JP2010521649A - Magnetic sensor device having a pair of detection units - Google Patents

Abstract

The present invention relates to a magnetic sensor device 100 having first and second detection units P, S, each of the detection units having a magnetic sensor element and a magnetic field generator. In a preferred embodiment, the magnetic sensor element is a GMR element having the same sensitivity direction D ₁₂ , D ₂₂ , and the magnetic field generator is supplied with an anti-parallel magnetic field excitation current supplied by the evaluation and control unit 40. Wire. The magnetic field excitation current generates excitation magnetic fields Bn and B2i having opposite rotational directions that induce response magnetic fields B ₁₁ ′ and B ₂₁ ′ in opposite directions in the magnetized particle 1 supplied in the investigation region 2. The response magnetic fields B ₁₁ ′, B ₂₁ ′ thus have the opposite effect on the GMR elements, resulting in an increase in the difference Δ between the output signals of these elements. In the preferred embodiment, four detection units are configured in a Wheatstone bridge.

Description

  The present invention relates to a magnetic sensor device for detecting magnetized particles having a pair of detection units having a magnetic field generator and a magnetic sensor element. Furthermore, it relates to the use of such a magnetic sensor device.

  From WO 2005/010543 A1 and WO 2005/010542 A2, magnetic sensor devices are known which can be used, for example, in microfluidic biosensors for detection of target molecules labeled with magnetic beads, for example biomolecules. The microsensor device comprises an array of detection units with wires for the generation of excitation magnetic fields and giant magnetoresistance (GMR) for the detection of magnetic reaction fields generated by magnetization-fixed beads. The GMR signal (resistance change) in this case indicates the number of beads close to the sensor.

  If extremely low concentrations of the target molecule are to be measured and / or if the measurement time is to be minimized, it is essential that a magnetic sensor device of the kind described above maximizes the signal-to-noise ratio. It is. However, this is a difficult task when considering many different interference sources such as power supply noise, temperature drift, common mode interference and crosstalk.

  Based on this situation, the object of the present invention is to provide a means for more accurate detection of magnetized particles in the investigation region, so that the associated magnetic sensor device can be manufactured without complicated manufacturing steps. Is desirable.

  This object is achieved by the magnetic sensor device according to claim 1 and the use according to claim 13.

The magnetic sensor device according to the invention mainly (but not exclusively) detects magnetized particles in the investigation region, for example the detection of magnetic beads attached as labels to target molecules in the sample fluid supplied into the sample chamber. To help. The magnetic sensor device has the following components.
a) "First detection unit" and "Second detection unit". Here the terms “first” and “second” are selected only to distinguish these units and should not mean that there must be a difference or hierarchy between them. Each of the first and second detection units has the following components.
a1) "Magnetic sensor element" with sensitivity direction. In this regard, it is first noted that the following terms and definitions are used throughout this sentence to describe the spatial relationship between geometric objects.
-(Geometric) "Lines" extend infinitely or infinitely in one or two directions and have no specific orientation.
-"Direction" is a line with a direction, that is, a direction running from the start point to the end point (these points may be located at infinity). The direction can be described mathematically as a vector. Usually, the direction has a finite extent and is visualized as an arrow.
-Two lines or directions are said to be "parallel" if they have the same distance from each other everywhere.
-Two directions are "equal" / "opposite" if they have the same / opposite orientation, or more precisely if the associated vectors a, b have positive / negative scalar products a · b It is called. The opposite parallel direction is sometimes referred to as "anti-parallel".
The “sensitivity direction” of the magnetic sensor element means in this case that the sensor element is (only or) most sensitive to the component of the magnetic field vector that is parallel to this spatial direction. Furthermore, a difference occurs when these components are in the same or opposite direction with respect to the sensitivity direction. Usually, the magnetic sensor element has only one single sensitivity direction and is substantially insensitive to the component of the magnetic field perpendicular to this direction.
a2) A “magnetic field generator” for generating an “excitation magnetic field” in (at least part of) the investigation area. Here, the excitation magnetic field can excite the “response magnetic field” of such particles when magnetized particles are present in the investigation region. Furthermore, the response magnetic field of the magnetized particle should have, by definition, an “intersection” that is the angle between the vector of the response magnetic field and the direction of sensitivity of the associated magnetic sensor element at the location of the associated magnetic sensor element. It is. In most cases, the response field is parallel (and equal) or anti-parallel to the sensitivity direction of the associated magnetic sensor element, which means that the crossing angle is 0 ° or 180 °, respectively. In general, the intersection angle, however, may assume any value between 0 and 180 °.
Strictly speaking, the direction of the response magnetic field depends not only on the excitation magnetic field applied but also on the actual distribution of the magnetized particles. For the unique definition of said intersection angle, “response field” therefore always refers to a given representative orientation, for example the average orientation of all possible response fields, in the context of the present invention. .
Furthermore, the component xyz defined on the detection unit (magnetic sensor element, sensitivity direction, magnetic field generator, excitation magnetic field, response magnetic field, intersection angle) is sometimes referred to below as the first or second respectively. Depending on the attribution to the detection unit, it is referred to as “first component xyz” or “second component xyz”. “First magnetic sensor element” is thus a short notation for, for example, “magnetic sensor element of the first detection unit”.
b) A control unit that controls the magnetic field generators of the first and second detection units so that the relevant intersection angles (defined above) are different from each other.
c) an evaluation unit for sensing the difference between the output signals of the magnetic sensor elements of the first and second detection units. The evaluation unit and the control unit may be implemented as a circuit on the same microelectronic chip as the detection unit, or may be realized externally (at least partially) from this chip.

