 1), selectivity, reproducibility and long term
stability [69].
To apply such sensors to breath analysis some of their characteristics (size, phase composition, structure) need to be tailored
during their synthesis and processing. First, sensors should exhibit
a high sensitivity to the low concentrations of analyte gases that
are present in the breath, ranging from ppt to ppm (Fig. 1). Second,
selectivity is crucial for the detection of a specific analyte (breath
marker) due to the large amount of similar compounds present in
the human breath. Third, the sensors also need to be able to work
at the high relative humidity (rh) of the breath (90%) [71] and to
be robust to its fluctuations. Last but not least, the sensors must
exhibit rapid response and recovery times for fast and on-line
measurements. Since sensor performance is closely related to
material characteristics and operational conditions, it becomes
crucial to investigate and optimize these parameters to fulfill the
above requirements.

Sensing mechanism

FIGURE 2

Number of publications related to breath analysis in general (blue) and

specifically on gas chromatography (GC) and mass spectrometry (MS,
yellow), spectroscopy (red) and chemical sensors (green) for breath analysis
(Web of Science, January 2014).

Chemo-resistive metal oxide gas sensors rely on changes of electrical conductivity due to a change in the surrounding atmosphere. Gas detection is related to the reactions between
ionosorbed surface oxygen and target analyte gas [72]. There is
a shift in the state of equilibrium of the surface oxygen reaction
due to the presence of a target analyte (receptor function) [73]. The
resulting change in chemisorbed oxygen is registered as a change
in the sensing material conductivity (transducer function) [73].
For example, when a reducing gas like CO or H2 comes into contact
with the sensors surface (Fig. 3, receptor function), it changes the
density of the ionosorbed oxygen. This is detected as a change
in the sensors conductance. Typically the sensing layer consists
of single crystalline grains that are loosely connected (Fig. 3,
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FIGURE 3

Receptor and transducer function of a semiconductor gas sensor (adapted from [73]). Parameters influencing sensor performance: (a) SnO2 sensor response
as a function of crystal size (adapted from [82]). (b) Sensor response of SnO2 and WO3 as a function of Si-content (adapted from [83,106]). (c) Influence of
Pd surface additives (at 0 [1], 0.12 [2] and 1.1 wt% [3]) on SnO2 gas sensor response (adapted from [76]). (d) Influence of the operating temperature of In2O3
sensors on sensor response and response time (adapted from [69]). Influence of SnO2 film thickness on gas sensors (e) response and response time
(adapted from [69]) and (f ) SnO2 film resistance (adapted from [78]).

transducer function) so the target gas can diffuse through the

porous sensing layer.
The usual operating temperature of metal oxide gas sensors is
from 200 to 500 8C [74]. To avoid long term changes, metal oxide
based gas sensors, should be operated at temperatures low enough
so that significant bulk variations are prevented [69], and high
enough so that gas reactions occur within the desired response
time.
The sensor response is determined by the efficiency of the
catalytic reactions with the analyte taking place at the sensor
surface. High catalytic reactivity of the sensor surface, and especially selectivity of this reaction to the target analyte are advantageous. For this reason the control of catalytic activity of a new
sensor material is often used as the main method for a preliminary
estimation of its suitability as a sensor along with its optimal
operation temperature (Fig. 3c,d). The maximum catalytic activity
is obtained as the maximum sensor response (Fig. 3c) at different
temperatures for different gases for different sensing materials.
Therefore optimization of the operating temperature could be also
used to increase selectivity toward a specific analyte [75].
166

