Patent Application
20090278534
The invention relates to a magnetic sensor device for sensing magnetic particles.
The invention further relates to a method of sensing magnetic particles.
Moreover, the invention relates to a program element.
Further, the invention relates to a computer-readable medium.
A biosensor may be a device for the detection of an analyte that combines a biological component with a physicochemical or physical detector component.
Magnetic biosensors may use the Giant Magnetoresistance Effect (GMR) for detecting biological molecules being magnetic or being labeled with magnetic beads.
In the following, biosensors will be explained which may use the Giant Magnetoresistance Effect.
WO 2005/010542 discloses the detection or determination of the presence of magnetic particles using an integrated or on-chip magnetic sensor element. The device may be used for magnetic detection of binding of biological molecules on a micro-array or biochip. Particularly, WO 2005/010542 discloses a magnetic sensor device for determining the presence of at least one magnetic particle and comprises a magnetic sensor element on a substrate, a magnetic field generator for generating an AC magnetic field, a sensor circuit comprising the magnetic sensor element for sensing a magnetic property of the at least one magnetic particle which magnetic property is related to the AC magnetic field, wherein the magnetic field generator is integrated on the substrate and is arranged to operate at a frequency of 100 Hz or above.
WO 2005/010543 discloses a magnetic sensor device comprising a magnetic sensor element on a substrate and at least one magnetic field generator for generating a magnetic field on the substrate, wherein crosstalk suppression means are present for suppressing crosstalk between the magnetic sensor element and the at least one magnetic field generator.
WO 2005/111596 discloses distinguishing a specific binding from a less specific binding between at least one magnetic nanoparticle and a surface of another entity by applying a magnetic field and detecting a physical parameter relating to magnetic nanoparticle rotational or motional freedom while the magnetic nanoparticle is attached to the surface. The sensor combines the detection of magnetic particles or labels and determination of the binding quality and the properties of magnetic particles or labels which are bound to the surface of another entity.
However, the sensitivity of such a sensor may still be insufficient under undesired circumstances.
It is an object of the invention to provide a sensor with a sufficient sensitivity, stability and accuracy.
In order to achieve the object defined above, a magnetic sensor device for sensing magnetic particles, a method of sensing magnetic particles, a program element, and a computer-readable medium according to the independent claims are provided.
According to an exemplary embodiment of the invention, a magnetic sensor device for sensing magnetic particles is provided, the magnetic sensor device comprising a magnetic field generator unit (for instance one or more wires to which an electric current is applied) adapted for generating a plurality of different magnetic field configurations (for instance by applying different electric current sequences to respective ones of the wires) assigned to a plurality of different magnetic excitation states of the magnetic particles (for instance, different electric current sequences applied to respective ones of the wires may magnetically influence a magnetic particle in a different manner, for instance with regard to amplitude and/or direction of the field influencing the magnetic particle), a sensing unit (for instance a GMR sensor) adapted for sensing a plurality of detection signals influenced by the magnetic particles in the different magnetic field configurations, and a combining unit (for instance a microprocessor or a CPU having processing capabilities and being capable of evaluating the individual sensor signals together in accordance with an appropriate calculation scheme) adapted for combining the plurality of signals to thereby derive information indicative of the presence of the magnetic particles (for instance for calculating a realistic gain value as a basis for a sensor result).
According to another exemplary embodiment of the invention, a method of sensing magnetic particles is provided, the method comprising generating a plurality of different magnetic field configurations assigned to a plurality of different magnetic excitation states of the magnetic particles, sensing a plurality of detection signals influenced by the magnetic particles in the different magnetic field configurations, and combining the plurality of signals to thereby derive information indicative of the presence of the magnetic particles.
According to still another exemplary embodiment of the invention, a program element is provided, which, when being executed by a processor, is adapted to control or carry out a method of sensing magnetic particles having the above mentioned features.
According to yet another exemplary embodiment of the invention, a computer-readable medium is provided, in which a computer program is stored which, when being executed by a processor, is adapted to control or carry out a method of sensing magnetic particles having the above mentioned features.