  The magnetic sensor device achieves a high signal-to-noise ratio because the evaluation unit senses the difference between two measurement signals, which is a disturbance that acts on both magnetic sensor elements in the same way (eg power supply noise). , Temperature drift, common mode interference, crosstalk) cancel each other. Cancellation of the desired measurement signal, i.e. the intensity of the response field excited in the magnetized particles, is however prevented. This is due to the fact that, according to feature a2), the excited response field has a different angle of intersection in the first and second magnetic sensor elements, thus producing different measurements.

  According to a preferred embodiment of the present invention, the first and second detection units have substantially the same design (ie have the same materials / components in the same dimensions and relative arrangement). Such an identical configuration ensures that the disturbance acts on both detection units in the same way and therefore (almost) accurately cancels in the difference of the output signals.

  In general, the first and second excitation fields may overlap somewhat in the study area. In a preferred embodiment, the first and second magnetic field generators, however, the excitation field is dominant in different parts of the investigation region (ie contributes at least 70% of the field strength of the part). Configured as follows. Most preferably, the excitation fields are substantially non-overlapping, which minimizes the associated crosstalk between the first detection unit and the second detection unit.

  In the general case, the first and second response magnetic fields (generated by the magnetized particles) at the location of the first magnetic sensor element and / or the second magnetic sensor element There may be overlap between them. However, the first and second magnetic sensor elements are preferably reached predominantly only by the first or second response field, respectively. Ideally, the first response magnetic field reaches only the associated first magnetic sensor element, and the second response magnetic field reaches only the associated second magnetic sensor element. In this case, magnetic crosstalk between the first detection unit and the second detection unit can be greatly reduced. The minimization of the crosstalk is of course reached in combination with the previous embodiment, i.e. where the first and second excitation fields do not overlap.

  Said (first and / or second) magnetic field generator can be realized, for example, by at least one conductor wire. In the exemplary embodiment, this is accomplished by two parallel extending wire pairs.

