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WO2003060501A1 - Procede permettant de detecter des acides nucleiques a l'aide d'un capteur capacitif a reseau de cellules - Google Patents

Procede permettant de detecter des acides nucleiques a l'aide d'un capteur capacitif a reseau de cellules Download PDF

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Publication number
WO2003060501A1
WO2003060501A1 PCT/IT2002/000818 IT0200818W WO03060501A1 WO 2003060501 A1 WO2003060501 A1 WO 2003060501A1 IT 0200818 W IT0200818 W IT 0200818W WO 03060501 A1 WO03060501 A1 WO 03060501A1
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WO
WIPO (PCT)
Prior art keywords
capacitance
sensor
process according
sample
detection
Prior art date
Application number
PCT/IT2002/000818
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English (en)
Inventor
Michele Cocco
Monica Pighini
Stefano Sinopoli
Original Assignee
Technobiochip S.C. A R.L.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Technobiochip S.C. A R.L. filed Critical Technobiochip S.C. A R.L.
Priority to EP02806391A priority Critical patent/EP1459058A1/fr
Priority to AU2002366990A priority patent/AU2002366990A1/en
Publication of WO2003060501A1 publication Critical patent/WO2003060501A1/fr

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Classifications

    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N27/00—Investigating or analysing materials by the use of electric, electrochemical, or magnetic means
    • G01N27/02—Investigating or analysing materials by the use of electric, electrochemical, or magnetic means by investigating impedance
    • G01N27/22—Investigating or analysing materials by the use of electric, electrochemical, or magnetic means by investigating impedance by investigating capacitance
    • G01N27/221—Investigating or analysing materials by the use of electric, electrochemical, or magnetic means by investigating impedance by investigating capacitance by investigating the dielectric properties

