a n a l y t i c a c h i m i c a a c t a 6 1 9 ( 2 0 0 8 ) 143–156

avai lab le at www.sc iencedi rec t .com

journa l homepage: www.e lsev ier .com/ locate /aca

Review

Micro gas analyzers for environmental andmedical applications

Shin-Ichi Ohiraa, Kei Todab,∗

a Department of Chemistry and Biochemistry, University of Texas at Arlington, Arlington, TX 76019-0065, USAb Department of Chemistry, Kumamoto University, Kurokami, Kumamoto 860-8555, Japan

a r t i c l e i n f o

Article history:

Received 8 February 2008

Received in revised form 4 May 2008

Accepted 6 May 2008

Published on line 14 May 2008

Keywords:

Micro gas analyzers

Environmental and medical

applications

Atmospheric analysis

Breath and skin gas

Microchannel scrubbers

Micro gas chromatograph

a b s t r a c t

In this review, novel microsystems and microdevices to measure gaseous species for envi-

ronmental analysis and medical diagnostics are described. Miniaturization of analyzers

makes field measurements affordable. As well, high sensitivity and good time resolution

can be achieved by miniaturization. Some such devices have already been successfully

applied to real environmental analyses. Mobile monitoring is available with the use of micro

gas analyzers to investigate the natural environment, air pollution and to detect nerve or

explosive gases released accidentally or through terrorist activities. Miniature devices are

also attractive for medical analyses. Gases produced from the human body reflect gases

contained in the blood and certain metabolic conditions. Noninvasive monitoring using

miniature devices is available in hospitals and in a patient’s home. Many investigations

have been conducted using wet and dry chemistry methods for both applications. Instru-

ments employing wet chemistries, which comprise liquid droplets, liquid film, miniature

diffusion scrubbers, and microfluidic devices have been studied. Among the instruments

using dry methods, miniature samplers, portable gas chromatographs, and microfabricated

Microfluidic devices gas chromatographs have all been investigated. These instruments are expected to usher in

a new era of environmental monitoring and will find uses in many medical applications.

© 2008 Elsevier B.V. All rights reserved.

Contents

1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1442. Miniature gas analysis system with wet chemistry . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 144

2.1. Liquid droplet and liquid film . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1462.2. Miniature membrane based diffusion scrubber . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1462.3. Porous tube collector/detector and liquid core waveguide . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1462.4. Chromatomembrane cell . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 146

2.5. Porous glass devices . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 146

3. Micro gas analysis system for water-soluble gases . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1464. Micro trap/desorption system for volatile compounds. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 149

∗ Corresponding author. Tel.: +81 96 342 3389; fax: +81 96 342 3389.E-mail address: todakei@sci.kumamoto-u.ac.jp (K. Toda).

0003-2670/$ – see front matter © 2008 Elsevier B.V. All rights reserved.doi:10.1016/j.aca.2008.05.010

144 a n a l y t i c a c h i m i c a a c t a 6 1 9 ( 2 0 0 8 ) 143–156

4.1. VOC measurements with detection by UV spectrophotometry . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1494.2. Volatile sulfur compounds and isoprene measurements with chemiluminescence detection . . . . . . . . . . . . . . . . . . . 149

5. Miniature gas sampler for gas chromatographic analysis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1496. Portable gas chromatograph . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1507. Microfabricated preconcentrator . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1508. Microfabricated gas chromatograph . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1509. Microfabricated detectors for micro GC . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 15210. Medical applications of gas analysis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 152

10.1. Exhaled NO. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 15310.2. Halitosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 15310.3. Volatile organic compounds in breath . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 15310.4. Ammonia and amines . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 15410.5. Analysis of gases emitted from human skin . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 154

. . . . .. . . . .

11. Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

1. Introduction

Gas analysis is more challenging for analytical chemists thanwater analysis because of the difficulty of handling and sam-pling air. Many recent efforts in this area have, however,resulted in attractive and practical methods now being avail-able for many uses. Miniaturization of gas analysis systemsis an especially attractive approach [1,2]. Air analysis mustbe performed on-site in environmental/atmospheric analy-sis and medical diagnostics. There are several reasons whyon-site measurements are needed in gas analysis.

• Gas analytes may be lost during sampling and subsequenttransport to the laboratory because of reactions and adsorp-tions.

• Time variation data is important in atmospheric analysis.Therefore, continuous or near real time measurements arerequired in the field.

• Mapping of gas concentrations is available by mobile mon-itoring around a pollutant source with a portable device.

• More effective data can be obtained by changing the sam-pling point with feedback of real time data. This is useful inidentification of pollutant sources and to assess a pollutedarea.

• To prevent significant damage in a civic area from an acci-dent or an act of terrorism, miniature instruments areneeded to be placed in airports, railway stations and stadi-ums to monitor levels of potential nerve or explosive gases.

• Analysis of gases emitted from the human body can be usedas a noninvasive diagnostic.

• Small instruments can be placed in a hospital room, notonly in an intensive care unit (ICU), but also next to a patientin a normal hospital room or even in a patient’s home.

• Medical test data can be made available in a short time andtreatment can be decided upon immediately.

Miniaturization is the key to establishing instrumentationfor on-site analysis. By employing miniaturization, sophisti-

cated instruments can be readily used in the field as sensors.Inorganic gases and water-soluble gases are measured by wetchemistry after collection into an aqueous phase. On the otherhand, organic gases are mainly measured by dry methods

. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 154. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 154

and mostly dry preconcentration process is incorporated intothe analysis. There are merits to miniaturization and use ofmicrodevices in the gas collection and measurement process.

• Microdevices achieve high-speed analyses due to fast reac-tions in a microfluidic channel.

• In the collection of gas samples, a high enrichment factoris easily available because of a high surface to volume ratioof microdevice. Therefore, high sensitivity and good timeresolution are available with a microsystem if the systemand procedure are appropriately designed.

• In some gas analyses, trapped gases are desorbed by heat-ing and chromatographic separation is performed usingchanging column temperatures. Very fast heating/coolingis available, because of the ultra small heat capacity of amicrodevice, to dramatically shorten measurement times.

• Power consumption is small, especially in heating devices.Hence, an entire system can be driven by a battery to use inthe field.

• Microdevices are environmentally friendly because of theirsmall consumption of chemicals. These devices are thusavailable as environmentally friendly instruments for envi-ronmental analysis [3].

In this paper, we present the recent progress that hasbeen made in miniaturization and developing microdevicesfor gas analysis from practical miniature systems to advancedmicrochannel devices. We also describe successful applica-tions of these devices in environmental analysis and medicaldiagnostics.

