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WO2010013169A1 - Dispositif de capteur magnétique avec élément de capteur conducteur - Google Patents

Dispositif de capteur magnétique avec élément de capteur conducteur Download PDF

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Publication number
WO2010013169A1
WO2010013169A1 PCT/IB2009/053154 IB2009053154W WO2010013169A1 WO 2010013169 A1 WO2010013169 A1 WO 2010013169A1 IB 2009053154 W IB2009053154 W IB 2009053154W WO 2010013169 A1 WO2010013169 A1 WO 2010013169A1
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WO
WIPO (PCT)
Prior art keywords
magnetic
magnetic sensor
sensitive region
sensor element
sensor device
Prior art date
Application number
PCT/IB2009/053154
Other languages
English (en)
Inventor
Bart M. De Boer
Hans Van Zon
Original Assignee
Koninklijke Philips Electronics N.V.
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 Koninklijke Philips Electronics N.V. filed Critical Koninklijke Philips Electronics N.V.
Publication of WO2010013169A1 publication Critical patent/WO2010013169A1/fr

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Classifications

    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01R—MEASURING ELECTRIC VARIABLES; MEASURING MAGNETIC VARIABLES
    • G01R33/00—Arrangements or instruments for measuring magnetic variables
    • G01R33/12—Measuring magnetic properties of articles or specimens of solids or fluids
    • G01R33/1269—Measuring magnetic properties of articles or specimens of solids or fluids of molecules labeled with magnetic beads
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B82—NANOTECHNOLOGY
    • B82Y—SPECIFIC USES OR APPLICATIONS OF NANOSTRUCTURES; MEASUREMENT OR ANALYSIS OF NANOSTRUCTURES; MANUFACTURE OR TREATMENT OF NANOSTRUCTURES
    • B82Y25/00—Nanomagnetism, e.g. magnetoimpedance, anisotropic magnetoresistance, giant magnetoresistance or tunneling magnetoresistance
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01R—MEASURING ELECTRIC VARIABLES; MEASURING MAGNETIC VARIABLES
    • G01R33/00—Arrangements or instruments for measuring magnetic variables
    • G01R33/02—Measuring direction or magnitude of magnetic fields or magnetic flux
    • G01R33/06—Measuring direction or magnitude of magnetic fields or magnetic flux using galvano-magnetic devices
    • G01R33/09—Magnetoresistive devices
    • G01R33/093—Magnetoresistive devices using multilayer structures, e.g. giant magnetoresistance sensors