Definitions

  • This invention relates to a process for sensing nucleic acids, such as desoxyribonucleic acids or DNA, ribonucleic acids or RNA and peptide nucleic acids or PNA, by means of a cell matrix (or array capacitive sensor, which, by operating without use of markers, such as radioactive and/or fluorescent substances, enables to sense and/or to recognise and/or to measure the amount or the concentration of nucleic acids, thereby furnishing in short times highly reliable high resolution results, under use of very small amounts and very low concentrations of nucleic acids, this process being not expensive and versatile in various applications.
  • nucleic acids such as desoxyribonucleic acids or DNA, ribonucleic acids or RNA and peptide nucleic acids or PNA
  • DNA - sensors are one of the most innovative branches of the molecular technology, in that it provides an easy, rapid and reliable way to analyse many diagnostically interesting probes at the same time.
  • DNA sensors have been developed, such as optical, electrochemical and nanogravimetric sensors, some of which are being largely utilised.
  • the microarray technology has been very successful in this field: it is based upon deposition of specific nucleotides (usually derived from the 3' terminals of ribonucleic transcripts) on solid supports.
  • the analyses are carried out by scanning the microarray surface by means of complementary DNA or cDNA, derived from the RNA of the sample and of a reference or control.
  • cDNA probes are generally marked with fluorescent molecules and a scanner collects the emission spectra after exposition of hybridised arrays to a laser light source. The so collected monochromatic images are pseudo-coloured by a suitable acquisition software.
  • the construction step of the above-mentioned monochromatic images which entails an artificial coloration thereof, is an extremely critic step, since the analysis of the fluorescent arrays is not generally easy and it additionally requires a noticeable experience for construction of the data.
  • the analytical procedures are very long and expensive, because they require radioactive markers, electrophoretic courses or sequence analysis based upon suitable software.
  • the amounts and the concentrations of the nucleic acids as needed in the analysis do not allow reliable results to be achieved in some applications in which the amounts of the substance to be analysed are very small.
  • a further object of this invention is to provide such a process that enables various types of nucleic acids to be reliably discriminated.
  • Another object of this invention is to provide a process of the above kind that can be utilised in various applications in versatile way.
  • Specific subject-matter of this invention is a process for detection of nucleic acids by means of a cell array capacitive sensor, comprising a number N of measurement cells, characterised in that it comprises the following steps:
  • said step E comprises the following sub-step: E.1 eliminating the noise figure of said sensor by forcing to 0 (zero) the values of said at least one distribution of capacitance difference included in the range f-d, +dj, where d >0.
  • said step A comprises the following sub-steps:
  • A.2 performing a second reference detection of the capacitance of said cell array, A.3 calculating the difference between the capacitance data of the first reference detection and the capacitance data of the second reference detection and determining the distribution of said capacitance difference;
  • said step E can comprise the following sub-step:
  • the presence of a nucleic acid in the substance to be analysed can be acknowledged when one of the parameters of said at least one distribution of capacitance difference as processed in said step E exceeds a threshold value.
  • the process can discriminate between two or more substances containing different nucleic acids, a sample of each substance to be analysed being deposited during step B upon a corresponding area of the sensor including a number M ⁇ N of measurement cells, wherein said step D calculates, for each sample, the difference between the portion of capacitance data, relating to the corresponding area covered by the sample, of the measurement detection and the capacitance data of the first reference detection, thereby determining the distribution of such capacitance difference.
  • the individual areas covered by the samples can have substantially the same surface extension.
  • said step E can comprise the following sub-step:
  • the values of the related distribution of capacitance difference can be divided by the number of sensor cells included in the sensor area covered by the sample.
  • the substances to be analysed can be discriminated by determining whether one of the parameters of the corresponding distribution of capacitance difference is included in a specific value range.
  • the process can determine the concentration of a nucleic acid contained in a substance to be analysed, said step E measuring such concentration as a function of the value of one of the parameters of said at least one distribution of capacitance difference.
  • the process can detect the interaction between an unknown substance to be analysed and at least a known substance, said step A being preceded by the following preliminary step:
  • step F depositing a sample of said at least one known substance upon at least one corresponding area of the sensor; said step B comprising the deposition of a sample of the unknown substance to be analysed upon said at least one area of the sensor corresponding to the sample of said at least one known substance, said step D calculating, for each sample of said at least one known substance, the portion of said capacitance data, relating to the area corresponding to the sample of said at least one known substance, of the measurement detection and the capacitance data of the first reference detection and determining the distribution of such capacitance difference.
  • At least one sample of the substance can be dissolved in liquid phase.
  • the deposition of at least one sample upon the sensor can be carried out by a "robot spotter”.
  • said steps D and E are automatically carried out by a computer program or software adapted to show the result of the detection in three-dimensional format on a display, whose axis and axis Y correspond to the geometric surface of the sensor, while its axis Z is proportional to the measurement magnitude.
  • each pixel of the image can represent one parameter of said at least one distribution of capacitance difference relating to a single cell of the sensor array, preferably the electric capacitance value measured by a single cell.
  • said software can assign a different colour according to the obtained measurement value.