2. Miniature gas analysis system with wetchemistry

Wet chemistry is classically used for gas analysis where gasesare collected in a suitable device (the use of an impingeris the most popular conventional method) and are subse-

quently determined by colorimetry or fluorometry. Micro gascollectors have recently been investigated and integrated withreaction/detection systems. Representative works are sum-marized in Table 1.

an

al

yt

ica

ch

imic

aa

ct

a6

19

(20

08

)143–156

145

Table 1 – Miniature gas analyzers for use with wet chemistry

Analyte Pumpa Collector Reaction Detectionb LOD (ppbv) Sampling time (min)c Application Year and Ref.

DropletNH3 SIA (EOF) H2SO4 Indophenols ABS – – – 1995 [4]SO2 H2O2/MnSO4 SO2 → SO4

2− CD – – – 1995 [4]Cl2 Syringe Tetramethylbenzidin ABS 3.3 1.1 – 1995 [6]H2S Gravity FMA/NaOH FMA FL 10 s 2 – 1997 [8]HCHO Syringe MBTH ABS 4.7 5 Indoor/outdoor 1997 [9]

FilmNH3 Peristaltic Water OPA, sulfite FL 0.004 18 – 2000 [5]HCOOH, CH3COOH EOF Water Na2CrO4 ABS 3 1 Outdoor 1998 [10]SO2 Solenoid pump H2O2 soap film SO2 → SO4

2− CD 37 1 – 2006 [11]NH3 Gravity H2SO4 Neutralization CD 1 3 Breath 2006 [12]

Annular DSH2O2 Gravity HCl/Nafion – AMP 0.11 9 Ambient air 1996 [7]H2O2 Peristaltic Water/Nafion Hematine/thiamine FL 0.025 CF Air on the sea 2003 [15]CH3HO2 Water/ePTFE HRP/thiamine 0.015 TampaHCHO Peristaltic H2SO4/Nafion 2,4-Pentanedione FL 0.07 CF Philadelphia, Atlanta,

Houston, Tampa,Nashville

2005 [16,17]

HCHO Peristaltic MBTH/pPP MBTH ABS 0.08 5 Room air, Atmosphere 2005 [27]H2S, CH3SH, SO2 Pneum FMA/NaOH

H2SO4/H2O2, ePTFE,Nafion, pPTFE, pPP

FMA, SO2 → SO42− FL, CD 0.03, 0.12 CF Oil filed, volcano

mobile, tidal flat,septic tank

2001 [18], 2004[19], 2005 [20]

NH3 HFA Water/pPP OPA FL 7.5 CF Atmosphere 2006 [22]HCHO HFA Water/pPP 2,4-Pentanedione FL 0.1 9 Atmosphere 2008 [23]H2O2, CH3HO2 Peristaltic Water/Nafion Hematine/thiamine LCW FL 0.0135 CF Atlanta 2000 [32]HCHO Peristaltic Water/Nafion 1,3-CHD LCW FL 0.03 CF Atlanta 2001 [33]H2O2 Peristaltic Water/Nafion Luminol/Co(NO3)2 LCW CL 0.025 CF – 2001 [34]

Long collector/absorbance cellNO2 Gravity, SF pPP Saltzman ABS 0.4 3 Atmosphere 2003 [27]O3 ITS ABS 0.3 9.5Cl2 Peristaltic Teflon AF TMB ABS – 1998 [28]H2S Pb(CH3COO)2 –NO2 Saltzman 0.15 –CO2 Phenol red BreathNO2, HONO SF Teflon AF Saltzman ABS 60 – 2001 [29]H2O2 Peristaltic Nafion Ti-TPyP ABS 0.026 CF – 2003 [30]O3 Gravity, SF pPP ITS ABS 1.2 1 Atmosphere 20 days 2008 [31]

a SF: stopped-flow.b ABS: absorbance FL: fluorescence; CD: conductivity.c CF: continuous flow.

a c t a

146 a n a l y t i c a c h i m i c a

2.1. Liquid droplet and liquid film

Liquid drops and liquid film are both small volumes suitablefor collecting water-soluble gases. In both of these, an ana-lyte gas comes into direct contact with the collection mediumthat has a large surface to volume ratio and is easily renew-able. Dasgupta’s group developed analysis systems with adroplet/film-based collector/reactor for analysis of SO2 [4],NH3 [4,5], Cl2 [6], H2O2 [7], H2S [8], atmospheric HCHO [9] andformic and acetic acids [10]. An absorbing solution was madeto flow by electroosmosis, the use of syringe pump, or justgravity. Challenges to a liquid film based device were per-formed for SO2, NH3 and O3. Soap film is very thin and sohas a very large surface to volume ratio. Soap film conductiv-ity has been monitored directly during the collection of gasand the concentration of SO2 determined [11]. Gaseous NH3

has also been determined by liquid film in situ conductivitymonitoring, and applied to continuous breath analysis [12].Ozone, which reacts on a liquid film with chromotropic acidand emits chemiluminescence at the water–air interface, hasbeen monitored with fast response and high sensitivity [13].

2.2. Miniature membrane based diffusion scrubber

To maintain liquid/air interface conditions, the two phases canbe separated with a gas permeable membrane. Hydrophobicporous membranes made of porous polytetrafluoroethylene(pPTFE), porous polypropylene (pPP), etc. and nonporousmembranes made of polydimethylsiloxane (PDMS) andNafion®, etc., can be used. Gas molecules in air diffuse throughthe membrane interface to be captured during the passageof sample air through the scrubber. Accordingly, the device iscalled the membrane-based diffusion scrubber. In contrast tothe sorbent-coated diffusion denuders, this device can be usedcontinuously and repeatedly. Among the membrane-baseddiffusion scrubbers, an annular arrangement is preferred forminiature systems [14]. The solution volume held in a smallmembrane tube is only ∼100 �L. Annular diffusion scrub-bers have been coupled to flow analyzers and applied toreal atmospheric analyses for peroxides (H2O2, CH3HO2) [15]and HCHO [16,17]. The sulfur gases (H2S, CH3SH and SO2)emitted from a volcano and tidal sediments have been mea-sured by portable analyzers equipped with membrane-baseddiffusion scrubbers and a compact pneumatic (�Pneum) liq-uid flow controller [18–20]. A channel type scrubber is alsoan attractive device to minimize the system [21]. Thesemembrane-based diffusion scrubbers can be placed in con-tinuous flow analysis systems (FIA), as well as in sequentialanalysis (SIA) [21] and hybrid flow analysis (HFA) systems[22,23]. The HFA system has the merits of both FIA and SIA;namely, good repeatability with low reagent consumption,fully automated analysis, good signal to noise ratio, and nosignal for a blank. If a gasifying process is coupled to thediffusion scrubber based FIA system, trace-gasifying speciescontained in water can be measured with ultra-high sensitiv-ity. Sub-�g L−1 level of arsenite and arsenate concentrations

in lake water were discriminately determined on a lake-side beach using a field instrument comprised of a hydridegas generator and AsH3 gas analysis miniature flow system[24,25].

