MAGNETIC SENSOR DEVICE WITH PAIRS OF DETECTION UNITS
The invention relates to a magnetic sensor device for the detection of magnetized particles which comprises pairs of detection units with a magnetic field generator and a magnetic sensor element. Moreover, it relates to the use of such a magnetic sensor device.
From the WO 2005/010543 Al and WO 2005/010542 A2 a magnetic sensor device is known which may for example be used in a microfluidic biosensor for the detection of target molecules, e.g. biological molecules, labeled with magnetic beads. The microsensor device is provided with an array of detection units comprising wires for the generation of a magnetic excitation field and Giant Magneto Resistances (GMR) for the detection of magnetic reaction fields generated by magnetized, immobilized beads. The signal (resistance change) of the GMRs is then indicative of the number of the beads near the sensor. When extremely low concentrations of target molecules shall be measured and/or when the measurement time shall be minimized, it is crucial for magnetic sensor devices of the aforementioned kind to maximize the signal-to-noise ratio. This is however a difficult task in view of many different sources of interferences, for example supply noise, temperature drift, common-mode interference, cross-talk and the like.
Based on this situation it was an object of the present invention to provide means for a more accurate detection of magnetized particles in an investigation region, wherein it is desirable that associated magnetic sensor devices can be manufactured without complicated production steps.
This object is achieved by a magnetic sensor device according to claim 1 and a use according to claim 13. Preferred embodiments are disclosed in the dependent claims.
A magnetic sensor device according to the present invention shall primarily (but not exclusively) serve for the detection of magnetized particles in an investigation region, for example for the detection of magnetic beads attached as labels to target molecules in a sample fluid that is provided in a sample chamber. The magnetic sensor device comprises the following components: a) A "primary detection unit" and a "secondary detection unit", wherein the terms "primary" and "secondary" are just chosen to distinguish these units and shall not imply that there must be any difference or hierarchy between them. Each of the primary and secondary detection units comprises the following components: al) A "magnetic sensor element" with a sensitive direction. In this context it is first noted that the following terms and definitions will be applied throughout this text in order to describe the spatial relationship between geometrical objects:
A (geometrical) "line" extends straightly, either infinitely in one or two directions or not, and has no particular orientation. - A "direction" is a line that has an orientation, i.e. a sense in which it runs from a starting point to an end point (wherein these points may lie in the infinity). A direction can mathematically be described as a vector. Usually, a direction has a finite extension and is visualized as an arrow.
Two lines or directions are called "parallel" if they have everywhere the same distance from each other.
Two directions are called "equally oriented'V'oppositely oriented" if they have the same/opposite orientations, or, more strictly, if the associated vectors a, b have a positive/negative scalar product a-b. Oppositely oriented, parallel directions are sometimes also called "anti- parallel".
The "sensitive direction" of the magnetic sensor element then means that the sensor element is most (or only) sensitive with respect to components of a magnetic field vector that are parallel to said spatial direction. Moreover, it makes a difference if these components are equally oriented or oppositely oriented with respect to the sensitive direction. Usually, the magnetic sensor element has only one single sensitive direction and is substantially insensitive to components of a magnetic field perpendicular to this direction. a2) A "magnetic field generator" for generating a "magnetic excitation field" in (at least a part of) the investigation region, wherein said magnetic excitation field can excite a "magnetic reaction field" of magnetized particles if such particles are present in the investigation region. Furthermore, said magnetic reaction field of the magnetized particles shall have an "intersection angle", which is by definition the angle between the vector of the reaction field and the sensitive direction of the associated magnetic sensor element at the location of this associated magnetic sensor element. In most cases, the magnetic reaction field is parallel (and equally oriented) or anti-parallel to the sensitive direction of the associated magnetic sensor element, meaning that the intersection angle is 0° or 180°, respectively. In general, the intersection angle may however assume any value between 0 and 180°.
