The invention relates to a magnetic sensor device comprising at least one magnetic field generator and at least one associated magnetic sensor element. Moreover, it comprises the use of such a magnetic sensor device and a method for the detection of magnetic particles in an investigation region.
From the WO 2005/010543 A1 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 biological molecules labeled with magnetic beads. The microsensor device is provided with an array of sensors comprising excitation wires for the generation of a magnetic excitation field and Giant Magneto Resistances (GMRs) for the detection of reaction fields generated by magnetized beads. The signal of the GMRs is then indicative of the number of the beads near the sensor. A problem of such magnetic sensor devices is that the GMR is subjected to the relatively strong magnetic excitation field and to other interference fields, which may lead to a corruption of the desired signal. It is therefore inter alia proposed in the WO 2005/010503 A1 to drive a wire near the GMR sensor with the sum of a sinusoidal current and an adaptive current, wherein the adaptive current just compensates reaction fields generated by beads which have been magnetized by a static external magnetic excitation field.
Based on this situation it was an object of the present invention to provide means that allow measurements with a magnetic sensor device that are robust against interferences by magnetic fields from different sources.
This object is achieved by a magnetic sensor device according to claim 1, a method according to claim 16, and a use according to claim 18. Preferred embodiments are disclosed in the dependent claims.
The magnetic sensor device according to the present invention serves for the detection of magnetized particles in an investigation region, e.g. magnetic beads in the sample chamber of a microfluidic device, and comprises the following components:
In a magnetic sensor element of the kind described above, the magnetic fields are (approximately) zero in its sensitive direction during a measurement. This has the advantage that interferences, particularly noise due to the Barkhausen effect, can be minimized, thus allowing an improved accuracy of the measurements.
According to a further development, the magnetic sensor device comprises an evaluation unit that is coupled to the magnetic sensor element or to the output of the feedback controller for determining signal components that are caused by the magnetic reaction fields of magnetized particles. Of course the magnetic sensor device can simultaneously comprise two such evaluation units, one coupled to the magnetic sensor element and one to the output of the feedback controller.
In a first important variant of the invention, the predetermined spectral components that are cancelled by the feedback controller comprise the frequencies of those signals that are caused by magnetic reaction fields of magnetized particles in the investigation region. Thus interferences are compensated just for the signals of interest. In this embodiment, the aforementioned evaluation unit would particularly be coupled to the output of the feedback controller because the direct output of the magnetic sensor element vanishes in the frequency range of interest.
In a second important variant of the invention, the predetermined spectral components that are cancelled by the feedback controller do not comprise the frequencies of those signals that are caused by magnetic reaction fields of magnetized particles in the investigation region. The feedback loop therefore does not (directly) change the magnetic signals of interest, and an evaluation unit of the kind mentioned above would typically be coupled directly to the magnetic sensor element. The removal of disturbances at other frequencies than those of interest has indirectly a positive effect on the measurements as for example sensitivity variations of the sensor element are reduced.
The magnetic sensor device may preferably comprise a demodulator between the magnetic sensor element and the feedback controller. Such a demodulator can be used to extract desired spectral components of the measurement signal if not the whole spectrum shall be processed.
The magnetic sensor element may particularly be driven with a nonzero sensing frequency f2. Such a frequency allows to detect influences of the driving operation in the sensor signal and to position signal components one is interested in optimally with respect to noise in the signal spectrum.
In a preferred design of the magnetic sensor device, the gain of the control loop which comprises (at least) the magnetic sensor element, the feedback controller, and the magnetic field compensator is (with its absolute value) larger than 10, preferably larger than 100. As will be explained with reference to the Figures, the influence of the magnetic sensor element can be minimized in this case, thus making the measurements robust against (gain) variations of said element.
In many cases, a linear design of the feedback controller will be sufficient to achieve a satisfactory control behavior at least at a given operating point. In a further development of the invention, the feedback controller comprises a nonlinearity-module that compensates non-linear behavior of the magnetic sensor element, the magnetic field generator and/or the magnetic field compensator. Known nonlinearities can then be taken into account, thus improving accuracy of the feedback controller and extending its operating range.
In the aforementioned embodiment, the nonlinearity-module preferably comprises a characteristic curve that depends only on the geometry of the sensor device. Such a curve can for example be determined once by theoretical considerations or by calibrations for a production series of identical sensor designs.
