EP2018438A1 - Dispositif de biocapteurs électroniques - Google Patents

Dispositif de biocapteurs électroniques

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Publication number
EP2018438A1
EP2018438A1 EP07718445A EP07718445A EP2018438A1 EP 2018438 A1 EP2018438 A1 EP 2018438A1 EP 07718445 A EP07718445 A EP 07718445A EP 07718445 A EP07718445 A EP 07718445A EP 2018438 A1 EP2018438 A1 EP 2018438A1
Authority
EP
European Patent Office
Prior art keywords
sub
sensor
capacitors
measuring
control logic
Prior art date
Legal status (The legal status 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 status listed.)
Withdrawn
Application number
EP07718445A
Other languages
German (de)
English (en)
Inventor
Christa NÖHAMMER
Meneses Rocha Daniel Paulo Wiese
Caspar Van Vroonhoven
Michael Johannes Vellekoop
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
AIT Austrian Institute of Technology GmbH
Original Assignee
Austrian Research Centers GmbH ARC
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 Austrian Research Centers GmbH ARC filed Critical Austrian Research Centers GmbH ARC
Publication of EP2018438A1 publication Critical patent/EP2018438A1/fr
Withdrawn legal-status Critical Current

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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
    • G01N27/26—Investigating or analysing materials by the use of electric, electrochemical, or magnetic means by investigating electrochemical variables; by using electrolysis or electrophoresis
    • G01N27/28—Electrolytic cell components
    • G01N27/30—Electrodes, e.g. test electrodes; Half-cells
    • G01N27/327—Biochemical electrodes, e.g. electrical or mechanical details for in vitro measurements
    • G01N27/3275—Sensing specific biomolecules, e.g. nucleic acid strands, based on an electrode surface reaction
    • G01N27/3276—Sensing specific biomolecules, e.g. nucleic acid strands, based on an electrode surface reaction being a hybridisation with immobilised receptors
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
    • C12Q1/00—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions
    • C12Q1/68—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions involving nucleic acids
    • C12Q1/6813—Hybridisation assays
    • C12Q1/6816—Hybridisation assays characterised by the detection means

