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Sensors and Actuators B 204 (2014) 578–587

Contents lists available at ScienceDirect

Sensors and Actuators B: Chemical

jo u r nal homep age: www.elsev ier .com/ locate /snb

easure chain for exhaled breath collection and analysis: A novelpproach suitable for frail respiratory patients

iorgio Pennazzaa, Marco Santonicoa,∗, Raffaele Antonelli Incalzib,c, Simone Scarlatab,omenica Chiurcob, Chiara Vernilea,d, Arnaldo D’Amicod,e,f

Center for Integrated Research - CIR, Unit of Electronics for Sensor Systems, “Università Campus Bio-Medico di Roma”, Via Alvaro del Portillo 21,0128 Rome, ItalyChair of Geriatrics, Unit of Respiratory Pathophysiology, Campus Bio-Medico University, Rome, ItalySan Raffaele- Cittadella della Carità Foundation, Taranto, ItalyDepartment of Electronic Engineering, University of Rome Tor Vergata, Via del Politecnico 1, 00133 Rome, ItalyCNR-IDASC, Via del Fosso del Cavaliere 100, 00133 Rome, ItalyCentro Studi e Documentazione sulla Sensoristica, University of Rome Tor Vergata, Via del Politecnico 1, 00133 Rome, Italy

r t i c l e i n f o

rticle history:eceived 31 March 2014eceived in revised form 10 July 2014ccepted 4 August 2014vailable online 12 August 2014

eywords:xhaled breathas sensor arrayolatile organic compoundsdsorbing cartridge

a b s t r a c t

Exhaled breath analysis, a non-invasive diagnostic procedure, is based upon a sampling device for breathcollection, an apparatus for the sample delivery into the measure chamber and a gas sensor array. Herea novel approach for the design and realization of these three components is presented. The volatilemixture composing the exhaled breath is entrapped onto an adsorbing cartridge via an innovative deviceable to collect exhaled breath from an individual normally breathing into a mouthpiece for three minutes.This procedure is very simple and cartridges outperform sampling bags in terms of preservation andtransportability. Moreover, a thermal desorption process of the volatiles adsorbed on the cartridge canpartially separate them by a given temperature profile. This separation, performed by the desorbingapparatus, improves sensor resolution via a preconcentration strategy. This method improves sensorresolution. The gas sensor array employed in this work is composed by a set of eight Quartz Micro Balances

(QMB) coated by eight different anthocyanins. The Pneumopipe, the innovative breath collecting device,is described and tested in a proof of concept study involving all the measure chain: two small groupsof Chronic Obstructive Pulmonary Disease (COPD) patients and control individuals have been perfectlydiscriminated and repeated measures on the same individuals showed an optimal reproducibility asverified by calculation of the relative standard deviation.

© 2014 Elsevier B.V. All rights reserved.

. Introduction

Exhaled breath finger-printing, in spite of its minimal invasivity,s not still employed in the clinical practice mainly due to the lack oftandard procedures [1]. This work aims to respond to some of theey questions regarding breath analysis standardization [1,2]. Theore innovation regards the exhaled breath sample. Exhaled breathhould be collected via a suitable interface with the individual and,

hen, the collected exhaled breath sample has to be delivered intohe measure cell via an ad hoc interface with the measuring instru-

ent. The design and realization of the interface impacts each step

∗ Corresponding author at: Via Alvaro del portillo 21, 00128 rome, italy.el.: +39 06225419610.

E-mail address: m.santonico@unicampus.it (M. Santonico).

ttp://dx.doi.org/10.1016/j.snb.2014.08.007925-4005/© 2014 Elsevier B.V. All rights reserved.

of the measure chain; thus, the whole measure chain will be theobject of this paper.

Exhaled breath collection asks for reproducible and standard-ized techniques in order to be representative and effective [3].Direct (subject directly breathing into the measuring system with-out any intermediate steps) or indirect methodologies exist. Thelatter requires the exhalate sample to be stored in an adequatemedium to be analyzed later.

Indirect sampling can be performed via bags of Tedlar or otherlow-emission plastic materials, glass vials, stainless steel contain-ers and cartridges containing adsorbent substances (sorbent traps).Tedlar bags and cartridges of absorbent material are the most com-

monly used media.