6 1 9 ( 2 0 0 8 ) 143–156

2.3. Porous tube collector/detector and liquid corewaveguide

The annular-type membrane-based diffusion scrubber, intro-duced in the previous section, has demonstrated goodperformance for the collection of gas samples. In addition, aporous membrane tube containing aqueous solution has goodlight transmitting ability along the tube like liquid core waveg-uide (LCW) [26]. Namely, the porous tube performs as both agas collector and a long and thin absorbance cell, where opti-cal fibers for light source and light detection are connected tothe ends of tube. The absorbance can be monitored in situ dur-ing the gas absorbing process. The long tube is advantageous,since the absorbance increases in proportion to the poroustube length L in a stopped flow mode and the square of thelength L2 in the case of a continuous flow mode [27]. There-fore, high sensitivity is obtained using absorbance methodseven though they employ small optical devices such as a lightemitting diode (LED) and a photodiode (PD). The long gas col-lection/absorbance cell tube was applied to the analysis of NO2

and O3 [27], Cl2, H2S, NO2 and CO2 [28], HONO and NO2 [29],H2O2 [30], and O3 [31].

The LCWs can be used as standalone fluorescence detec-tors to measure atmospheric peroxides [32] and HCHO [33]as demonstrated at the Atlanta supersite campaign, and forchemiluminescence detector to measure H2O2 [34]. All detec-tors were placed downstream of annular diffusion scrubbers.A microfabricated LCW detector has also been developed witha coating of Teflon AF in a silicon microchannel [35].

2.4. Chromatomembrane cell

The chromatomembrane cell (CMC) proposed by Moskvin andSimon [36] acts as a superior gas collector. A CMC is comprisedof a bi-porous membrane. Aqueous liquid is held in microp-ores and air can pass through macropores. The CMC systemhas been combined with a flow analysis system to determineHF [36], acid gases and NH3 [37], NO2 [38,39], SO2 [36,40] andHCHO [41]. The advantage of using a CMC system is that lowconcentrations of gases can be determined with a small vol-ume of air, typically introduced by a syringe into the CMC.

2.5. Porous glass devices

The concentration of NO2 can be measured using a porousglass plate impregnated with Saltzman reagent [42,43].Absorbance of the glass plate increased in a reaction withatmospheric NO2. The NO2 concentration is determined fromthe rate of increase in the plate absorbance. Fluorescencechemistry has also been examined for NO2 determination [44],but further instrumentation using the Saltzman chemistry hasbeen done [45,46] and this method applied to the analysis ofatmosphere in Sapporo, Japan [47].

3. Micro gas analysis system for

water-soluble gases

Microfluidic devices are much smaller than the conventionalflow analysis systems and are expected to be more useful. Fur-

a n a l y t i c a c h i m i c a a c t a 6 1 9 ( 2 0 0 8 ) 143–156 147

Fig. 1 – Schematic of micro gas analyzer based on collection of water-soluble gas and detection with wet chemistry.Diagram in the top shows typical flow system. Pictures in the bottom are microchannel gas collectors; the left and rightp [56]

tifa(

C

(ttlfsrwssm

clmi[abs1tc1

ictures are from references [61] (Anal. Chim. Acta, 2004) and

hermore, microdevices will achieve dramatic improvementsn sensitivity and response times. As can be seen from theollowing equation, sensitivity is inversely proportional to thebsorbing solution layer thickness d if the absorbing time Tcorresponding to response time) is constant.

s = kTCg

d(1)

Here, Cs is the concentration of the analyte collected in solu-ion, k is the gas permeation rate of the membrane, and Cg ishe analyte concentration in the sample.) Absorbing solutionayer with very small d is formed with microchannels, there-ore, a microchannel scrubber is expected to achieve higherensitivity with shorter absorption time T. Typical configu-ation of microsystem for water-soluble gases is presentedith pictures of microchannel scrubber devices in Fig. 1. The

ystem comprises of a micropumping system for absorbingolution, a microchannel gas collector, a microreactor and aicrodetector.Recently reported microsystems are listed in Table 2. The

rucial piece of equipment for gas analysis is the micro gas col-ector, which is available with a gas permeable membrane and

icrochannel plates. (The many kinds of uses for membranesn microfluidic devices have been summarized in a review48].) In the first generation of micro gas collection devices,

channel for a solution layer was prepared with a gasket ory mechanical machining. Toda et al. demonstrated the fea-ibility of SO analysis with a gasket type wet scrubber in the

2

990s [49]. A similar device for determination of SO2 concen-rations was made by Guo et al. [50]: however, prior to that,ollection cells were dramatically minimized to 800 nL from4 �L [49] and 72 �L [50], and a microconductivity electrode

(Lab Chip, 2005), respectively.

was incorporated in the cell [51]. Conductivity was monitoredin real time and SO2 concentration determined from the rateof increase of conductivity. A liquid pump was not needed andthe absorbing solution was renewed simply by gravity wherethe solution was supplied to the cell from a reservoir hungabove a solenoid valve that was placed between the cell andthe reservoir.

Second generation microchannel devices were investigatedfor gas collection and measurement. In the 1990s, Ohiramade a gas collector in which a gas permeable membranewas sandwiched by two glass plates equipped with an arrayof microchannels [3]. Practical devices became available inthe 2000s. Korenaga et al. covered a quartz channel platewith a porous glass plate (500 �m in thickness) treated witha hydrophobic agent to develop a gas collector [52]. Thisdevice was used for NO2 determinations using a fluorescencereagent, diaminonaphthalene (DAN) [53]. The same device wasalso applied to SO2 measurement using a fluorescence reagentN-(9-acridinyl)maleimide (NAM) [54].

Toda et al. developed a membrane-based microchannelscrubber where a zigzag microchannel was covered with a verythin PDMS film (∼7 �m) [55]. The sensitivity was inversely pro-portional to the membrane thickness, and good performancewas obtained by minimizing the thickness. The microchannelscrubber, the micro fan for sample supply and the fluorescencedetector were integrated in only 30 mm × 30 mm × 20 mm ofspace. A commercial liquid pump was not utilized and amicropneumatic flow control system (�Pneum) was incor-porated. Not only the device itself, but the entire system

incorporating the device was very small. Such a system iscalled a micro Gas Analysis System (�GAS): microdevice forGAS. The fluorescence cell was made in an optical fiber tominimize dead volume (500 nL) and to provide a sufficient

148 a n a l y t i c a c h i m i c a a c t a

Tabl

e2

–M

icro

dev

ices

for

gas

anal

yses

usi

ng

wet

chem

istr

y

An

alyt

eFl

owra

te(�

Lm

in−1

),p

um

pM

embr

ane:

t(�

m),

mat

eria

lC

han

nel

,w,t

,l(m

m)

Rea

ctio

na

Det

ecti

onb

LOD

(pp

bv)

Res

pon

se(m

in)

Fiel

dap

pli

edc

Yea

ran

dR

ef.