Definitions

  • the invention relates to a magnetic sensor device and a method for detecting magnetic particles in a sensitive region with the help of a magnetic sensor element.
  • a magnetic sensor device is known from the WO 2007/132372 Al which may for example be used in a micro fluidic biosensor for the detection of molecules, e.g. biological molecules, labeled with magnetic beads.
  • the magnetic sensor device is provided with an array of sensor units comprising wires for the generation of a magnetic field and Giant Magneto Resistances (GMR) for the detection of stray fields generated by magnetized beads.
  • GMR Giant Magneto Resistances
  • the signal of the GMRs is then indicative of the number of the beads that are bound to an adjacent sensitive region.
  • the magnetic sensor device serves for the detection of magnetic particles in a sensitive region.
  • the term "magnetic particle” shall denote any particle (e.g. molecule, complex, nano-particle, micro-particle etc.) which is (permanently) magnetic or which is magnetizable when exposed to an external magnetic field.
  • Typical magnetic particles are beads with a size between 3 nm and 50000 nm that can for example be used as labels in biochemical assays.
  • the magnetic sensor device comprises the following components:
  • the magnetic sensor element shall have an internal electrically conductive channel, for example realized by a metal line or layer between two terminals.
  • the attribute "internal” shall indicate that there is an intimate relation between the conductive channel and the sensing capability of the magnetic sensor element.
  • the interaction of an external magnetic field with the magnetic sensor element which is the basis of the detection process will typically (at least partially) take place within the conductive channel. In many cases, the conductive channel will extend over the whole magnetic sensor element.
  • this magnetic field will be called “magnetic excitation field” in the following.
  • the power supply may for example be realized by a current source or a voltage source that generates in a controlled way a predetermined current or voltage, respectively, in the conductive channel.
  • the evaluation unit may be realized by dedicated electronic hardware components (amplifiers, capacitors etc.), by digital data processing hardware with associated software, or by a mixture of both.
  • the magnetic sensor element and optionally also the power supply and the evaluation unit (or at least parts thereof) are realized as integrated circuits on a common substrate.
  • the proposed magnetic sensor device has the advantage that the magnetic excitation field, which is needed to induce magnetic reaction fields from magnetic particles, is generated with the very same magnetic sensor element that detects said reaction fields. Thus there is no need for separate conductors that would have the only purpose of generating the magnetic excitation fields.
  • This provides several advantages: First of all, the sensitive area on the sensor device can be increased, providing a higher sensitivity particularly at low concentrations of magnetic particles.
  • Another advantage is that magnetic excitation fields are generated most closely to the location where the magnetic reaction fields of the particles shall be detected; for typical magnetic sensor elements like GMR sensors this provides a better alignment of the magnetic reaction field with the sensitive direction of the sensor element, thus further improving the sensitivity and accuracy.
  • the magnetic sensor element can be realized by a variety of different technologies. It may for instance comprise a coil with one or more loops, a Hall sensor, a planar Hall sensor, a flux gate sensor, a SQUID (Superconducting Quantum Interference Device), a magnetic resonance sensor, a magneto -restrictive sensor, or a magneto -resistive sensor of the kind described in the WO 2005/010543 Al or WO 2005/010542 A2, especially a GMR (Giant Magneto Resistance), a TMR (Tunnel Magneto Resistance), or an AMR (Anisotropic Magneto Resistance).
  • the magnetic sensor device may comprise components other than the magnetic sensor element by which a magnetic field can be generated in the sensitive region.
  • the space-economy of the design is however maximized in an embodiment in which the magnetic sensor element is the only component of the magnetic sensor device that can generate a magnetic field in the sensitive region which is large enough to measurably magnetize magnetic particles.
  • the criterion of a "measurable" magnetization has to be used in this context because every current flow in a circuit of the device will theoretically generate an associated magnetic field that may reach the sensitive region. These spurious magnetic fields will however usually not have any effect on the magnetic moment of magnetic particles in the sensitive region, at least no effect above the detection limit of the magnetic sensor element.
  • the magnetic sensor element of a device according to this invention can be realized with small aspect ratios.
  • the ratio between the length and the width of the magnetic sensor element may range between 1 :5 and 5:1, wherein the "length” refers to the direction of current flow through the conductive channel (i.e. the direction between the terminals to which the power supply is connected) and the "width" to a direction perpendicular to the length and parallel to a plane defined by the sensitive region (usually the surface of a substrate that comprises the sensor).
  • the aspect ration preferably has a value of about 1 :1, corresponding to an (approximately) square geometry of the magnetic sensor element.
  • the aforementioned elongated magnetic sensor elements of the state of the art typically have a width of about 3 ⁇ m.
  • the conductive channel of the magnetic sensor element may therefore optionally have a width of at least 5 ⁇ m, preferably at least 10 ⁇ m, more preferably of at least 15 ⁇ m, and most preferably of at least 20 ⁇ m.