Definitions

  • the invention relates to an electronic biosensor arrangement having a receiving region for biological material, to which a sensor electrode arrangement with comb-like interdigitated sensor electrodes is assigned, to which a measuring circuit for measuring an organic quantity influenced by biological material can be connected to the sensor electrodes.
  • Such a biosensor arrangement is known for example from the article E. Laureyn et al. , "Nanoscaled Interdigitated Titanium Electrodes for Impedimetric Biosensing", Sensors and Actuators B, Vol. 68 (2000), pages 360-370, which is directed to the detection of affinity-based interactions between complementary molecules cause binding of target molecules to selective probe coatings in the electrical properties in the region of the comb-like interdigitated electrodes These changes can be detected as an impedance shift, giving a direct electrical signal related to affinity binding In this way, the immobilization of glucose oxidase can be monitored using impedance spectroscopy.
  • the invention is based on the finding that in the commonly used on-chip analysis systems for biochemistry there is no problem in realizing individual biosensors in the aforementioned large number on a chip and at a correspondingly high rate with respect to these biosensors read out a capacity drop, wherein for the capacitance measurement further basically a known per se from other measurement applications principle, namely the SAR technique (SAR - Successive Approximation Registers - successive approximation register), are used for quickly obtaining a sufficiently accurate measurement result in digital form can.
  • This SAR technique is known, for example, in acceleration sensors and pressure sensors and is based on capacitance difference measurements, cf.
  • cf capacitance difference measurements
  • the individual sensor capacitors which are driven by the respective sensor electrodes i. Biosensors are formed, connected in series to the measuring voltage and "read out", wherein for each reading, ie for each measured value, a SAR approximation is performed at the - at a correspondingly higher rate - the individual measuring capacitors, starting with the Most significant measuring capacitor, according to the most significant bit in the output of the digital measurement result, turned off and, depending on the respective difference result, be switched off or remain switched on, when the next low measuring capacitor is then turned on.
  • This successive approximation finally leads to a digital signal that a predetermined resolution, corresponding to the smallest measuring capacitor, which indicates the capacitance difference between the reference capacitor and the respective sensor capacitor ensorkondensators received.
  • the capacity difference value which is obtained directly in digital form and thus can be further processed directly, is sufficient for further data processing.
  • the differential amplifier has a feedback branch from its output to the one input, said feedback branch having a controlled by the control logic switch for closing and opening the feedback branch, wherein the differential amplifier with open feedback branch in the SAR approximation phase as comparator func-
  • the switch provided in the feedback branch after the initialization phase simultaneously with or immediately before switching the reference capacitor associated switching means to switch the reference capacitor instead of the measuring voltage to the ground, controlled by the control logic becomes.
  • the one input of the differential amplifier is preceded by a resistor for frequency attenuation in conjunction with an input capacitance of the differential amplifier in the initialization phase.
  • the reference capacitor may be similar to the sensor capacitors formed on the common chip, however, the reference capacitor remains free of biological material, i. no reaction process takes place in its area, so that its capacity value does not change.
  • the capacitance value of the reference capacitor is chosen equal to the maximum possible capacitance value of the individual sensor capacitors, wherein the capacitance values of the sensor capacitors are reduced by reactions in the biological material.
  • the measuring capacitors can also be realized on the same chip.
  • FIG. 1 shows schematically an electronic biosensor arrangement according to the invention, including a downstream data processing unit;
  • 2A is a schematic circuit diagram of the individual biosensors or sensor capacitors with the associated measuring circuit
  • FIG. 2B shows a diagram of some voltage signals occurring in the circuit according to FIG. 2;
  • FIG. 3A is a schematic diagram of the control logic of the measuring circuit of FIG. 2A;
  • 3C shows a schematic illustration of a number of biosensors, which are formed by sensor electrodes, together with associated switching means, wherein the reference capacitor formed by comparable electrodes and associated switching means are also shown.
  • FIG. 1 schematically illustrates the basic principle of the present electronic biosensor arrangement 1, wherein a sensor electrode arrangement 3 is provided on a common chip 4 in a receiving region 2 for biological material which is indicated only schematically.
  • a reference capacitor C ref and measuring capacitors C 0 to C 5 are further realized outside the receiving area 2 for the biological material through the sensor electrode assembly 3, a reference capacitor C ref and measuring capacitors C 0 to C 5 are further realized.
