US20100117641A1 - Detection of magnetic beads using a magnetoresistive device together with ferromagnetic resonance - Google Patents

Detection of magnetic beads using a magnetoresistive device together with ferromagnetic resonance Download PDF

Info

Publication number
US20100117641A1
US20100117641A1 US11/528,878 US52887806A US2010117641A1 US 20100117641 A1 US20100117641 A1 US 20100117641A1 US 52887806 A US52887806 A US 52887806A US 2010117641 A1 US2010117641 A1 US 2010117641A1
Authority
US
United States
Prior art keywords
bead
sensor
field
magnetic
fmr
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Granted
Application number
US11/528,878
Other versions
US7729093B1 (en
Inventor
Yuchen Zhou
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Headway Technologies Inc
Original Assignee
Headway Technologies Inc
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Headway Technologies Inc filed Critical Headway Technologies Inc
Priority to US11/528,878 priority Critical patent/US7729093B1/en
Assigned to HEADWAY TECHNOLOGIES, INC reassignment HEADWAY TECHNOLOGIES, INC ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: Zhou, Yuchen
Priority to US12/800,322 priority patent/US7835118B2/en
Priority to US12/800,324 priority patent/US7978444B2/en
Priority to US12/800,323 priority patent/US7835117B2/en
Priority to US12/800,321 priority patent/US7898777B1/en
Publication of US20100117641A1 publication Critical patent/US20100117641A1/en
Application granted granted Critical
Publication of US7729093B1 publication Critical patent/US7729093B1/en
Active legal-status Critical Current
Adjusted expiration legal-status Critical

Links

Images

Classifications

    • GPHYSICS
    • G01MEASURING; TESTING
    • G01NINVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N24/00Investigating or analyzing materials by the use of nuclear magnetic resonance, electron paramagnetic resonance or other spin effects
    • G01N24/10Investigating or analyzing materials by the use of nuclear magnetic resonance, electron paramagnetic resonance or other spin effects by using electron paramagnetic resonance
    • GPHYSICS
    • G01MEASURING; TESTING
    • G01NINVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N24/00Investigating or analyzing materials by the use of nuclear magnetic resonance, electron paramagnetic resonance or other spin effects
    • G01N24/08Investigating or analyzing materials by the use of nuclear magnetic resonance, electron paramagnetic resonance or other spin effects by using nuclear magnetic resonance
    • G01N24/088Assessment or manipulation of a chemical or biochemical reaction, e.g. verification whether a chemical reaction occurred or whether a ligand binds to a receptor in drug screening or assessing reaction kinetics
    • GPHYSICS
    • G01MEASURING; TESTING
    • G01RMEASURING ELECTRIC VARIABLES; MEASURING MAGNETIC VARIABLES
    • G01R33/00Arrangements or instruments for measuring magnetic variables
    • G01R33/20Arrangements or instruments for measuring magnetic variables involving magnetic resonance
    • G01R33/44Arrangements or instruments for measuring magnetic variables involving magnetic resonance using nuclear magnetic resonance [NMR]
    • G01R33/48NMR imaging systems
    • G01R33/54Signal processing systems, e.g. using pulse sequences ; Generation or control of pulse sequences; Operator console
    • G01R33/56Image enhancement or correction, e.g. subtraction or averaging techniques, e.g. improvement of signal-to-noise ratio and resolution
    • G01R33/5601Image enhancement or correction, e.g. subtraction or averaging techniques, e.g. improvement of signal-to-noise ratio and resolution involving use of a contrast agent for contrast manipulation, e.g. a paramagnetic, super-paramagnetic, ferromagnetic or hyperpolarised contrast agent