  • said software can further perform an image classification and/or analysis.
  • a cell array capacitive sensor comprising a number N of measurement cells, for detection of the interaction between an unknown substance to be analysed and at least a known substance, characterised in that a sample of said at least one known substance is deposited upon at least one corresponding area of the sensor, the sensor being adapted to be utilised in the process for detection of the interaction between an unknown substance to be analysed and at least a known substance as above described.
  • Equally subject-matter of the invention is a computer readable memory medium having a program stored therein, characterised in that the program is a computer program as above described.
  • Figure 1 diagrammatically shows an equivalent circuit of a single cell of the sensor array as utilised in the process according to this invention
  • Figure 2 diagrammatically shows the equivalent circuit of a first electronic configuration of the circuit of Figure 1 ;
  • Figure 3 diagrammatically shows the equivalent circuit of a second electronic configuration of the circuit of Figure 1 ;
  • Figure 4 shows an illustrative histogram of the results obtained by measuring the noise figure of a sensor by the process according to this invention
  • Figure 5 diagrammatically shows the surface of a cell array of a sensor utilised in a first detection by the process according to this invention
  • Figure 6 shows a first histogram representing a first result obtained during the first detection of Figure 5;
  • Figure 7 shows a second histogram representing a second result obtained during the first detection of Figure 5;
  • Figure 8 shows a third histogram representing a third result obtained during the first detection of Figure 5
  • Figure 9 shows a fourth histogram representing a fourth result obtained during the first detection of Figure 5;
  • Figure 10 diagrammatically shows the surface of the cell array of a sensor utilised in a second detection by the process according to this invention
  • Figure 11 diagrammatically shows the surface of the cell array of a sensor utilised in a third detection by the process according to this invention
  • Figure 12 shows a histogram representing a result obtained in a fourth detection by the process according to this invention
  • Figure 13 shows a histogram representing a result obtained during a fifth detection by the process according to this invention
  • Figure 14 shows two histograms representing a result obtained during a sixth detection by the process according to this invention.
  • Figure 15 shows the behaviour of the detections carried out by the process according to this invention as the concentration of a first nucleic acid to be measured is varied
  • Figure 16 shows the behaviour of the overage value of the detections obtained by the process according to this invention as the concentration of a second nucleic acid to be measured is varied
  • Figure 17 shows the behaviour of the detections obtained by the process according to this invention as the concentration of a third nucleic acid to be measured is varied.
  • Figure 18 shows the behaviour of the detections obtained by the process according to this invention as the concentration of a fourth nucleic acid to be measured is varied.
  • the same reference numerals will be utilised hereinbelow to designate the same items in the Figures.
  • the process according to this invention utilises just a cell matrix or cell array capacitive sensor to this effect.
  • FIG. 1 diagrammatically shows an equivalent circuit, immediately comprehensible to a person skilled in the art, of an individual cell of the array.
  • capacitor 1 is formed by a circuit unit comprising two metal electrodes, unconnected with one another, operating as the two plates of the concerned capacitor and it is additionally formed by the sample to be measured, preferably deposited upon a dielectric layer adjacent to the above mentioned two electrodes. The electric characteristics of the sample affect the capacitance value of said capacitor 1.
  • the array is arranged for activation of a single cell by means of an addressing function, which provides for power supply to the electronic components of the cell.
  • the first voltage source 2 inside the array is utilised to charge a first half cycle of capacitor 1 , having unknown capacitance.
  • Reference capacitor 3, inside the array is charged during a second half cycle by the charge amount stored in capacitor 1.
  • the second voltage source is utilised as a reference voltage to which the voltage of capacitor 3 is compared.
  • Operational amplifier 5 compares the voltages at its two inputs in such a way that, when the voltage of capacitor 3 reaches the level of the second voltage source 4, it generates an output signal which stops counting of counter 6.
  • the operation of the cell of Figure 1 is divided into two half cycles that can be repeated a number of times by suitably acting upon a first and a second switch 7 and 8, respectively. Since the unknown capacitance of capacitor 1 has a too small value for it to be directly measured, the array utilises an indirect measurement method. Before starting the measurement operation, namely before the first half cycle is carried out the first time, said counter 6 is cleared.
  • the cell is configured as in Figure 1 , where the first switch 7 is closed and the second switch 8 is open.
  • capacitor 1 is charged by the first voltage source 2.
  • the first switch 7 is open and the second switch 8 is closed.
  • capacitor 1 releases the charge amount stored during the first half cycle into reference capacitor 3, thereby raising its voltage.
  • the two half cycles are repeated until the voltage of the reference capacitor 3 reaches or exceeds the level of the second voltage source 4.
  • the value reached by counter 6, which is blocked, is inversely proportional to the, value of the unknown capacitance of capacitor 1.
  • the value of counter 6 is stored and another cell of the array is addressed and measured. It is also possible to utilise different cells, with different circuit diagrams (for instance, circuits including more than one voltage source for charging capacitor 1 during the first half cycle and/or more than one reference voltage source).
  • the process according to this invention also keeps the noise of the utilised sensor under examination into account.
  • the data of the cell array comprising the sensor is preliminarily acquired two times, without any material being deposited thereon, and the difference between the values obtained in said two measurements is considered.