  • the large width of the conductive channel - and accordingly the large width of the magnetic sensor element which comprises this channel - has the advantage to provide a sensitive region with uniform conditions in a large area. This is for example advantageous in connection with GMR devices that have a reduced sensitivity near their edges.
  • the power supply is preferably adapted to provide a current and/or a voltage that is modulated with a given frequency.
  • This current/voltage may for example be a superposition of a DC component and a sinusoidal AC component of frequency f.
  • the frequency of a modulated current/voltage allows for example to shift the frequency of the signal of interest into frequency regions where 1/f noise of the magnetic sensor element and/or electronic components like amplifiers is minimal.
  • the sensitive region may preferably comprise binding sites for target substances, for instance for biological substances like biomolecules, complexes, cell fractions or cells. Magnetic particles can then be used to label the target substances or substances related thereto. The amount of magnetic particles in the sensitive region will provide clues about the amount of bound target substances which is usually the information one is actually interested in.
  • the invention further relates to a method for detecting magnetic particles in a sensitive region with the help of a magnetic sensor element comprising an internal conductive channel.
  • the method may particularly be executed with a magnetic sensor device of the kind described above. It comprises the following steps:
  • the method comprises in general form the steps that can be executed with a magnetic sensor device of the kind described above. Therefore, reference is made to the preceding description for more information on the details, advantages and improvements of that method.
  • the sensed magnetic reaction fields are evaluated with respect to the amount (e.g. concentration, surface density etc.) of magnetic particles that are present in the sensitive region.
  • the invention further relates to the use of the magnetic device described above for molecular diagnostics, biological sample analysis, or chemical sample analysis, food analysis, and/or forensic analysis.
  • Molecular diagnostics may for example be accomplished with the help of magnetic beads that are directly or indirectly attached to target molecules.
  • Figure 1 schematically shows a perspective on a section through a sensor device according to the present invention
  • Figure 2 shows a simplified circuit diagram of the magnetic sensor device
  • Figure 3 shows exemplary measurement results with the sensor device.
  • Figure 1 illustrates a microelectronic magnetic sensor device 100 according to the present invention in the particular application as a biosensor for the detection of magnetic particles, e.g. superparamagnetic beads 1, in a sensitive region.
  • Magneto -resistive biochips or biosensors have promising properties for bio-molecular diagnostics, in terms of sensitivity, specificity, integration, ease of use, and costs. Examples of such biochips are described in the WO 2003/054566, WO 2003/054523, WO 2005/010542 A2, WO 2005/010543 Al, and WO 2005/038911 Al, which are incorporated into the present application by reference.
  • a biosensor typically consists of an array of (e.g. 100) magnetic sensor devices 100 of the kind shown in Figure 1 and may thus simultaneously measure the concentration of a large number of different target molecules (e.g. protein, DNA, amino acids, drugs of abuse) in a solution (e.g. blood or saliva).
  • target molecules e.g. protein, DNA, amino acids, drugs of abuse
  • a solution e.g. blood or saliva
  • the so-called “sandwich assay” this is achieved by providing a binding surface with first antibodies to which the target molecules may bind.
  • Superparamagnetic beads 1 carrying second antibodies may then attach to the bound target molecules. For simplicity, only the beads 1 are shown in the Figure.
  • a narrow, elongated GMR element is located next to and/or between conductor wires that generate magnetic excitation fields for magnetizing the beads. These conductor wires occupy chip area and require two bond pads for electrical connection each. Moreover, the signal response of the GMR element to a single magnetic particle depends significantly - even with a change of sign - on the lateral (x-) position of this particle.
  • Figure 1 illustrates an embodiment of this general concept for the example of a GMR element 11 serving as magnetic sensor element.
  • the GMR element 11 is embedded as a planar stripe in some substrate 10, for example in silicon.
  • the GMR element 11 has however a width W (measured in x-direction perpendicular to the direction of current flow through the GMR element 11) that is (considerably) larger than the mean diameter of the magnetic particles 1 to be detected.
  • the width W of the GMR element 11 is about 25 ⁇ m.
  • Its length L i.e. its extension in y-direction between its electrical terminals (not shown), is typically 50 ⁇ m.
  • the GMR element 11 As the GMR element 11 is electrically conductive, it constitutes as a whole an "internal conductive channel" through which a current I provided by a power supply can flow. This current is symbolized in the Figure by arrows in y-direction.
  • the current I generates a magnetic excitation field B around the GMR element 11 , which is substantially parallel to the surface of the substrate 10 in the sensitive region 12 above the GMR element 11.
  • Magnetic particles 1 that are present in the sensitive region e.g. bound to binding sites
  • said reaction field B r is to a high degree parallel to the sensitive direction (x-direction) of the GMR element 11.
  • FIG 2 shows a simplified circuit diagram for the magnetic sensor device 100 of Figure 1.
  • the GMR element 11 behaves like an Ohmic resistor with a resistance that depends on the external magnetic field (B+B r ) it is exposed to (or, more precisely, the component of this field pointing in the sensitive direction of the GMR element).
  • the GMR element 11 is supplied by the current source 13 with a sinusoidal current