SO2

20,P

neu

m60

,pPT

FE2,

0.5,

14H

2SO

4/H

2O

2C

D<

101.

2(V

olca

no)

1998

[49]

SO2

10,S

yrin

ge60

,pPT

FE0.

15,0

.05,

6,ar

ray

H2SO

4/H

2O

2C

DN

AN

A19

99[3

]SO

285

0,Pe

rist

alti

c10

0,p

PVD

F3,

0.8,

30D

TN

BA

BS

410

nm

200

120

03[5

0]SO

2SF

,Gra

vity

89,p

PP0.

5,0.

1,16

H2SO

4/H

2O

2C

D0.

71.

5V

olca

no

2002

[51]

NO

22,

Syri

nge

500,

pG

lass

0.25

,0.1

,15,

arra

yD

AN

FL,L

ED37

0n

m10

4020

00,2

006

[52,

53]

SO2

2,Sy

rin

ge50

0,p

Gla

ss0.

25,0

.1,1

5,ar

ray

NA

MFL

,LED

360

nm

2.8

NA

Roo

mai

r20

05[5

4]H

2S

2,�

Pneu

m7,

PDM

S0.

2,0.

05,2

00,z

igza

gFM

AFL

,LED

460

nm

12

2004

[55]

H2S,

SO2

35,�

Pum

p30

,pPT

FE0.

23,0

.7,(

52),

hon

eyco

mb

FMA

,SO

2→

SO4

2−FL

,LED

460

nm

CD

0.1,

11

Atm

osp

her

e20

05,2

007

[56,

59]

H2S,

SO2

15,F

eed

back

30,p

PTFE

0.23

,0.7

,(52

),h

oney

com

bFM

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fluorescence signal. The next stage was the minimizationof the pumping pressure and the maximization of the gasabsorbing area; a honeycomb-shaped microchannel scrubberwas developed for �GAS [56]. For this, a thin porous poly-tetrafluoroethylene (pPTFE) membrane (30 �m in thickness)was chosen as the best material. The enrichment factor innM ppb−1 min−1 was the best of all of the conventional/microwet scrubbers and was 20,000 times greater than that for aconventional impinger. Two sets of micropumps, microchan-nel scrubbers, and fluorescence/conductivity detectors wereintegrated in a 10 cm × 9 cm × 2 cm plate, including a zero gasgeneration bed. Two gases, H2S and SO2, at ppbv levels weresuccessfully measured simultaneously. The same system wasapplied to NO2/NO determinations using Saltzman chemistryand absorbance measurements [57]. In the NO measurementmode, NO was converted into NO2 by a UV-lamp after remov-ing NO2 contained originally in the sample.

To increase the accuracy of the analysis and field afford-ability, new techniques were investigated for �GAS. In theflow-based analysis, accurate flow control is required becausethe liquid flow rate affects the absorption time, and sensitiv-ity will change with the flow rate. Also, pumping noise is aproblem that degrades the detection limit. A syringe pump,usually preferred for use in microfluidic devices, is not suit-able for mobile monitoring. To obtain stable and constantliquid flow with a miniature system, feedback control of liquidflow has been investigated [58]. A miniature flow sensor thatmeasures flow rates in the order of �L min−1 was developedbased on a thermal equilibration profile along the microchan-nel. A thermal flow sensor was fabricated on a PDMS channel.Electroosmotic flow through the honeycomb microchannelscrubber was generated by applying a high voltage betweenthe reagent and waste reservoirs by a dice-sized dc/dc con-verter. The feedback system between the flow signal and theapplied high voltage ensured that the flow rate was main-tained at a constant 5 �L min−1 or 15 �L min−1 successfully.This was the first such demonstration of flow rate control ofan electroosmotic flow. Also, a piezo valve made with a siliconediaphragm and PDMS blocks was developed and the flow wasmaintained at a constant rate by the chemically compatiblepiezo valve and assistance of the micro flow sensor. Anotherchallenge is in situ calibration of �GAS [57,59]. A honeycombmicrochannel device can be used as a gas scrubber and as agas desorber. For this, a source reagent solution and a reac-tion reagent solution are mixed and then introduced into themicrochannel device, where the gas generated in the reactionis extracted into the air phase. The gas is formed quantitativelyand its concentration can be controlled by the concentrationand flow rate of the source solution.

Devices that were downsized even more were investi-gated by Timmer et al., a group working in the Netherlands.Their major work was on analysis of NH3 and for thisthey developed unique devices to determine gaseous NH3.The first device employed direct absorption of NH3 gas ina microchannel without a membrane [60]. Air sample andwater were introduced into Y-shape channels and mixed

directly. The principle of gas–liquid mixing/collection is thesame as in a conventional coil denuder, which is often usedfor atmospheric analysis, but size was dramatically down-sized. The air and water flow rates were 1.0 mL min−1 and

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0 �L min−1, respectively, and were controlled by a mass flowontroller and a syringe pump. Gas molecule diffusion is fast1.21 × 10−5 m2 s−1 at 293 K for NH3) and water solubility ofH3 is very high (31.3 M). Therefore, dissolution of NH3 inmicrochannel (25 �m × 220 �m) was estimated to be com-

leted very quickly in ∼10 ms. A flow restrictor was placedownstream of the mixing channel, and pressurized air wasemoved through a membrane port. A microconductivity elec-rode was used to measure the conductivity of the remainingolution. They succeeded in measuring ppmv and sub-ppmvevels of NH3 with this device. The response time of ca. 15 min

ay be reduced even further. The second device developedy Timmer et al. was for use in breath analysis, and its per-ormance was an improvement over that of the first device61,62]. Selectivity of this device to NH3 was achieved by gasi-cation/recollection; mixing the absorbed solution with anlkaline solution and recollection of NH3 into water. The mea-urable range was decreased to ppbv levels, and the responseime improved to just a few minutes. A similar gasifica-ion/collection process has also been demonstrated with a

icrochannel device, where a reaction channel and an accep-or channel were separated by a 25 �m PDMS membrane [63].he concentration of aqueous NH3 was measured by moni-

oring the change in absorbance of bromothimol blue reagentBTB) using a red LED and a photomultiplier (PMT) in the chan-el. Tipple et al. developed a micro-impinger produced on alass substrate using standard glass microfabrication tech-iques and a Teflon membrane [64]. This was applied to thenalysis of gaseous HCN. The limit of detection (LOD) was.486 mg m−3 (0.45 ppmv) with 1 min sampling at a flow ratef 2 mL min−1.