  • the result of this difference when it is represented as a histogram, would comprise a single frequency value located at 0 (zero) having an amplitude equal to the number of cells in the array.
  • Figure 4 shows the result obtained by a specific sensor: after a number of statistically significant trials, the noise figure of the sensor in differential analysis is located within the value range of [-1, +1].
  • the noise figure range in differential analysis can be located as [-d, +d], where d should be determined by a number of trials sufficient from the statistical significance viewpoint.
  • the process analyses the data in differential mode.
  • it operates upon a data matrix (namely, the values furnished by the sensor), the items of which are determined by the difference between a measurement matrix and a reference matrix.
  • a drop of the sample to be analysed having a volume preferably equal to 1 ⁇ l, is deposited upon the sensor .
  • the image acquisition takes place after complete evaporation of the solubilisation water.
  • Such image comprises a histogram having the capacitance values (or possible counting values of counter 6) as abscissa and the number of cells corresponding to the capacitance value as ordinate.
  • the various distributions of the differences between the acquired measurements are automatically computed, by forcing the values of the histogram of the frequencies falling within the range [-d, +d relating to noise to 0 (zero).
  • the detection of the presence of DNA is provided by the shape and amplitude of the histogram and it can be connected for instance to the average value and/or to the maximum value and/or to the variance and/or to the integral of the histogram.
  • the reference matrix is the one obtained by acquiring the data with bare sensor.
  • the surface of sensor 9 is ideally divided into two halves, each of which includes the same number of the array cells. Two separate drops having the same area and equal concentrations are deposited upon sensor 9: a first drop 10 related to the first substance and a second drop 11 related to a second substance, each drop being associated to a corresponding half sensor, with the same amount of the substance to be analysed, and the measurement data is acquired.
  • each distribution can be represented by a vector characterising the examined drop.
  • a vector subtraction operation enables a difference vector to be obtained, which indicates to which extent the sensor can distinguish the substances with respect to each other.
  • Figures 8 and 9 illustrate the difference vectors that can be obtained from Figures 6 and 7 by inverting the minuend and the subtrahend vectors.
  • the procedure for discrimination among a number of different substances is an extension of the procedure related to two substances.
  • the concerned drops will have the same area and the same concentration and this means that a differential operation mode is adopted, the noise is eliminated, the histograms relating to each of them are considered and lastly the related difference histograms are analysed, thereby obtaining information about the capability of the sensor to distinguish the substances under examination.
  • the processed measurement furnishes, as it is shown in Figures 12 and 13, a peak value of about 1.1 U.A., where U.A. is the nondimensional measurement unit of the dielectric constant of the concerned substance, equal to the ratio of the dielectric constant ⁇ of the material and the dielectric constant ⁇ 0 in vacuum; while, by depositing the same sample amount (f.i. 50 ng) in the same volume (f.i. 1 ⁇ l) of genome DNA, a peak value of about 1.9 U.A. appears.
  • the same trial has been repeated a significant number of times and with three different types of plasma DNA (pBR328 of Roche ® , pUc 18 and pUc9 of Sigma ® ) obtaining always the same result.
  • the process according to this invention also enables genome DNAs of different kinds to be distinguished.
  • the inventors have set up various trials, by functionalising the surface of the sensor with the same amount in the same volume of two kinds of genome DNA: human and herring, both cut by means of the restriction enzyme EcoRI.
  • the obtained results furnish a clear evidence of the sensor capability to locate a threshold level, under which only human DNA can be found and over which only herring DNA can be found.
  • This offers a number of advantages with respect to the processes of the prior art, because up to now results of this kind could be obtained only by utilising long procedures requiring sequence analyses.
  • the latter is more influenced by the background noise, as it is located in a position corresponding to the unit value along the abscissa axis, which is just the value allotted to the reference sample (void sensor).
  • the obtained results are not bound to the surface extension of the drop, since all found values have been divided by such surface extension value.
  • the process according to this invention is also capable to distinguish single strand DNA (or ssDNA) and double strand DNA (or dsDNA).
  • the process provides for simply depositing two drops of the DNA having the same volume upon the sensor: a first drop containing 1 ⁇ g of dsDNA, a second drop containing the same amount of ssDNA.
  • the analytical process is the same as in the previous cases. Depositing different concentrations of the same substance upon the sensor has carried out the demonstration that the concerned process is capable to recognise different concentrations of a known substance.
  • a first way requires use of a spectrophotometer; in a second operation way, it is derived from a comparison to a DNA marker with known concentration, after an electrophoretic run on agarose gel; in both cases, it is not possible to measure low DNA concentrations and much time and expensive materials are needed.
  • the process according to this invention provides for an accurate and quite reliable measurement to be carried out in a few seconds, without the need of expensive instruments and materials.
  • the average value of the measurements carried out by the sensor is shown in the graph of Figure 6, in the frame of a meaningful set of trials; the indications of the standard deviations clearly evidences the reproducibility and the reliability of the results.
  • the maximum deviation from the average value is 9%; the minimum deviation is 0,1%.
  • the process according to this invention is adapted to distinguish among very small DNA amounts, in the nanogram range; this is not possible either with other sensor kinds, or with conventional molecular biology methods.
  • Figure 17 the behaviour of the recording curve, with finer resolution, evidences a small increase in the reading at low concentration increments (within a range of 0 to 5 ng), followed by an exponential segment between 5 and 15 ng, up to reaching an asymptotic value at 150 ng.