  • the individual sensor capacitors C sensor , i and the reference capacitor C ref are formed by comb-like interdigitated electrodes, as can be seen schematically from FIG. 3C.
  • These capacitors C r ⁇ f and C sensor , i are switching means S 1 and S 2 , x, S 2 , ... S 2 , i ... S 2 , N and S 3 , o ⁇ S 3 , 1 . .. S 3 , 5 , which emerge from FIGS. 2A and 3C and which are concretely formed by electronic switching means, for example directly in the region of the semiconductor chip 4, wherein for driving a bus to the individual switching means S 1 to S 3 of the measuring circuit 5 leads.
  • the switching means S 1 , S 2 , i and S 3 , 0 to S 3 are controlled by a control logic 8 of the measuring circuit 5, wherein the switching means S 1 and S 2, depending on the current measurement phase in operation an electrical connection to a measuring - Voltage V dr i Ve or to ground produce, but may also remain open (the latter the switches S 2 , i for the biosensors, ie for the sensor capacitors C se nsor, i relates).
  • Another control bus 9 of the control logic 8 leads to the switching means S 3 , 0 to S 3 , 5 , which connect the binary weighted measuring capacitors C 0 to C 5 selectively with a voltage source V array or ground.
  • the other side of these measuring capacitors C 0 to C 5 is led to a node A, with which the reference capacitor C ref and the sensor capacitors C sen sor, i are connected.
  • This node A is connected via a resistor R comp to the one input, namely the inverting input (-), of a differential amplifier 10 whose other non-inverting input (+) is connected to ground, wherein in FIG is illustrated that may occur in operation, an offset voltage V os .
  • the differential amplifier 10 has a feedback branch 11 with a switch So provided therein.
  • This electronic switch S 4 is in turn driven by the control logic 8, via a control line 12, in the aforementioned initialization phase I, before the actual measurement or approximation phase, a phase of successive approximation, this measurement phase M for one of the sensor capacitor C sen s or , i as well as the initialization phase I is illustrated in Fig. 3B.
  • a parasitic capacitance given in the chip 4 is also illustrated by a capacitor C paraS i t
  • a register 13 for storing the series of bits forming the measurement result per sensor capacitor C s nsor, i is provided, these measurement results then being taken over by a data processing unit 14 (see FIG. 1) for further processing.
  • This register 13 is incremented for each sensor capacitor, see the pulse signal "ready" in Figs. 2A and 2B, which uses these pulses as clock pulses for the register 13 become.
  • the switching means S 3 , 0 to S 3 , 5 supplied by the potential comparison of the measuring capacitors C 0 to C 5 with the respective sensor capacitor C S ensor, i dependent switching signals, this dependence in Output signal (comp_in) of the differential amplifier 10 expresses which output signal is fed to the control logic 8 at the correspondingly designated input comp_in.
  • FIG. 2B further illustrates a control signal V B applied to the switching means S 1 and a control signal V 6 applied to the switching means S 2 , i, as well as a clock signal V cik . It follows that the switching means S 2 , i - always with the exception of the specific switching means for the currently measured sensor capacitor C sensor , i ⁇ can remain open ("floating"), as will be explained in more detail below.
  • FIG. 3A the control bus 6 with individual lines for individual switching signals V sensorl / 2 , 3 ..., for the individual sensor capacitors C S ensor, i ..., closer illustrated.
  • These switching signals are also as that for the switch means Si for the reference capacitor C ref delivered via the control line 7 switching signal V B and, furthermore, a switching signal for individual bit stages bit5, bit4, bit3, bit2, BITL and Bito, in correspondence with the measurement capacitors C 5, C 4 , ... Ci, C 0 , generated by an initialization and Sensor techlscrien 15 within the control logic 8.
  • the individual bit stages bit 0 to bit 5 receive the output signal of the differential amplifier 10, that is to say the signal comp_in, in order to connect it logically to the pulse signal V A , see also FIG. 3B, the result being used to indicate the (indicated by arrows) Control signals (on the bus 9) for the measuring capacitors C 5 , C 4 ... C 0 associated switching means S 3 , 5 , S 3 , 4 ... S 3 , 0 to generate. These control signals are shown in Fig.
  • the clock signal V clk assumes, with its rising edges, all the respective processes.
  • the sampling of the output signal comp_in of the differential amplifier 10 occurs at the rising edge of the inverted clock signal, ie, after the respective bit had half a period of time to charge.
  • the outputs of the bit stages bit5 to bit0 are the control signals for the switching means S 3 , 5,... S 3 , o, which are also referred to as SAR switches (SAR - Successive Approximation Register).
  • SAR switches SAR - Successive Approximation Register
  • the signal V A triggers the actual measurement or approximation phase. If the reference capacitor C ref is charged, during which charging time (initialization phase I) all measurement capacitors C 5 to C 0 , must be grounded, this signal V A triggers, when it goes high, the delivery of the first array bit, the MSB Bits, in the present case of bit no. 5, off. It should be mentioned here that an embodiment with six bits is selected by way of example, which in practice represents a good compromise between the number of weighted capacitors C 0 , C 1 ... And the detection limit. Of course, but also For example, more (or less) measuring capacitors, such as 12 measuring capacitors C, may also be provided.