The electronic sensing scheme according to embodiments of the invention can be realized by a computer program, that is by software, or by using one or more special electronic optimization circuits, that is in hardware, or in hybrid form, that is by means of software components and hardware components.
According to an exemplary embodiment, a magnetic (bio)sensor device for sensing magnetic particles using the magnetic properties (for instance beads attached to biological molecules) may be operated in different operation states correlated with different magnetic field configurations (for instance generated by a plurality of wires located at different positions of such a sensor), thereby achieving gain stabilization for the (particularly GMR) sensor by measuring the signal to crosstalk relation. In other words, when detecting detection signals in the different magnetic field configurations, signal conditioning and signal processing may be performed in order to suppress effects which conventionally disturb the accuracy of the sensor.
According to an exemplary embodiment, such a gain stabilization for magnetic biosensors by measuring the signal to crosstalk relation may be obtained by performing magnetic particle imaging. For improving magnetic particle detection, the sensitivity and stability of the magnetic particle sensor may be enhanced. By alternating between multiple excitation states and combining detected signal, an average gain factor can be determined, thus improving accuracy.
Therefore, a magneto-resistive biochip may be provided having improved properties for biomolecular diagnostics in terms of sensitivity, specificity, integration, ease of use, and costs.
Exemplary embodiments of the invention may also suppress variations in the detection electronic, for instance fluctuating sense current, fluctuating excitation current, as everything is determined by the geometry of the sensor. Furthermore, exemplary embodiments of the invention provide a stabilizing method, as it may stabilize the overall detection gain using the situation at t=0 as a reference.
Conventionally, the sensitivity (for instance of a GMR sensor), and therefore the effective gain for the bio-measurement may be sensitive or non-controllable parameters like non-stochastic sensitivity variations due to magnetic instability in the sensor. This error cannot be removed easily by using a reference sensor or bridged structure. Other non-controllable parameters (or parameters which cannot be controlled easily) are externally applied magnetic fields, production tolerances, aging effects, temperature effects, and memory effects (for instance for magnetic actuation fields).
Furthermore, internal compensation techniques for magnetic and capacitive crosstalk may fail when the GMR sensitivity varies.
In the light of these recognitions, exemplary embodiments of the invention intend to stabilize the sensor gain during the actual biological measurement.
According to an exemplary embodiment of the invention, the gain of the sensor is measured during the actual biological measurement by continuously varying the relation between the internal (geometry) dependent magnetic crosstalk and the signal from the beads by switching between magnetic excitation states. Furthermore, it is possible to calculate a gain factor (sGMR) from a combination of the observed sensor signals in said states. Said gain factor may be used in a feedback or in a feedforward (normalize) circuit to stabilize the biosensor detection gain.
For applying such a method, it may be not necessary to have detailed knowledge about the concentration of the beads near the sensor. It may be possible to suppress uncorrelated (for instance sGMR) errors as well as correlated errors like temperature effects. For example, embodiments of the invention may be used on top of approaches of sensor multiplexing suppressing correlated gain factors.
The time between two gain measurements may be fast enough to follow the expected gain variations. Furthermore, the gain measurement time may be preferably short enough to avoid gain fluctuations between the excitation states during a gain measurement.
Alternatively, the excitation states are not applied in a time-multiplex mode (one after each other), but in a frequency multiplex mode. Then, the excitation states are measured simultaneously by using different excitation frequencies for each state. As a result, gain variations during the measurement affecting the result wrongly may be securely avoided because gain varies equally for each state, resulting in the average gain during the measurement time. This embodiment may have the advantage that the measuring time may be longer, which may increase the signal-to-noise ratio obtainable with this method.
Embodiments of the invention may be applied for a biosensor based on integrated excitation of super paramagnetic nanoparticles, but also the application in other magneto-resistive sensors like AMR or TMR is possible. Furthermore, embodiments can be applied to an external excitation method. Such an external excitation method is based on the application of a magnetic field externally to a substrate in which a sensor is integrated. However, it is also possible that sensor and the magnetic field generator unit are both integrated in and/or on a substrate.