  The (first and / or second) magnetic sensor element can in particular comprise a Hall sensor, the direction of sensitivity of which is determined by the direction of the current through the sensor. Two identical parallel Hall sensors generate signals of opposite polarity when, for example, antiparallel current is conducted through them. The (first and / or second) magnetic sensor element may comprise a magnetoresistive element such as a GMR (giant magnetoresistive), TMR (tunnel magnetoresistive) or AMR (anisotropic magnetoresistive) element. The sensitivity direction of the GMR element can be determined by, for example, a pinned layer. Furthermore, the magnetic field generator and the magnetic sensor element can be realized as an integrated circuit, for example using CMOS technology together with the additional step of realizing the magnetoresistive component on a CMOS circuit. The integrated circuit can optionally also comprise the control unit and / or the evaluation unit of the magnetic sensor device.

  The first and second sensitivity directions can generally be arbitrarily positioned in space, and are preferably parallel and equally oriented. In principle, it is known to generate neighboring GMRs as magnetic sensor elements with anti-parallel sensitivity directions (see WO 2004/109725 A1), which means that all the magnetic sensor elements on the microchip have the same sensitivity direction. If you can have it, it will be much easier. Different effects of the signal of interest (i.e. of the response field) can be achieved in the proposed magnetic sensor device in spite of equal direction of sensitivity due to the application of different excitation fields.

  In a preferred embodiment of the invention, the control unit supplies equal and opposite currents to the first and second magnetic field generators, respectively. Assuming that the magnetic field generator is a parallel conductor wire on the microchip, the current in the opposite direction generates an excitation magnetic field with an opposite direction of rotation, which results in an opposite direction in the magnetized particle. Induction of the response magnetic field. The intersection angles between these response magnetic fields and the first and second sensitivity directions are therefore 180 ° different, respectively, and the output signal of the first magnetic sensor element and the output of the second magnetic sensor element The largest difference between the signals is produced.

  The magnetic sensor device can have (typically have) more than one pair of first and second detection units. In a preferred embodiment of such a magnetic sensor device having a plurality of pairs of first and second detection units, the magnetic sensor elements of the plurality (optionally all) of the detection units are connected to a common line, for example ground. Connected. In this way, the number of wires can be greatly reduced.

  In another important embodiment of the invention, the magnetic sensor device comprises a second pair of first and second detection units, the magnetic sensor elements of all four detection units being as Wheatstone bridges. Connected. If the magnetic sensor element is realized by a (magnetic) resistance, the Wheatstone bridge allows a very sensitive detection of the resistance change while at the same time suppressing disturbances such as temperature drift.

  In another development of the previous embodiment, the sensitivity directions of all magnetic sensor elements of the Wheatstone bridge are parallel to each other and equal. As already mentioned above, this allows the simplest production without additional production steps.

  In another development of the Wheatstone bridge embodiment, the angle of intersection (as defined above between the response field and the sensitivity direction) of two magnetic sensor elements connected in series differs by about 180 °. . The response magnetic field acting on these magnetic sensor elements thus has the opposite effect, eg increasing one resistance and decreasing the resistance of the other magnetic sensor element. The voltage between the magnetic sensor elements is therefore shifted in the same direction by both elements. Preferably, the proposed design is realized-with opposite signs-on both branches of the Wheatstone bridge. The drop voltage at the node between the two magnetic sensor elements of the first branch in this case is accompanied by a rise voltage at the node between the magnetic sensor elements of the other branch, and vice versa, and vice versa. Produces the maximum voltage difference between.

  The invention further relates to the use of the microelectronic magnetic sensor device described above for molecular diagnostics, biological sample analysis, and / or chemical sample analysis, in particular for the detection of small molecules. Molecular diagnostics can be achieved, for example, with the aid of magnetic beads attached directly or indirectly to the target molecule.

  These and other aspects of the invention are apparent from and will be elucidated with reference to the embodiments described hereinafter. These embodiments are described by way of example with the help of the accompanying drawings.

1 schematically shows a first and a second detection unit of a magnetic sensor device according to the invention. The crossing angle between the response magnetic field and the sensitivity direction of the magnetic sensor element is shown. Figure 2 schematically shows two pairs of first and second detection units connected as a full Wheatstone bridge. 1 schematically shows one pair of first and second detection units connected as a half-Wheatstone bridge. 5 shows a variation of the embodiment of FIG. 4 in which two half-Wheatstone bridges are coupled to a common line.

