WO2010013169A1

WO2010013169A1 - Magnetic sensor device with conductive sensor element

Info

Publication number: WO2010013169A1
Application number: PCT/IB2009/053154
Authority: WO
Inventors: Bart M. De Boer; Hans Van Zon
Original assignee: Koninklijke Philips Electronics N.V.
Priority date: 2008-07-29
Filing date: 2009-07-21
Publication date: 2010-02-04

Abstract

The invention relates to a method and a magnetic sensor device (100) for detecting magnetic particles (1) in a sensitive region (12) with the help of a magnetic sensor element (11) that comprises a conductive channel (11). When a current is applied to the conductive channel, a magnetic excitation field (B) is generated in the sensitive region (12) which in turn induces magnetic reaction fields (B_r) of magnetic particles (1). The reaction fields (B_r) are detected by the magnetic sensor element (11), which allows for example to determine the amount of magnetic particles (1). As the same component (11) is used for magnetic excitation and sensing, a compact yet accurate design is achieved.

Description

MAGNETIC SENSOR DEVICE WITH CONDUCTIVE SENSOR ELEMENT

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. The signal of the GMRs is then indicative of the number of the beads that are bound to an adjacent sensitive region. Though such a biosensor achieves a high accuracy, there is always a lower limit in the concentration of magnetic beads for which particle statistics and noise severely affect the measurement results.

Based on this background it was an object of the present invention to provide means for detecting magnetic particles with a high accuracy and sensitivity.

This object is achieved by a magnetic sensor device according to claim 1, a method according to claim 8, and a use according to claim 10. Preferred embodiments are disclosed in the dependent claims.

The magnetic sensor device according to the present invention serves for the detection of magnetic particles in a sensitive region. In this context, 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:

A "magnetic sensor element" for providing a sensor signal that is related to the strength of a magnetic field (or at least a component of this field) the sensor element is exposed to. 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. Thus 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.

A power supply for applying an electrical current to the aforementioned conductive channel of the magnetic sensor element, wherein said current shall be able to induce a magnetic field in the sensitive region. For purposes of reference, 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. - An evaluation unit for determining the magnetic effect of magnetic particles (if present) that were magnetized by the magnetic excitation field on the signal that is provided by the magnetic sensor element. 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. Preferably, 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. Finally, the realization of the magnetic sensor device in integrated technology is facilitated and becomes more cost-effective as the separate excitation wires can be saved. In general, 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).

If desired, 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.

In magnetic biosensors of the state of the art, separate magnetic excitation wires have to be disposed as close as possible to the associated magnetic sensor element, which usually implies a narrow, elongated geometry of this element. In contrast to this, the magnetic sensor element of a device according to this invention can be realized with small aspect ratios. In particular, 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. Thus it is possible to cover compact sensitive regions with the magnetic sensor element.

The aforementioned elongated magnetic sensor elements of the state of the art typically have a width of about 3 μm. In contrast to this, the present invention allows to build (much) broader elements. The conductive channel of the magnetic sensor element may therefore optionally have a width of at least 5 μm, preferably at least 10 μm, more preferably of at least 15 μm, and most preferably of at least 20μm. 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:

Generating a current flow through the internal conductive channel of the magnetic sensor element such that a magnetic excitation field is induced in the sensitive region.

Sensing with the magnetic sensor element magnetic reaction fields of magnetic particles in the sensitive region that were magnetized by the magnetic excitation field.

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.

According to preferred embodiment of the 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.

These and other aspects of the invention will be apparent from and elucidated with reference to the embodiment(s) described hereinafter. These embodiments will be described by way of example with the help of the accompanying drawings in which:

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.

Like reference numbers in the Figures refer to identical or similar components. 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). In one possible example of a binding scheme, 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. When the particles 1 are magnetized, their reaction field B_r introduces a magnetization component in the Giant Magneto Resistance (GMR) 11 of the sensor device 100 that has vector components in the sensitive (x-) direction of the GMR 11 and therefore generates a measurable resistance change.

In the sensor designs known from the state of the art, 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.

In view of the aforementioned problems, it is proposed here to use the magnetic sensor element itself for generating the required magnetic excitation fields.

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. In contrast to known biosensors, 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. In the example, the width W of the GMR element 11 is about 25 μm. Its length L, i.e. its extension in y-direction between its electrical terminals (not shown), is typically 50 μm. Thus a large sensitive area with small aspect ratio can be achieved. 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) will thus be magnetized in x-direction, and their magnetic moments will induce a magnetic reaction field B_r. Inside the GMR element 11, said reaction field B_r is to a high degree parallel to the sensitive direction (x-direction) of the GMR element 11.