Despite the obvious similarities between chemical sensing and

heterogeneous catalysis, the choice of the material for gas sensor
applications is not determined only by catalytic activity. For
example, by surface modification of SnO2 films by noble metals
(e.g. Pd) a shift in the sensor response maximum toward lower
operating temperatures can be obtained together with an increase
in sensor response at an optimal additive content (Fig. 3c) [76]. The
surface modification (Fig. 3) creates optimal conditions for both
electron and ion (spillover effect) exchange between noble metal
and metal oxide support [75]. However, excessive increase in the
additive loading leads to a reduction in sensor response attributed
to a catalytic conversion without electron transfer, as exemplified
by Pt-doped SnO2 sensors during CO detection [77].
The sensor film thickness affects the response time (Fig. 3e).
Additionally, thin sensor films exhibit enhanced sensitivity [69].
For instance, the response of a SnO2-based sensor to ethanol was
increased five times by decreasing the film thickness from 600 to
50 nm [78] and this was attributed to the deeper penetration of the
analyte within the sensing film [79]. However, decreasing the film
thickness excessively, can dramatically increase the film resistance

(Fig. 3f) [78] that should be as low as possible to minimize power

consumption and increase measurement accuracy.
Therefore optimization of these parameters is essential in order
to obtain high performance sensors for breath analysis. The sensing mechanism, briefly discussed here and more in detail in other
reviews [74,80], could be extended to the sensing mechanism
toward not only a single gas but to a much more complex mixture
as the human breath. However, it is important to take into account
the effect of having different gases at different concentrations on
the sensing element. There might be additional effects, such as
competition mechanisms between gases reaching the grain surface
and different diffusion rate between gases through the porous
sensing layer.

Sensor structure and morphology

Nanomaterials can improve the sensitivity of gas sensors [81].
During sensor synthesis, the size as well as the shape of nanomaterials can be controlled, for example, in the form of particles
(spherical), rods, wires, and coreshell structures, which determine
their chemical, optical, magnetic, and electrical properties. For
instance, SnO2 gas sensors exhibited higher sensitivity toward H2
and CO when their crystallite size was decreased (Fig. 3a) [82]. The
gas sensitivity increased steeply as the crystallite size decreased and
became comparable to about twice the Debye length (6 nm for
SnO2) [82]. As a result, the sensitivity to ethanol could be enhanced by tuning accordingly the SnO2 grain diameter through Sidoping of SnO2 sensors [83].
Taking into account the complexity of the gas-sensing mechanism, it becomes clear that one has to consider the influence of
various structural parameters of the metal oxide matrix on gas
sensor performance [84]. The sensing mechanism of chemo-resistive gas sensors is mainly driven by reactions of the analyte gas
with chemi- and physisorbed surface oxygen species. Therefore

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sensitivity depends on the surface area of the sensing particles [74].

Spheres are inferior in terms of surface-to-volume ratio to quasi
one (1D) and two (2D) dimensional geometries like rods and
plates, respectively. Therefore considerable effort has been made
during the last two decades to optimize the geometry of produced
nanostructured particles to increase their surface-to-volume ratio
(Fig. 4) [85].
One dimensional nanostructures have attracted considerable
interest due to their high surface-to-volume ratio and unique
electro-conductive properties, making them promising candidates
for highly sensitive and potentially low temperature gas sensors
(Fig. 4). Depending on the aspect ratio, one can differentiate
several 1D architectures in ascending order: nanorods [86], nanotubes [87], nanobelts [88], nanowires/nanofibers [89]. A major
advantage of nanobelts is their lack of crystallographic defects
due to their rectangular shape, promoting ideal sensing [84]. For
example, vanadium pentoxide (V2O5) nanobelts (Fig. 4f) showed
to be highly selective to ethanol against different gases even at
relatively low temperature (150 8C), which is advantageous for
cheap and low power device applications [88].
Figure 5 shows the response to H2S of WO3 nanoparticles
(dotted line) in comparison with 2D platelets (dashed line) and
1D wires (black line), respectively [90]. Possibly due to the mentioned reduction in aspect ratio and the associated reduction in
surface-to-volume ratio, nanoplatelets showed inferior sensing
performance compared to 1D nanostructures but still preferable
to not specifically designed nanoparticles at all temperatures [90].
The increased sensor sensitivity for increasing surface-to-volume
(SV) ratio is attributed to the increased adsorption of analyte gas
molecules onto the sensor surface [85]. Furthermore, the WO3
nanowire and platelet sensors exhibited constant sensitivity when
increasing the relative humidity up to 60%. However, upon increasing the rh up to 90% the sensitivity slightly decreased [90].

