US20090224755A1 - Means and method for sensing a magnetic stray field in biosensors - Google Patents

Means and method for sensing a magnetic stray field in biosensors Download PDF

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US20090224755A1
US20090224755A1 US11/719,953 US71995305A US2009224755A1 US 20090224755 A1 US20090224755 A1 US 20090224755A1 US 71995305 A US71995305 A US 71995305A US 2009224755 A1 US2009224755 A1 US 2009224755A1
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magneto
gmr
resistive element
signal
sensor
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Josephus Arnoldus Henricus Maria Kahlman
Bart Michiel De Boer
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Koninklijke Philips NV
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    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01R—MEASURING ELECTRIC VARIABLES; MEASURING MAGNETIC VARIABLES
    • G01R33/00—Arrangements or instruments for measuring magnetic variables
    • G01R33/02—Measuring direction or magnitude of magnetic fields or magnetic flux
    • G01R33/06—Measuring direction or magnitude of magnetic fields or magnetic flux using galvano-magnetic devices
    • G01R33/09—Magnetoresistive devices
    • G01R33/093—Magnetoresistive devices using multilayer structures, e.g. giant magnetoresistance sensors
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B82—NANOTECHNOLOGY
    • B82Y—SPECIFIC USES OR APPLICATIONS OF NANOSTRUCTURES; MEASUREMENT OR ANALYSIS OF NANOSTRUCTURES; MANUFACTURE OR TREATMENT OF NANOSTRUCTURES
    • B82Y25/00—Nanomagnetism, e.g. magnetoimpedance, anisotropic magnetoresistance, giant magnetoresistance or tunneling magnetoresistance
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01R—MEASURING ELECTRIC VARIABLES; MEASURING MAGNETIC VARIABLES
    • G01R33/00—Arrangements or instruments for measuring magnetic variables
    • G01R33/12—Measuring magnetic properties of articles or specimens of solids or fluids
    • G01R33/1269—Measuring magnetic properties of articles or specimens of solids or fluids of molecules labeled with magnetic beads

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  • the invention relates to a method for sensing a magnetic stray field generated by a magnetizable object when magnetized and for generating an electrical object signal which depends on the sensed magnetic stray field.
  • the invention further relates to a magnetic sensor comprising a magneto-resistive element for sensing the magnetic stray field generated by the magnetizable object when magnetized and for generating the electrical object signal, and to a biochip comprising such a sensor for use in e.g. molecular diagnostics biological sample analysis or chemical sample analysis.
  • micro-arrays or biochips are revolutionizing the analysis of samples for DNA (desoxyribonucleic acid), RNA (ribonucleic acid), nucleic acids, proteins, cells and cell fragments, tissue elements, etcetera.
  • Applications are e.g. human genotyping (e.g. in hospitals or by individual doctors or nurses), medical screening, biological and pharmacological research, detection of drugs in saliva.
  • the aim of a biochip is to detect and quantify the presence of a biological molecule in a sample, usually a solution.
  • Biochips also called biosensors, biosensor chips, biological microchips, gene-chips or DNA chips, consist in their simplest form of a substrate on which a large number of different probe molecules are attached, on well defined regions on the biochip, to which molecules or molecule fragments that are to be analyzed can bind if they are matched.
  • substrate may include any underlying material or materials that may be used, or upon which a device, a circuit or an epitaxial layer may be formed.
  • substrate may also include a semiconductor substrate such as e.g. a doped silicon, a gallium arsenide (GaAs), a gallium arsenide phosphide (GaAsP), an indium phosphide (InP), a germanium (Ge), or a silicon germanium (SiGe) substrate.
  • the “substrate” may include, for example, an insulating layer such as a SiO 2 or an Si 3 N 4 layer in addition to a semiconductor substrate portion.
  • substrate also includes glass, plastic, ceramic, silicon-on-glass, silicon-on-sapphire substrates.
  • substrate is thus used to define generally the elements for layers that underlie a layer or portions of interest.
  • substrate may be any other base on which a layer is formed, for example a glass or metal layer.
  • a fragment of a DNA molecule binds to one unique complementary DNA (c-DNA) molecular fragment.