The magnetic field compensator has to be arranged such that its desired effects in the magnetic sensor element can optimally be achieved while disturbing other components of the device as little as possible. The compensator is therefore typically disposed in the vicinity of the magnetic sensor element, e.g. not farther away from it than about 10-times the maximal diameter of the magnetic sensor element. Moreover, it is preferably disposed in a mirrored position with respect to the magnetic field generator.
The magnetic field compensator may be a hardware component of its own, e.g. a separate conductor wire. One and the same electronic hardware component may however also function as the magnetic field compensator on the one hand side and as the magnetic field generator or the magnetic sensor element on the other hand side. In this case it depends on the mode of operation of said component if a magnetic compensation field is generated, a magnetic excitation field is generated, or a magnetic field is measured. Such a dual use of hardware components is particularly possible if magnetic field compensations and magnetic measurements are made in different parts of the spectrum.
As was already mentioned, the magnetic field generator and/or the magnetic field compensator may especially comprise at least one conductor wire. The magnetic sensor element may particularly be realized by a magneto-resistive element, for example a Giant Magnetic Resistance (GMR), a TMR (Tunnel Magneto Resistance), or an AMR (Anisotropic Magneto Resistance). Moreover, the magnetic field generator, the magnetic field compensator, 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 circuitry. Said integrated circuit may optionally also comprise the control circuits of the magnetic sensor device.
In the aforementioned case, the magnetic sensor device preferably comprises signal processing circuits which are disposed in the vicinity of the magnetic sensor element, e.g. not farther away from it than about 50-times the maximal diameter of the magnetic sensor element. Such a close arrangement between magnetic sensor element and associated processing circuits has the advantage to minimize signal loss and signal disturbances on the connecting leads; it is made possible because crosstalk effects of magnetic fields generated in the processing circuits do not harm as they are compensated by the feedback controller.
The invention further relates to a method for the detection of magnetized particles in an investigation region, for example of a magnetic beads immobilized on a sensor surface, the method comprising 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.
In a preferred embodiment of the method, characteristics of the system behavior are determined by calibration measurements and taken into account during the generation of the magnetic compensation field, wherein the “system” comprises all components that take part in the execution of the method (e.g. magnetic field generators, sensors, etc.). This approach is for example useful when compensating a non-linear relation between the magnetic compensation field and the amount of magnetized particles in the investigation region.
The invention further relates to the use of the magnetic sensor device described above for molecular diagnostics, biological sample analysis, or chemical sample 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:
Like reference numbers in the Figures refer to identical or similar components.
Magneto-resistive biochips have promising properties for bio-molecular diagnostics, in terms of sensitivity, specificity, integration, ease of use, and costs. Examples of such biochips are for example described in WO 2003/054566, WO 2003/054523, WO 2005/010542 A2, WO 2005/010543 A1 or Rife et al. (Sens. Act. A vol. 107, p. 209 (2003)), which are incorporated into the present application by reference.
In magnetic sensor devices of the kind described above, the basic sensor elements (e.g. AMR or GMR) often have a size that encloses more than one magnetic domain and are therefore prone to Barkhausen noise. The Barkhausen effect is a series of sudden changes in the size and orientation of ferromagnetic domains, or microscopic clusters of aligned atomic magnets, that occurs during the magnetization or demagnetization of ferromagnetic materials. As known, (Barkhausen) noise associated with a magnetic structure is directly proportional to the strength of any time-varying magnetic field applied to it.
The problem is now that any magnetic interference originating from e.g. actuation coils 16, mains, PC-monitors, permanent magnets, etc. can cause a shift in the sensor sensitivity sGMR and generate a broadband (Barkhausen) noise spectrum. Since this interference can severely degrade the measurement accuracy and one cannot rely on the probability of the absence of interference, protective measures are highly desirable.
As a solution it is proposed here to include the sensor 12 in a control loop together with at least one “magnetic field compensator” which will adaptively force in-plane magnetic fields in the sensitive layer to zero. The sensor 12 will thus be dynamically shielded from any interference.
In
In a static situation an additional current can further be forced by the feedback controller 50 through the field compensator 15, which will compensate for the magnetic field caused by the internal magnetic crosstalk of the sensing current which drives the GMR sensor 12.