  • the signal V 3 is high during the initialization phase I before the actual measurement and drives the switching means S 1 for the reference capacitor C ref in the closed state.
  • this signal V B causes a closure of the switch S 3 in the feedback branch 11 of the differential amplifier 10 to ensure unity feedback in this phase.
  • the number of clock periods during which this signal V B is high depends on the necessary decay time after the approximation phase.
  • the output signal comp_in of the differential amplifier 10 is of interest when the differential amplifier 10 operates as a comparator, ie in the actual measurement phase or approximation phase.
  • the signal comp_in is positive if the total of the measuring capacitors switched on at the given time is higher than the absolute capacitance difference between the sensor capacitor C sensO r, i and the reference capacitor C ref .
  • the signal comp_in is negative if several measuring capacitors have to be switched on. It is assumed that this differential amplifier output signal comp_in rises rapidly enough after a respective bit (on the bus 9) has been turned on. In this respect, pay attention to a fast operation of the differential amplifier 10.
  • the circuit comprising the SAR converter 16, the measuring capacitors C 0 to C 5 and a starting capacitor C min together with the associated control logic 8 and the differential amplifier or comparator 10 is realized in an extremely compact circuit with low power consumption can be realized.
  • the initialization phase I in which the reference capacitor C re £ , which has a fixed capacitance value, is charged
  • the actual measurement phase M in which the respective sensor capacitor C sensorri is turned on, followed by switching on the measuring capacitors C 5 to C 0 in the SAR array.
  • the positions of the switches for the initialization phase in the measurement of, for example, the sensor capacitor C senso r, i are as follows:
  • the feedback switch S 0 is closed, and the reference capacitor C ref is connected to the measurement voltage V drive , while at least the first sensor capacitor C sen s or , i is grounded, as well as the measurement capacitors C n .
  • the differential amplifier 10 virtually forces ground potential at its (-) input.
  • resistor R comp is used to achieve phantom-zero frequency compensation along with an input capacitance.
  • the resistance R comp has practically no effect, since the current through this resistance is negligible.
  • the gain at the operating frequency of the differential amplifier 10 is high to boost the smallest input voltages, in the last stage of the approximation, to a logical "high” or "low".
  • this measuring phase M one sensor capacitor after another is connected to the measuring voltage V 3 , the voltage at node A then becoming proportional to the capacitance difference.
  • the successive approximation algorithm is used to converge to a digital measurement signal representing this capacitance difference.
  • the measuring capacitors starting with the capacitor C 5 with the large ten capacitance value (32 C min ) to the voltage V arr ay switched on and kept switched on, if necessary. This depends on the resulting sign of the voltage in node A.
  • the reference capacitor C ref is a capacitor on which no reaction takes place; its capacity value is 1OpF.
  • the measuring capacitors C 0 to C 5 have, according to a binary series, the capacitance values 5OfF, 10OfF, 20OfF, 40OfF, 80OfF and 1, 6pF.
  • the difference in the capacitance of the sensor capacitor C se nsor, i and the reference capacitor C ref is stored at node A.
  • the measurement capacitors C 5 to C 0 are then connected in sequence to the voltage V array as described in order to determine whether the equivalent charge is positive or negative. This results in the following example a following table of values:
  • Residual capacity l 6pF -1.42pF + 0.18pF negative 0
  • the result of 8.6pF results from the difference between the capacitance of the reference capacitor (1OpF) less of the measured capacitance (1, 4pF, corresponding to the 6-bit output 011100).
  • the measurement capacitors C 0 to C 5 are also preferably realized on the chip 4 in order to achieve a particularly compact design of the entire biosensor arrangement 1.
  • a capacitor C min which is parallel to the actual measuring capacitors C 0 to C 5 and which is always connected between the node A and ground is functionless for the sensor operation and only for a calibration and test procedure before the sensor is put into operation advantageous.
  • This capacitor C m i n can also be omitted.
  • the voltage V at node A can be written as follows:
  • C array ⁇ o ⁇ is the total measurement capacitor capacitance
  • C array indicates the linear combination of those weighted measurement capacitors representing the approximation to the point just described.
  • the offset sensitivity of the arrangement can be substantially reduced.
  • the offset of the differential amplifier 10 is stored in the node A during the initialization phase I and then eliminated by differential amplification in the approximation phase (measurement phase M). Assuming that the biosensor array 1 is operated at high switching frequencies, the 1 / f noise can be considered as offset.