  • the voltage drop U GMR across the GMR element 11 represents its sensor signal and is provided to an amplifier 14.
  • the output of the amplifier is further fed to an evaluation unit 15 which comprises analogue and digital hardware as well as software for further signal and data processing.
  • B cos(2 ⁇ ft)-A cos(2 ⁇ ft) 1A AB + V 2 AB cos(2 ⁇ (2f)t) with A being the amplitude of the GMR resistance change ⁇ R that is inter alia dependent on the density of magnetic particles in the sensitive region 12.
  • the formula shows that the amount of magnetic particles in the sensitive region 12 (comprised in the value of A) can be determined by measuring the amplitude of the DC component and/or the component at frequency 2f of the sensor signal U GMR , which is done in the evaluation unit 15.
  • a voltage source could alternatively be used as power supply, in which case the current through the GMR would be the signal of interest that could be evaluated similarly as the voltage signal U GMR described above.
  • Figure 3 shows measurement results obtained with the sensor device 100 of Figures 1 and 2.
  • these particles slowly sediment to the sensor surface where they are detected, causing an increase in the sensor signal U GMR (which is represented in arbitrary units on the vertical axis).
  • U GMR which is represented in arbitrary units on the vertical axis.
  • the signal goes back to the level before the application of magnetic particles.
  • the large signal before applying the magnetic particles is caused by selfmodulation of the GMR, i.e. the sense current I itself results in a magnetic field in the GMR, which in turn causes a resistance change that is detected.
  • This signal can be considered a constant offset that should be measured before the start of the assay and later on subtracted from the measurement result.
  • the invention relates to a sensor geometry and an associated excitation/detection principle. According to this principle it is possible to do without separate field generating conductors and/or long narrow GMR elements; instead, only a magnetic sensor element (e.g. a GMR) is used both for excitation and sensing, wherein this element can preferably have a more or less square shape.
  • the excitation field is generated by application of a current to the sensor element. This results in an excitation field that is practically homogeneous across the sensor surface and moreover magnetizes the surface bound magnetic particles such that their stray field is largest in the sensitive direction of a GMR (x-direction), resulting in a larger and less position-dependent signal per magnetic particle.
  • the chip area is used efficiently and can be equipped with many sensors. This means that for low concentration measurements, and corresponding low surface bead densities, the influence of counting statistical errors as noise source is reduced.
  • Each sensor has just two connections and therefore requires only two of the available bond pads.
  • the signal contribution of a single magnetic particle is heavily dependent on its position in the x-direction on the sensor (the signal from a magnetic particle bound right on top of the GMR is even opposite in sign to the signal from a magnetic particle bound between the GMR and the excitation wires). This position dependency is in many cases the dominant noise source in conventional systems.
  • the conditions above the sensor are substantially uniform, i.e. problems with a position dependency are avoided.
  • the signal drawn from each magnetic particle is maximal since the direction of magnetization of the magnetic particle is optimal, i.e. parallel to the sensitive (x-) direction of the GMR element.
  • the magnetic sensor element can be any suitable sensor based on the detection of the magnetic properties of the particle on or near to a sensor surface, e.g. a coil, magneto -resistive sensor, magneto -restrictive sensor, Hall sensor, planar Hall sensor, flux gate sensor, SQUID, magnetic resonance sensor, etc.
  • a sensor surface e.g. a coil, magneto -resistive sensor, magneto -restrictive sensor, Hall sensor, planar Hall sensor, flux gate sensor, SQUID, magnetic resonance sensor, etc.
  • moieties can be detected with sensor devices according to the invention, e.g. cells, viruses, or fractions of cells or viruses, tissue extract, etc.
  • Measurement data can be derived as an end-point measurement, as well as by recording signals kinetically or intermittently.
  • the particles serving as labels can be detected directly by the sensing method. As well, the particles can be further processed prior to detection. An example of further processing is that materials are added or that the (bio)chemical or physical properties of the label are modified to facilitate detection.
  • the device and method can be used with several biochemical assay types, e.g. binding/unbinding assay, sandwich assay, competition assay, displacement assay, enzymatic assay, etc. It is especially suitable for DNA detection because large scale multiplexing is easily possible and different oligos can be spotted via ink-jet printing on a substrate.
  • the device and method are suited for sensor multiplexing (i.e. the parallel use of different sensors and sensor surfaces), label multiplexing (i.e. the parallel use of different types of labels) and chamber multiplexing (i.e. the parallel use of different reaction chambers).
  • the device and method can be used as rapid, robust, and easy to use point-of-care biosensors for small sample volumes.
  • the reaction chamber can be a disposable item to be used with a compact reader, containing the one or more field generating means and one or more detection means.
  • the device, methods and systems of the present invention can be used in automated high- throughput testing.
  • the reaction chamber is e.g. a well-plate or cuvette, fitting into an automated instrument.
  • nano-particles are meant particles having at least one dimension ranging between 3 nm and 50000 nm, preferably between 10 nm and 3000 nm, more preferred between 50 nm and 1000 nm.