For example, sGMR may be measured in the same frequency range as the bead excitation. This is because of reasons of signal-to-noise ratio (to reduce the influence of 1/f noise, small current, small voltage) and to be consistent to the bead measurement.
Furthermore, exemplary embodiments of the invention may be applied to other magneto resistive sensor configurations, for instance to configurations with sensors having Wheatstone bridges or half-Wheatstone bridges, or to other amplifier and sensor current elements than explicitly described herein.
Beyond this, embodiments of the invention are applicable to any biochemical- or small molecule measurements in blood, saliva and other body fluids or fluids extracted from body tissue or for instance faeces.
Moreover, embodiments of the invention may be applied to the detection of magnetic beads as well as to the measurement of bead properties (like frequency dependence, relaxation time), and biochemical binding quality (like bead rotation).
Embodiments of the invention may suppress artifacts resulting from the fact that sensor gain or sensor sensitivity may fluctuate in an undesired manner due to geometry effects or the like. According to an exemplary embodiment, multiple measurements may be performed in various excitation states of the magnetic particles to be detected. This may allow to eliminate or reduce such artifacts by combining the results in a mathematical manner, by calculating gain values which are more accurate or meaningful. For instance, the various measurements may be assigned to different angles/orientations of the exciting entity and/or the detecting entity with regard to the magnetic particles.
For exciting the magnetic field generator (for instance the wires), there is essentially no limitation with regard to specific current profiles. It is possible to use sine waves and square waves, particularly at a frequency well above a crossover point of the (magnetic) 1/f noise from the sensor and its thermal noise, which may be around 100 kHz.
Next, further exemplary embodiments of the magnetic sensor device will be explained. However, these embodiments also apply for the method of sensing magnetic particles, for the program element, and for the computer-readable medium.
The magnetic field generator unit may be adapted for generating the plurality of different magnetic field configurations sequentially in time. According to such an embodiment, a first specific magnetic field configuration is adjusted (for instance activating one of two magnetic field generator elements, and deactivating the other one). After having measured detection signals in this operation state, another magnetic field configuration may be adjusted, for instance by deactivating the previously activated magnetic field generator element and by activating the previously deactivated one. By such a time-multiplex scheme, geometry effects or the like may be suppressed or eliminated.
Additionally or alternatively, the magnetic field generator unit may be adapted for generating the plurality of different magnetic field configurations by frequency multiplexing. By taking this measure, it is not necessary to apply the different magnetic field configurations one after the other, but to mix different frequency contributions at the same time. This may be advantageous in terms of measurement time and efficiency.
The combination unit may be adapted for averaging fluctuations of the sensor gain. The combination of the plurality of signals for deriving information indicative of the presence of the magnetic particles may be performed by a mathematical procedure. By calculating an average gain value, artifacts on the measurement may be efficiently suppressed.
The magnetic field generator may comprise a plurality of magnetic field generator elements. With such a plurality of (spatially separated and separately controllable) magnetic field generator elements, the different magnetic field configurations may be adjusted by performing a specific activation/deactivation scheme, thereby defining a spatial dependence of the magnetic fields and therefore of the detection signals.
The plurality of magnetic field generator elements may be activable individually or in a groupwise manner for generating a plurality of different magnetic field configurations. This may allow for implementing a simple scheme which is highly flexible and allows to adjust the magnetic field environment in any desired manner.
The sensing unit may be arranged symmetrically or asymmetrically with respect to the plurality of magnetic field generator elements. For instance, the sensing unit, like a GMR sensor, may be positioned in the centre of gravity between two magnetic field generator elements (for instance two magnetic wires) to which a current may be applied. By providing an asymmetric geometry in which the GMR sensor is not provided (exactly) in the centre of gravity of the two or more magnetic field generator elements, the spatial asymmetry may be mapped into an asymmetry of the detection signals, which, by the combination unit, may further allow to remove artifacts.
The plurality of magnetic field generators may have different dimensions. For instance, the (cross-section) sizes of magnetic wires through which a current may flow may vary for the different magnetic field generator elements, thereby involving a further asymmetry and therefore a further degree of freedom for manipulating the detection signal.