Collection of exhaled breath on adsorbent cartridges allowssample pre-concentration to increase the resolution power ofthe instrument (typically round tens of ppb). Moreover sample

G. Pennazza et al. / Sensors and Actuators B 204 (2014) 578–587 579

aetea

rtir

oc(tacafcttacp(

dIto

(

aritcmt

Fig. 1. Individual performing breath collection via pneumopipe.

dsorbed in a cartridge can be easily stored and transported. How-ver, adsorbent cartridges offer a high resistance to air transit,hus a dedicated pneumatic device must ‘help’ the subject pushingxhaled air into them. All the methods realizing these operationsre based on complex procedures or/and awkward systems [4–8].

Exhaled breath collection on adsorbing cartridge could be alsoealized via two sequential indirect operations: first the subject fillshe bag, and then bag content fills the cartridge. This latter method,n spite of its simplicity, has low reproducibility and it is not fullyeliable.

The solution here proposed is articulated in the descriptionf novel contributions in the three main steps of the measurehain: a device for exhaled breath sampling directly on cartridgesnamed Pneumopipe), an apparatus for cartridge thermal desorp-ion into a measure-cell (named Breathstiller) and a gas sensorrray based on Quartz Microbalance functionalized by antho-yanins (named Bionote). The Pneumopipe has been designednd fabricated by the authors (EU patent pending [9]). The maineatures of this device are the simplicity of the sampling pro-edure (also feasible for respiratory impaired subjects), and theransportability of the collected samples (usually not applicableo a sampling bag). The Pneumopipe designed by the authorst the University Campus Bio-medico allows the exhaled breathollection from an individual normally breathing through a mouth-iece, catching the volatile compounds on an adsorbing cartridgesee Fig. 1).

The sampling procedure and the interface for the followingesorption of the sample must be suitable for different instruments.

n fact, breath-print consists of exhaled breath measurement andranslation in a numerical pattern [10] and this pattern can bebtained by:

(a) analytical chemistry instruments (Gas Chromatography–MassSpectrometry (GC-MS), Proton Transfer Reaction–MS (PTR-MS), Selected Ion Flow Tube–MS (SIFT-MS)) [11–14];

b) direct non-selective fingerprinting techniques [15].

The latters are usually performed by gas sensor arrays designeds artificial olfactory systems [16–18]. Gas sensor array outputesponses consist of a pattern (breath-print) characteristic of thendividual and of his/her health conditions. The breathprints regis-ered in several experiments showed evidences of correlation with

ertain diseases: lung cancer [19–21], Chronic Obstructive Pul-onary Diseases (COPD) [22–24], asthma [22,25], just to mention

he main respiratory diseases investigated among many others.

Fig. 2. General overview of the Pneumopipe.

Regarding gas sensor arrays, thermal desorption of cartridgecontent into the measure cell is not a routine operation as for theanalytical chemistry instrument. This work describes the use ofthe breathstiller (see Fig. 2) designed, fabricated and tested by theauthors, for the thermal desorption of cartridge directly into thegas sensor array measure cell.

2. Materials and methods

2.1. Pneumopipe

The Pneumopipe allows collecting exhaled breath into an adsor-bent cartridge, overcoming the drawbacks mentioned above withreference to the state of the art.

The Pneumopipe (see Fig. 2 for a general overview), thanks toits double-chamber structure (Fig. 3), permits a continuous samp-ling of exhaled air, even during an inhalation step. Fig. 3 showsthat the lower chamber of the device is the first encountered bythe exhalation which is then directed into the upper chamber byopening valve number 2 as effect of the exhalation act. During thisphase (denoted with (a) in Fig. 3) the influence by environmentalair is prevented by the valve number 1. Valve number 3, normallyopened by the patient exhaling, avoids the perceiving of a resistanceto respiration by the individual performing the exhalate collec-tion. In the second phase, during the inspiration act, valves 3 and2 are normally closed, isolating the exhaled breath collected in theprevious phase. This, prevents the contamination of the exhaledbreath by the environmental air entering through valve number1, opened by the inspitration act itself, and minimizing the resis-tance to respiration. During phases (a) and (b) the sampling of theexhaled breath is operated by a pump, which sucks the exhaled

breath collected in the main chamber of the pneumopipe at a con-stant flow of 80 ml/min for 3 min. The pump delivers the exhaledbreath into an adsorbent cartridge located before the pump itself.