After the magnetic particles 2 are introduced on top of the binding surface 14, the excitation field B1 magnetizes them (together with the compensations field B3). The resulting reaction field B2 coming from said particles 2 can then be compensated for at the location of the GMR sensor 12 by a feedback current in the compensator 15, which is a measure for the amount of the magnetic particles.
An advantage of the shown “vertical” arrangement is that the magnetic particles 2 are very close to the excitation wire 11 and will therefore experience a strong excitation field B1. Moreover, the complete geometry is relatively small in the horizontal direction, thus allowing a better surface-area utilization. Finally, the dynamic range of the required feedback loop can be kept small because a large part of the magnetic fields are already suppressed by the geometry.
The required feedback control of a field compensator 15 will now be explained in more detail with reference to the general system diagram of
According to
The GMR signal Y0 can be processed (as usual) by a first evaluation unit Det_1 to determine the signal components of interest (i.e. the one which is generated by the reaction fields B2). In the feedback approach proposed here, the sensor signal Y0 is fed to a feedback controller 50 with transfer function C(s). The output Y of this controller drives the compensator 15 to generate the compensation field B3, which closes the loop. The output Y of the controller 50 can further be provided to a second evaluation unit Det_2 to determine the signal component of interest.
In a steady-state situation, the feedback loop provides a PSD II that compensates for the magnetic fields at the input of the sensor 12, which results in a close to zero signal indicated by PSD IV. For the sake of simplicity, the thermal noise is neglected here. Finally, PSD V is obtained at the output of the feedback controller 50 and is proportional to the effort that is needed to compensate the magnetic fields at the input of the sensor 12.
In order to suppress the quantization-like effects of the domain-wall movements (Barkhausen), dither may additionally be injected into the control loop to linearize the sensor response, which is a well-known technique in Analog-to-Digital Converters. Obviously, this effect may also be achieved by residual (f1 or f2) field components.
By forcing the magnetic field inside the GMR sensor 12 to zero, the sensor (Barkhausen) noise is drastically reduced. If the magnetic field cancellation is well maintained for all frequencies and at each position in the sensor, this technique can lead to superior measurement accuracy. Furthermore the generation of new domain walls is prevented due to the absence of large magnetic fields.
The reduction of the magnetic field at the input of the sensor 12 is determined by the loop gain, which can be calculated as C(s)·G(s)·D(s). The system transfer H(s) can be made independent of the (unstable) sensor gain G(s) by choosing the controller gain C(s) such that the loop gain C(s)·G(s)·D(s)>>1:
The system transfer H(s) is thus determined only by the process P(s) and the compensator transfer D(s). D(s) is highly stable and depends only on the physical position and magnetic coupling between the sensor and the compensator, which is mechanically fixed for the lifetime of each sensor device. It is important to notice that the compensator transfer D(s) should be made independent of the temperature. If the compensation wire is for example driven by a voltage source, the current (and thus the magnetic field strength) will be dependent on the temperature of the wire (typically with a factor of (1+α·(T−T0))−1). However, the effect of self-heating and alike can be avoided by driving the compensation wire with a current source. Current sources that are temperature independent (or proportional to the absolute temperature) are commonly realized in monolithically integrated circuits.
The aforementioned H(s)-independency of the sensor gain G(s) allows for a static auto-calibration procedure, wherein a calibration point can be (repeatedly) established as follows: Prior to the actual biological measurement the system transfer is measured and used as a zero value. Since the magnitude of the magnetic excitation field X(s)=B1 is fixed, any change in the process transfer P(s) due to the magnetic particles will cause a change in the output signal Y(s), which is exactly what is to be measured.
A further advantage of the system of
As a first extension,
As a particular source of interference, the magnetic crosstalk XT has been introduced, i.e. the magnetic field components BXT of the excitation field B1 that directly affect (with frequency f1) the GMR sensor 12.
On the side of the controller, a demodulator Demod and a modulator Mod have been inserted as optional components before and after the controller 50, respectively. Moreover, optional current sources 28 and 29 have been added. They are controlled by the controller 50 and add current to the excitation current I1 and the sensing current I2, respectively. The function of all aforementioned components will be discussed below in connection with preferred embodiments.