. Micro trap/desorption system for volatileompounds

olatile organic compounds (VOC) are atmospheric pollutantshat have recently become of great concern. They are toxicnd contribute to photochemical reactions in the atmosphere.ost VOCs are not water soluble, and so wet chemistry is

ifficult to apply to their analysis. Therefore, dry collectionnd dry analysis have been investigated for the VOC measure-ents.

.1. VOC measurements with detection by UVpectrophotometry

eno et al. developed a chip-based thermal desorption (TD)ystem combined with a miniature UV spectrophotometer toeasure contents of gaseous benzene, toluene and xylene

BTX) and BTEX (BTX + ethylbenzene). Adsorbents used weremorphous silicon dioxide powder [65,66] and nanosized poreesoporous silicate powder [67,68]. Microchannels for adsor-

ents were made by a dicing saw and the powders wereovered with a Pyrex glass to encage. A platinum (Pt) heateras fabricated on the backside of the channel plate. After

0 min of gas collection, the plate was heated by the Pteater to desorb the gases. The gases were introduced intomicrochannel cell, which was connected to an optical fiberV spectrophotometer. The optical path length was 20 mm.

1 9 ( 2 0 0 8 ) 143–156 149

Differentiation of individual components of BTEX was per-formed with a multi-wavelength analysis of the spectrum.Performance has been improved by a hybrid structure of thethermal desorber and optical chips [69]. The LOD for toluenewas 50 ppbv with 30 min sampling.

4.2. Volatile sulfur compounds and isoprenemeasurements with chemiluminescence detection

Concentrations of the volatile sulfur compounds (VSCs) andisoprene have been successfully measured by a miniature sys-tem comprising of a mini-collection/thermal-desorption (TD)column and a gas phase chemiluminescence (CL) detector[70]. Silica gel and carbon powders were used as adsorbentsfor VSCs [71] and isoprene [72], respectively. These volatilecompounds are highly adsorptive and reactive. Therefore, itis difficult to measure their levels with conventional samplecollection in the field, and then transport to and subsequentanalysis in the laboratory. However, these gases were success-fully analyzed on-site using field affordable TD–CL devices. AVSC system has been applied to continuous analysis of the airin toilets as well as to analysis of breath air [70].

5. Miniature gas sampler for gaschromatographic analysis

Gas chromatography (GC) remains one of the most powerfultools for environmental and medical gas analysis, though itis mainly used in the laboratory. The gas for analysis can beinjected directly into the GC with a gas tight syringe. However,a special interface is needed to obtain sufficient sensitivityfor trace gas analysis. There are several useful devices thathave been successfully applied to environmental and medicalanalyses.

An innovative solid phase microextraction (SPME) methodwas introduced by Pawliszyn’s group in 1990 [73]. This deviceis already available on the market and is well known in thefield of water and air analysis. For details of the SPME, readersare referred to another report that well describes SPME fromtheir principle to their applications [74].

In modern GC, analytes are generally separated by a capil-lary column. Dudek et al. placed a commercial capillary, as adiffusion denuder, in a six port valve upstream of a separationcapillary column, and analyzed BTEX using a flame ioniza-tion detector (FID) [75]. Absorbents Tenax TA and Carbotrapwere packed in series in part of the capillary chromatographiccolumn of a wall coated open tubular (WCOT) type, 0.32 mmo.d. × 12 cm long.

Ciucanu and Pawliszyn demonstrated analysis of six VOCsusing a GC coupled with membrane extraction with a sorbentinterface (MESI) for continuous monitoring [76]. The sampleand carrier gas were flowed through a membrane interfacewhere the VOCs permeated through the membrane into thecarrier gas. The carrier gas transported the permeated speciesto a microtrap. Next, the microtrap was heated and the ana-

lytes introduced into a separation column. Ciucanu improvedthe membrane interface by using a helical coil of PDMS mem-brane tube (50 �m in thickness) [77,78]. As well, the helicalcoil itself has been used as a sorbent trap [79]. The helical

a c t a

150 a n a l y t i c a c h i m i c a

sorbent microtrap was successfully applied to monitoring ofdiesel exhaust with interval of only 3 min [80].

A portable GC combined with the MESI device was usedfor on-site monitoring of biogenic gas emissions from plantleaves [81]. Changes in terpene emissions were monitoredevery 24 min using this system.

Needle type preconcentrators have recently been inves-tigated. Wang et al. packed a sorbent in a tip of a syringeneedle [82]. The needle trap device was used for monitoringthe concentration of benzene in indoor air. The LODs obtainedwith the FID detection for a 25 mL sample were 0.23 ng L−1

(0.074 ppbv), 2.10 ng L−1 (0.50 ppbv) and 1.12 ng L−1 (0.27 ppbv)for benzene, ethylbenzene and o-xylene, respectively. Saito etal. packed polymer-coated fibers in a needle for use in the anal-ysis of volatile carbonyl compounds [83]. Prior to use, the fiberswere impregnated with 2,4-dinitrophenylhydrazine (DNPH). A50 mL sample of air was introduced into the coated needle bya large syringe for a period of 8 min. Aldehydes and ketonesreacted with DNPH in the needle, and their derivatives wereintroduced into a GC by the syringe. This device is useful foranalysis of in-house environments.

6. Portable gas chromatograph

With miniature samplers being developed, portable GCs showpotential as instruments for field monitoring. For example, aportable microchip GC was applied to the identification andreduction of fugitive emissions in a pharmaceutical manufac-turing plant [84]. Also, emissions of VOCs were monitored atlandfills using a portable GC [85]. Lu et al. developed a portablegas chromatograph with tunable retention and sensor arraydetection for determination of complex vapor mixtures [86].Two capillary columns were connected in series and the col-umn temperatures were individually controlled. Since thecarrier gas was air and the detector was a surface acous-tic wave (SAW) sensor array, this GC did not need a gascylinder. The entire system was incorporated in a box just35 cm × 35 cm × 10 cm. Ji et al. applied a similar portable GC,coupled with SPME sampling, to water BTEX analysis [87].

7. Microfabricated preconcentrator

Microfabricated devices were investigated for miniaturizationand invention of new analytical techniques. For example, Li etal. developed a microchip preconcentrator, called a microflu-idic gas centrifuge, that selects and enriches heavy molecules[88]. A nozzle throat, 3.6 �m in width, was fabricated on achip with reactive ion etching and anodic bonding. Using thisdevice, 1% SF6 in N2 was enriched to double this level in 10 �s.