The magnetic sensor device may comprise a substrate in which at least a part of the plurality of magnetic field generator elements is integrated. Such a (for instance semiconductor) substrate may have the magnetic field generator elements monolithically integrated therein, wherein the layout of such an integrated circuit may allow to involve the desired asymmetry or spatial dependence of the magnetic field generator elements to perform the combining or averaging scheme.
The plurality of magnetic field generator elements integrated in the substrate may be arranged parallel to a main surface of the substrate. Above the substrate, the sample to be analyzed may be provided (for instance a fluidic sample). The surface of the substrate to which such a sample may be supplied may be denoted as the main surface of the substrate. Along a surface region of this main surface, the various magnetic field generator elements may be aligned one next to the other.
The plurality of magnetic field generator elements may be integrated in the substrate to be arranged vertically with respect to a main surface of the substrate. Therefore, a vertical stack of magnetic field generator elements, optionally combined with a horizontal alignment of a plurality of magnetic field generator elements may be provided. By taking this measure, an array of magnetic field generator elements may be provided allowing to adjust a large variety of magnetic field configurations.
The magnetic sensor device may be adapted in such a manner that a predetermined spatial dependence of the magnetic particles is adjustable above a main surface of the substrate. For instance, a half of the surface above the substrate may be free of magnetic particles, or any gradient may be applied along the surface. Therefore, a particle asymmetry may be adjusted which further allows to detect individual detection signals which, in combination, may allow to suppress gain artifacts. It may be advantageous to foresee a gradual decrease of a surface density of the beads as a function of the position. In a biosensor, magnetic beads may be immobilized via target molecules to specific antibodies deposited (for example inkjet printed) on the sensor surface. The antibody density may thus determine the bead binding density. During production of the sensor device, said density may be varied by varying the droplet geometry and its position with respect to the sensor.
The magnetic field sensor device may be adapted in such a manner that another part of the plurality of magnetic field generator elements is provided on (not in) a main surface of the substrate. Therefore, the magnetic field generator elements may not only be provided monolithically integrated within the substrate, but also on the surface of the substrate. For instance, a gold layer which is in many cases deposited on a substrate when manufacturing a biosensor, and which may be particularly provided on top of the main surface of the substrate, may be patterned in such a manner so as to serve as a further magnetic field generator element (for instance by carrying out an appropriate etching and lithography procedure).
The magnetic sensor device may further comprise a magnetic body influencing the plurality of magnetic field generator elements in a plurality of different magnetic field configurations. Such a magnetic body may be any structure provided on and/or in a substrate and having a value of the magnetic permeability μ larger than one. The provision of such a magnetic body may introduce a further asymmetry in the detector and therefore in the detection scheme, allowing to remove or suppress gain fluctuations. An example for such a magnetic body is any soft magnetic material located between the (GMR) sensor and the excitation wire(s).
The magnetic field generator unit may be adapted for generating a plurality of different magnetic field configurations differing with regard to the magnetic field direction. For example, in a first operation state, a magnetic field may be applied (for instance using an external instead of an internal magnetic field source) having a first direction in a portion of the device in which the beads are arranged. In a second operation state, the magnetic field provided externally may be tilted with respect to the first configuration, and two or more of such angular operation states may be applied sequentially to the magnetic sensor device.
The combination unit may be adapted for combining the plurality of signals to thereby stabilize a detection gain factor. Therefore, the signal-to-noise ratio may be improved and the accuracy may be increased.
The magnetic sensor device may comprise a switch unit adapted for switching between the plurality of different magnetic field configurations. The algorithm according to which the switch unit operates on the different magnetic field generator elements may be controlled by a control unit, like a CPU.