580 G. Pennazza et al. / Sensors and Actuators B 204 (2014) 578–587

F se: valve 2 and 3 open; valve 1 closed. (b) Inspiratory phase: valve 1 open; valve 2 and 3c

Tf

psnpftiddebpP

eub

uib

GgdGaTtdcs

2

d

Fig. 4. General overview of the device for the thermal desorption of the cartridge

ig. 3. Schematic of the functioning system of the Pneumopipe: (a) expiratory phalosed.

hus the chronological order of the three part intervention is asollows: pneumopipe main chamber, adsorbent cartridge, pump.

The exhalation and inhalation resistance perceived by theatient is minimal, guaranteeing a comfortable procedure, alsouitable for subjects with breathing difficulties. Furthermore, cog-itive impairment is unlikely to hamper the procedure. This makesneumopipe a potential alternative to spirometry and, likely, a plusor selected patients. In fact, frailty and cognitive impairment arehe main obstacle to the execution of a high quality spirometry,.e. to a spirometry fulfilling the ATS/ERS acceptability and repro-ucibility criteria [26]. Accordingly, a breath print based respiratoryiagnosis might substitute for a spirometric based one in these cat-gories of patients, provided that the breath collecting system isoth totally user friendly and reliable and the e nose classificatoryroperties are fine. The former of these conditions is met by theneumopipe.

Moreover, the device is susceptible of a portable and compactmbodiment, which is rather useful in clinical practice, of simplese both for the physician and the patient, and it is suitable also foredside operation.

The structural simplicity of the device also fosters full safety ofse, without risk of infection for the patient, as it is possible to

mplement the device so that all parts that may contact the subjecte single-use or sterilizable by conventional methods.

Tenax tubes (the adsorbent cartridge used in this work: tenaxR [27]) are adsorbent cartridges commonly used in gaschromato-raphic (GC) analyses with preconcentration purposes. Thus manyevices are commercially available to desorb tenax tubes into theC inlet. The use of tenax tubes as sampling medium is also suit-ble for the analysis of volatile mixtures with gas sensor arrays.he potential interface problem between the tenax cartridge andhe instrument measuring the breath sample is solved by theesorbing unit designed and calibrated on the basis of theoreti-al models. These models are calculated on the characteristics ofelected volatile compounds present in the exhaled breath.

.2. Desorbing unit

An interface-apparatus (Fig. 4) was built for the cartridgeesorption into the sensors chamber. This apparatus was

content into a measure cell.

studied with the goal of obtaining a uniform heating of thetube from 50 ◦C to 200 ◦C, and finally cleaning the cartridge,holding the temperature at 300 ◦C for five minutes. This con-trolled desorption procedure was planned in order to fit any kindof sensors technology: gas arrays cells and GC-MS inlet ports.The final fingerprint of the exhaled breath (breathprint: BP) isa sequence of four n-dimensional patterns, composed of the nresponses of an n-dimensional gas sensor array at four temper-atures (50 ◦C–100 ◦C–150 ◦C–200 ◦C). This means that for each ofthese temperature step the tenax cartridge content is desorbed intothe sensor cell. Thus, each sensor gives four responses, one for eachtemperature.

The apparatus is composed of a muffle-furnace properlydesigned to maintain a constant temperature in the center of car-tridge. The muffle-furnace chamber is a hollow cylinder whosecavity perfectly fits the tenax cartridge volume, in order to granta uniform and efficient heating. The temperature control is reg-ulated by a feedback action between an electronic interface

with a PID control and a sensor temperature type thermocouplePT100.

G. Pennazza et al. / Sensors and Actuators B 204 (2014) 578–587 581

amily.

H

2

bfitm

Fig. 5. rt vs T curves calculated for the hydrocarbon compound f

A mass flow controller (Brooks SLA smart II, Brooks Instruments-atfield, PA 19440-0903 USA) sets the flow.