Strictly speaking, the orientation of the magnetic reaction field will not only depend on the applied magnetic excitation field but also on the actual distribution of magnetized particles. For a unique definition of the intersection angle, "the magnetic reaction field" will therefore in the context of the present invention always refer to a predetermined representative orientation, for example to the mean orientation of all practically possible magnetic reaction fields.
Moreover, the above defined components xyz of the detection units (magnetic sensor element, sensitive direction, magnetic field generator, magnetic excitation field, magnetic reaction field, intersection angle) will in the following sometimes be referred to as of the "primary component
xyz" or as the "secondary component xyz" dependent on their membership to the primary or secondary detection unit, respectively. "Primary magnetic sensor element" will thus for example be a short notation for the "magnetic sensor element of the primary detection unit". b) A control unit for controlling the magnetic field generators of the primary and the secondary detection unit in such a way that the associated intersection angles (as defined above) are different from each other. c) An evaluation unit for sensing the difference of the output signals of the magnetic sensor elements of the primary and of the secondary detection unit. The evaluation unit and the control unit may be implemented as a circuitry on the same microelectronic chip as the detection units, or they may be realized (at least in part) externally from this chip. The described magnetic sensor device achieves a high signal-to-noise ratio as the evaluation unit senses the difference between two measurement signals, which implies that disturbances which affect both magnetic sensor elements similarly (e.g. supply noise, temperature drift, common-mode interference, cross-talk) will mutually cancel. A cancellation of the desired measurement signal, i.e. the magnitude of the magnetic reaction fields excited in the magnetized particles, is however prevented. This is due to the fact that, according to feature a2), the excited reaction fields have different intersection angles in the primary and the secondary magnetic sensor element and will therefore yield different measurements.
According to a preferred embodiment of the invention, the primary and the secondary detection unit have substantially the same design (i.e. they comprise the same materials/components with the same dimensions and relative arrangement). Such an identical construction guarantees that disturbances will affect both detection units similarly and will therefore (almost) exactly cancel in the difference of the output signals.
In general, the primary and the secondary magnetic excitation field may more or less overlap in the investigation region. In a preferred embodiment, the primary and secondary magnetic field generators are however arranged in such a way that their
magnetic excitation fields are predominant in different parts of the investigation region (i.e. they contribute to at least 70% of the field strength in said part). Most preferably, their magnetic excitation fields have substantially no overlap, which minimizes the related cross-talk between the primary and the secondary detection unit. In the general case there may also be an overlap between the primary and the secondary magnetic reaction fields (generated by the magnetized particles) at the location of the primary and/or the secondary magnetic sensor element. It is however preferred that the primary and secondary magnetic sensor elements are predominantly reached only by the primary or secondary magnetic reaction field, respectively. Ideally, the primary magnetic reaction field will reach only the associated primary magnetic sensor element, and the secondary magnetic reaction field will reach only the associated secondary magnetic sensor element. In this case the magnetic cross-talk between the primary and the secondary detection unit can considerably be reduced. A minimization of the cross-talk is of course reached in a combination with the aforementioned embodiment, i.e. if also the primary and the secondary magnetic excitation fields do not overlap.
The (primary and/or secondary) magnetic field generator may for example be realized by at least one conductor wire. In typical embodiments, it will be realized by a pair of two parallel extending wires. The (primary and/or secondary) magnetic sensor element may particularly comprise a Hall sensor, wherein the sensitive direction of this sensor is determined by the direction of current flow through it. Two identical, parallel Hall sensors will for example produce signals of opposite polarity if anti-parallel currents are conducted through them. The (primary and/or secondary) magnetic sensor element may also comprise a magneto- resistive element like a GMR (Giant Magneto Resistance), a TMR (Tunnel Magneto Resistance), or an AMR (Anisotropic Magneto Resistance) element, wherein the sensitive direction of a GMR element is for example determined by its pinned layer. Moreover, the magnetic field generator and the magnetic sensor element may be realized as an integrated circuit, for example using CMOS technology together with additional steps for realizing the magneto -resistive components on top of a CMOS circuit. Said
integrated circuit may optionally also comprise the control unit and/or the evaluation unit of the magnetic sensor device.