The sensing unit may be adapted for sensing the magnetic particles based on an effect of the group consisting of GMR, AMR, and TMR. Particularly, a magnetic field sensor device may make use of the Giant Magnetoresistance Effect (GMR) being a quantum mechanical effect observed in thin film structures composed of alternating (ferro)magnetic and non-magnetic metal layers. The effect manifests itself as a significant decrease in resistance from the zero-field state, when the magnetization of adjacent (ferro)magnetic layers are antiparallel due to a weak anti-ferromagnetic coupling between layers, to a lower level of resistance when the magnetization of the adjacent layers align due to an applied external field. The spin of the electrons of the nonmagnetic metal align parallel or antiparallel with an applied magnetic field in equal numbers, and therefore suffer less magnetic scattering when the magnetizations of the ferromagnetic layers are parallel. Examples for biosensors making use of the Giant Magnetoresistance Effect (GMR) are disclosed in WO 2005/010542 or WO 2005/010543.
The combination unit may be adapted for combining the plurality of signals to thereby derive information indicative of a quantity of the magnetic particles. In other words, the magnetic sensor device may have the goal to detect the concentration or amount of the particles, according to an exemplary embodiment, and not only the “digital” information whether they are present or absent. Other properties of the beads may be estimated as well.
The magnetic sensor device may be adapted for sensing magnetic beads attached to biological molecules. Such biological molecules may be proteins, DNA, genes, nucleic acids, polypeptides, hormones, antibodies, etc.
Therefore, the magnetic sensor device may be adapted as a magnetic biosensor device, that is to say as a biosensor device operating on a magnetic detection principle.
At least a part of the magnetic sensor device may be realized as a monolithically integrated circuit. Therefore, components of the magnetic sensor device may be monolithically integrated in a substrate, for instance a semiconductor substrate, particularly a silicon substrate. However, other semiconductor substrates are possible, like germanium, or any group III-group V semiconductor (like gallium arsenide or the like).
Next, further exemplary embodiments of the method of sensing magnetic particles will be explained. However, these embodiments also apply for the magnetic sensor device, for the program element and for the computer-readable medium.
The method may comprise determining calibration information prior to the generation, sensing and combining procedures. By calibrating the sensor, the detection signals and the different operation modes may become more meaningful, and artifacts related to individual properties of a specific magnetic sensor (for instance manufacture tolerances) may be efficiently suppressed.
Particularly, determining calibration information may comprise at least one of the group consisting of generating and sensing in the absence of magnetic particles, generating and sensing in the presence of sedimented magnetic particles, generating and sensing in the presence of immobilized magnetic particles, and generating and sensing under reference conditions. By taking such measures, parameters like α and β (as will be explained below in more detail) may be determined prior to performing an actual sensor measurement, thereby increasing accuracy.
The aspects defined above and further aspects of the invention are apparent from the examples of embodiment to be described hereinafter and are explained with reference to these examples of embodiment.
The invention will be described in more detail hereinafter with reference to examples of embodiment but to which the invention is not limited.
The illustration in the drawing is schematically. In different drawings, similar or identical elements are provided with the same reference signs.
In a first embodiment the device according to the present invention is a biosensor and will be described with respect to
The device may comprise a substrate 10 and a circuit e.g. an integrated circuit.
A measurement surface of the device is represented by the dotted line in
The circuit may comprise a magneto-resistive sensor 11 as a sensor element and a magnetic field generator in the form of two separate conductors 12. The magneto-resistive sensor 11 may, for example, be a GMR, a AMR, Hall or a TMR type sensor. Moreover, the sensing unit 11 can be any suitable sensing unit 11 based on the detection of the magnetic properties of particles to be measured on or near to the sensor surface. Therefore, the sensing unit 11 is designable as a coil, magneto-resistive sensor, magneto-restrictive sensor, Hall sensor, planar Hall sensor, flux gate sensor, SQUID (Semiconductor Superconducting Quantum Interference Device), magnetic resonance sensor, or as another sensor actuated by a magnetic field.
The magneto-resistive sensor 11 may for example have an elongated, e.g. a long and narrow stripe geometry but is not limited to this geometry. Sensor 11 and conductors 12 may be positioned adjacent to each other within a close distance g and h, respectively. The distances g and h between sensor 11 and conductors 12 may for example be between 1 nm and 1 mm; e.g. 3 μm. The minimum distance is determined by the IC process.