Microabsorbents are practical preconcentrators for envi-ronmental and medical analysis. Microfabricated GCs andpreconcentrators are shown in Table 3. A monolithic sil-ica capillary was tested for preconcentration of airbornetrichloroethylene and tetrachloroethylene [89]. Voiculescu

et al. developed a micropreconcentrator for detection ofexplosives and chemical agents [90]. In this device, amicrobridge heater was coated with a sorbent polymer,such as hyperbranched polycarbosilane functionalized with

6 1 9 ( 2 0 0 8 ) 143–156

hexafluoroisopropanol pendant groups, that is strongly hydro-gen bond acidic. The microhotplate heat capacity wasonly 10−12 J �m−2 K−1, and temperature climbed to 180 ◦Cwithin 40 ms. The device was attached to an ion mobilityspectroscopy (IMS) detector. Nerve agent stimulant dimethyl-methylphosphonate and explosive 2,4,6-trinitrotoluene (TNT)were successfully tested using this device and signal enhance-ment was observed.

Tian et al. developed a multiple-stage microfabricatedpreconcentrator-focuser for micro GC systems [91,92]. Amicroheater contained an array of high-aspect-ratio, etched-Siheating elements, bound by an annulus of Si and was ther-mally isolated from the remaining substrate by an air gap.Spherical graphite absorbents such as Carbopack B, CarbopackX and Carboxene 1000 were packed in the chamber array. Thepreconcentrator-focuser was attached to a commercial microGC, and 30 common organic vapors were separated with peakwidths at half height of less than 2.05 s.

8. Microfabricated gas chromatograph

Miniaturization of GCs has brings many advantages such asportability for field applications and fast operations includ-ing the GC–GC system. Miniaturizations have been attemptedwith conventional fluidic tubes and connectors [93]. Micro-fabrication is an attractive option for developing greatlyimproved instruments and many investigations have beenreported. Composition of micro GC system is shown inFig. 2.

Almost three decades ago, a GC fabricated on a siliconwafer was invented by researchers at Stanford University [94].It consisted of a sample injection valve, a 1.5 m separation col-umn and a TCD detector, all fabricated on a silicon wafer andsealed with a glass wafer by anodic bonding. This inventionwas sensational in the fields of micromachining and analyt-ical chemistry. The device was commercialized and is stillavailable on the market.

Recently, some groups have been investigating newconcepts in microchip GC technology. Lu et al. at theUniversity of Michigan integrated on-board calibration, sam-ple preconcentrator-focuser-thermal desorber, temperature-programmed separations, and “spectral” detection with anarray of microsensors [95]. The components were connectedwith a capillary tube. Ambient air was used as a carrier gas,thus making the use of a cylinder gas unnecessary. Eleventypes of VOCs were separated in only 90 s and the LODs were inthe low ppbvs for a 0.25 L sample. This device was also appliedto analyses of markers of environmental tobacco smoke (ETS)[96]. The target ETS species were 2,5-dimethylfuran and 4-ethenylpyridine (4-EP) (as a surrogate for 3-EP), and their LODswere 0.58 ppbv and 0.08 ppbv, respectively. Sample volume was1 L and the analysis could be repeated every 15 min. Chemicalsensors were used as the GC detector: resistances of gold-thiolate monolayers were measured, and five types of thiolateswere used in the sensor array.

Very rapid analysis is available with a micro GC system.Lambertus et al. integrated a preconcentrator and a GC sep-aration/detection system [97]. The separation column in thisdevice was 150 �m w × 250 �m d × 25 cm l coiled in a 1.2 cm

a n a l y t i c a c h i m i c a a c t a 6 1 9 ( 2 0 0 8 ) 143–156 151

Table 3 – Microsystems for gas analyses with dry methods

Method Features Anal. time(min)a

LOD (ppbv) Analytes and field applied Year and Ref.

�Centrifuge 3.6 �m nozzle throat,two-fold enrichment of SF6

in 10 �s

SF6 enrichment 2007 [88]

TD–UV 30 min collection by glassplate TD, UV spectrumanalysis

C 30 50 BTEX 2001–2003 [65–69]

TD–CL 5 min collection, stepwisetemperature increase TD,CL detection

C 5, T 23 0.3, 0.05 CH3SH, DMS, Breath air,toilet air

2006 [71]

TD–CL 5 min collection at 55 ◦C,5 min TD at 150 ◦C

C 5, T 10 0.6 Isoprene, breath in exercise 2007 [72]

�GC First �GC fabricated onSi/glass wafer

1979 [94]

�TD–�GC–MS 40 min collection on Tenax C 40 0.1 VOCs, Landfill site 2007 [85]Portable GC Multisorbent

preconcentrator, tunableretention withtandem-column separation,SAW sensor array

S 10 <10 30 VOCs 2003 [86]

Multisorbentpreconcentrator, tunableretention withtandem-column separation,SAW sensor array

S 10 0.58, 0.08 2,5-DMF, 4-EP (ETS markers) 2007 [96]

Micro-preconcentrator Sorbent-coatedmicrofabricatedpreconcentrator, Heat to180 ◦C in 40 ms, IMSdetection

C 1 Nerve gas stimulant, TNT 2006 [90]

�TD–�GC Micropreconcentratorfabricated on Si chip, microGC, FID,25 mL min−1 × 10 minpreconcentration

C 10 30 VOCs 2003, 2005 [91,92]

�TD–�GC On-board calibration,preconcentration,microsensor array

C 10, S 1.5 5–36 11 VOCs 2005 [95]

�GC High speed MEMS-basedGC, temperature ramp10 ◦C s−1

S 0.2 Alkanes C5–C16, stimulantsfor C–4, TNT, sarin, mustard

2006 [97]

�GC Static coating of PDMS,12,500 theoretical plates

S 8.3 or 2.5 Alkane C5–C12 2006 [98]

�TD–�GC Two- and three-Dmicro-preconcentrator, GCchannel, quartz SAWsensor array, integratedwith circuit board

BTX, stimulants of nerveagent and sulfur mustard

2006 [99]

�GC-plasma Double-tee microchannel,dc plasma emissiondetector for Cl and Br

0.81 ngClb CH2Cl2, CHCl3 2002 [100]

�GC–DMS microGC, microfabricateddifferential mobilityspectrometer

45 VOCs 2005 [101]

men

sp1wi

a C: collection time, S: separation time, T: total for one cycle measureb ngCl s−1.

quare die. At 25 cm s−1 of carrier velocity, 625 theoretical

lates and a hold-up time of 1.9 s were obtained. A mixture of1 gases was separated into individual components in only 10 sith a column temperature increasing at a rate of 10 ◦C s−1. To

mprove the separation, a longer column (3 m), with retained

t.

channel geometry, was tested [98]. The wall of the channel

was statically coated with PDMS by filling the channel with0.4% dimethyl polysiloxane to form a thinner and more uni-form coating compared to the dynamic coating. As a result,∼12,500 theoretical plates were obtained.