While the primary and the secondary sensitive direction may in general be arbitrarily positioned in space, it is preferred that they are parallel and equally oriented. Though it is in principle known to produce neighboring GMRs as magnetic sensor elements that have anti-parallel sensitive directions (cf. WO 2004/109725 Al), it is much easier if the magnetic sensor elements on a microchip may all have the same sensitive direction. Different effects of the signals of interest (i.e. of the magnetic reaction fields) can in the proposed magnetic sensor device be achieved in spite of equally oriented sensitive directions by the application of different magnetic excitation fields.
In a preferred embodiment of the invention, the control unit is adapted to supply oppositely directed currents of equal magnitude to the primary and the secondary magnetic field generator, respectively. Assuming that the magnetic field generators are parallel conductor wires on a microchip, the oppositely directed currents will then generate magnetic excitation fields with opposite senses of rotation, which will consequently induce oppositely oriented magnetic reaction fields in the magnetized particles. The intersection angles between these reaction fields and the primary and the secondary sensitive direction, respectively, will therefore differ by 180°, yielding a maximal difference between the output signals of the primary and the secondary magnetic sensor element.
The magnetic sensor device may (and typically will) comprise more than just one pair of primary and secondary detection units. In a preferred embodiment of such a magnetic sensor device with a plurality of pairs of primary and secondary detection units, the magnetic sensor elements of several (optionally of all) detection units are connected to a common line, for example to ground. In this way the number of interconnections can be reduced significantly.
In another important embodiment of the invention, the magnetic sensor device comprises a second pair of a primary and a secondary detection unit, wherein the magnetic sensor elements of all four detection units are connected as a Wheatstone bridge. In case the magnetic sensor elements are realized by (magneto-) resistances, the
Wheatstone bridge allows a very sensitive detection of any resistance changes while disturbances like temperature drifts are optimally suppressed.
In a further development of the aforementioned embodiment, the sensitive directions of all magnetic sensor elements of the Wheatstone bridge are parallel to each other and equally oriented. As was already mentioned above, this allows for the simplest manufacturing without additional production steps.
In another further development of the Wheatstone-bridge embodiment, the intersection angles (between magnetic reaction field and sensitive direction, as defined above) of two magnetic sensor elements that are connected in series differ by about 180°. The magnetic reaction fields acting on these magnetic sensor elements will therefore have opposite effects, e.g. increase the resistance of the one and reduce the resistance of the other magnetic sensor element. The voltage between the magnetic sensor elements will therefore be shifted in the same direction by both elements.
Preferably, the proposed design is realized - with opposite sign - in both branches of the Wheatstone bridge. A falling voltage at a node between the two magnetic sensor elements of a first branch will then be accompanied by a rising voltage at a node between the magnetic sensor elements of the other branch and vice versa, yielding a maximal voltage difference between these two nodes.
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, particularly the detection of small molecules. 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 shows schematically a primary and a secondary detection unit of the magnetic sensor device according to the present invention;
Figure 2 illustrates the intersection angle between magnetic reaction fields and the sensitive directions of magnetic sensor elements; Figure 3 shows schematically two pairs of primary and secondary detection units connected as a Full Wheatstone bridge; Figure 4 shows schematically one pair of primary and secondary detection units connected as a Half Wheatstone bridge;
Figure 5 shows a variant of the embodiment of Figure 4, in which two Half Wheatstone bridges are coupled to a common line.
Like reference numbers refer in the Figures 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 magnetically interactive particles, e.g. superparamagnetic beads 1 in an investigation region (sample chamber 2). 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 3 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.