In
When a magnetic material (this can e.g. be a magnetic ion, molecule, nano-particle 15, a solid material or a fluid with magnetic components) is in the neighborhood of the conductors 12, it develops a magnetic moment m indicated by the field lines 16 in
The magnetic moment m then generates dipolar stray fields, which have in-plane magnetic field components 17 at the location of the sensor 11. Thus, the nano-particle 15 deflects the magnetic field 14 into the sensitive x-direction of the sensor 11 indicated by arrow 13 (
For further details of the general structure of such sensors, reference is made to WO 2005/010542 and WO 2005/010543.
Reference numeral 20 in
In the following, referring to
The magnetic sensor device 300 is adapted for sensing beads or other magnetic nanoparticles 15 attached (for instance via linker molecules) to DNA strands 301 to be actually detected. The magnetic sensor device 300 comprises a magnetic field generator unit formed by two separate magnetic wires 12 and adapted for generating a plurality of different magnetic field configurations assigned to a plurality of different magnetic excitation states of the magnetic particles 15. In a first magnetic field configuration, the magnetic wire 12 shown on the left hand side of
The activation and deactivation states of the magnetic wires 12 are controlled by a control unit 20, like a CPU (central processing unit).
Furthermore, a GMR sensing unit 11 is provided for sensing a plurality of detection signals influenced in a characteristic manner by the magnetic particles 15 in the different magnetic field configurations, depending on their concentration.
A combining unit 30 having processing and/or memory capabilities or resources may have access to algorithms for evaluating the detected signals, and may combine the plurality of signals to thereby derive information indicative of the presence of the magnetic particles 15. The combination unit 30 combines the plurality of signals to thereby stabilize a detection gain factor, as will be explained below in more detail.
As can further be taken from
The biosensor 300 may be part of an array of a plurality of such sensors (for instance one hundred) which may be integrated in a common substrate 302. The sensor principle may be based on the detection of super paramagnetic beads and may be used to simultaneously measure a concentration of a large number of different biological molecules (for instance proteins, DNA) in a solution (for instance blood). This may be achieved by attaching super paramagnetic beads 15 to the target molecules 301, magnetizing this bead 15 using an applied magnetic field and using a Giant Magnetoresistance (GMR) sensor 11 to detect the stray field of the magnetic beads 15.
Auxiliary molecules 401 are immobilized on a surface 402 of the biosensor shown in
A current flowing in the wire 12 generates a magnetic field which magnetizes a super paramagnetic bead 15. The stray field from the super paramagnetic bead 15 introduces an in-plane magnetization component Hext in the GMR sensor 11, which results in a resistance change ΔRGMR(Hext).
Thus,
By applying a sensor gain stabilization algorithm during the actual measurement, artifacts arising from the discussed effects may be efficiently suppressed according to an exemplary embodiment of the invention.
In the following, referring to
In the embodiment of
The surface coverage of the beads 15 is limited to one half 601 of the sensor 600, whereas a second half 602 is free of beads 15. The excitation field is switched continuously between two states:
The first state is shown in
In the state on
u
1
=s
GMR
{H
MXT1
+H
B1}
In this equation, sGMR is the sensitivity of the GMR sensor 11, HMXT1 is the magnetic crosstalk field given by the geometry of the sensor 600, and HB1 is the stray field from the magnetic beads 15 on the surface 303.
In the second operation state shown in
u
2
=s
GMR
{H
MXT1
+βH
B1}
where the constant factor β expresses the change in the field from the beads 15 compared to the first state shown in
Then the weighted difference of the observed signals in both states may be calculated:
u
2−βu1=sGMR{HMXT1+βHB1}−βsGMR{HMXT1+HB1}=sGMR(1−β)HMXT1
By calculating
s
GMR=(βu1−u2)/[(β−1)HMXT1]
this value may be used to normalize or stabilize the detection gain. Prior to the actual bio-measurement, SGMR HMXT1 may be calibrated without beads 15.
By adding more excitation states (for instance both wires 12 activated), and more excitation wires (that is to say a larger number than two), more information may become available for calculating sGMR, allowing to further increase accuracy.