Definitions

  • the invention relates to the general field of magnetic field measurement with particular reference to that of magnetic beads that have been selectively bound to biological structures and/or large molecules.
  • the invention discloses a methodology for detecting magnetic beads, magnetic particles and magnetic nano-particles by inducing ferromagnetic resonance (FMR) of their magnetic moment and by using a magneto-resistive (MR) sensor to detect the magnetic field produced by the FMR. Binding these magnetic beads or particles to biological or chemical molecules thus enables the presence of these molecules to be detected.
  • FMR ferromagnetic resonance
  • MR magneto-resistive
  • Detection of biological or chemical molecules by using super-paramagnetic beads and particles as the labeling component and by using magneto-resistive sensors for detection of such labels is regarded as a promising technique to achieve accurate molecule counting with a resolution of several molecules or even a single molecule. It has the potential to enable fast, efficient, and economical biological applications, such as in-field virus and bacteria detection.
  • Binding assays to detect target molecules is a widely used technique in the biological, biochemical, and medical communities.
  • the selective bindings commonly used include polynucleic acid bindings or hybridizations involving RNA and DNA, many types of ligand-to-receptor bindings, as well as antibody to antigen bindings.
  • the target molecules in these bindings for example, proteins or DNA, can also be a distinctive component or product of viruses, bacteria and cells, which may be the actual objects of interest for the detection.
  • the binding molecules are attached to a solid substrate as “capture molecules”.
  • capture molecules When the assay is exposed to a liquid-form sample, where the target molecules attached to a physical label are contained, the binding molecules capture the target molecules with the selective bindings and immobilize the target molecules on the surface. This capture process is called “recognition”.
  • the recognition events can be made to generate detectable signals from the attached labels and, consequently, the presence or absence of a target molecule can be detected.
  • the labels originally attached to the target molecule are also immobilized on the surface after the recognition process.
  • the labels are either bound together with the target molecules on the surface (“sandwich” assay) or are by themselves (“competitive” assay). After the removal of non-bound labels, the bound labels can then be made to generate measurable signals.
  • the MR devices When using magnetic beads or particles as the labeling component and a MR sensor as the detector, the MR devices are embedded below the binding surface and are usually covered by a protective layer. When the magnetic beads or particles are bound to the surface above a MR sensor, they can generate a magnetic field spontaneously or, in the case of super-paramagnetic beads or particles, if an applied magnetic field is present. This magnetic field from the beads or particles can be sensed by the MR device, which can then provide a voltage signal.
  • the magnetic labels described in published studies or as patents are usually super-paramagnetic beads—nano-particles (or larger beads that comprise nano-particles suspended in a non-magnetic matrix) that have no magnetization at room temperature without an externally applied magnetic field because of the super-paramagnetic effect.
  • Such labels are desired in biological applications because they do not aggregate (at zero field).
  • the beads or particles described in the prior art usually range in size from tens of nanometers to several microns.
  • the magnetic labels When the magnetic labels are attached to the MR sensor top surface, the field generated by the magnetic moment of the beads or particles will either act directly on the underlying MR sensor or it may cancel a portion of the applied magnetic field acting on the sensor. For sensors that have no attached labels, the magnetic field from the magnetic labels is not present.
  • FIG. 1 is a schematic representation of the scheme outlined above.
  • Magnetic bead 1 (which term will, hereinafter, be assumed to include magnetic beads, as well as particles and nano-particles) is attached to the MR sensor surface by the binding pairs 5 after recognition.
  • the MR sensor used or referred is usually a giant-magneto-resistive (GMR) or a tunneling-magneto-resistive (TMR) sensor, which contains a magnetic free layer 2 , a non-magnetic spacer layer 3 and a magnetic reference layer 4 .
  • Spacer 3 is usually a conductive layer for GMR sensors and insulator for TMR sensors.
  • Magnetization of reference layer 4 as represented by M reference is fixed (i.e. ‘pinned’) in the X axis direction by an exchange field from other magnetic layers below it, which are not shown in the figure.
  • the pinned layer does not change its magnetization direction under normal magnetic fields.