Figure 1 further shows a "primary detection unit" P and a "secondary detection unit" S which are substantially of identical design and realized in a substrate below the surface 3. The detection units P and S each comprise primary and secondary
excitation wires 11 and 21 (serving as magnetic field generators) and primary and secondary GMR elements 12 and 22 (serving as magnetic sensor elements), respectively. A current flowing in the excitation wires 11 and 21 will generate a primary magnetic excitation field Bn and a secondary magnetic excitation field B21, respectively, which in turn magnetize the superparamagnetic beads 1. The primary and secondary magnetic reaction fields B'π, B'2i from the superparamagnetic beads 1 will finally introduce an in- plane magnetization component in the GMRs 12 and 22, respectively, which results in a measurable resistance change.
The primary GMR element 21 and the secondary GMR element 22 are connected to a combined evaluation and control unit 40 which senses the signal difference Δ (typically a difference in the voltage drop across the GMR elements when equal sensing currents are applied to them).
The evaluation/control unit 40 is further connected to the parallel excitation wires 11 and 21 for supplying them with excitation currents. These excitation currents have the same magnitude and are oppositely directed (i.e. "anti-parallel") such that the generated magnetic excitation fields Bn and Bi2 have opposite senses of rotation. As a consequence, the induced magnetic reaction fields B'π and B'i2 have opposite senses of rotation, too. This implies in the shown example that the intersection angle CCi between the primary magnetic reaction field B'π and the primary sensitive direction D2i is 180°, while the intersection angle CC2 between the secondary magnetic reaction field B'i2 and the secondary sensitive direction D22 is 0°. While the resistance of the primary GMR element 21 is decreased, the resistance of the secondary GMR element 22 increases correspondingly, wherein these opposite effects sum up in the output difference Δ. Figure 2 contains a principal sketch regarding the general case with respect to the primary and secondary sensitive directions Di2 and D22 and the associated primary and secondary magnetic reaction fields B'π and B'2i. While the sensitive directions were parallel and equally oriented in that example of Figure 1, they may in general have any spatial orientation. The intersection angle between a sensitive direction and an associated magnetic reaction field, for example the intersection angle CCi between
the primary sensitive direction Di2 and the primary magnetic reaction field B'π, is then defined as the angle between the associated vectors.
To be able to observe a difference in effects of the primary and the secondary magnetic reaction fields in the primary and secondary GMR element, respectively, it is now demanded that the primary intersection angle CCi and the secondary intersection angle (CC2 in Figure 2) are different. This condition is fulfilled for many configurations with the exception of the two directions of the secondary magnetic reaction field B'2i that are indicated by dotted lines in the Figure; these directions are "forbidden" as they would yield the same intersection angle CC2 = CCi as in the primary detection unit.
A maximal spread of the signals generated by the primary and the secondary GMR elements is achieved if the difference between the primary and secondary intersection angles, |θCi-CC2|, assumes the maximal value of 180°, as was the case in the arrangement of Figure 1. Such an optimization can be achieved both by (i) parallel sensitive directions and anti-parallel magnetic reaction fields (Figure 1) as well as by (ii) anti-parallel sensitive directions and parallel magnetic reaction fields. The latter option is however unfavorable as it is difficult to produce. Moreover, anti-parallel sensitive directions have the disadvantage that an external magnetic field which is approximately homogeneous in the region of the primary and the secondary detection units P, S induces measurement signals that sum up in the output difference, while they would cancel in the arrangement of Figure 1.
Figure 3 shows the layout of a preferred magnetic sensor device 200 according to the invention, in which two primary detection units P, P' and two secondary detection units S, S' are arranged as a Full Wheatstone bridge. More precisely, the associated GMR elements 12, 22, 32 and 42 are connected as a full Wheatstone bridge. The evaluation/control unit 40 may generate a voltage difference between the terminals A and B in order to provide a bias current through the GMR elements 12, 22, 32, 42. The differential sensor output signal Δ between the terminals C and D is then subsequently picked up, and further processed, by a differential amplifier in the evaluation/control unit 40. The sensor output signal Δ may be a differential voltage or current.