  • the occurrence of a binding reaction can be detected, e.g. by using fluorescent markers that are coupled to the molecules to be analyzed.
  • fluorescent markers magnetizable objects can be used as magnetic markers that are coupled to the molecules to be analyzed. It is the latter type of markers which the present invention is dealing with.
  • said magnetizable objects are usually implemented by so called superparamagnetic beads. This provides the ability to analyze small amounts of a large number of different molecules or molecular fragments in parallel, in a short time.
  • One biochip can hold assays for 10-1000 or more different molecular fragments.
  • a biochip consisting of an array of sensors (e.g. 100) based on the detection of superparamagnetic beads may be used to simultaneously measure the concentration of a large number of different biological molecules (e.g. protein, DNA) in a sample fluid (e.g. a solution like blood or saliva).
  • the sample fluid comprises a target molecule species or an antigen. Any biological molecule that can have a magnetic label (marker) can be of potential use.
  • the measurement may be achieved by attaching a superparamagnetic bead to the target, magnetizing this bead with an applied magnetic field, and using (for instance) a Giant Magneto Resistance (GMR) sensor to detect the stray field of the magnetized beads.
  • GMR Giant Magneto Resistance
  • the magnetic field generator may comprise a current flowing in a wire which generates a magnetic field, thereby magnetizing a superparamagnetic bead.
  • the stray field from the superparamagnetic bead introduces an in-plane magnetization component in the GMR, which results in a resistance change.
  • FIGS. 1 and 2 For further explanation of the background of the invention reference is made to FIGS. 1 and 2 .
  • FIG. 2 shows an embodiment of a magnetic sensor MS on a substrate SBSTR.
  • a single or a multiple of such (a) sensor(s) may be integrated on the same substrate SBSTR to form a biochip BCP as is schematically indicated in FIG. 1 .
  • the magnetic sensor MS comprises a magnetic field generator which, in this example, is integrated in the substrate SBSTR e.g. by a first current conducting wire WR 1 . It may also comprise a second (or even more) current conducting wire WR 2 . Also other means in stead of a current conducting wire may be applied to generate the magnetic field H.
  • the magnetic field generator may also be located outside (external excitation) the substrate SBSTR.
  • each magnetic sensor MS a magnetoresistive element, for example a giant magnetoresistive resistor GMR, is integrated in the substrate SBSTR to read out the information gathered by the biochip BCP, thus to read out the presence or absence of target particles TR via magnetizable objects thereby determining or estimating an areal density of the target particles TR.
  • the magnetizable objects are preferably implemented by so called superparamagnetic beads SPB.
  • Binding sites BS which are able to selectively bind a target TR are attached on a probe element PE.
  • the probe element PE is attached on top of the substrate SBSTR.
  • Each probe element PE is provided with binding sites BS of a certain type.
  • Target sample TR is presented to or passed over the probe element PE, and if the binding sites BS and the target sample TR match, they bind to each other.
  • the superparamagnetic beads SPB are directly or indirectly coupled to the target sample TR.
  • the superparamagnetic beads SPB allow to read out the information gathered by the biochip BCP.
  • Superparamagnetic particles are ferromagnetic particles of which at zero applied magnetic field the time-averaged magnetization is zero due to thermally induced magnetic moment reversals that are frequent on the time scale of the magnetization measurement. The average reversal frequency is given by
  • KV (with K the magnetic anisotropy energy density and V the particle volume) is the energy barrier that has to be overcome, and ⁇ 0 is the reversal attempt frequency (typical value: 10 9 s ⁇ 1 ), k is the Boltzmann constant, and T is the absolute temperature (in Kelvin).
  • the magnetic field H magnetizes the superparamagnetic beads SPB which as a response generate a stray field SF which can be detected by the GMR.
  • the GMR should preferably be positioned in a way that the parts of the magnetic field H which passes through the GMR is perpendicular to the sensitive direction of the layer of the GMR.
  • a total external field for which the GMR is sensitive is indicated by H ext in FIG. 2 .