  • a bias DC field H bias is usually applied in the Y direction by a pair of opposing hard magnets on the sides of the sensor, so that the free layer's magnetization will be in the Y axis direction when no magnetic field is applied.
  • this free layer alignment to Y axis can also be achieved by making the sensor dimension in the Y axis longer than in X axis due to the shape anisotropy.
  • the magnetization of the free layer 2 can only rotate freely in the XY plane when a transverse field is applied along the X axis direction and it is very difficult to rotate outside the XY plane, i.e. towards the Z axis.
  • R 0 is the base resistance of the sensor
  • ⁇ R is the full range resistance change of the sensor
  • is the angle between the magnetization of the reference layer and the free layer.
  • a reference sensor to which beads will not attach to at any time is normally used for comparison of this voltage difference.
  • the applied field can also be a modulated by an AC field that will induce a same frequency AC voltage across the sensor.
  • Another bead sensing scheme is to apply a DC field perpendicular to the film plane, i.e. along the Z axis direction in FIG. 1 , with no bias field at all being present.
  • This DC field serves to magnetize the super-paramagnetic bead moment vertically.
  • the in plane component of the field generated by the vertical bead moment will rotate the free layer magnetizations in the upper XY plane and low XY plane towards or away from the Y axis at the same time.
  • the reference layer magnetization is aligned along the Y axis, or a multi-layer MR structure is used, this rotation will produce a resistance change. It is also called “scissoring mode” [11].
  • This scheme also needs a reference sensor for detection.
  • a potential problem common to all the previously published or patented bead-MR sensor detection methods is that they are prone to fluctuations in the magnetic signal. Since all these detection methods are mainly practiced in the low frequency region from several Hertz to several kHertz, 1/f noise is very significant. Although the lock-in technique can successfully suppress the noise from the electrical sources by its narrow bandwidth, the noise from magnetic sources, for example Barkhausen noise, popcorn noise and telegraph noise cannot be prevented from affecting the locked-in signal. These magnetic noise sources are related to domain and local magnetization switching of MR sensors and are always most predominant in the low frequency region and usually show up as signal level random fluctuations. For the scheme that requires a reference sensor for detection, this combined noise effect from both the detection sensor and the reference sensor will at least double this parasitic fluctuation of the signal level.
  • the bead itself will always have shape, size and magnetic content variations as well as binding site variations. These variations will also cause fluctuations of the amount of the bead magnetic field going into the sensor. With all the noise sources added together, these can be quite large and can cause significant signal fluctuations to inhibit practical binding assay applications that are based on the detection of the absolute field strength.
  • Another problem specifically for the field cancellation method is that a magnetic field needs to be applied in the sensing direction, i.e. X axis, to magnetize the magnetic beads and thus generate the cancellation field.
  • this relatively large amplitude field will rotate the MR sensor free layer magnetization to the place where its sensitivity is not the highest. In other words, when the bead field is highest, the sensor sensitivity is lowest.
  • second harmonic detection [7] can minimize the sensitivity loss.
  • the signal generated by the cancellation effect from the bead field is significantly decreased because it is only operating with a single bead field polarity and not a full reversal of the bead field direction in the transverse direction.
  • a current-in-plane (CIP) multilayer GMR sensor usually has a lower dR/R, i.e. lower signal, than the state-of-the-art TMR or carefully designed spin valve GMR sensors.
  • the current-perpendicular-to-plane (CPP) multilayer GMR sensors although possessing a much higher dR/R than the CIP ones, have also shown extraordinary magnetically related 1/f type noise in previous studies.
  • Another object of at least one embodiment of the present invention has been that said sensor be relatively insensitive to the precise location of a bead relative to the sensor as well as to the exact size of the bead.
  • Still another object of at least one embodiment of the present invention has been that said sensor be relatively insensitive to the presence of other nearby beads.
  • a further object of at least one embodiment of the present invention has been that said method not require the measurement of the absolute value of a magnetic field generated by the bead.
