This paper describes a biosystem (biological system) used to measure the concentration of biochemical substances in urine, serum,
plasma or cerebrospinal fluid. Rather than just one channel, it comprises 16 optical-channels that enable the measurement of the concentration
of 16 different biochemical substances. An array of 16 optical filters based on Fabry-Perot thin-films optical resonators has
been designed. Each optical-channel is sensitive in a single wavelength with a full-width-half-maximum (FWHM) of 7 nm. The filter
fabrication requires only four masks, used with different etch time. A commercially available band-pass optical filter with a band-pass
wavelength in 450–650 nm is used. The biosystem requires only a white light source for illumination due the use of selective optical
filters.Fundação para  a Ciência e a Tecnologia (FCT) - SFRH/BD/1281/2000,  POCTI/33747/ESE/1999 – Fundo Europeu para o Desenvolvimento Regional

G. Minas

J.C. Ribeiro

J.H. Correia

J.S. Martins

Jakeway

Kabasakalian

Minas

R.F. Wolffenbuttel

Song

Sensors and Actuators A Physical

This paper describes a biosystem (biological system) used to measure the concentration of biochemical substances in urine, serum, plasma or cerebrospinal fluid. Rather than just one channel, it comprises 16 optical-channels that enable the measurement of the con-centration of 16 different biochemical substances. An array of 16 optical filters based on Fabry-Perot thin-films optical resonators has been designed. Each optical-channel is sensitive in a single wavelength with a full-width-half-maximum (FWHM) of 7 nm. The filter fabrication requires only four masks, used with different etch time. A commercially available band-pass optical filter with a band-pass wavelength in 450–650 nm is used. The biosystem requires only a white light source for illumination due the use of selective optical filters

CiteSeerX

An array of Fabry-Perot optical-channels for biological fluids analysis

Crossref

Minas, Graça

Ribeiro, J. C.

Martins, Júlio S.

Wolffenbuttel, R. F.

Correia, J. H.