.3. Calibration and models calculation

A list of 52 compounds present in the exhaled breath [28] has

een used for this study. They are reported in Fig. 10, grouped inve families. In order to design a desorbing unit linking the tenaxube and the sensor chamber, flow and temperature are the most

eaningful parameters to be controlled. To this purpose a list of

Fig. 6. rt vs T curves calculated for the alcohol and glycol compound fam

The list of the compounds considered is reported in the legend.

retention times (rt) have been calculated for each of the selectedcompounds in a temperature (T) range from 20 ◦C to 300 ◦C withreference to the given breakthrough volume data [29] at a constantflow of 40 ml/min, and using the following formula:

rt = (Bv × Wa) + Dv

f

where Bv is the Breakthrough volume; rt is the retention time; Dvis the dead volume (2 ml); Wa is the Tenax mass (290 mg); f is thecarrier flow (N2 at 40 ml/min).

ily. The list of the compounds considered is reported in the legend.

582 G. Pennazza et al. / Sensors and Actuators B 204 (2014) 578–587

und fa

r

f

2

sLM

Fig. 7. rt vs T curves calculated for the aldehydes and ketones compo

The best fitting for all rt data is the following exponential curve

t(T) = a e−bT

rom which 52 curves (T, rt) for each compound have been obtained.

.4. Bionote

Bionote is the new instrument used in this measure chainet-up. This instrument was designed and fabricated at theaboratory of Electronics for Sensor Systems of the Campus Bio-edico University of Rome and it was already presented in

Fig. 8. rt vs T curves calculated for the halogens compound family. T

mily. The list of the compounds considered is reported in the legend.

[30]. The gas sensor array, included in the Bionote and hereused for exhaled breath analysis, is composed of 7 quartz crys-tals with a resonance frequency of about 20 MHz. These QuartzMicrobalances are functionalized with anthocyanins extractedfrom three different plant tissues: red rose, red cabbage, bluehortensia. The list of the seven sensing materials is reported in[30].

2.5. Measure chain preliminary clinical test

Validation of this measure chain in the frame of a clinicalstudy is beyond the scope of this paper. Besides, the system here

he list of the compounds considered is reported in the legend.

G. Pennazza et al. / Sensors and Actuators B 204 (2014) 578–587 583

nd fam

pTbPsbfd

uca

Fig. 9. rt vs T curves calculated for the aromatic and terpen compou

resented was designed in breath analysis related to frail subjects.hus a good proof of concept of measure chain functionality cane given by a reproducibility test involving Chronic Obstructiveulmonary Diseased (COPD) patients: often elderly and intrin-ically frail. Five COPD subjects and five control subjects haveeen enrolled for this very short test, both in an age rangingrom 55 to 75. Each of them has been daily measured for threeays.

Finally, the breathprints of a COPD population of 18 individ-als have been measured twice: at baseline, in relatively unstableonditions, and after a course of therapy intended to improvend to stabilize the health status. This experiment allows test the

Fig. 10. Flowchart of the thermal profile from 50 to 250 ◦C with the dif

ily. The list of the compounds considered is reported in the legend.

discriminatory properties of the whole system with regards to theeffects, if any, of therapy on the breathprint.

2.6. Data analysis

For the multivariate data analysis approach, Principal Com-ponent Analysis (PCA) has been used as unsupervised method;as supervised method Partial Least Square Discriminant Analysis

(PLS-DA) has been applied, with Leave-One-Out as Cross-validationcriterion. PCA and PLS-DA has been performed using the PLS-Toolbox SW (Eigenvector, Wenatchee, WA, USA) in the Matlabenvironment (The Mathworks, Natick, MA, USA).

ferent compounds released for each temperature step (of 50 ◦C).

584 G. Pennazza et al. / Sensors and Actuators B 204 (2014) 578–587

of n-butanol desorbed by a tenax cartridge at 120 ◦C.

3

3

shgtctmtfWmbsrpbbofibiPbtsh

thtdt1

Table 1Confusion matrix of the PLS-DA model built on the 18 COPD patients before andafter stabilization. The percentage of correct classification for the stabilized patientsis of 89%.