  Like reference numbers indicate identical or similar components in the figures.

  FIG. 1 shows a microelectronic magnetic sensor device 100 according to the invention in a specific application as a biosensor for the detection of magnetically interacting particles, for example superparamagnetic beads 1, in an investigation area (sample chamber 2). Magnetoresistive biochips or biosensors have promising properties for biomolecular diagnostics with respect to sensitivity, specificity, integration, ease of use and cost. Examples of such biochips are described in WO2003 / 054546, WO2003 / 054533, WO2005 / 010542A2, WO2005 / 010543A1, and WO2005 / 038911A1, which are incorporated herein by reference.

  A biosensor typically consists of an array of magnetic sensor devices 100 of the type shown in FIG. 1 (eg 100), and thus a large number of different target molecules (eg proteins) in solution (eg blood or saliva). , DNA, amino acids, drugs of abuse) can be measured simultaneously. In one possible example of a binding scheme, the so-called “sandwich assay”, this is achieved by providing a first antibody to which the target molecule can bind to the binding surface 3. The superparamagnetic beads 1 with the second antibody can in this case be attached to the bound target molecule. For simplicity, only beads 1 are shown in the figure.

FIG. 1 further shows a “first detection unit” P and a “second detection unit” S of substantially the same design and realized on the substrate under the surface 3. The detection units P and S respectively include first and second excitation wires 11 and 21 (which function as magnetic field generators) and first and second GMR elements 12 and 22 (which function as magnetic sensor elements). Have each. The currents flowing through the excitation wires 11 and 21 generate a first excitation magnetic field B ₁₁ and a second excitation magnetic field B ₂₁ , respectively, which magnetize the superparamagnetic beads 1. The first and second response magnetic fields B ₁₁ ′, B ₂₁ ′ from the superparamagnetic beads 1 eventually incorporate in-plane magnetization components of GMRs 12 and 22, respectively, which results in a measurable resistance change. To do.

  The first GMR element 21 and the second GMR element 22 are coupled to sense a signal difference Δ (typically the difference in voltage drop across the GMR element when equal sensing currents are applied). Connected to the evaluation and control unit 40.

The evaluation / control unit 40 is further connected to parallel excitation wires 11 and 21 that supply the excitation current. These excitation currents have the same intensity and are directed in the opposite direction so that the generated excitation magnetic fields B ₁₁ and B ₁₂ have opposite rotation directions. As a result, the induced response magnetic fields B ₁₁ ′ and B ₂₁ ′ also have opposite directions of rotation. This is because, in the example shown, the intersection angle α ₁ between the first response magnetic field B ₁₁ ′ and the first sensitivity direction D ₂₁ is 180 °, and the second response magnetic field B ₂₁ ′ and the second response magnetic field B ₂₁ ′ The intersection angle α ₂ with the sensitivity direction D ₂₂ means 0 °. While the resistance of the first GMR element 21 is decreased, the resistance of the second GMR element 22 is correspondingly increased and the opposite effect is summed to the output difference Δ.

FIG. 2 contains the main sketches for the general case for the first and second sensitivity directions D ₁₂ and D ₂₂ and the associated first and second response magnetic fields B ₁₁ ′ and B ₂₁ ′. The sensitivity directions are parallel and equally oriented in the example of FIG. 1, but the sensitivity directions can generally have any spatial orientation. The intersection angle between the sensitivity direction and the associated response magnetic field, for example the intersection angle α ₁ between the first sensitivity direction D ₁₂ and the first response magnetic field B ₁₁ ′, is in this case defined as the angle between the associated vectors. Is done.

Here, the first intersection angle α ₁ and the second intersection angle (see FIG. ₁₎ can be observed so that the difference between the effects of the first and second response magnetic fields in the first and second GMR elements can be observed. 2 α ₂ ) are preferably different. This condition is satisfied for many configurations except for the two directions of the second response field B ₂₁ ′ indicated by the dotted lines in the figure, which directions are the same angle of intersection α ₂ as the first detection unit. = since they produce α ₁ "is prohibited".