Figure 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

I = I(t) = B cos(2πft) of (constant) amplitude B and frequency f (with t being the time). 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. The sensor signal U_GMR can be expressed by the formula: U_GMR(t) = I(t)-ΔR(t)

B cos(2πft)-A cos(2πft) 1A AB + V₂ AB cos(2π(2f)t) with A being the amplitude of the GMR resistance change ΔR 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.

It should be noted that the described design can be modified in various ways. In particular, 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. After applying magnetic particles to the sensor at times ti and t₃, 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). After washing at times t₂ and t₄, 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.

In summary, 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.

Advantages of the proposed design are:

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.

In state-of-the-art magnetic biosensors having separate excitation wires parallel to a GMR element, 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.

In the design of the present invention, 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.

Most of the detection can be done above the inner area of the (broad) GMR element, which is more sensitive than the edges. - The power requirements are minimized as the excitation currents are close to the magnetic particles and magnetize these particles in an optimal direction.

No magnetic or capacitive cross talk occurs between the GMR element and separate excitation wires. While the invention was described above with reference to particular embodiments, various modifications and extensions are possible, for example:

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.

In addition to molecular assays, also larger 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. Also, the device, methods and systems of the present invention can be used in automated high- throughput testing. In this case, the reaction chamber is e.g. a well-plate or cuvette, fitting into an automated instrument.

With "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.

Finally it is pointed out that in the present application the term "comprising" does not exclude other elements or steps, that "a" or "an" does not exclude a plurality, and that a single processor or other unit may fulfill the functions of several means. The invention resides in each and every novel characteristic feature and each and every combination of characteristic features. Moreover, reference signs in the claims shall not be construed as limiting their scope.

Claims

CLAIMS:

1. A magnetic sensor device (100) for detecting magnetic particles (1) in a sensitive region (12), comprising: a magnetic sensor element (11) with an internal conductive channel (11); - a power supply (13) for applying a current (I) to the conductive channel of the magnetic sensor element (11) which induces a magnetic excitation field (B) in the sensitive region (12); an evaluation unit (15) for determining the magnetic effects of magnetic particles (1), that were magnetized by the magnetic excitation field (B), on the signal of the magnetic sensor element (11).

2. The magnetic sensor device (100) according to claim 1, characterized in that the magnetic sensor element (11) comprises a coil, a

Hall sensor, a planar Hall sensor, a flux gate sensor, a SQUID, a magnetic resonance sensor, a magneto -restrictive sensor, or magneto -resistive sensor like a GMR, a TMR, or an AMR element.

3. The magnetic sensor device (100) according to claim 1, characterized in that the magnetic sensor element (11) is the only component of the device that can generate a magnetic field in the sensitive region (12) which is large enough to magnetize magnetic particles (1) in a measurable way.

4. The magnetic sensor device (100) according to claim 1, characterized in that the ratio between the width (W) and the length (L) of the magnetic sensor element (11) ranges between 1 :5 and 5:1.

5. The magnetic sensor device (100) according to claim 1, characterized in that the conductive channel (11) has a width (W) of at least 5 μm, preferably at least 10 μm.

6. The magnetic sensor device (100) according to claim 1, characterized in that the power supply (13) is adapted to provide a current (I) and/or a voltage that is modulated with a given frequency f.

7. The magnetic sensor device (100) according to claim 1, characterized in that the sensitive region (12) comprises binding sites for target substances.

8. A method for the detection of magnetic particles (1) in a sensitive region (12) with the help of a magnetic sensor element (11) comprising an internal conductive channel (11), the method comprising the following steps: generating a current flow through the internal conductive channel (11) such that a magnetic excitation field (B) is induced in the sensitive region (12); sensing with the magnetic sensor element (11) a magnetic reaction field (B_r) of magnetic particles (1) in the sensitive region (12) that were magnetized by the magnetic excitation field (B).

9. The method according to claim 8, characterized in that the sensed magnetic reaction field (B_r) is evaluated with respect to the amount of magnetic particles (1) in the sensitive region (12).

10. Use of the magnetic sensor device (100) according to any of the claims 1 to 7 for molecular diagnostics, biological sample analysis, or chemical sample analysis.