Predicted

I evaluation II evaluation

Fig. 11. Sensor response (Bionote S1) to 115 ppb

. Results

.1. Calibration measurements and model test

Figs. 5–9 show, respectively, the rt versus T curves for theelected compounds belonging to each of the following family:ydrocarbons, alcohols and glycols, aldehydes and ketones, halo-ens, aromatics and terpenes. As example a line corresponding0 = 200 s has been evidenced. The intercept of this line with eachurve highlights the temperature necessary for the desorption ofhe related compound at that time. On the basis of the calculated

odels a temperature flow-chart has been designed (Fig. 11) forhe desorption unit development, indicating the best temperatureor the different compound families at a fixed flow of 40 ml/min.

ith such interface the VOCs entrapped into the cartridge can beeasured by gas sensor arrays using a temperature profile. On the

asis of these considerations the temperature profile can augmentensor array potentialities adding also a partial separation of theeleased compounds (see Fig. 10), which is typical of instrumentsertaining analytical chemistry. Thus the number of sensors coulde virtually increased obtaining a total amount of responses giveny the number of the effective sensors multiplied for the numberf temperature steps scheduled in the thermal desorption pro-le. Here the Breath fingerprint is presented as a radarplot-profileuilt-up of 28 responses, and its effectiveness in a complex med-

cal context is fully described. Anyway, the demonstration of theneumopipe (and its interfaces) ability in a practical application iseyond the scope of the present paper, which is instead addressedo the collection device design and fabrication and to a theoreticaltudy on its potentialities, when employed in the measure chainere presented.

The n-butanol, a compound considered as a standard for olfac-ometry, has been used to test model effectiveness. Tenax cartridgeas been ‘charged’ with 115 ppb of n-butanol. The system used for

his operation is the breathstiller itself, but used in the oppositeirection: the mass flow controller delivered the desired concentra-ion sampling it by a permeation tube [31]. It has been desorbed at20 ◦C using the breathstiller. The word breathstiller is the acronym

Real I evaluation 12 6II evaluation 2 16

the authors choose to define the apparatus for the cartridge desorp-tion into the sensor cell. It is the contraction of the phrase ‘exhaledbreath distiller’. The temperature has been selected on the basis ofthe model calculated for the alcohols (Fig. 6). The response of thesensor 1 of the Bionote is reported in Fig. 11. The maximum shift ofthe response is obtained 50 s after desorption starting point. Thusthe model here elaborated for n-butanol is confirmed.

3.2. Pneumopipe reproducibility

Fig. 12 has three panels each showing a boxplot relative to theCOPD population, the control population and one of the controlindividuals, respectively. Each boxplot shows a very good repro-ducibility (comparable with the results already obtained by theauthors of this paper [23]). These results confirm a promising repro-ducibility both in a heterogeneous group of patients affected bythe disease (panel a) and of individuals selected as controls (panelb); moreover an excellent intra-individual reproducibility is alsoobserved (panel c).

3.3. Short pilot study

A PLS-DA model has been built on the 36 collected breath-prints.The classification performance is summarized by Table 1. The het-

erogeneity of the patients population justifies a higher number oferroneous classification for the first measurement (6 of 18: 33%),while a very low number of misclassified individuals in the second

G. Pennazza et al. / Sensors and Actuators B 204 (2014) 578–587 585

popu

sb

4

cdba

Fig. 12. Boxplots dysplaing the 28-sensor response relative to (a) COPD

tage (2 of 18: 11%) accounts for a promising standardization of thereathprint for the patient undergone medical therapy.

. Conclusions

A measure chain designed and developed for exhaled breath

ollection, delivery and analysis has been here described. Theseevices are suitable interface between an individual exhalingreath and an adsorbing cartridge for its collection and stor-ge (Pneumopipe) and between the adsorbing cartridge and any

lation, (b) the control population and (c) one of the control individuals.

possible instrument to measure the VOCs entrapped into the car-tridge itself (Breathstiller). The augmented potentialities of thistechniques with respect to the state of the art can be summarizedby the following four points:

- The exhaled breath collection procedure is non invasive at all and

can be performed also by patients with impaired respiratory andcognitive functions.

- Direct collection onto adsorbing cartridge increases sample reli-ability and preservation.

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Transportability of the cartridge containing the sample, makesthem suitable for remote analysis, point-of-care systems, multi-center medical studies.

Thermal desorption into a sensors chamber augments sensorperformance in terms of resolution (via preconcentration pro-cedures) and of discrimination (via the thermal separation of theVOCs mixture).