  • the stray field SF has a horizontal component (the sensitive direction of the layer of the GMR) and will thus generate a difference in the resistance value of the GMR.
  • an electrical output signal e.g. generated by a current change through the GMR when biased by a DC voltage, not shown in FIG. 1
  • the sensor MS which is a measure for the amount of targets TR.
  • the total gain of the sensor determines the amplitude of the output voltage of the sensor. Therefore the total gain should be known e.g. by measuring the total gain before the actual bio-measurement. Preferably also this total gain is calibrated to be equal to a desired value. Furthermore it is desirable to perform cross-talk isolation techniques for measuring the effect of the magnetic cross-talk caused by the magnetic field which results directly (thus not via the paramagnetic beads) from the magnetic field generator.
  • the total gain of the sensor is dependent on various elements such as an amplifier (or buffer), and the steepness of the GMR.
  • the steepness is the derivative of the resistance of the magneto-resistive element as a function of the magnetic field through the magneto-resistive element in a magnetically sensitive direction of the magneto-resistive element. Even if cross-talk cancellation is performed any change in the value of the gain of the amplifier or said steepness of the GMR during the bio-measurements can adversely affect the accuracy of the measurement. In this respect the most critical component in the sensor is the GMR.
  • the steepness of the GMR, and therefore the total gain of the sensor is dependent on parameters which are difficult to control for instance applied magnetic fields, production tolerances, aging effects, and temperature. There is thus a high need to stabilize the sensitivity of the GMR.
  • the invention provides a magnetic sensor comprising a magneto-resistive element for sensing a magnetic stray field generated by a magnetizable object when magnetized and for generating an electrical object signal which depends on the sensed magnetic stray field, the sensor comprising a magnetic field generator for generating a magnetic field having a first frequency for magnetizing the magnetizable object, a current source for at least generating an AC-current having a second frequency through the magneto-resistive element, and electronic means for generating an electrical output signal derived from the electrical object signal, the electronic means comprising stabilization means for stabilizing the amplitude of the electrical output signal, the stabilization means deriving its information which is needed for said stabilization from the amplitude of a signal component, which is present in the object signal during operation, which is linearly dependent on the steepness of the magneto-resistive element.
  • the invention is based on the insight that by applying the AC-current with the second frequency, the sensed object signal will not only comprise a signal component which depends on the sensed magnetic stray field but will also comprise one or more signal components of which the amplitude is linearly dependent on the sensitivity of the GMR.
  • the electronic means such a signal component can be isolated from the remainder of the signal in the object signal and gives a measure for the sensitivity of the GMR. This makes it possible to stabilize the total gain.
  • the AC-current through the GMR causes an internal magnetic field in the GMR. Due to asymmetric current distribution in the GMR stack, the current through the GMR will introduce an in-plane magnetic field component in the sensitive layer of the sensor. This effect can be interpreted as internal magnetic cross talk and will give rise to a voltage component which is linear to the squared amplitude of the AC-current and which is linear to the sensitivity of the GMR. Linear to the squared amplitude of the AC-current also means linear to the second harmonic component (thus having a frequency which is twice as high as the second frequency) in relation to the AC-current.
  • stabilizing the sensitivity of the GMR can be performed by detecting the second harmonic component (in relation to the second frequency) in the object signal and by performing some action to cancel the influence of the previously mentioned difficult to control parameters.
  • Other harmonic components e.g. the fourth harmonic component, can be used in stead of the second harmonic.
  • the second harmonic since generally the second harmonic is predominately present it is preferred to use the second harmonic in view of reaching the highest possible signal-to-noise ratio in the sensor and thus in reaching the highest accuracy for the bio-sensor measurements.
  • the invention may further be characterized in that the stabilization means comprises means for generating a further AC-current, having a third frequency, through the magneto-resistive element, and in that the signal component is a harmonic component in the current through the magneto-resistive element having a frequency which is equal to the third frequency, or to the difference of the third and the second frequency, or to the sum of the third and the second frequency.
  • the further AC-current is preferably generated by the presence of a further magnetic field generator for generating the further magnetic field.