Due the symmetrical geometry of the sensor 600, it may be assumed in proper approximation that the magnetic crosstalk in both states (
The embodiment shown in
A gradual increase of the surface height with respect to the sensor may effectively reduce the effect of beads on one side of the sensor, because they are further away from the sensor, and may avoid the use of a steep border between left and right. More generally speaking: there is no need for a sharp distinction between left and right.
In the following, referring to
In this embodiment, a switch between wires 12 at different positions in a direction perpendicular to a main surface 303 is performed.
According to this embodiment, additional current wires 12 are located at different vertical positions and are used to vary the relation between the internal crosstalk and the beads 15 signal.
According to another exemplary embodiment shown in
In
In the first stage shown in
u
1
=s
GMR
{H
MXT1
+H
B1}
where sGMR is the sensitivity of the GMR sensor 11, HMXT1 is the magnetic crosstalk given by the geometry of the sensor 900, and HB1 is the signal from the magnetic beads 15 on the surface 303.
In the second state shown in
u
2
=s
GMR
{αH
MXT1
+βH
B1}
Here, the constant factors α and β express the change in magnetic crosstalk and bead signals respectively compared to the first state shown in
Then the weighted difference of both measurements is calculated:
βu1−u2=βsGMR{HMXT1+HB1}−sGMR{αHMXT1+βHB1}=sGMR(β−α)HMXT1
By using
s
GMR=(βu1−u2)/[(β−α)HMXT1]
the gain of the detector 900 may be stabilized or normalized.
The factors α and β may be determined by the geometry of the sensor 900 and may be calibrated prior to the actual measurement, for instance by measuring for both states the magnetic crosstalk without beads 15 and for both states the sensor 900 response on beads 15 sediment on the surface.
Additional information may be achieved by adding more actuation states and/or more field generating wires 12, 901.
In this configuration, beads 15 within a few micrometers in a bulk above the sensor surface 303 may affect the stabilization process. This is because of a different z-position of the excitation wires 12, 901. Removal of said beads 15 above the sensor 900 during stabilizing may avoid or suppress this effect.
In the following, referring to
In the embodiment shown in
In
In the following, referring to
As can be taken from
In
The working principle and the calibration procedure in the embodiment shown in
Here, the GMR sensor 11 is displaced over a distance Δx across the x-axis 1201 What now follows is an analysis of the GMR signals in the two excitation states shown in
Next, the first excitation state will be explained, that is to say a state in which the wire 12 shown on the left hand side of
The in-plane magnetic crosstalk field in the sensitive layer of the GMR as a function of the x-position is thereby shown in
By averaging the crosstalk field over the width of the GMR and substituting IGMR=1 mA and sGMR=0.003 Ωm/A, the crosstalk GMR voltage equals to uMXT1=−14.78 μV.
The next step is to calculate the x-normalized GMR voltage induced by a row of beads 15 along the y-axis having a unit row width, as a function of the x-position of said row at the sensor surface (z=0.64 μm).
The result is plotted in
The diagram 1500 illustrates an x-normalized GMR voltage on an ordinate 1502 in dependence of the x-position plotted along an abscissa 1501.
Therefore,
The curve shown in
The total GMR signal in the first state shown in
u
1
=u
MXT1
+u
B1=−14.03 μV.
In the following, the second state with both wires 12 activated will be explained.
The magnetic crosstalk in the second state, when both wires 12 are activated, is plotted in
Therefore,
This is caused by the fact that the second wire 12 (shown on the right hand side of
The GMR voltage from the beads 15 equals
and
u
2
=u
MXT2
+u
B2=−45.85 μV.
Now the factors α and β will be defined, which express the ratio between the magnetic crosstalk and the bead signal in the second state and in the first state, hence
α=uMXT2/uMXT1=3.25
β=uB2/uB1=2.92
From said factors α and β, also the absolute magnetic gain may be calculated or derived.
Next, the calibration of the factors α and β will be explained.