  • the process according to this invention is adapted to detect very small amounts of nucleic acids, thereby enabling to appreciate DNA amounts with sensitivities up to two magnitude orders higher than the ones reachable with conventional systems.
  • the slope of the curve shows an abrupt change at concentrations of about 25 ng and an asymptotic value between 50 and 100 ng is subsequently reached.
  • the analysis process provides for depositing a known substance (which should chemically react with the substance to be analysed) upon the sensor and for carrying out a first measurement: in contrast with the previous cases, the obtained data matrix is utilised as a reference matrix.
  • the substance to be analysed is deposited, it is allowed to react with the substance previously deposited upon the surface of the sensor and then the data matrix relating to this measurement is acquired.
  • the process according to this invention provides for the data to be processed in automatic procedure by means of a specifically dedicated computer program or software, adapted to automatically optimise each image in real time.
  • This software translates each measurement into an image, thereby allowing the analysis of the obtained measurements by utilising the conventional algorithms as developed to image classification and analysis operations. It further enables a differential measurement between a reference sample and a measurement sample to be carried out in a few seconds. It is adapted to furnish two result kinds: a first more sensitive for air measurements and a second more sensitive for liquid measurements.
  • the concerned software is further adapted to display the obtained results in three-dimension on a display: in this case the X axis and the Y axis correspond to the geometric surface of the sensor, while the Z axis is proportional to the magnitude value of the measurement.
  • the concerned software is also adapted to acquire high quality images even in continuous mode and it is further provided with an amplifying system for the differential image, so as to make it possible to determine also very small variations between the sample to be analysed and the reference sample.
  • the so acquired image comprises a variable number of rows and columns (in the order of hundreds): each pixel of the image represents, therefore, the dielectric capacitance value as measured by a single cell.
  • this software assigns a different colour according to the obtained measurement, so that the final result is realised as a coloured image.
  • the process according to this invention represents a valid alternative in connection with gene expression studies: it is possible to contemporaneously analyse the expression of thousands different genes by depositing tens thousands oligonucleotides corresponding to different genes (each of which represents a probe for a particular gene) upon the sensor. Since no fluorescent marker is employed, whose emission spectra should be collected by a scanner after the hybridised matrixes have been exposed to a laser light source, the process according to this invention allows to obtain noticeable time and material savings and the hybridisation is directly detected by the sensor, thereby eliminating the need to utilise an extremely expensive scanner, while the construction of the data turns out to be very easy and accessible to anyone.
  • the process according to this invention is further adapted to accurately record the various concentrations of the analysed DNA as well as to ascertain really very low concentrations, hard to be measured by utilisation of conventional systems (less than 1 ng). Since the spots are deposited upon a matrix larger than the underlying pixel (for instance, 4 pixels/spot), it is possible to detect the same signal by means of 4 contemporaneous and independent measurements, which is useful to standardise the measurements, to identify "dirty" signals or to measure the background emission.
  • a further advantage offered by this process is to allow to distinguish between genome DNAs of different nature: it is adapted to find out a correlation between the nature of the material to be analysed and its dielectric constant, based upon separation thresholds of the various DNA kinds deriving from different organisms.
  • This system is quite innovative: in fact, these results could be obtained up to now only by utilising long procedures requiring radioactive markers, electrophoretic runs and sequence analyses based upon dedicated software.
  • the process according to this invention is capable to discriminate DNA samples of different lengths and DNA samples having different compositions in G + C (guanine + adenine): this capability can be explained by the different presence of hydrogen bonds (2 for bases A and T and 3 for bases G and C) that are detected by the sensor as a different dielectric constant between the two DNA types. This feature allows to advantageously utilise this process to carry out philogenetic studies and genetic analysis of the population in short times and with a noticeable expense saving.
  • the advantageous feature to visualise the sample also in three-dimensional format allows to control at any time the surface condition of the sensor (for instance, the evaporation grade of the solubilisation liquid or any presence of contaminant inclusions).
  • Possible applications of the sensor according to this invention are as follows: diagnostic screening of human pathologies, correlated to known genetic mutations; detection of genetic mutations and DNA deletions or amplifications; studies of genetic expression, correlated to various human pathologies; screening of genetic predisposition to many pathology kinds; differential genomic studies, aimed at determining philogenetic trees or paternity tests or identity tests for humans or animal species for legal sciences, or descent or pedigree analysis; detection of genetic mutations, correlated to the presence of advantageous or aberrant phenotypes in vegetal species; analysis of the response to various environment stress types.
  • a further possible application is the identification of patients suffering of a high tumor risk figure and the possibility to pin point the correct therapy.
  • many molecular factors are potential indicators of tumoral aggressivity and have sensitivity/resistance to immune response of the host, for these reasons, they are potential indicators of initial prognoses or of therapeutical course.
  • the capability of the process to "perceive" the dielectric capacitance of the sample under examination allows to carry out hybridisation experiments of nucleic acids and offers the possibility to detect DNA in a few seconds without loss of time and money and without the need of expensive equipment.