The maximum spread of the signals generated by the first and second GMR elements is the difference | α ₁ −α ₂ | between the first and second intersection angles in the case of the configuration of FIG. This is achieved when a maximum value of 180 ° is assumed. Such optimization can be achieved with both (i) a parallel sensitivity direction and an antiparallel response field (FIG. 1) and (ii) both an antiparallel sensitivity direction and a parallel response field. The latter option is not preferred, however, because it is difficult to manufacture. Furthermore, the anti-parallel sensitivity direction cancels out the measurement signal in the configuration of FIG. 1, whereas the external magnetic field, which is approximately uniform in the region of the first and second detection units P, S, It has the disadvantage of inducing a measurement signal that is summed with the output difference.

  FIG. 3 shows a layout of a preferred magnetic sensor device 200 according to the invention in which two first detection units P, P ′ and two second detection units S, S ′ are configured as a full Wheatstone bridge. More precisely, the associated GMR elements 12, 22, 32 and 42 are connected as a full Wheatstone bridge. Evaluation / control unit 40 can generate a voltage difference between terminals A and B to provide a bias current through GMR elements 12, 22, 32, 42. The differential sensor output signal Δ between terminals C and D is then obtained later and further processed by a differential amplifier in the evaluation / control unit 40. The sensor output signal Δ can be a differential voltage or a current.

  Excitation wires 11, 21, 31, and 41 are shown adjacent to the corresponding GMR elements. The evaluation / control unit 40 can also provide excitation currents through the excitation wires 11, 21, 31 and 41, and the corresponding connections are not fully drawn for simplicity. Furthermore, although only one excitation wire is shown, there may generally be more than one in each detection unit.

  The current is located either when the local response field (from the magnetic particles) is parallel (in the case of GMRs 12 and 42) to the associated GMR pinning layer or anti-parallel (GMR 22, 32). Excitation wires 11, 21, 31, and 41 are passed through to be matched.

The advantages of the magnetic sensor device shown are
The device is insensitive to common mode magnetic interference;
The DC operating point of the device is insensitive to temperature changes of the GMR elements 12, 22, 32, 42;
-Temperature change, noise, spread of voltage difference between terminals A and B, etc. appear as common mode signal across C and D terminals, due to common mode rejection of said differential amplifier in evaluation / control unit 40 Being suppressed,
-Common mode capacitive and inductive crosstalk from the excitation wire to the bridge is also suppressed by the differential amplifier;
Have

  FIG. 4 shows, as a modification of the previous embodiment, a magnetic sensor device 300 in which the half Wheatstone bridge is realized by one pair of first and second detection units P and S. The evaluation / control unit 40 again supplies the excitation current to the excitation wires 11 and 21. In addition, it supplies a bias current through the GMR elements 12, 22 via terminals A and B on the one hand and terminal C on the other hand. A differential output signal Δ is obtained at terminals A and B. This can be a differential voltage or current.

  An additional advantage of this embodiment is that fewer sensor elements and wiring are required than a full Wheatstone bridge.

  FIG. 5 shows a magnetic sensor device 400 having a half Wheatstone bridge with fewer wires as a variation of the previous embodiment. Compared to FIG. 4, two half-Wheatstone bridges (possibly among many) are provided, all of which use a common node C, eg a substrate (ground). In this way, multiple sensor units share the same terminal C, which leads to fewer wires for the evaluation / control unit 40.