Universidade do Minho: RepositoriUM

Sensors and Actuators A 115 (2004) 362–367An array of Fabry-Perot optical-channels for biological fluids analysisG. Minas a,∗, J.C. Ribeiro a, J.S. Martins a, R.F. Wolffenbuttel b, J.H. Correia aa Department of Industrial Electronics, University of Minho, Campus de Azurém, 4800-058 Guimarães, Portugalb Fac. ITS Department Microelectronics, Delft University of Technology, Mekelweg 4, 2628 CD Delft, The NetherlandsReceived 6 November 2003; received in revised form 26 March 2004; accepted 27 March 2004Available online 19 June 2004AbstractThis paper describes a biosystem (biological system) used to measure the concentration of biochemical substances in urine, serum,plasma or cerebrospinal fluid. Rather than just one channel, it comprises 16 optical-channels that enable the measurement of the con-centration of 16 different biochemical substances. An array of 16 optical filters based on Fabry-Perot thin-films optical resonators hasbeen designed. Each optical-channel is sensitive in a single wavelength with a full-width-half-maximum (FWHM) of 7 nm. The filterfabrication requires only four masks, used with different etch time. A commercially available band-pass optical filter with a band-passwavelength in 450–650 nm is used. The biosystem requires only a white light source for illumination due the use of selective opticalfilters.© 2004 Elsevier B.V. All rights reserved.Keywords: Biosystem; Optical filter array; Fabry-Perot1. IntroductionSpectrophotometric analysis (the study of the interactionof electromagnetic radiation with chemical compounds)is one of the most commonly used analytical techniquesfor biological fluids analysis in clinical diagnostics. Thistechnique is used to determine the concentration and/oramount of a particular compound in biological fluidssamples [1]. Usually, the samples need to be sent to alaboratory for spectrophotometric analysis, and the re-sults become available after several hours or days. Theneed for rapid and on-line measurements led to the de-velopment of biosystems with the fluidic, detection andreadout systems integrated in a single-chip [2]. The advan-tages associated with shrinking clinical analysis systemsinclude improved efficiency with respect to sample size,integration, automation, response times, analytical perfor-mance, laboratory safety and costs. Previously developedbiosystems on-a-chip with absorbance detection require awavelength dependent light or waveguides inserted into thebiosystem for illumination [3,4]. Illumination using onlya white light source requires the use of selective opticalfilters.∗ Corresponding author. Tel.: +351 253510190; fax: +351 253510189.E-mail address: gminas@dei.uminho.pt (G. Minas).2. Design of the 16 optical-channels array2.1. Background of the biosystem applicationThe application of the particular biosystem presented hereis the measurement of the concentration, by optical absorp-tion, of 16 different biochemical substances in human’s flu-ids. However, many of the analytes1 of interest for clinicalanalysis do not have chromophores that absorb light in a use-ful part of the visible range. Specific chemical reactions areavailable (reagents) to transform these analytes into coloredproducts that do have adequate absorbance [1]. In addition,the concentration of biochemical substances is measured byusing a mixture of a reagent with an analyte sample. Themeasurement method has the following characteristics: (1)the intensity of the color produced by the mixture is directlyproportional to the concentration of the biochemical sub-stances in analysis; (2) the absorption spectra of the mixtureshow a maximum peak at a specific wavelength; (3) eachmixture presents a linear behavior within the interest con-centration range.A biosystem to measure the concentration of biochemicalsubstances in biological fluids, by optical absorption, waspreviously implemented [4]. Its operation was successfully1 An analyte is the substance (element, ion, compound or molecule)being analyzed.0924-4247/$ – see front matter © 2004 Elsevier B.V. All rights reserved.doi:10.1016/j.sna.2004.03.077G. Minas et al. / Sensors and Actuators A 115 (2004) 362–367 36330%40%50%60%70%80%90%100%350 400 450 500 550 600 650 700Wavelength (nm)Transmittance (%)Rise of uric acid concentrationFig. 1. Measured transmittance spectra for different uric acid concentra-tions [4].p substrateSiO2n+p+Glass channelFabry-Perotoptical filterCommercialband-pass filter[450-650 nm]SilicondieGlassdie AlAgFig. 