  • the earlier mentioned in-plane magnetic field component is very weak and as a consequence the second harmonic component is also very weak. This makes detection of the second harmonic component very difficult. It may result in a too noisy signal thereby negatively influence the accuracy of the bio-measurement.
  • signal components in the object signal are generated having frequencies equal to the third frequency, or to the difference of the third and the second frequency, or to the sum of the third and the second frequency. All these signal components are linearly dependent to the sensitivity of the GMR and can be isolated, individually or combined, and used to stabilize the total gain of the sensor in a corresponding manner as previously explained with reference to the detection of the second harmonic component.
  • One way of stabilizing the sensitivity of the GMR is by adding steepness adaptation means for adapting the steepness of the magneto-resistive element. This may for instance be performed by changing the value of the DC-current through the magneto-resistive element. Alternatively the adaptation of the steepness is performed by changing a DC value component in the further magnetic field e.g. by changing a DC component in the further DC-current.
  • the gain adaptation means may comprise a synchronous detector for synchronously detecting the signal component, and means for comparing the detected signal component with a target value for the steepness of the magneto-resistive element and for delivering an error signal as a result of the comparison.
  • the error signal changes the DC value of the current through the GMR or in the further magnetic field (or further current). By doing so a negative feedback loop is created in which the error signal will be controlled to be equal (or close) to zero. As a consequence the sensitivity of the GMR will be made equal to the target value (and is thus stabilized).
  • the gain adaptation means may comprise a synchronous detector for synchronously detecting the signal component, and means for comparing the detected signal component with a target value for the steepness of the magneto-resistive element and for delivering a control signal as a result of the comparison. This control signal is used for the changing of the gain value.
  • superparamagnetic beads are applied to the reference-sensor during production. This can be achieved by either e.g. spotting (like ink-jet spotting) a well defined surface density concentration of beads or a well defined volume density of beads.
  • these beads may be utilized for calibration of the transfer function. If the sensor is shielded for free moving beads in the sample fluid, which is the case if the bead coverage is large enough, the transfer function may also be stabilized during the actual bio-measurement.
  • the sensitivity of the GMR is controlled by varying the strength of the magnetic field produced by an external magnet or by varying the position of the external magnet by translation or rotation.
  • the electronic means may comprises a further synchronous detector for synchronously detecting the object signal, or a gain adapted version of the object signal, on the first frequency and/or on the difference of the first and the second frequency, and/or on the sum of the first and second frequency, and a frequency low pass filter for filtering the resulted signal from the further detector and for delivering the electrical output signal as a result of the filtering.
  • the electrical output signal is a pure DC-signal which is a measure for the amount of targets TR and thus for the concentration of biological molecules in the sample fluid.
  • the gain of the reference sensor is obtained by measuring the response to at least one field generating wire in the vicinity of the reference sensor. It is important to be not sensitive to the beads on the reference sensor surface or into the solution as the number of beads may fluctuate during the bio-measurement and disturb the stabilization mechanism. Therefore preferably magnetic beads are avoided near the reference sensor surface by omitting binding regions on the surface, by proper shielding, by pulling beads away from the sensor or by measuring at a frequency above the response bandwidth of the super paramagnetic beads. As an alternative beads are attracted in a well defined way to the sensor surface. The advantage of this method is that it may shield the reference sensor from free moving beads above the sensor, which avoid said beads to influence on the stabilization mechanism of the GMR. The attracting forces may be generated by a magnetic field gradient introduced by magnetic field generating wires near the sensor.
  • beads near the surface are removed by (magnetically) washing it away.
  • beads are applied to the reference sensor during production. This can be achieved by either e.g. spotting (like ink-jet spotting) a well defined surface density concentration of beads or a well defined volume density of beads. These beads may be used for gain stabilizing during the bio-measurement. Preferably said beads shield the magnetic field from free moving beads in the sample fluid.
  • the response of paramagnetic beads are “switched off”. As a consequence only magnetic cross-talk is measured which can be used to stabilize the total gain. This can be done by applying a vertical magnetic field, e.g.
  • the invention further provides a biochip comprising an inventive magnetic sensor.