  • the oscillating magnetic field used to excite the bead to FMR may be generated in a number of ways including external means and in-situ generation.
  • FIG. 1 shows a prior art magnetic bead detector.
  • FIG. 2 illustrates the basic method of the invention, including the various magnetic fields that are needed to bring about FMR.
  • FIG. 3 is FIG. 2 viewed along the Y direction.
  • FIG. 4 plots the X component of the bead magnetization vs. time after the AC field is applied in the Y axis direction for three different values of h AC .
  • FIGS. 5A-5D show four embodiments of the invention that have the following features in common: H DC in the Z direction and h AC in the Y direction.
  • FIGS. 6A-6F show five embodiments of the invention that have the following features in common: H DC in the Z direction and h AC in the X direction.
  • FIGS. 7A-7D show four embodiments of the invention that have the following features in common: H DC in the Y direction and h AC in the Z direction.
  • FIGS. 7E-7F show two embodiments similar to FIGS. 7A and 7B respectively, but with H bias provided by external magnets as in FIG. 5A .
  • FIGS. 8A-8B are similar to FIGS. 5 thru 6 and FIG. 7 , respectively, except that the overlapping field generating stripes are not required to be orthogonal to one another.
  • FIG. 9 illustrates a method for determining the spatial location of any particular bead that is part of an array of beads.
  • FIG. 2A shows a schematic view of the detection of FMR in an excited magnetic bead by a MR sensor.
  • Free layer 2 of the MR sensor is in the XY plane.
  • a Y axis direction DC field H bias (applied or anisotropy driven) in the sensor serves to maintain the free layer magnetization along the Y axis direction when there is no transverse X axis field applied. Note that, although we refer to a free layer when we describe the invention, we do so as a matter of convenience rather than to exclude other methods for detecting magnetic fields such as normal (i.e. not giant) magnetoresistance.
  • Magnetic bead 1 lies above the top surface of the sensor.
  • An externally applied static field H DC perpendicular to the sensor film plane orients the bead magnetization in the Z axis direction. Since the sensor only responds to X axis direction transverse fields, this DC field will not cause sensor resistance to change.
  • a low amplitude, high frequency, sinusoidal AC field h AC is applied in the Y axis direction to induce ferromagnetic resonance of the bead magnetization.
  • This Y axis sinusoidal field does not itself cause the free layer magnetization to rotate as long as it is much smaller than H bias .
  • FIG. 2 we illustrate the basic effect of FMR on the magnetic moment of a bead excited by an AC magnetic field h AC in the presence of a DC magnetic field H DC .
  • MR sensor magnetization is oriented in the Y axis direction by a bias DC field H bias .
  • the magnetic field generated by the resonating bead's magnetic moment is sensed by the MR sensor's free layer below.
  • the X component of the resonating bead's moment generates a transverse field in the sensor free layer which leads to an AC voltage across the sensor at the FMR frequency.
  • this causes the free layer magnetization to rotate. Since m x has the same frequency, the free layer magnetization will be modulated at this frequency by the bead field. This modulation further leads to a voltage alternating at the same frequency as that of the sensor (which usually implies the free layer). Thus, by tuning the structure so as to achieve resonance, one can be certain that any modulation of the sensor's output derives from the bead(s).
  • FIG. 4 shows simulation of the X component of the magnetic bead's moment as a function of time for the detection structure shown in FIG. 2 .
  • the FMR frequency at a DC field of 100 Oe is about 280 MHz. 4.
  • a reference sensor is not needed for signal detection. Measurement of the relative amplitude or phase of the FMR signal at different AC field frequencies at a constant DC field, or at the same AC field frequency but varying DC fields, will indicate the presence of a magnetic bead. For example, by keeping the DC and AC field amplitudes constant while sweeping the AC field frequency from a value lower than ⁇ r to a frequency higher than ⁇ r , while simultaneously measuring the sensor signal at the same frequency.
  • the sensor signal When a magnetic bead is present the sensor signal peaks at ⁇ r but if there is no bead, the signal vs. AC field frequency will stay flat. Peak detection of the swept curve can thus be used as an indicator of a bead's presence. 5.
  • the method is insensitive to the precise location of the binding site of the bead on the MR sensor. In absolute field level detection methods the magnetic field level that the sensor sees (due to the bead) will be different for different binding sites. However, as discussed in the preceding paragraph, the frequency dependence of the signal on the AC field frequency will stay the same for a given bead. Therefore, if detection is achieved by sweeping the AC field frequency, local binding site variations will not affect the peaking of the AC signal at ⁇ r .