FIGURE 4

TEM images of, (a) WO3 nanoparticles, (b) ZnO nanorods [86], (c) Au decorated WO3 nanorods [91], (d) In2O3 carbon nanotubes (CNT) [87], (e) SnO2
nanofibers [89], (f ) V2O5 nanobelts [88], (g) ZnO nanoplatelets (sheets) [92], (h) ZnO hollow spheres [96], and (i) Au decorated SnO2 hollow spheres [97].
Reproduced with permission from the corresponding journals.
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FIGURE 5

WO3 sensor response to 1000 ppm H2S for different structures as a function
of temperature. The WO3 nanowires exhibited better sensitivity to H2S than
nanoplatelets or nanoparticles at all temperatures (adapted from [90]).

Additionally these structures can be decorated with sensing enhancing elements, as for example catalytically active palladium or
gold, supporting and facilitating the gas sensing mechanism as
illustrated in Fig. 6a where WO3 nanowires were decorated with Au
nanoparticles (Fig. 4c) increasing both sensitivity and selectivity
[91].
Decreasing the aspect ratio and maintaining rectangular crosssection yields two-dimensional structures like nanoplatelets [90].
Gas sensors made of two-dimensional ZnO nanosheets of about
1020 nm thickness (Fig. 4g) detected selectively acetone and
gasoline at 360 and 180 8C, respectively [92]. Thin-walled WO3
hemitubes made by polymeric fiber-templating were used as sensors for possible diagnosis of halitosis and diabetes, through the
detection of H2S and acetone (down to 120 ppb), respectively [93].
These structures exhibited very high H2S selectivity (Fig. 6b) at
high (85%) relative humidity, mandatory for breath analysis
applications. However, even though the sensor response was
relatively decreased by Pt-functionalization, such Pt/WO3 hemitubes exhibited superior acetone sensing with negligible response
to H2S and toluene (Fig. 6b). This was attributed to the spillover
effect [94] of the Pt catalyst, which can effectively dissociate
adsorbed oxygen molecules into ionized oxygen (O , O2 ) on
the WO3 surface, accompanied by the capture of electrons from
the WO3 conduction band [93].
As controlled mass transfer toward the active sites is of crucial
importance in catalysis, gas sensing or battery applications, a great
effort has been made to compose films of hollow multilayered
porous spheres maximizing mass transfer throughout the bulk
films and maintaining a high surface-to-volume ratio [95]. Such
composed hollow spheres showed enhanced performance compared to usual nanoparticles in gas sensing and lithium-ion batteries [95]. Figure 6c shows the response toward various analytes by
a gas sensor consisting of ZnO hollow spheres (Fig. 4h) compared
to a sensor based on commercial ZnO [96]. The sensor response
and selectivity to NO2 was strongly enhanced with the hollow
sphere based gas sensors (Fig. 6c). Additionally, and similarly to
Fig. 6a,b, decorating SnO2 hollow spheres with Au (Fig. 4i) enhanced their sensitivity and selectivity to ethanol over bare SnO2
168

FIGURE 6

Sensing performance was affected by different structures: (a) Decoration of

WO3 nanorods with Au nanoparticles increased the sensitivity and
selectivity to hydrogen (adapted from [91]). (b) Gas sensor response to H2S,
acetone and toluene of pristine and Pt-functionalized WO3 hemitubes
(adapted from [93]). (c) Comparison of sensitivity to several analytes
(adapted from [96]) between commercial ZnO particles and hollow spheres
(Fig. 4g). (d) Decoration of SnO2 hollow spheres with Au nanoparticles
increased the sensitivity and selectivity to ethanol against acetone (adapted
from [97]).