  • the biochip may comprise a multiple of magnetic sensors wherein at least one inventive sensor is used as a reference sensor and wherein the adaptation of the steepness of the magneto-resistive elements or the gain adaptation means for adapting the gain value in the electronic transfers from the electrical object signals to the electrical output signals in the other sensors is performed by using information derived from the reference sensor.
  • the sensitivity of the GMR is measured in the same frequency range as the beads excitation is performed. By doing so the highest signal-to-noise ratio can be reached.
  • the sensor may comprise a so called Wheatstone bridges or half-Wheatstone bridges in which one or more GMRs are incorporated.
  • FIG. 1 shows a biochip comprising a substrate and a plurality of magnetic sensors
  • FIG. 2 shows an embodiment of a magnetic sensor with integrated magnetic field excitation
  • FIG. 3 shows the resistance of a GMR as a function of the magnetic field component in the direction in which the layer of the GMR is sensitive to magnetic fields
  • FIG. 4 shows part of a magnetic sensor in which besides the magnetic field from the beads also the internally generated field generated by the GMR itself is illustrated for explanatory reasons;
  • FIG. 5 shows a schematic of an inventive embodiment in which means are present for adapting the DC-current through the GMR
  • FIG. 6 shows a cross-section of a GMR stack in which the current through the stack is schematically indicated
  • FIG. 7 shows a schematic of an inventive embodiment which comprises gain adaptation means for adapting the gain value in the electronic transfer from the electrical object signal to the electrical output signal;
  • FIG. 8 shows a schematic of an alternative inventive embodiment for adapting the gain value
  • FIG. 9 schematically shows an example of an advantageous location for a wire for generating the further magnetic field having the third frequency
  • FIG. 10 shows a schematic of an inventive embodiment in which means are present for adapting the DC-current through the GMR and in which the further magnetic field having the third frequency is present;
  • FIG. 11 shows a schematic of an inventive embodiment which comprises gain adaptation means for adapting the gain value in the electronic transfer from the electrical object signal to the electrical output signal and in which the further magnetic field having the third frequency is present;
  • FIG. 12 shows a schematic of an inventive embodiment, as an alternative for the embodiment as shown in FIG. 10 , in which the DC-value in the further magnetic field is adapted;
  • FIGS. 13 and 14 show an array of sensors in which one inventive sensor acts as a reference sensor and in which the steepness of the GMRs in the other sensors is stabilized with the help of information derived from the reference sensor.
  • FIG. 3 shows the resistance of the GMR as a function of the magnetic field component H ext . It is to be noted that the GMR sensitivity
  • any other means which have a property (parameter) which depends on magnetic field such as certain types of resistors like a tunnel magnetoresistive (TMR) or an anisotropic magnetoresistive (AMR) can be applied.
  • TMR tunnel magnetoresistive
  • AMR anisotropic magnetoresistive
  • GMR is the magnetoresistance for layered structures with conductor interlayers in between so-called switching magnetic layers
  • TMR is the magneto-resistance for layered structures comprising magnetic metallic electrode layers and a dielectric interlayer.
  • a first magnetic film is pinned, what means that its magnetic orientation is fixed, usually by holding it in close proximity to an exchange bias layer, a layer of antiferromagnetic material that fixes the first magnetic film's magnetic orientation.
  • a second magnetic layer or free layer has a free, variable magnetic orientation. Changes in the magnetic field, in the present case originating from changes in the magnetization of the superparamagnetic particles SPB, cause a rotation of the free magnetic layer's magnetic orientation, which in turn, increases or decreases the resistance of the GMR structure. Low resistance generally occurs when the sensor and pinned layers are magnetically oriented in the same direction. Higher resistance occurs when the magnetic orientations of the sensor and pinned layers (films) oppose each other.
  • TMR can be observed in systems made of two ferromagnetic electrode layers separated by an isolating (tunnel) barrier.
  • This barrier must be very thin, i.e., of the order of 1 nm. Only then, the electrons can tunnel through this barrier.
  • the magnetic alignment of one layer can be changed without affecting the other by making use of an exchange bias layer. Changes in the magnetic field, in the present case originating from changes in the magnetization of the superparamagnetic particles SPB, cause a rotation of the sensor film's magnetic orientation, which in turn, increases or decreases resistance of the TMR structure.