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  • Chemical & Material Sciences (AREA)
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  • Health & Medical Sciences (AREA)
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Abstract

La présente invention concerne un procédé qui permet de détecter des acides nucléiques à l'aide d'un capteur capacitif à réseau de cellules comprenant un nombre N de cellules de mesure, lequel procédé est caractérisé en ce qu'il comprend les étapes suivantes : A. on effectue une première détection de référence de la capacité dudit réseau de cellules ; B. on dépose au moins un échantillon d'au moins une substance à analyser sur au moins une zone du capteur comprenant un nombre M de cellules de mesure, où M ≤ N ; C. on effectue une détection de mesure de la capacité du réseau de cellules ; D. on calcule au moins une différence entre au moins une partie des données de capacité de la détection de mesure et les données de capacité de la première détection de référence et on détermine la distribution de cette différence de capacité ; E. on traite la distribution de la différence de capacité et on obtient le résultat de la détection. L'invention se rapporte également à l'appareil qui permet de mettre en oeuvre le procédé précité.
PCT/IT2002/000818 2001-12-28 2002-12-20 Procede permettant de detecter des acides nucleiques a l'aide d'un capteur capacitif a reseau de cellules WO2003060501A1 (fr)

Priority Applications (2)

Application Number Priority Date Filing Date Title
EP02806391A EP1459058A1 (fr) 2001-12-28 2002-12-20 Procede permettant de detecter des acides nucleiques a l'aide d'un capteur capacitif a reseau de cellules
AU2002366990A AU2002366990A1 (en) 2001-12-28 2002-12-20 Process for sensing nucleic acids by means of a cell array capacitive sensor

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
ITRM2001A000774 2001-12-28
ITRM20010774 ITRM20010774A1 (it) 2001-12-28 2001-12-28 Procedimento di rilevazione di acidi nucleici mediante sensore capacitivo a matrice di celle.

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CN112666233B (zh) * 2020-12-09 2022-09-20 中南民族大学 一种基于平面电极阵列的藻类检测系统

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WO1999026187A1 (fr) * 1997-11-17 1999-05-27 Veridicom, Inc. Processus de reglage automatique pour dispositifs capteurs
WO2001018246A1 (fr) * 1999-08-26 2001-03-15 The Trustees Of Princeton University Dispositifs electroniques microfluidiques et nanofluidiques permettant de detecter des modifications de la capacite de fluides et techniques d'utilisation
WO2001082218A1 (fr) * 2000-04-27 2001-11-01 Veridicom, Inc. Amplificateur de gain automatique pour dispositif de detection biometrique

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Title
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J.R. STETTER, U. GÖPEL, W.R. PENROSE AND L. MANNO: "Impedance Imaging of Chemical and Biochemical Systems", TRANSDUCERS '01- EUROSENSORS XV (SPRINGER VERLAG), 10 June 2001 (2001-06-10) - 14 June 2001 (2001-06-14), Berlin, pages 810 - 813, XP002239711 *

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ITRM20010774A1 (it) 2003-06-30
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