152 a n a l y t i c a c h i m i c a a c t a 6 1 9 ( 2 0 0 8 ) 143–156

Fig. 2 – Microsystem for gas chromatographic determination. The top scheme shows typical micro gas chromatograph forair sample analysis. The pictures are examples of micropreconcentrator (left), microchip column (center) and micro DMS

006)

detector (right); the left is from references [99] (IEEE Sen. J., 22005).

Lewis et al. reported the recent development of a gas-phase“microchemlab” [99]. The system’s composition was similarto that described before; namely, a preconcentrator, a separa-tion column and a SAW device detector, with each componentsophisticated and well arranged. The three-dimensional pre-concentrator demonstrated better performance than a planarpreconcentrator. Two GC systems were set in a handheld case.

9. Microfabricated detectors for micro GC

If a separation system is miniaturized, the detector mustbe much smaller than the separation column to obtain ade-quately separated signals. As well, the use of auxiliary gasesis not suitable for field application. Hence, a typical detector,such as FID, is not suitable. A thermal conductivity detec-tor (TCD) is simple, and a microfabricated TCD sensor is alsoavailable [94]. A micro TCD consumes very little power andis suitable for use in field monitoring. However, its sensitiv-ity is low, and so its application is limited. New technologiesfor compact and highly sensitive detectors have been devel-oped. SAW devices were attached downstream of a separationcolumn [99]. To improve performance, several kinds of SAWdevices were arranged in an array.

Bessoth et al. produced a micro GC using a double teejunction channel on a glass chip that is often used for wetelectrophoresis [100]. In a manner analogous to microchip liq-uid electrophoresis, an air sample was introduced with thecrossing channel. Separated species were measured by a dcplasma emission detector. Chlorine and bromine contained inthe gases were detected by a capillary or on-chip microplasma.The LOD for chlorine was 0.81 ngCl s−1. Microplasma is an ele-

ment selective and highly sensitive detector. A differentialmobility spectrometer (DMS) is also an attractive detector forGC systems. Lumbertus et al. combined a microfabricated DMSdetector with a silicon microfabricated column [101]. The both

and the others are both from reference [101] (Anal. Chem.,

beautiful devices are shown in Fig. 2. Separated analytes wereionized by 63Ni at atmospheric pressures and the ions wereintroduced into an asymmetric electric field. By scanning theRF voltage, ions with different mobilities could be detectedby the electrodes. Both positive and negative ions could bemonitored in this way.

Mass spectrometry (MS) is one of the most attractive detec-tion methods for GC. Mass spectrometer itself can be usedwithout a GC system. Increased efforts are being directedto develop miniature mass spectrometers, including hand-portable ones, and to achieve the performance characteristicsof traditional laboratory instruments [102]. Microelectrome-chanical systems (MEMS)-based mass spectrometers havebeen investigated as ion traps [103–105], a synchronous ionshield mass filter [106], and for time-of-flight [107]. Also, ahand-held mass spectrometer including a vacuum system anda data process board has been developed [108]. The devel-opment of these micro MS systems is in progress, and suchdevices are expected to be available for use in environmentaland on-site hospital applications in the near future.

10. Medical applications of gas analysis

Exhaled species often reflect the health conditions of thehuman body. To date, many investigations have been con-ducted for diagnostics of health conditions and disease basedon analysis of breath air [109,110]. Breath analysis has manyapplications and so is of great interest. For example, the con-

tent of CO gas in breath air can be used as an indicationof cigarette smoking, with a level exceeding of 8 ppmv for asmoker [111]. Most of the measurements so far described havebeen performed in a laboratory [112,113].

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0.1. Exhaled NO

he most interesting target of medical gas analysis is exhaleditric oxide (eNO), especially as a marker of asthma. eNO isainly measured by conventional CL analyzers. Recently, a

pecial NO analyzer (NIOX) based on CL came into use withignificantly improved response speed [114]. It was success-ully applied to the investigation of the relationship betweenNO and asthma in 590 patients [115]. Only 50 mL breath sam-les were used for each analysis. A hand-held eNO analyzer

s also on the market [116,117]. Robinson et al. developed anNO analysis method based on a liquid base CL [118]. First,O was converted to NO2 by CrO3, then the resulting NO2

as introduced into a hollow fiber reactor containing a solu-ion of luminol/H2O2 flowing through fiber inside. GaseousO2 reacted on the surface of the fibers, and the emitted

hemiluminescence was measured by a PMT attached on theollow fiber cell. A carbon nanotube can be also used as areath NO sensor [119]. Similarly to liquid base CL analysis, NOas converted to NO2 by CrO3 prior to sensing by the carbonanotube. Any NO2 in the original sample was first removedy ascarite prior to the oxidation of NO to NO2. The carbonanotube, chemically functionalized with polyethylene imine,as coated on a gate of a field effect transistor. The sensorutput was affected by humidity and CO2 contained in the airample.

A quantum cascade laser-based integrated cavity outputpectroscopy (ICOS) is a fast and sensitive method for gas anal-sis. McCurdy et al. applied an ICOS to eNO monitoring [120].xhaled air sample, collected into a Tedlar bag, was intro-uced into a 50 cm long ICOS cell via a Nafion dryer. Laser

ight (5.47 �m) was introduced into the cell and the integratedavity output was measured by thermoelectrically cooled IRetector. The LOD of this system was 3.6 ppbv with 4 s datacquisition, but later this was improved to 0.4 ppbv with 1 sntegration [121]. The results obtained for samples of breathir using the ICOS method agreed well with data provided byIOX.

It is thought that NO gas is present in the breath ofsthma patients as a self-defense mechanism, as NO inhala-ion appears to improve the condition of these patients. Thus,nhalation of NO can be used as a therapeutic treatment. Forxample, a micro NO generation/monitoring system (�GAS)as developed for use in treating high-pressure lung disease.

57]. A microchannel membrane device was used as not onlygas absorber, but also as a gas desorber for on-site NO gas

eneration.

0.2. Halitosis

alitosis is caused by NH3, amines, and most importantlyertain sulfur gases, such as H2S, CH3SH, dimethylsulfideDMS). Halimeters® are now mostly used in dental clin-cs [122–125]. However, a Halimeter does not identify theomposition of sulfur compounds. Responses of Halime-ers to H S, CH SH and DMS have been studied in detail,

2 3

nd it was confirmed that Halimeters responded to theseases in the order of H2S > CH3SH > DMS and the Halimeterndication did not represent real oral malodors [126]. Spe-ial techniques are required to measure individual VSCs.