  • the AMR of ferromagnetic materials is the dependence of the resistance on the angle the current makes with the magnetization direction. This phenomenon is due to an asymmetry in the electron scattering cross section of ferromagnet materials.
  • FIG. 4 shows part of a magnetic sensor in which besides the magnetic field H ext (coming from the beads) also the internally generated field H int generated by the GMR itself is indicated.
  • a current source I BIAS which supplies a DC-current I DC and an AC-current source AC 2 which supplies an AC-current I 2 sin ⁇ 2 t having a second frequency ⁇ 2 are coupled to the magneto-resistive element GMR.
  • the sense current i s causes a signal (voltage) U GMR across the GMR.
  • the voltage U GMR is amplified by an amplifier AMP which delivers an object signal U OB .
  • the GMR voltage contains a second harmonic signal, which is utilized to stabilize the GMR sensitivity. This is illustrated as follows.
  • the signal U GMR can be expressed by:
  • u GMR I DC ⁇ ( R GMR + s GMR ⁇ ⁇ ⁇ I DC ) + 1 2 ⁇ I 2 2 ⁇ s GMR ⁇ ⁇ + I 2 ⁇ sin ⁇ ⁇ ⁇ 2 ⁇ t ⁇ ( R GMR + s GMR ⁇ ⁇ ⁇ 2 ⁇ I DC ) + I DC ⁇ s GMR ⁇ H 1 ⁇ sin ⁇ ⁇ ⁇ 1 ⁇ t + 1 2 ⁇ I 2 ⁇ s GMR ⁇ H 1 ⁇ [ cos ⁇ ( ⁇ 1 - ⁇ 2 ) ⁇ t - cos ⁇ ( ⁇ 1 + ⁇ 2 ) ⁇ t ] - 1 2 ⁇ I 2 2 ⁇ s GMR ⁇ ⁇ ⁇ cos ⁇ ⁇ 2 ⁇ ⁇ 2 ⁇ t
  • the sensitivity s GMR of the GMR is linearly present in this last term.
  • the sensitivity can be stabilized. This can be performed by synchronously demodulating the object signal U OB , which is an amplified version of the signal U GMR .
  • the result of this demodulation is a DC component which is proportional to s GMR and independent from H 1 .
  • FIG. 5 shows a schematic of an inventive embodiment in which means are present for adapting the DC-current through the GMR.
  • the following elements are present: a first multiplier MP 1 , a second multiplier MP 2 , a (first) frequency low pass filter LPF 1 , a subtracter DFF, and an integrating filter INT.
  • the first multiplier MP 1 synchronously demodulates the object signal U OB by multiplying the object signal U OB with a signal cos 2 ⁇ 2 t. (For simplification the amplitude in this Figure and other Figures is chosen to be equal to “1”, but this may not be interpreted as a restriction.)
  • the resulted signal is a DC-value and is subtracted from a target value s TR .
  • the resulting error signal is delivered to the integrating filter INT.
  • the output signal of the integrating filter INT is used to adapt the DC-value I DC of the current source IBIAS.
  • the thus stabilized object signal U OB is synchronously demodulated by the second multiplier MP 2 which multiplies the object signal U OB with either cos( ⁇ 1 ⁇ 2 )t or cos( ⁇ 1 ⁇ 2 )t or sin( ⁇ 1 )t, or a combination of these three signals.
  • the resulted signal UMP 2 at the output of the second multiplier MP 2 is filtered by the low pass filter LPF 1 and delivers the electrical output signal U 0 which is a pure DC-signal and which is a measure for the amount of targets TR (see FIG. 2 ) and thus for the concentration of biological molecules in the sample fluid.
  • FIG. 6 shows a cross-section of a GMR stack in which the current through the stack is schematically indicated.
  • the previous mentioned parameter ⁇ and s GMR both are a function of the current distribution in the GMR stack.