(Fig. 6d) [97]. Recently, even more complex structures have been
prepared to obtain high performance sensors such as urchin,
flowers, cubes and various hollow structures [95].

Sensor composition
Tin oxide is the most common metal oxide for gas sensing [68,81].
It is sensitive to many gases and organic compounds [68] but this is
also its major drawback: selective sensors based on sole SnO2 are
not available yet. Great effort has been made to improve that, by
varying crystal structure or morphology, adding dopants, changing the operating temperature, etc. [69]. The application, however,
of SnO2 as a gas sensor for breath analysis has been limited by its
cross-sensitivity to humidity (major component of the human
breath). Additional efforts have been made to overcome this, such
as the embedding of active filters placed above the SnO2 semiconductor layer in order to exclude undesired gases [98]. Flame-made
SnO2 doped with about 5% TiO2 resulted in a solid solution
material with reduced cross-sensitivity to humidity and increased
sensitivity to ethanol [99].
A further challenge is the relatively poor stability, intrinsic to
nano-sized materials at the usually high operating temperature.
This might result in drifts of the baseline resistance and sensor

response. A common practice to improve thermal stability is the

use of dopants [100], that may decrease, however, the overall
performance [69]. For example, Si-doping increased thermal stability and enhanced sensing performance for ethanol detection
down to 100 ppb (Fig. 3b) [83]. Furthermore one dimensional
SnO2 structures enhanced sensitivity and selectivity [85].
Tungsten oxide was used for the first time as a H2 detector in
1967 for safety applications [101]. It has attracted a lot of interest
due to its various crystal structures: monoclinic (e phase), triclinic
(d phase), monoclinic (g phase), orthorhombic (b phase) and
tetragonal (a phase) [102]. A highly sensitive gas sensor based
on a WO3 thick film has been developed for the detection of trace
amounts of aromatic hydrocarbons [103]. That WO3 sensor had
enough sensitivity to detect traces of VOC gases, especially aromatic hydrocarbons, at the ppb level with excellent selectivity
[103].
As with SnO2 also WO3 is sensitive to many gases. However, its
different phases have different sensing properties. In particular, its
e-WO3 phase is highly sensitive and selective to acetone [104]. On
the other hand, g-WO3 is promising for selective NO detection
[105]. Epsilon-WO3 that was thermally stabilized by Cr- [104] or Sidoping [106] selectively detected acetone down to 20 ppb at 90%
rh [107]. Furthermore, the Si-doped WO3 sensor response was only
decreased by 4% when increasing the rh from 80 to 90% indicating
sufficiently precise detection regardless of humidity fluctuations
[107].
Other materials such as TiO2, ZnO, MoO3, etc. have been
investigated also for gas sensing. Titania-based gas sensors are
particularly attractive for their lower cross-sensitivity to humidity
than SnO2 sensors [99]. Titania sensors were applied to detection
of organic compounds such as acetone and isoprene and showed
high sensitivity down to 1 ppm [108]. Zinc oxide has been studied
for its large scale and low-cost synthesis by hydrothermal methods
resulting in 1D structures (Fig. 4c) [86] like ZnO nanorods stable
and highly sensitive sensors, especially for ethanol detection with
short response time. Similarly to WO3, also MoO3 can be synthesized in different crystal structures for the selective detection of
specific gases such as orthorhombic MoO3 [109]. Most notably
promising results were obtained by MoO3 films for selective detection of NH3 in simulated exhaled breath that contained CO2, NO2
and isoprene [110]. Additionally the NH3 selectivity could also be
improved by optimizing the operating temperature (400450 8C)
[111].