Finally, a leakage branch Lk has been added between the compensation field B3 and the input of the process P(s). In real situations, the magnetic particles 2 are not isolated from the compensation field B3, so that there is some feedback magnetic field “leaking” through the magnetic particles 2 into the sensor 12. It can however been shown that this effect usually has a negligible influence on the total signal (the strength of magnetic fields drops with distance; both the GMR sensor and the beads will therefore experience a declined compensation field; the correspondingly reduced magnetization of the beads generates a reaction field that drops once again on its way to the sensor. The effect of distance drop therefore roughly squares in the reaction fields).
Due to the leakage, the transfer function of the compensation wire, D(s), may become non-linear for large concentrations of magnetic particles. This introduces an error in the measurements, in particular a ‘systematic error’ that can be compensated for. By doing a certain number of experiments, the shape of the non-linear relation between D(s) and the amount of magnetized particles can be predetermined and stored in some system memory. This curve will be the same for all sensors that have the same geometry (within certain production tolerances). Since the influence of this effect is a-priori known, e.g. a micro-controller can be used to compensate for it.
In a first particular embodiment of the invention, the sensor 12 is driven with a DC current (i.e. f2=0), and the complete magnetic field spectrum up to the excitation frequency f1 is compensated (“broadband cancellation”).
If for example a 100-fold reduction at the excitation frequency f1=100 kHz is required, then a closed-loop bandwidth of at least 10 MHz is needed, hence
Additionally, a DC-block can be added in the controller C(s) to remove DC voltage originating from the sensing current I2.
In a second particular embodiment of the invention, the demodulator Demod and the modulator Mod from
Compared to the first embodiment, the required closed-loop bandwidth to reduce amplitude variations at f1 may be significantly lower, namely e.g. 1 kHz instead of 10 MHz. It should be noted that the f1 modulator Mod must be able to cope with a large dynamic range and high accuracy (0.1 per mil).
The demodulated signal is fed in the controller 50 via a capacitor 51 and a resistor 52 to the inverting input of an operational amplifier 54. Said input is coupled via a second capacitor 53 to the output of the amplifier, and the non-inverting input of the amplifier 54 is coupled to ground. The output of the amplifier 54 drives the compensator 15.
The measurement signal of the GMR sensor 12 is further sent in an evaluation unit Det_1 via a high-pass filter (capacitor 23, resistor 24) and a low-noise amplifier 25 to a demodulator 26 of frequency f1±f2, where the signal of interest is extracted. The excitation wire 11 and the GMR sensor 12 are driven by current sources 21, 22 with frequencies f1 and f2, respectively.
If the output of the control loop (i.e. of the amplifier 54) is used to determine the bead signal by an evaluation unit Det_2 (not shown in
The described approach has the strong advantage that the frequencies can be chosen such that the detection signal f1±f2 is beyond the control bandwidth, so that the leakage has no influence. As a result the typical sensor geometry using planar excitation wires may be used. Additionally, a DC blocking means (a zero in the loop filter 50, or an f2 notch filter or bridge structure prior to demodulation) may be added to remove DC originating from f2.
If for example f1=2 MHz, f2=100 kHz, and the closed loop bandwidth BW=10 kHz, then the feedback loop will reduce magnetic fields from 0.1 Hz up to 10 kHz, which is sufficient to reduce actuation fields and power supply interference (50/60 Hz).
Obviously, by applying a DC sensing current (f2=0 Hz), the demodulator 40 and a DC-block in the LF feedback loop of
In the embodiment shown in
The described embodiments can be varied in many ways. In particular, more complex compensation field generating means can be applied to provide appropriate field cancellation at each sensor position (e.g. several actuator segments in a CMOS top-metal layer).
In summary, the invention solves the problem that any magnetic interference originating from e.g. actuation coils, magnetic bead excitation- and stray field (at f1), self-magnetization field from the sense current (at f2), mains, PC-monitors, permanent magnets, CMOS biasing circuits, etc. can cause a shift in the sensor calibration point and generate a broadband (Barkhausen) noise spectrum by including the magnetic sensor element in a control loop together with a (plurality of) field-cancellation actuator(s). Said actuators adaptively force the in-plane magnetic field in the sensitive layer of the sensor element to zero, thus shielding the sensor dynamically from the interference.
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.
Number | Date | Country | Kind |
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06114696.5 | May 2006 | EP | regional |
Filing Document | Filing Date | Country | Kind | 371c Date |
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PCT/IB07/51786 | 5/11/2007 | WO | 00 | 11/24/2008 |