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  • Physics & Mathematics (AREA)
  • Condensed Matter Physics & Semiconductors (AREA)
  • General Physics & Mathematics (AREA)
  • Chemical & Material Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Nanotechnology (AREA)
  • Spectroscopy & Molecular Physics (AREA)
  • Crystallography & Structural Chemistry (AREA)
  • Investigating Or Analyzing Materials By The Use Of Magnetic Means (AREA)

Abstract

L'invention porte sur un procédé et sur un dispositif de capteur magnétique (100) pour détecter des particules magnétiques (1) dans une région sensible (12) à l'aide d'un élément de capteur magnétique (11) qui comprend un canal conducteur (11). Lorsqu'un courant est appliqué au canal conducteur, un champ d'excitation magnétique (B) est généré dans la région sensible (12) qui à son tour induit des champs de réaction magnétiques (Br) de particules magnétiques (1). Les champs de réaction (Br) sont détectés par l'élément de capteur magnétique (11), ce qui permet par exemple de déterminer la quantité de particules magnétiques (1). Comme le même composant (11) est utilisé pour l'excitation magnétique et la détection, un agencement précis et compact est obtenu.
PCT/IB2009/053154 2008-07-29 2009-07-21 Dispositif de capteur magnétique avec élément de capteur conducteur WO2010013169A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
EP08104911 2008-07-29
EP08104911.6 2008-07-29

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WO2010013169A1 true WO2010013169A1 (fr) 2010-02-04

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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2015044027A1 (fr) * 2013-09-24 2015-04-02 Siemens Aktiengesellschaft Procédé multiplex pour une cytométrie de flux magnétique
US9567626B2 (en) 2012-01-04 2017-02-14 Magnomics, S.A. Monolithic device combining CMOS with magnetoresistive sensors
WO2017156149A1 (fr) * 2016-03-08 2017-09-14 Texas Instruments Incorporated Réduction de variation de composant de capteur magnétique en raison d'éléments magnétiques par l'application d'un champ magnétique

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2005010543A1 (fr) * 2003-07-30 2005-02-03 Koninklijke Philips Electronics N.V. Dispositif du type capteur magnetique monte sur puce et caracterise par une suppression de la diaphonie
WO2007129262A1 (fr) * 2006-05-10 2007-11-15 Koninklijke Philips Electronics N.V. Capteurs magnétorésistants aux caractéristiques du signal de sortie améliorées
DE102006037226A1 (de) * 2006-08-09 2008-02-14 Fraunhofer-Gesellschaft zur Förderung der angewandten Forschung e.V. Im Messbetrieb kalibrierbarer magnetischer 3D-Punktsensor

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2005010543A1 (fr) * 2003-07-30 2005-02-03 Koninklijke Philips Electronics N.V. Dispositif du type capteur magnetique monte sur puce et caracterise par une suppression de la diaphonie
WO2007129262A1 (fr) * 2006-05-10 2007-11-15 Koninklijke Philips Electronics N.V. Capteurs magnétorésistants aux caractéristiques du signal de sortie améliorées
DE102006037226A1 (de) * 2006-08-09 2008-02-14 Fraunhofer-Gesellschaft zur Förderung der angewandten Forschung e.V. Im Messbetrieb kalibrierbarer magnetischer 3D-Punktsensor

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US9567626B2 (en) 2012-01-04 2017-02-14 Magnomics, S.A. Monolithic device combining CMOS with magnetoresistive sensors
WO2015044027A1 (fr) * 2013-09-24 2015-04-02 Siemens Aktiengesellschaft Procédé multiplex pour une cytométrie de flux magnétique
WO2017156149A1 (fr) * 2016-03-08 2017-09-14 Texas Instruments Incorporated Réduction de variation de composant de capteur magnétique en raison d'éléments magnétiques par l'application d'un champ magnétique

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