The theoretical value of α and β are influenced by production tolerances at the sensor, which makes calibration steps prior to the bio-measurement likely to be necessary. What follows is a detailed description of an embodiment for such an optional calibration:
Factor α may be calibrated and determined prior to the bio-chemical reaction by measuring the sensor responses without beads.
u
1,α
=u
MXT1
,u
2,α
=αu
MXT1, hence α=uMXT2/uMXT1
Here, u1,α and u2,α are measured during a very short time in order to be sure that gain variations are neglectable. Because of the short measuring time, the signal-to-noise ratio may be poor. Therefore, the calculated α values may be averaged to achieve an acceptable signal-to-noise ratio.
The factor β may be calibrated from the sensor response to a bead sediment or immobilization, probably on, for instance, a reference sensor.
When it is assumed that
u
1,β
=u
MXT1
+u
B1
and
u
2,β
=αu
MXT1
+βu
B1
then factor β is equal to
β=(u2,β−αuMXT1)/(u1,β−uMXT1)
To avoid gain variations during calibration, u1,β and u2,β may be measured during a very short time after which the calculated β values are averaged. It is remarkable that the β calibration does not require knowledge about the bead concentration.
As already mentioned, for estimating β for calibration purposes, beads may be sedimented or immobilized on a reference sensor. However, it may be possible to omit such a reference sensor and to use the actual sensor for estimating β. The immobilized beads may then be removed after calibration. For instance, the beads may be washed away by a laminar flow or pulled away by a magnetic field, produced by e.g. an external magnet.
Next, gain calibration during the biochemical measurement will be explained.
By continuously measuring the detector signals and the two excitation states, the relative gain with respect to the initial value at the time that the biochemical reaction started may be calculated as follows.
At t=0, when the biochemical reactions starts, no beads 15 are present on the sensor and
u
1(0)=G(0)uMXT1uMXT1=u1(0)/G(0)
where G(0) represents the gain factor t=0.
During the course of the reaction, beads 15 immobilize on the sensor, hence
u
1
=G(t){uMXT1+uB1}
and
u
2
=G(t){αuMXT1+βuB1}
By calculating
βu1−u2=G(t)(β−α)uMXT1G(t)/G(0)=(βu1−u2)/((β−α)u1(0))
This represents the relative gain with respect to t=0 when the reaction has started.
G(t)/G(0) may be used in a feed-forward configuration to normalize the detection gain or in a feedback system to stabilize the gain by for instance controlling the sense- or excitation current amplitude.
The time between the two gain measurements is fast enough in many cases to follow the expected gain SGMR variations.
Furthermore, the gain measurement time is preferably short enough to a avoid gain fluctuations between the excitation state during the gain measurement.
As mentioned earlier, the two excitation states may be applied in frequency multiplexing measured simultaneously. Hence, the wire currents are
I
wire1=sin ωS1t+sin ωS2t
Iwire2=sin ωS2t
In such an embodiment, again variations during the measurement interval will not affect the result wrongly, because the gain varies essentially for every state.
This method has the advantage that the measuring time may be longer. It produces an average gain at increased signal-to-noise ratio.
The allowed dissipation and the electro-migration limit constraints the maximum current at each frequency component in wire 1 by factor of two, which effect degrades the signal-to-noise ratio.
In the following, referring to
In this embodiment, a magnetic body 1801 is integrated in the silicon substrate 302 in an asymmetric manner with respect to magnetic wires 12.
The addition of such an entity 1801 having μr≠1 changes the magnetic symmetry between the wires 12, which changes the signal crosstalk ratio for the two wires 12.
In
In the following, referring to
In the embodiment shown in
In
In other words, in the embodiment of
The combination with any of the previous embodiments is of course easily possible.
In
A further variation shown in
In
In
It should be noted that the term “comprising” does not exclude other elements or features and the “a” or “an” does not exclude a plurality. Also elements described in association with different embodiments may be combined.
It should also be noted that reference signs in the claims shall not be construed as limiting the scope of the claims.
| Number | Date | Country | Kind |
|---|---|---|---|
| 06116227.7 | Jun 2006 | EP | regional |
| Filing Document | Filing Date | Country | Kind | 371c Date |
|---|---|---|---|---|
| PCT/IB07/52325 | 6/18/2007 | WO | 00 | 12/18/2008 |