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  • Life Sciences & Earth Sciences (AREA)
  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Molecular Biology (AREA)
  • Physics & Mathematics (AREA)
  • Biochemistry (AREA)
  • Immunology (AREA)
  • General Health & Medical Sciences (AREA)
  • Analytical Chemistry (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Organic Chemistry (AREA)
  • General Physics & Mathematics (AREA)
  • Spectroscopy & Molecular Physics (AREA)
  • Pathology (AREA)
  • Electrochemistry (AREA)
  • Zoology (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Engineering & Computer Science (AREA)
  • Wood Science & Technology (AREA)
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  • Biotechnology (AREA)
  • Biophysics (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • General Engineering & Computer Science (AREA)
  • Genetics & Genomics (AREA)
  • Investigating Or Analyzing Materials By The Use Of Electric Means (AREA)
  • Measurement Of Resistance Or Impedance (AREA)

Abstract

La présente invention concerne un dispositif de biocapteurs électroniques (1) avec une zone logement (2) pour un matériau biologique, à laquelle est adjoint un dispositif (3) d'électrodes de capteurs muni d'électrodes de capteurs (3a, 3b) en forme de peigne imbriquées l'une dans l'autre, auxquelles est connecté un circuit de mesure (5) servant à mesurer une valeur de mesure électrique influencée par le matériau biologique au niveau des électrodes de capteur (3a, 3b). Les électrodes de capteur (3a, 3b) constituent une pluralité de condensateurs de capteurs (C<SUB>sensor,1</SUB> à C<SUB>sensor,N</SUB>) auxquels sont associés des éléments de commutation (S<SUB>2,1</SUB> à S<SUB>2,N</SUB>) électroniques commandés par une logique de commande (8) pour la connexion à la masse ou à une source de tension fournissant une tension de mesure (V<SUB>drive</SUB>), avec un condensateur de référence (C<SUB>ref</SUB>) auquel est également associé un élément de commutation (S<SUB>1</SUB>) commandé par la logique de commande (8) pour une connexion au choix à la masse ou à la tension de mesure (V<SUB>drive</SUB>). Les condensateurs (C<SUB>ref,</SUB> C<SUB>sensor,1</SUB> - C<SUB>sensor,N</SUB>) sont d'autre part réunis en un noed (A), qui est relié à une entrée (-) d'un amplificateur différenciateur (10) et auquel sont reliés des condensateurs de mesure (C<SUB>0</SUB> à C<SUB>5</SUB>) supplémentaires avec des capacités pondérées binaires (C<SUB>min</SUB> à 32C<SUB>min</SUB>) pour constituer une unité de comparaison SAR, ces condensateurs de mesure pouvant d'autre part être connectés sélectivement à une source de tension (V<SUB>array</SUB>) ou à la masse au moyen d'éléments de commutation (S<SUB>3,0</SUB> à S<SUB>3,5</SUB>) commandés par la logique de commande (8) afin de réaliser une différence de charge pour la conversion SAR.
EP07718445A 2006-05-15 2007-05-15 Dispositif de biocapteurs électroniques Withdrawn EP2018438A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
AT0083006A AT503742B8 (de) 2006-05-15 2006-05-15 Elektronische biosensoranordnung
PCT/AT2007/000233 WO2007131255A1 (fr) 2006-05-15 2007-05-15 Dispositif de biocapteurs électroniques

Publications (1)

Publication Number Publication Date
EP2018438A1 true EP2018438A1 (fr) 2009-01-28

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Application Number Title Priority Date Filing Date
EP07718445A Withdrawn EP2018438A1 (fr) 2006-05-15 2007-05-15 Dispositif de biocapteurs électroniques

Country Status (7)

Country Link
US (1) US8043563B2 (fr)
EP (1) EP2018438A1 (fr)
KR (1) KR20090056932A (fr)
CN (1) CN101512015A (fr)
AT (1) AT503742B8 (fr)
CA (1) CA2652407A1 (fr)
WO (1) WO2007131255A1 (fr)

Families Citing this family (1)

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CN111108398A (zh) * 2017-09-29 2020-05-05 勃林格殷格翰维特梅迪卡有限公司 电路布置的测试和校准

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JP2003529773A (ja) 2000-03-30 2003-10-07 インフィネオン テクノロジーズ アクチエンゲゼルシャフト 電極配置を用いた巨大分子生体高分子の検出方法
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Also Published As

Publication number Publication date
AT503742B1 (de) 2011-06-15
WO2007131255A8 (fr) 2008-02-28
US8043563B2 (en) 2011-10-25
CN101512015A (zh) 2009-08-19
AT503742A1 (de) 2007-12-15
WO2007131255A1 (fr) 2007-11-22
AT503742B8 (de) 2011-08-15
CA2652407A1 (fr) 2007-11-22
KR20090056932A (ko) 2009-06-03
US20090206847A1 (en) 2009-08-20

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