2. Schematic structure of the biosystem for an individual optical-channel in cross-section.demonstrated in uric acid concentration detection (Fig. 1).However, the measurements were carried out with a wave-length dependent light source (monochromatic light).2.2. Complete structureAn optical filter placed on the top of the biosystem allowsthe use of only a white light source, giving portability to thebiosystem. Fig. 2 shows schematically the cross-section ofthe biosystem for an individual optical-channel. It is com-posed of a glass die and a silicon die. The glass die containsthe fluidic channels (Fig. 3) and the optical filters. The sili-Fig. 3. The fluidic channels. It comprises three fluidic channels. Channel Ais needed to obtain the baseline reference and to calibrate the light source.Channel B allows the mixed solution analysis (reagent plus sample).Channel C is needed to calibrate the biochemical substance concentration(well-known biochemical calibrator).Only a narrow band aroundthe resonance wavelengthis transmittedWidespectrumlight beam MirrorAgMirrordMultiple reflectionscause resonancefor  =2λq ndAlSiO2Fig. 4. Fabry-Perot filter.Fig. 5. An artist impression of the 16 optical filters (4× 4 array) and thecommercial band-pass filter. Each of the Fabry-Perot cavities is tuned totransmit in different spectral band.con die contains the photodetectors and readout electronics.A commercially available band-pass optical filter on the topof the biosystem is used to avoid the non-visible spectrum.The device operation is based on optical absorption in awell-defined wavelength of the visible spectrum. The im-pinging spectrum is filtered by the optical filters to a singlewavelength, and the intensity of the selected spectral com-ponent transmitted through the fluid is measured using anunderlying photodetector. The optical-channel is composedTable 1The 16 biochemical substances that can be analyzed in the biosystem [1]Biochemical substance BiologicalfluidAbsorption spectramaximum peak (nm)Uric acid U, CSF 495Cholesterol S 500Glucose S 505Glutamic oxalacetic/pyruvictransaminaseS, P, CSF 510Creatinine U, S, P 515Magnesium S 520Aldolase S 525Bile acids S 530Blood urea nitrogen S, P 535Salicylate S 540Hemoglobin P 545-Glucuronidase S, U 550Urea nitrogen U, S, P 555Bilirubin S 560Leucine aminopeptidase U 565Calcium S 570Note: U: urine, S: serum, P: plasma, CSF: cerebrospinal fluid.364 G. Minas et al. / Sensors and Actuators A 115 (2004) 362–36703691215450 475 500 525 550 575 600 625 650Wavelength (nm)Transmittance (%) Commercial band-pass filterFig. 6. Simulated transmittance vs. wavelength for the 16 optical fil-ters array. The Fabry-Perot layer stack is 20 nm Al/SiO2/40 nm Ag.The SiO2 layer thickness changes from 637 to 742 nm in 7 nmincrements.by a Al/SiO2/Ag layer stack functioning as a Fabry-Perotoptical filter with an optical detector underneath (a CMOSstandard photodiode).The Fabry-Perot filter consists of two parallel mirrors witha resonance cavity in the middle (Fig. 4) [5]. The equationλq = 2nd shows its operation principle, where n is the re-fractive index of the cavity medium, d the cavity length, λthe incident wavelength and q the interference order (q = 1,2, 3, . . . ). The optical filters use metallic mirrors insteadof high-performance dielectric mirrors due to the simplic-ity of their fabrication: only three layers are deposited andthe wavelength selection is performed by changing only thethickness of the SiO2 layer. Silver and aluminum have beenselected due to their high reflectivity at visible wavelengths[6]. Aluminum is the most suitable material in terms of fab-1 masktime=Tetch=56nmst 2 masktime=T/2ndetch=28nm3 masktime=T/4rd etch=14nm4 masktime=T/8thetch=7nm(a) Filter number71513658161410 12 4 29 11 3 1(b) Fig. 7. (a) The four masks used in the SiO2 etching process. The crossesare alignment marks; (b) the position of each filter in the array. The filternumber 1 (λ = 495 nm) is for uric acid, the filter number 2 (λ = 500 nm)is for cholesterol, and so one according to Table 1.rication compatibility (despite its higher absorption losses).Silver exhibits poor long-term stability (tendency to tarnish)[7]. However, that biosystem is sealed, using the commer-cial band-pass filter, to avoid the oxidation of the silver layercaused by the environment. A special glue is used aroundthe Fabry-Perot optical filter for adhesive bonding the glasscommercial band-pass filter to the glass die. It also couldbe used an intermediate layer of polysilicon to obtain theglass-to-glass anodic bonding.Rather than just one optical filter it has been developed a16 optical filters array based on