  • the method is relatively insensitive to bead size distribution.
  • Field cancellation methods are strongly affected by the beads' physical size distribution because each bead's magnetic moment is proportional to its volume. With a large bead size distribution, the magnetic field from the beads will fluctuate substantially.
  • the frequency dependence of the AC signal from each bead still stays the same. As long as this frequency dependence is used for detecting the beads' presence (and assuming sufficient bead field strength) the scheme that is taught by this invention will be insensitive to the bead size distribution.
  • the method is insensitive to the bead-sensor distance (see d in FIG. 3 ).
  • This feature may be used as the basis for a method to determine the spatial location of a single bead which may, or may not, be part of an array of similar, or identical, beads.
  • the method facilitates the simultaneous use of multiple beads whose resonance frequencies are not necessarily all the same, even in the same DC field.
  • examples include, but are not limited to, elongated magnetic beads and beads with a magnetic shell and a non-magnetic core. These structures will have different FMR frequencies from a spherical magnetic bead because of the shape anisotropy. It is also possible to vary the damping constant of the bead through control of its composition in order to shift the FMR frequency. In addition, magnetic beads formed from magnetic particles suspended in a nonmagnetic matrix will also exhibit different FMR resonance behavior, depending on the densities of the particles in the matrix. 10.
  • the magnetic beads used in the embodiments vary in shape, structure and composition as needed to obtain different bead FMR frequencies under the same DC field to enable bead labeling.
  • the applied DC magnetic field in the following embodiments is also the field used to magnetize the beads should they be super-paramagnetic.
  • the MR sensor for FMR detection is not limited to GMR and TMR sensors, but rather any thin film sensing device that can show a measurable change in the presence of a magnetic field.
  • the excited FMR of the bead moment produces an AC magnetic field in the MR sensor and subsequently an AC voltage signal across the sensor when a sensing current is applied.
  • the detection of the presence of the bead can be achieved by the following methods (list not intended to be exhaustive):
  • the absolute value of the bead field is detected i.e. if there is no bead there is no field.
  • This method is susceptible to bead field strength fluctuations caused by various sources. However, it still has the advantages that when detection is in the high frequency region, the MR sensor is at its maximum sensitivity and maximum bead magnetic field at a small FMR excitation field. Note that, for method (e) the AC field is not to be applied in the sensing direction of the MR sensor.
  • H DC is typically in the range of from about 1 and 1,000 Oe while h DC is typically in the range of from about 1 to 100 Oe.
  • FMR for beads on line 1 will occur at about 280 MHz while for a bead at the intersection of lines 92 and 93 it will occur at about 285.6 MHz.
  • the magnetic bead 1 is attached to the MR sensor 2 through biological or chemical binding pair 5 following a recognition process.
  • Two permanent magnets 6 on the sides of the sensor provide a biasing field in the MR sensor to orient the sensing layer magnetization in the Y axis direction.
  • a static field H DC is applied perpendicular to the sensor plane in the Z axis direction. This static field determines the FMR frequency of the bead magnetic moment. It also magnetizes the bead when the bead is super-paramagnetic.
  • a stripe line (or lines) 7 exists underneath the sensor or between the sensor and the bead, where an AC current I AC is used to produce an AC magnetic field h AC in the Y axis direction to excite the FMR of the bead magnetic moment.
  • the bead FMR then produces a rotating component in the XY plane.
  • the MR sensor 2 detects the oscillating magnetic field
  • every other aspect is the same as embodiment 1A except that the AC magnetic field h AC in the Y axis direction is generated not by stripe line (or lines), but externally by other means.
  • the AC magnetic field h AC in the Y axis direction is generated not by stripe line (or lines), but externally by other means.
  • RF coils or electromagnetic waves in a microwave cavity For example, RF coils or electromagnetic waves in a microwave cavity.
  • biasing DC field H bias is applied externally or generated by the anisotropy field of the sensor.
  • H DC and H bias as well if applied externally determines the FMR frequency of the bead magnetic moment.
  • every other aspect is the same as embodiment 1C except that the AC magnetic field h AC is generated not by stripe line (or lines), but externally by other means.