  • FIG. 6 shows the current distribution in the GMR stack, which is centered in the nonmagnetic layer NML between the free (sensitive) layer FL and the pinned layer PL. Moving the center of gravity of the sense current i s to an optimal position just below the sensitive layer FL, results in more magnetic field strength being induced by the sense current i s in the sensitive layer FL, which increases the control range and the gain of the stabilizing circuitry. This can be achieved by optimizing the resistance balance in the stack, e.g. by adding a low-ohmic layer to the stack or by changing the thickness of the different layers in the stack.
  • the applied magnetic field H int (see FIG. 5 ), generated by the sense current i s , is concentrated in the GMR, so that there is a neglectable interaction between the magnetic beads SPB (see FIG. 2 ) near the sensor surface and the applied sensor current. Therefore this method can be applied simultaneously with the actual magnetic bead measurement.
  • FIG. 7 shows a schematic of an inventive embodiment which comprises gain adaptation means for adapting the gain value in the electronic transfer from the electrical object signal U OB to the electrical output signal U 0 .
  • the circuit of FIG. 7 differs from the circuit of FIG. 5 in the following.
  • the integrating filter INT and the subtracter DFF are not present, and thus there is no feedback loop.
  • the DC-value I DC of the current source IBIAS is not controlled by an error signal.
  • the circuit of FIG. 7 comprises, in addition to the circuit of FIG.
  • a gain adapter G ADPT which is with a signal input coupled to the output of the amplifier AMP for receiving the object signal U OB and with a signal output coupled to an input of the second multiplier MP 2 for delivering the signal U OBG which is a gain adapted version of the object signal U OB .
  • the circuit of FIG. 7 comprises, in addition to the circuit of FIG. 5 , a further frequency low pass filter LPF 2 which is coupled between the output of the first multiplier MP 1 and a control input of the gain adapter G ADPT .
  • the circuit operates as follows.
  • the object signal U OB is multiplied (synchronously demodulated) with a signal cos 2 ⁇ 2 t like in the circuit of FIG. 5 .
  • the resulted signal is filtered by the further low pass filter LPF 2 which delivers a control signal to the control input of the gain adapter G ADPT .
  • this control signal is a pure DC-signal.
  • the control signal is compared to the target value s TR which is present at a reference input of the gain adapter G ADPT .
  • the gain of the gain adapter G ADPT is expressed by the following equation:
  • G is the value of the DC-signal delivered by the further low pass filter LPF 2 , and is thus related to the sensitivity s GMR of the GMR, and ⁇ determines the maximum possible gain of the gain adapter G ADPT .
  • G is the value of the DC-signal delivered by the further low pass filter LPF 2 , and is thus related to the sensitivity s GMR of the GMR, and ⁇ determines the maximum possible gain of the gain adapter G ADPT .
  • FIG. 8 shows a schematic of an alternative inventive embodiment for adapting the gain value.
  • the circuit of FIG. 8 differs in construction with the circuit of FIG. 5 in the following.
  • a third multiplier MP 3 is with a first input coupled to the output of the amplifier AMP and with an output coupled to a common connection point of the first and second multipliers MP 1 and MP 2 .
  • the output of the integrating filter INT is not coupled to the current source IBIAS but to a second input of the multiplier MP 3 .
  • FIG. 8 is similar to the principle of operation of the circuit of FIG. 7 .
  • the (negative) feedback loop formed by the elements: “MP 3 ”, “MP 1 ”, “DFF”, “INT” in FIG. 8 perform a similar function as the feedforward loop formed by the elements: “MP 1 ”, “LPF 2 ”, “G ADPT ” in FIG. 7 .
  • the circuit of FIG. 8 comprises a feedback loop possible complication for the design with respect to stability, like in FIG. 5 , is not to be expected since this feedback loop contains less elements in the loop; the current source IBIAS and the GMR are not present in the feedback loop.
  • FIG. 10 shows a schematic of an inventive embodiment in which means are present for adapting the DC-current through the GMR and in which a further magnetic field H 3 sin ⁇ 3 t having the third frequency ⁇ 3 is present.
  • the constructional difference of the circuit of FIG. 10 with the circuit of FIG. 5 is the presence of a further magnetic field generator implemented by a further AC-current source AC 3 and a further wire WR 3 .