Fabry-Perot thin-films op-tical resonators. The complete 4 × 4 array, schematicallyshown in Fig. 5, allows the measurement of the concentra-tion of 16 different biochemical substances in human’s flu-ids. These substances are described in Table 1. Each of theoptical filters is tuned for a specific wavelength (third col-Fig. 8. The SiO2 etching process. (a) applying the first mask, two differentSiO2 thickness are obtained; (b) applying the second mask, four differentSiO2 thickness are obtained; (c) applying the third mask, eight differentSiO2 thickness are obtained; (d) applying the fourth mask all the 16 SiO2thickness are obtained.G. Minas et al. / Sensors and Actuators A 115 (2004) 362–367 365Fig. 9. SEM photograph showing the cross-section of one of theFabry-Perot filters (SiO2 thickness = 637 nm).umn of Table 1). The thickness of the SiO2 layer determinesthe tuned wavelength.2.3. Optical simulations of the Fabry-Perot filtersA thin-film optics software package (TFCalc 3.4) wasused for the structural optimization of the optical filters.Fig. 10. Photograph of the packaged biosystem.Simulation results show that a 20 nm Al/SiO2/40 nm Aglayer stack (Ag on top) is the best option for the opti-cal filters in terms of optical characteristics and feasibil-ity. The SiO2 layer thickness changes between 637 and742 nm with 7 nm steps. The simulated transmittances forall the 16 optical filters show that each of the channels issensitive to a single spectral band, with a FWHM = 7 nm(Fig. 6).3. Fabrication of the 16 optical-channels arrayThe filter fabrication starts with the deposition of a 20 nmAl layer by evaporation. Then a 742 nm thick SiO2 layer isdeposited by chemical vapor deposition (equal to the maxi-mum cavity length). In subsequent plasma etching steps, forwhich a mask is used and each of them with different etchtime (see Fig. 7a), the total thickness of the SiO2 layer isdecreased from 742 to 637 nm, in 7 nm steps, forming thefilters number 16 (λ = 570 nm) to 1 (λ = 495 nm), respec-tively. Fig. 7b shows the position of each filter in the array.The SiO2 etching process is visualized in Fig. 8. The fab-rication ends with the deposition of a 40 nm Ag layer. ASEM photograph presenting the cross-section of one of thechannels (filter number 1) is shown in Fig. 9. The 16-filterfabrication requires only four masks and four etching steps.366 G. Minas et al. / Sensors and Actuators A 115 (2004) 362–3670246810450 475 500 525 550 575 600Wavelength (nm)Transmittance (%) Rise of uric acid concentrationFig. 11. Measured transmittance for a single channel for the same uricacid concentrations measured in Fig. 1 (λ = 495 nm).The filters can be easily tuned to different spectral bands byadjusting only the thickness of the SiO2 layer without affect-ing the biosystem layout. Fig. 10 shows a photograph of thecomplete device. The holes and channels were drilled andmilled, respectively, by using a computer numerically con-trolled (CNC) machine. The glass die is glued to the CMOSchip.4. Experimental resultsThe 16 optical filters are now being fabricated. Meanwhilea single channel was previously fabricated and its operationdemonstrated in the measurement of uric acid concentra-tion (λ = 495 nm). The reagent used in those measurementswas the infinityTM uric acid reagent from Sigma–Aldrich[8]. A 200 W quartz tungsten halogen lamp was used as thewhite light source for biosystem illumination. The photo-diode current was measured using a Keithley 487 picoam-meter. A monochromator is also used in order to obtain thephotodiode current versus the wavelength. The optical filteris composed of the 20 nm Al/637 nm SiO2/40 nm Ag layerstack. Optical spectra measurements on the biosystem showthat the single channel is sensitive to its specific wavelength(λ = 495 nm), with a FWHM of 7 nm (Fig. 11). These mea-surements, when compared with the measurements withoutthe optical filter (Fig. 1), allow concluding that it can be usedonly a white light source for the biosystem illumination.However, Fabry-Perot filters using metallic mirrors cannotprovide both high-transmittance and low FWHM due to theoptical absorption in the metal layers. From Fig. 11 it canbe seen that with a FWHM = 7 nm the transmittance of thehighest concentration fall off from 35% (see Fig. 1) to 4.5%.This can be avoided using high-performance dielectric mir-rors. However, the filters fabrication will be significantlymore complex.5. ConclusionsThe reported biosystem offers a new approach for clinicalanalysis due to the measurements of the concentration of 16different biochemical substances in human’s fluids, with thesame device. This performance is obtained with an array of16 optical filters based on Fabry-Perot thin-films optical res-onators. Moreover, the 16 optical-channels array allows theuse of only a white light source for illumination. Therefore,the measurements can be performed in any place and the re-sults of those measurements become available immediately.AcknowledgementsThis work is supported by the Portuguese Foundation ofScience and Technology (FCT projects SFRH/BD/1281/2000and POCTI/33747/ESE/1999) and by FEDER.References[1] Biochemical and Organic Reagents, Sigma, 2002.