1 9 ( 2 0 0 8 ) 143–156 153

The levels of H2S in breath, as well as in the atmosphere,can be measured selectively by �GAS with the LOD of0.1 ppbv [56]. These levels were 10–30 ppbv for healthy peo-ple. Rodrıgues–Fernandez developed an optical fiber sensor foranalysis of H2S from breath samples. A colorimetric reagent,2,6-dichlorophenolindophenol (DCPI), was immobilized on asilica gel support and the change in reflectance was mea-sured at 520 nm [127]. The addition of Cu(II) to the impregnatedreagent improved the response time and the reversibility ofthe coloration. The LOD for H2S was 10 ppbv with a responsetime <2 min. The same group has proposed a new visiblesorbent tube for oral malodor monitoring, particularly formonitoring of H2S levels [128]. Neocuproine + Cu(II) impreg-nated in a silica gel reacted with adsorbed H2S and becamea neocuprine–Cu(I) complex that turned slightly green to yel-low in color when the concentration of H2S exceeded 250 ppbvas indicated on a Halimeter. Methyl mercaptan (CH3SH) andto a lesser extent H2S are the main contributors to intra-oralhalitosis, and DMS is the main contributor to extra-oral orblood-borne halitosis [129]. Therefore, convenient methods todetermine CH3SH and DMS are very important. However, thereare few reports on miniature devices for VSCs. Among these,the portable TD–CL system, previously introduced, was suc-cessfully applied to breath analysis [71]. Levels of CH3SH andDMS were successfully analyzed by both TD–CL and conven-tional GC methods for non-smokers. However, the sulfur gasescould be detected from smokers only with the TD–CL system.

10.3. Volatile organic compounds in breath

The TD–CL system has been applied to the analysis of iso-prene in breath [72,130]. In a human body, isoprene is formedin the synthesis of cholesterol. The level of isoprene in breathis also proportionally related to the heart rate because thereis limited solubility of isoprene in aqueous solutions such asblood. In the TD–CL system, water vapor interferences maycause problems for an analysis. The water vapor interferencein the TD–CL could be alleviated by heating the column dur-ing the sampling procedure. An Ag+-form ion exchange resinmini-column helped removing interference from sulfur gases.The LOD with 10 L sampling volume was 0.6 ppbv. Isoprenemonitoring was also conducted during the exercise.

Acetone is formed in the metabolism of glucose. Therefore,blood acetone and breath acetone are measures of uncon-trolled diabetes mellitus. Acetone is water soluble and canbe collected in a wet scrubber and subsequently measuredby flow analysis [131]. The breath acetone levels in 15 anal-yses were 176–518 ppbv. For general VOC analysis, GC is stillthe most used system because of its wide availability asa commercial instrument, in spite of its size, the need forgas cylinders, and the skill required for its operation. How-ever, sample introduction is crucial for successful breathVOC analysis. Pawliszyn’s group at the University of Water-loo demonstrated VOC GC–FID analysis using a MESI method[132]. Though breath air is saturated with water vapor at36–37 ◦C, the effect of moisture could be eliminated by using

the membrane interface. It was demonstrated by MESI–GC thatthe level of acetone in breath samples increased when the sub-ject became progressively hungrier and decreased after a lightlunch. The effect from drinking vodka on the level of ethanol

a c t a

r

154 a n a l y t i c a c h i m i c a

in breath and the effect of smoking were demonstrated usinga MESI–GC. In addition, Pawliszyn’s group noted that some lev-els of chloroform were observed in breath samples after thesubject had been swimming in chlorinated pool water.

Acetone can be detected by cavity ringdown spectroscopy[133]. A palm size 266 nm laser source was connected to a45-cm long ringdown cell with highly reflective mirrors. Exam-ination was conducted using an aqueous acetone solution,and the LOD was estimated to be 0.49 ppmv in the gas phase.The authors stated that this level of sensitivity is sufficient toapply this method to monitoring acetone in breath air.

10.4. Ammonia and amines

Cavity ringdown spectroscopy has been applied to the analysisof NH3 [134] and of amines in breath samples [135]. The levelof NH3 was measured with a pulsed mid-IR quantum cascadelaser (970 cm−1); a LOD of 50 ppbv was obtained with a timeresolution of 20 s. The concentrations of gaseous monomethy-lamine and dimethylamine were measured based on the firstovertone of the N–H stretch vibration; LODs were 0.35 ppmvand 1.6 ppmv, respectively.

Ammonia has an effect on halitosis, but NH3 is more impor-tant as a marker of impaired kidney or liver function. Patelet al. measured NH3 in breath by photoacoustic spectrometrywith a CO2 laser [136,137]. They demonstrated that the level ofNH3 in a patient’s breath could be used to decide on the endpoint of hemodialysis instead of using an invasive measure-ment of blood urea nitrogen (BUN) [138]. NH3 levels in breathwere also successfully monitored using a simpler device, a liq-uid film-based conductivity sensor [12]. A small liquid film wasformed on top of a 1.2-mm diameter capillary with good repro-ducibility of liquid thickness, and conductivity was monitoredin situ. No interference from acids contained in breath air sam-ples, such as CO2, was observed in this study. The NH3 contentin the breath was monitored continuously and it was observedthat the NH3 level increased after a protein meal.

10.5. Analysis of gases emitted from human skin

Most investigators have analyzed breath air for medical diag-nostics. However, Tsuda’s group investigated gases emittedfrom human skin. They found that many kinds of gases wereemitted from skin and that these were related to the person’shealth condition. Measurement of gas from skin has variousmerits as continuous monitoring is easier and there are nointerferences from oral compounds, as is the case in the anal-ysis of breath air samples. Acetone [139,140], NH3 [141], CH4,C2H4 and C2H6 [142], and several aromatic compounds [143]have been identified in the gas emitted from skin. Relation-ships between skin gases and those in blood have also beeninvestigated. Gases were sampled from fingers or hands andwere analyzed by GC. Miniature devices for skin gas analysisare expected to be developed in the near future.

11. Conclusions

There are several approaches to miniaturization of gas analyz-ers. Many efforts have been directed towards the development

6 1 9 ( 2 0 0 8 ) 143–156

of miniature gas analysis devices where either wet or drymethods are used. There are many advantages of miniaturiza-tion: such as effective enrichments of analytes, fast response,affordability of mobile monitoring. Different from biochemicalmicrodevices, high sensitivity can be achieved by miniatur-ization if devices are designed and used appropriately. Also,ultimate miniaturization is not required in most of the gasanalysis applications compared to the biochemical devices. Todevelop instruments that are even more practical, entire sys-tems will in the future be miniaturized. Already some suchsystems have been employed in actual environmental andmedical applications. Unfortunately, the range of gas speciesthat have been tested as analytes is thus far limited. Furtherprogress in the development and application of microdevicescan surely be expected. Especially, joining of environmentalscientists and medical doctors is encouraged for further devel-opment of micro gas analyzers and the dramatic progresson the fields of environmental science and medical technol-ogy. Combination of electronic and mechanical engineeringare also required for elevating and spreading the micro gasanalyzer for practical uses.

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