Applications to human breath

Today only a few studies involving human subjects have been
made with chemo-resistive gas sensors. To start using sensors for
breath analysis, their measurements need to be benchmarked
against spectroscopic techniques that provide breath speciation.
For instance WO3-based thin films have been used for quantitative
detection of NO in the human breath of four people collected in
Tedlar bags (off-line) and compared with a chemiluminescence
NO analyzer for validation [112]. The sensor prototype demonstrated the capability of breath NO monitoring in the range
between 0 and 100 ppb. However, this was accomplished by first
oxidizing NO to NO2 by a catalyst (KMnO4) and the response to
other organic compounds was reduced by non-polar molecular
sieves (e.g. silicalite) [112].

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Portable Si-doped WO3 gas sensors accurately monitored

breath acetone concentrations of healthy humans both on-line
[113] and off-line (Tedlar bags) [114] with proton-transfer-reaction time of flight mass spectrometry (PTR-TOF-MS) [115]. Online sensor measurements enabled the monitoring of acetone
concentrations during rest and physical activity of five human
subjects, in good agreement with PTR-MS (five healthy persons)
[113]. Off-line measurements of eight healthy volunteers showed
high correlations between acetone, sensor response and blood
glucose after overnight fasting [114]. This highlighted the potential of gas sensors to replace glucose testing, at least, after overnight fasting.
Nevertheless clinical studies with several patients are required in
order to assess such sensors further and make them a clinical
reality. Recently, a prototype portable breath acetone analyzer
was developed for on-line monitoring fat burning and was tested
on 17 healthy adults [116]. The acetone concentrations were
validated successfully by GC measurements of breath collected
into Tedlar bags. The device included two sensors (SnO2 and WO3)
that enabled the acetone concentration to be calculated while
taking into account other background gases present in the breath
such as ethanol, hydrogen and humidity [116].
An interesting alternative to metal oxide nanomaterials is
represented by conducting polymers. Polyaniline (PANI), for example, displays high sensitivity at room temperature that is advantageous for reduction of power consumption and increased
portability [117]. For example, very promising results have been
obtained by inkjet-printed PANI nanoparticle sensors for breath
ammonia detection (down to 40 ppb), related to dysfunction of
the kidney and liver, and operated at room temperature [118]. A
cohort of 20 hemodialysis patients breath samples was evaluated
and showed good correlation between breath ammonia and blood
urea nitrogen levels. These sensors were validated by photoacoustic laser spectroscopy (PALS) [118]. Additionally, inorganic nanoparticles, such as metal oxides, are combined with conductive
polymers in a sensing layer to exploit synergies in terms of the
sensing performance [119] while reducing the sensor operating
temperature [118].

Potential and challenges

Recent studies have led to increased sensor portability, decreased
power consumption (low operating temperature), lower limit of
detection and in some cases even increased selectivity. Furthermore, due to their miniaturization potential sensors could be
easily integrated in daily used commodities, such as mobile
phones. The first step toward the use of such devices for breath
analysis remains the validation of sensor with well-established and
selective techniques, such as GCMS, PTR-MS or similar as described above. Figure 7 shows an example of the different sampling
methods for that purpose. The breath sample can either be directly
analyzed [113] (1) (2) or first sampled (3) (4) in a container (e.g.
Tedlar bag) [114]. Additionally, the portion of the breath can be
either controlled (e.g. end tidal fraction) for example with a CO2
trigger or the whole lung capacity can be considered. Then the
same breath sample should be analyzed by both sensor and an
analytical device. Again it is of crucial importance that the sampling procedure is performed accurately. For example, to avoid
condensation and thus alteration of the breath composition, all
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FIGURE 7

Schematic of breath analysis (on-line and off-line) by gas sensors and to

spectroscopic methods. The breath can be either directly analyzed on-line
where the whole breath pulse is sampled (1) or (2) only a portion (e.g. end
tidal fraction) after being separated by a control unit. Similarly for off-line
measurements the whole breath (3) or a portion of it (4) was sampled in
bags or rigid canisters (3).