  • the AC magnetic field h AC is generated not by stripe line (or lines), but externally by other means.
  • RF coils or electromagnetic waves For example, RF coils or electromagnetic waves.
  • every other aspect is the same as embodiment 1A except that the stripe line (or lines) 7 that is underneath the sensor or between the sensor and the bead, is now used to produce an AC magnetic field h AC in the X direction to excite the FMR of the bead magnetic moment when an AC current I AC flows through it.
  • the MR sensor 2 detects both h AC and the field generated by the bead moment.
  • the difference of the bead field cancellation of h AC in the MR sensor at different driving frequencies can be used as the mechanism for detection.
  • the cancellation of h AC is preferably measured in the same phase as h AC .
  • every other aspect is the same as embodiment 2A except that the AC magnetic field h AC in the X axis direction to excite the FMR of the bead magnetic moment is generated not by a stripe line (or lines), but externally with other means.
  • a stripe line or lines
  • other means for example, RF coils or electromagnetic waves.
  • biasing DC field H bias is applied externally or generated by the anisotropy field of the sensor.
  • H DC and H bias as well if applied externally determines the FMR frequency of the bead magnetic moment.
  • every other aspect is the same as embodiment 2C except that the AC magnetic field h AC in the X axis direction to excite the FMR of the bead magnetic moment is generated not by a stripe line (or lines), but externally by other means. For example, coils or electromagnetic waves.
  • every other aspect is the same as embodiment 2A except that the DC field H DC is applied in the Y axis direction, which also serves as a biasing field to orient the sensor layer magnetization of the MR sensor in the Y axis direction.
  • the AC magnetic field h AC in the X axis direction to excite the FMR of the bead magnetic moment is generated not by a stripe line (or lines), but externally by other means.
  • a stripe line or lines
  • other means for example, RF coils or electromagnetic waves.
  • bead 1 is attached to the MR sensor 2 through biological or chemical binding pair 5 after the recognition process.
  • a DC field H DC is applied in the sensor plane in the Y axis direction.
  • H DC determines the FMR frequency of the bead magnetic moment and can also serve as a bias field to orient the sensor layer magnetization of the MR sensor in the Y axis direction. It also magnetizes the bead when the bead is super-paramagnetic.
  • An AC magnetic field h ac is applied in the Z direction to excite the FMR of the bead magnetic moment. This AC field is generated by a pair of stripe lines 7 on the sides or over the top or underneath the MR sensor. The AC currents flowing in the lines are constantly in the opposite direction to produce a net vertical AC field in the sensor.
  • the MR sensor 2 detects the field generated by the bead moment during the excited FMR.
  • every other aspect is the same as embodiment 3A except that the pair of stripe lines 7 that produce the AC magnetic field h AC in the Z direction is now oriented in the X direction.
  • this pair of lines can be oriented in any direction in the XY plane as the Z axis field is not affected by their orientation.
  • every other aspect is the same as embodiment 3A except that the AC magnetic field h AC in the Z axis direction to excite the FMR of the bead magnetic moment is generated by coil 7 (single or mufti turn) around, below or above the top of the sensor.
  • the AC current flowing in the coil produces a vertical AC field.
  • every other aspect is the same as embodiment 3A except that the AC magnetic field h AC in the Z direction to excite the FMR of the bead magnetic moment is applied externally with RF coils or electromagnetic waves.
  • m x magnitude is a function of frequency
  • the voltage signal generated by the MR sensor at the same AC field amplitude but different AC field frequencies will have different output amplitudes as well.
  • This amplitude dependence of the sensor's voltage output on frequency can be used as the mechanism for the detection of the presence of the magnetic beads.
  • the sensor will theoretically have no output dependence on the AC field frequency because of the absence of the bead m x component.
  • FIGS. 7E and 7F these are the same as embodiments 3A and 3B respectively, except that the longitudinal bias is supplied by permanents as shown, for example, in FIG. 5A .
  • FIGS. 8A and 8B these relate to embodiments 1A-2F and 3A, 3B, 3E, 3F respectively but show that the field generating stripes and the free layer's long axis do not have to be orthogonal to one another but, rather, are required only to be as close to coplanar as their thickness permits.
  • phase of m relative to h AC
  • h AC the phase of m, relative to h AC
  • this phase dependence on the h AC frequency will also show up in the sensor's AC voltage signal and can be used as a detectable physical quantity as well.