  It has already been described that the described embodiment has the advantage that the sensitivity direction of all GMR elements can be the same. After microfabrication of the sensor device, the pinned layers of all GMR elements have the same orientation. Thus, an additional post-processing step is required if a portion of the pinned layer of the two GMR elements is to be flipped (eg, the layer of GMR elements 22 and 32 of the Wheatstone bridge of FIG. 3). The technique to achieve such a flip involves the application and heating of a hard magnetic “stamp” close to the sensor surface to locally reprogram the direction of the pinned layer (replicated from the stamp). . Another technique is based on the controlled application of current pulses through the GMR element for local heating with simultaneous application of an external magnetic field (see WO 2004/109725 A1). Both technologies require additional steps in the manufacturing process that involve either high current and associated high voltage application or precise mechanical alignment, which can greatly exceed the breakdown voltage of standard CMOS processes, for example. And Furthermore, reprogramming of the pinned layer orientation can result in the creation of additional magnetic domains and can be a cause for sensor instability (Barkhausen noise, baseline popping noise).

  The above embodiments with flipped sensitivity directions of (neighboring) GMR elements are within the scope of the present invention, but without additional processing steps and without exposing the sensor to high temperatures and large magnetic fields. It is preferable to provide a means for manufacturing. The embodiments of the invention described above have particular advantages in providing such means. The embodiment is based on the proposal to reverse the direction of the excitation field in the sensor segment rather than reversing the orientation of the pinned layer. This can be achieved, for example, by reversing the excitation current and has the effect that the associated GMR element shows an opposite response to the magnetic particles. Thus, full differential sensor operation can be established.

  Finally, in this application, the term “having” does not exclude other elements or steps, “one” does not exclude a plurality, and a single processor or other unit fulfills the functions of multiple means It is pointed out that it can. The present invention exists in every and every novel characteristic feature and every and every combination of characteristic features. Furthermore, reference signs in the claims shall not be construed as limiting the scope of the claims.

Claims (13)

In the magnetic sensor device for detection of magnetized particles in the investigation area,
a) a first detection unit and a second detection unit,
a1) Magnetic sensor element having a sensitivity direction,
a2) a magnetic field generator for generating an excitation magnetic field in the investigation region capable of exciting a response magnetic field of the magnetized particles, wherein the response magnetic field is in a sensitivity direction of the magnetic sensor element in the related magnetic sensor element; The magnetic field generator having an angle of intersection with
The first detection unit and the second detection unit having:
b) a control unit for controlling the magnetic field generators of the first detection unit and the second detection unit so that the related intersection angles are different from each other;
c) an evaluation unit for sensing a difference between output signals of the magnetic sensor elements of the first detection unit and the second detection unit;
A magnetic sensor device.   The magnetic sensor device according to claim 1, wherein the first detection unit and the second detection unit have the same design.   The magnetic sensor device according to claim 1, wherein the magnetic field generator is arranged such that the excitation magnetic field is dominant in different parts of the investigation region.   The magnetic sensor device according to claim 1, wherein the magnetic sensor element is arranged to be predominantly reached by the response magnetic field of the associated detection unit.   The magnetic sensor device according to claim 1, wherein at least one of the magnetic field generators has at least one conductor wire.   The magnetic sensor device according to claim 1, wherein at least one of the magnetic sensor elements includes a magnetoresistive element such as a Hall sensor or GMR, an AMR element, or a TMR element.   The magnetic sensor device according to claim 1, wherein the sensitivity directions of the detection units are parallel and have equal directions.   The magnetic sensor device of claim 1, wherein the control circuit supplies an opposite direction current of equal strength to the magnetic field generator.   2. The magnetic sensor device according to claim 1, wherein the magnetic sensor device has a plurality of pairs of a first detection unit and a second detection unit, and the magnetic sensor elements of the detection unit are connected to a common line. Magnetic sensor device.   The magnetic sensor device has a second pair of a first detection unit and a second detection unit, and the magnetic sensor elements of four detection units are connected as a Wheatstone bridge, The magnetic sensor device according to claim 1.   The magnetic sensor device according to claim 10, wherein sensitivity directions of all the magnetic sensor elements are parallel to each other and are equal to each other.   The magnetic sensor device according to claim 10, wherein an intersection angle of the magnetic sensor elements connected in series is different by about 180 °.   Use of the magnetic sensor device according to claim 1 for molecular diagnostics, biological sample analysis and / or chemical sample analysis, in particular for the detection of small molecules.

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