the lines and the Tedlar bags need to be heated at 40 8C during offline breath sampling (Fig. 7).
The majority of the studies on metal oxide gas sensors are
carried out in dry air conditions, far away from the high relative
humidity of the breath (90%). Therefore there is the need to
perform additional studies at realistic conditions to asses those
sensors for breath analysis and come a step closer to their implementation in clinical studies. Moreover the restricted selectivity is
yet the most limiting factor, especially for trace concentrations
(ppt) of target analytes. Several strategies in addition to tailoring
the material properties, addition of dopants and optimizing the
operating temperature have been used to improve the selectivity,
such as pre-treatments (e.g. sodium hydroxide filter) [120], layer
filters (e.g. Pd/Al2O3) [121] or even additional sensors to monitor
humidity or background gases (e.g. CO2). For instance these
methods improved the sensor performance at high relative humidities [120] and the selectivity to NH3 against water and CO2
[120] or to CH4 against water, CO and ethanol [121].
Up to now only a few chemo-resistive gas sensors have been
applied to breath analysis and most of recent studies, especially for
cancer research, were obtained by sensor arrays [60], therefore,
avoiding the problem of selectivity. For example, recently, it has
been demonstrated that a breath test based on a nanoscale artificial nose could distinguish patients having breast, lung, colon, and
prostate cancer and healthy controls [122]. The e-nose was based
on an array of highly cross-reactive gas sensors [56] that could
identify and separate different traces. Each sensor showed an
individual response to all (or to a certain subset) of the volatile
biomarkers that make up the cancer-odor. The odor was identified
by pattern recognition of the sensor signals [122]. In general
pattern recognition algorithms can be used to obtain information
on the overall breath composition [56] as well as concentration of
specific breath compounds [58]. Moreover due to the fact that the
accelerated metabolism of tumor cells may produce a number of
VOCs that could differ both qualitatively and quantitatively from
VOCs released by healthy subjects, in most of the studies for cancer
research a pattern of VOC instead of a single one has been studied
and therefore sensor arrays that are not limited by a single gas
detection are required [123].
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Finally, the possibility of using this sensor at room temperature

and therefore avoiding the need of heating, reducing power
consumption and facilitating miniaturization, would be advantageous in terms of device portability. This would avoid long term
instability of the nanoparticle layer as resistance baseline and
sensor response might drift [124]. Yet the major drawbacks of
room temperature sensors are usually the increased response and
recovery times [69] that are critical for on-line breath analysis.
However, reduction in the sensor response time can be achieved
by reduction in film thickness [69], appropriate morphologies
(e.g. nanowires) [85] or addition of catalytic particles (e.g. noble
metals) [77].

Summary and outlook

Breath analysis has attracted increasing interest among the scientific and clinical communities. It is a powerful technique for noninvasive and rapid (on-line) provision of information about the
disease state/progression and monitoring of therapy. Currently
only a small fraction of the exhaled gases from the human breath
can be related to specific physiological conditions. For those
components, however, chemo-resistive gas sensors have a great
potential for the development of devices that could dramatically
reduce the medical costs and improve the quality of life. The
technological improvement of gas sensors is therefore crucial in
terms of selectivity, sensitivity and response time at high relative
humidity. Different materials, structures, morphologies and even
different crystal phase properties of specific materials could enhance further the performance of chemo-resistive gas sensors and
therefore allow the selective detection of specific breath markers
related to different diseases. Nevertheless, considerable progress
and research is still required to identify such specific breath
markers or patterns of VOCs. The majority of diseases, including
various types of cancers, is related to several breath markers and
therefore might require a multiple component analysis provided
for example by sensor arrays (e-noses) that will benefit of high
performance chemo-resistive gas sensors. Though a lot needs to be
learned, enough is known to start using systematically chemoresistive gas sensors in clinical studies, with large number of
patients for specific illnesses.

Acknowledgements
This research was supported by the Swiss National Science
Foundation, grant 200021_130582/1, and the European Research
Council under the European Unions Seventh Framework Program
(FP7/2007-2013, ERC grant agreement n8 247283).
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