The excitation wires 11, 21, 31, and 41 are indicated next to the corresponding GMR elements. The evaluation/control unit 40 may also provide the excitation currents through the excitation wires 11, 21, 31, and 41, wherein the corresponding connections are not completely drawn for simplicity. Moreover, only one excitation wire is shown, while in general there might be more than one in each detection unit.
An electric current is passed through the excitation wires 11, 21, 31, and 41 in such a way that the local magnetic reaction fields (originating from the magnetic particles) is aligned either parallel to the pinned layer of the associated GMRs (this is the case for GMRs 12 and 42) or anti-parallel (GMRs 22, 32).
Advantages of the shown magnetic sensor device comprise:
The device is insensitive to common-mode magnetic interference. The DC operating point of the device is insensitive to temperature variations of the GMR elements 12, 22, 32, 42. - Temperature variations, noise, spreading, etc. of the voltage difference between terminals A and B appear as common-mode signals across the C and D terminals, and are suppressed by the common-mode rejection of the differential amplifier inside the evaluation/control unit 40.
The common-mode capacitive and inductive cross-talk from the excitation wires to the bridge is also suppressed by the differential amplifier.
Figure 4 shows as a modification of the previous embodiment a magnetic sensor device 300, in which only a Half Wheatstone bridge is realized by one pair of a primary and a secondary detection unit P and S. The evaluation/control unit 40 again provides excitation currents to the excitation wires 11 and 21. Moreover, it provides bias currents through the GMR elements 12, 22 via terminals A and B on the one hand, and terminal C on the other hand. The differential output signal Δ is obtained at terminals A and B. It may be a differential voltage or current.
An additional advantage of this embodiment is that fewer sensor elements and interconnections are required than for a full Wheatstone bridge. Figure 5 shows as a variant of the previous embodiment a magnetic sensor device 400 comprising Half Wheatstone bridges with fewer interconnects. In
comparison to Figure 4, two (of possibly many) Half Wheatstone bridges are provided which all use a common node C, e.g. substrate (ground). In this way multiple sensor units share the same terminal C, which leads to fewer interconnections to the evaluation/control unit 40. It was already mentioned that the described embodiments have the advantage that the sensitive directions of all GMR elements can be the same. After micro-fabrication of a sensor device, the pinned layers of all GMR elements will have the same orientation. Therefore, an additional post-processing step is required if some of the pinned layers of two GMR elements shall be flipped (e.g. the layers of the GMR elements 22 and 32 in the Wheatstone bridge of Figure 3). Techniques to achieve such a flipping involve the application of hard-magnetic "stamps" closely above the sensor surface and heating it up, in order to reprogram locally the directions of the pinned layers (which are copied from the stamp). Another technique is based on controlled application of current pulses through the GMR elements for local heating, with simultaneous application of an external magnetic field (cf. WO 2004/109725 Al). Both techniques require additional steps in the manufacturing process that involve either precise mechanical alignment, or application of high currents and associated high voltages, which may be far above the breakdown voltage of e.g. a standard CMOS process. Moreover, reprogramming the pinned-layer orientation may cause generation of extra magnetic domains and can be a cause to the sensor instabilities (Barkhausen noise, Baseline Popping Noise).
Though the aforementioned embodiments with flipped sensitive directions of (neighboring) GMR elements belong to the scope of the present invention, it is preferred to provide means for manufacturing a differential sensor without extra processing steps and without exposing the sensor to high temperatures and large magnetic fields. The embodiments of the present invention that were described above have the particular advantage to provide such means. They are based on the proposal to reverse the direction of the magnetic excitation fields in the sensor segments, rather than reversing the pinned-layer orientation. This may be achieved by e.g. reversal of the excitation currents, which has the effect that the associated GMR elements show the
opposite response to the magnetic particles. Hence, a full-differential sensor operation can be established.
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.