[2] S.C. Jakeway, A.J. de Mello, E. Russell, Miniaturized total analysissystems for biological analysis, Fresenius J. Anal. Chem. 366 (2000)525–539.[3] J.H. Hahn, K.W. Ro, B.C. Shim, K. Lim, US2003/0017079A1, Ab-sorbance detection system for lab-on-a-chip, 23 January 2003.[4] G. Minas, J.S. Martins, C. Pereira, C. Lima, R.F. Wolffenbuttel,J.H. Correia, Lab-on-a-chip for measuring uric acid in biologicalfluids, in: Proceedings of the Eurosensors XVI, Czech Republic, 2002,pp. 66–69.[5] B. Saleh, M.C. Teich, Fundamentals of Photonics, Wiley, 1991.[6] G. Minas, J.S. Martins, J.H. Correia, Highly selective optical detectionin a lab-on-a-chip for biological fluids analysis, Sens. Mater. 14 (2002)77–89.[7] D.Y. Song, R.W. Sprague, H.A. Macleod, M.R. Jacobson, Progressin the development of a durable silver-based high-reflectance coatingfor astronomical telescopes, Appl. Opt. 24/8 (1985) 1164–1170.[8] P. Kabasakalian, S. Kalliney, A. Westcott, Determination of uric acidin serum, with use of uricase and a tribromophenol-aminoantipyrinechromogen, Clin. Chem. 19/5 (1973) 522–524.BiographiesGraça Minas graduated in industrial electronics engineering in 1994 andobtained her MSc degree in 1998 both titles at University of Minho,Portugal. Since 1995 she has been a Lecturer in Department of Indus-trial Electronics, University of Minho, Portugal and she is involved inbiomedical microdevices research. She won the second place for bestoral presentation in Eurosensors XVII, presenting the reported work.José Carlos Ribeiro graduated in electrical engineering at Universityof Minho, Portugal in 2003. Since September 2002, he is working inthe microelectronics group at University of Minho, Portugal and he isinvolved in biomedical microdevices research.Júlio Sousa Martins graduated in electrical engineering at Universityof Oporto, Portugal in 1979. He obtained his PhD degree on computerengineering at University of Minho, Portugal in 1993. Since 1998, hehas been an associate professor at the Department of Industrial Elec-tronics of the University of Minho and he is involved in electronics andinstrumentation research.Reinoud F. Wolffenbuttel received the MSc and PhD degrees from theDelft University of Technology, Delft, The Netherlands, in 1984 and 1988,respectively. Between 1986 and 1993, he was an assistant professor, andG. Minas et al. / Sensors and Actuators A 115 (2004) 362–367 367since 1993, an associate professor, at the Laboratory of Electronic Instru-mentation of the Delft University of Technology, where he is involvedin instrumentation and measurement in general and on-chip integrationof microelectronic circuits and silicon sensor, fabrication compatibilityissues, and micromachining in silicon and microsystems, in particular. Hewas a visitor at the University of Michigan, Ann Arbor, in 1992, 1999,and 2001, at Tohoku University, Sendai, Japan, in 1995, and at EPFL,Lausanne, Switzerland, in 1997. Dr. Wolffenbuttel was the recipient of a1997 NOW pioneer award. He served as General Chairman of the DutchNational Sensor Conference in 1996 and Eurosensors in 1999.José Higino Correia graduated in physical engineering from Univer-sity of Coimbra, Portugal in 1990. He obtained in 1999 a PhD de-gree at the Laboratory for Electronic Instrumentation, Delft Universityof Technology, working in the field of microsystems for optical spec-tral analysis. Presently, he is an associate professor in Department ofIndustrial Electronics, University of Minho, Portugal. He was the Gen-eral Chairman of Eurosensors 2003, Guimarães, Portugal. His profes-sional interests are in micromachining and microfabrication technology formixed-mode systems, solid-state integrated sensors, microactuators andmicrosystems.

An array of fabry-perot optical-channels for biological fluids analysis

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An array of fabry-perot optical-channels for biological fluids analysis

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