  • the further AC-current source AC 3 supplies the further AC-current I 3 sin ⁇ 3 t through the further wire WR 3 which as a response generates the further magnetic field H 3 sin ⁇ 3 t.
  • the object signal U OB is now not synchronously detected on a frequency 2 ⁇ 2 but on either ⁇ 3 ⁇ 2 , ⁇ 3 + ⁇ 2 , or ⁇ 1 .
  • This is performed by the first multiplier MP 1 which multiplies the object signal U OB with either cos( ⁇ 3 ⁇ 2 )t, cos( ⁇ 3 + ⁇ 2 )t, sin ⁇ 1 t, or a combination of these three signals.
  • FIG. 9 schematically shows an example of an advantageous location for the further wire WR 3 for generating the further magnetic field H 3 sin ⁇ 3 t. Because the further wire WR 3 is located below the GMR the further magnetic field does not (or hardly) reach the superparamagnetic beads SPB. This is because the GMR forms a shield for the further magnetic field. Further also the distance from the further wire WR 3 to the superparamagnetic beads SPB is relatively large compared to the distance from the beads to the GMR.
  • the wire WR 3 may also be located adjacent to the GMR. Now the beads SPB are closer to the wire WR 3 , so that the beads SPB may disturb the measurement of the sensitivity S GMR of the GMR. This effect can be suppressed by measuring the sensitivity S GMR at a frequency well above the response bandwidth of the magnetic beads SPB, thus at a frequency
  • the time constant ⁇ neel is the so-called Neel relaxation time (see for Neel relaxation: “Journal of Magnetism and Magnetic Materials 194 (1999) page 62 by R. Kötiz et al.)
  • a wire WR 3 adjacent (or below the GMR) generates a DC magnetic field in order to control the sensitivity s GMR .
  • This approach will probably generate a non-neglectable field gradient, which may actuate beads SPB. Generating the DC field only during gain stabilization and during the bio-measurement (measuring the response from the beads) can minimize this effect.
  • the sensitivity s GMR is controlled by varying the strength or the position (translation, rotation) of an external magnet (permanent or electromagnet) with respect to the biochip.
  • the external magnet also generates a fluctuating magnetic field in the GMR in order to perform the measurement of the sensitivity s GMR .
  • FIG. 11 shows a schematic of an inventive embodiment which comprises gain adaptation means for adapting the gain value in the electronic transfer from the electrical object signal U OB to the electrical output signal U 0 and in which the further magnetic field generator having the third frequency ⁇ 3 is present.
  • the construction of this circuit is similar to the circuit of FIG. 7 but with the addition of the further magnetic field generator comprising the wire WR 3 , and the AC-current source AC 3 .
  • the addition of the further magnetic field generator is for the same reasons as mentioned earlier with reference to FIG. 10 .
  • FIG. 12 shows a schematic of an inventive embodiment, as an alternative for the embodiment as shown in FIG. 10 , in which the DC-value in the further magnetic field is adapted by adapting an addition DC-current source which supplies a DC-component I DC3 through the wire WR 3 in stead of adapting the DC-current source I BIAS .
  • FIGS. 13 and 14 show an array of sensors in which one inventive sensor acts as a reference sensor RFS and in which the steepness of the GMRs in the other biosensor arrays BSA is stabilized with the help of information derived from the reference sensor RFS.
  • the DC sense current i s of each sensor is corrected by the same gain correcting value.
  • ⁇ represents the detection of the second harmonic of the sense current i s in the reference sensor RFS.
  • the output of loop filter ⁇ which represent the gain correcting value, controls the amplitude of the DC sense current in each sensor. It is assumed that the GMR gain variations are the same for each sensor in the array. This is a good assumption since the sensors are located close to each other on the same biochip.
  • the system of FIG. 14 comprises wires (coils) which generate adaptable DC-magnetic fields towards the respective GMRs for controlling the GMRs (in stead of controlling the GMRs by adapting the DC-currents through the GMRs).

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US7508200B2 (en) 2009-03-24
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WO2006059270A2 (en) 2006-06-08
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