To conclude it is worth remarking that the present work, evenf methodological, already shows some results of clinical validity.hese results strongly support the utilization of this measure chainor a substantial improvement of breathprinting technology.

onflict of interest

We hereby declare that no conflict of interest related to theublication of this manuscript exists.

cknowledgments

Thanks to Eng. Massimo Petriaggi, who pioneered pneumopipeesign.

This study was partly granted by the European Space Agency inhe context of the project: “KOSMOMED”.

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Biographies

Giorgio Pennazza received his master degree in Electronic Engineering in 2001and his doctorate in Sensorial and Learning System Engineering in 2004, both bythe University of Rome Tor Vergata. He is currently assistant professor at the Uni-versity Campus Bio-Medico di Roma since 2010. His research interests includeselectronics for sensors system, in particular for artificial sensorial systems appliedas non-invasive diagnostic tool in the medical field and for the development ofnon-destructive techniques in the assessment of food quality and freshness. In thisresearch area he co-authored more than 25 papers on international peer-reviewedjournals.

Marco Santonico received his master degree in Electronic Engineering in 2004 andhis doctorate in Sensorial and Learning System Engineering in 2008, both by theUniversity of Rome Tor Vergata. He is currently assistant professor at the UniversityCampus Bio-Medico di Roma. His research interests includes electronics for sensorssystem, in particular interfaces and integration of artificial olfactory systems andits utilization in medical, food and industrial applications. In this research area heco-authored more than 25 papers on international peer-reviewed journals.

Raffaele Antonelli Incalzi full professor of Geriatrics at the Campus Bio-MedicoUniversity, Rome, he has a great experience in respiratory diseases of the elderly.The multidimensional assessment of the respiratory patients and the tailoring ofrespiratory function tests to needs and possibilities of elderly and disabled peopleare his main themes of research, largely developed within the SaRA (RespiratoryHealth in the Elderly) multicenter study. Pharmacotherapy in the elderly, effects ofaging on renal function and bone health and nutrition are further research themesof primary interest.

Simone Scarlata He has carried on his activities at the University “Campus BioMedico” of Rome up to the attainment of the specialization with a task of responsiblefor the activities of respiratory physiopathology and sleep medicine appended thearea of Geriatrics. In particular has gained experience in the field of the respiratorydiseases in geriatric age, techniques of respiratory rehabilitation and oxygen ther-apy, respiratory complications of systemic chronic diseases and obstructive sleepdisorders. Author and co-author of numerous publications on national and inter-

national journals, in 2007 and 2009 was also reviewer for the international peerreviewed respiratory journals “Thorax”, “International Journal of COPD”, “EuropeanJournal of Neurology”, “European Respiratory Journal”.

Domenica Chiurco Domenica Chiurco received her master degree in Medicine andSurgery in 2004 by the University of Tor Vergata of Rome and Specialization in

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eriatrics in 2009 by the University Campus Biomedico di Roma. From 2010 she isonsultant at the Geriatrics department of University Campus Biomedico di Roma,ith direct responsibilities in respiratory physiopathology ambulatory and the not-

nvasive ventilation. Author and co-author of publications on international journals.

hiara Vernile received her master degree in Medical Engineering in 2012. She isorking on the technology used for breath-printing with a research grant. She is

o-authors of some papers presented in International conferences.

rnaldo D’Amico received the Laurea degrees in physics and in electronic engineer-ng from the University La Sapienza, Rome, Italy. For several years, he has been withhe National Research Council (CNR) leading the Semiconductors Laboratory at the

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Solid-State Electronics Institute, Rome. In 1988, he was appointed full professor ofelectronics at the University of L’Aquila, and, since 1990, he has been with the Uni-versity of Rome Tor Vergata where he leads the Sensors and Microsystems Group andis full professor of electronics. He teaches courses on electronic devices, micro andnano systems, and sensors at the Faculty of Engineering. Currently, his main researchactivities are concerned with the research and development of physical and chemicalsensors, low voltage electronics, noise, and advanced electronic devices. He is author

of more than 550 papers in international journals and conference proceedings. Hehas been chairman of several conferences on sensors, electronics, and noise anda member of the editorial board of the journals Sensors and Actuators A (Physi-cal) and Sensors and Actuators B (Chemical). He served as chairman of the SteeringCommittee of the Eurosensors conference series from 1999 to 2004.