Abstract

A method and apparatus for detecting the presence of magnetic beads is disclosed. By providing both a static magnetic field and a magnetic field that alternates in the MHz range, or beyond, the bead can be excited into FMR (ferromagnetic resonance). The appearance of the latter is then detected by a magneto-resistive type of sensor. This approach offers several advantages over prior art methods in which the magnetic moment of the bead is detected directly.

Description

    FIELD OF THE INVENTION
  • The invention relates to the general field of magnetic field measurement with particular reference to that of magnetic beads that have been selectively bound to biological structures and/or large molecules.
  • BACKGROUND OF THE INVENTION
  • The invention discloses a methodology for detecting magnetic beads, magnetic particles and magnetic nano-particles by inducing ferromagnetic resonance (FMR) of their magnetic moment and by using a magneto-resistive (MR) sensor to detect the magnetic field produced by the FMR. Binding these magnetic beads or particles to biological or chemical molecules thus enables the presence of these molecules to be detected. In the form of a binding assay, where a matrix of MR sensors are patterned, this method can be used to identify the presence of a molecule of interest as well as to quantify its population. This method can address many other issues in the prior art that also utilize magnetic bead labeling and MR sensing, thus making this technology widely applicable.
  • Detection of biological or chemical molecules by using super-paramagnetic beads and particles as the labeling component and by using magneto-resistive sensors for detection of such labels is regarded as a promising technique to achieve accurate molecule counting with a resolution of several molecules or even a single molecule. It has the potential to enable fast, efficient, and economical biological applications, such as in-field virus and bacteria detection.
  • Binding assays to detect target molecules is a widely used technique in the biological, biochemical, and medical communities. The selective bindings commonly used include polynucleic acid bindings or hybridizations involving RNA and DNA, many types of ligand-to-receptor bindings, as well as antibody to antigen bindings. The target molecules in these bindings, for example, proteins or DNA, can also be a distinctive component or product of viruses, bacteria and cells, which may be the actual objects of interest for the detection.
  • In a binding assay, the binding molecules are attached to a solid substrate as “capture molecules”. When the assay is exposed to a liquid-form sample, where the target molecules attached to a physical label are contained, the binding molecules capture the target molecules with the selective bindings and immobilize the target molecules on the surface. This capture process is called “recognition”. The recognition events can be made to generate detectable signals from the attached labels and, consequently, the presence or absence of a target molecule can be detected.
  • In various prior art techniques utilizing the labeled binding process, the labels originally attached to the target molecule are also immobilized on the surface after the recognition process. The labels are either bound together with the target molecules on the surface (“sandwich” assay) or are by themselves (“competitive” assay). After the removal of non-bound labels, the bound labels can then be made to generate measurable signals.
  • When using magnetic beads or particles as the labeling component and a MR sensor as the detector, the MR devices are embedded below the binding surface and are usually covered by a protective layer. When the magnetic beads or particles are bound to the surface above a MR sensor, they can generate a magnetic field spontaneously or, in the case of super-paramagnetic beads or particles, if an applied magnetic field is present. This magnetic field from the beads or particles can be sensed by the MR device, which can then provide a voltage signal.
  • The magnetic labels described in published studies or as patents are usually super-paramagnetic beads—nano-particles (or larger beads that comprise nano-particles suspended in a non-magnetic matrix) that have no magnetization at room temperature without an externally applied magnetic field because of the super-paramagnetic effect. Such labels are desired in biological applications because they do not aggregate (at zero field). The beads or particles described in the prior art usually range in size from tens of nanometers to several microns. When the labels are attached to a surface after the recognition process, either single or multiple labels are attached to each MR device. However, the sensing mechanism has generally been the same for all the previous designs. When the magnetic labels are attached to the MR sensor top surface, the field generated by the magnetic moment of the beads or particles will either act directly on the underlying MR sensor or it may cancel a portion of the applied magnetic field acting on the sensor. For sensors that have no attached labels, the magnetic field from the magnetic labels is not present.
  • FIG. 1 is a schematic representation of the scheme outlined above. Magnetic bead 1 (which term will, hereinafter, be assumed to include magnetic beads, as well as particles and nano-particles) is attached to the MR sensor surface by the binding pairs 5 after recognition. The MR sensor used or referred is usually a giant-magneto-resistive (GMR) or a tunneling-magneto-resistive (TMR) sensor, which contains a magnetic free layer 2, a non-magnetic spacer layer 3 and a magnetic reference layer 4. Spacer 3 is usually a conductive layer for GMR sensors and insulator for TMR sensors. Magnetization of reference layer 4, as represented by Mreference is fixed (i.e. ‘pinned’) in the X axis direction by an exchange field from other magnetic layers below it, which are not shown in the figure.
  • The pinned layer does not change its magnetization direction under normal magnetic fields. In a conventional MR sensor, a bias DC field Hbias is usually applied in the Y direction by a pair of opposing hard magnets on the sides of the sensor, so that the free layer's magnetization will be in the Y axis direction when no magnetic field is applied. However, this free layer alignment to Y axis can also be achieved by making the sensor dimension in the Y axis longer than in X axis due to the shape anisotropy. Because of the shape anisotropy, the magnetization of the free layer 2, as represented by Mfree, can only rotate freely in the XY plane when a transverse field is applied along the X axis direction and it is very difficult to rotate outside the XY plane, i.e. towards the Z axis.
  • If a magnetic field is applied in the X axis direction, the free layer magnetization rotates away from the Y axis and the resistance of the entire MR junction will change according to

  • R=R 0 −ΔR cos θ
  • where R0 is the base resistance of the sensor, ΔR is the full range resistance change of the sensor and θ is the angle between the magnetization of the reference layer and the free layer. With a DC current applied to the device, where the current can either flow in the XY plane or perpendicularly through the device, the voltage across the device will change, because of the resistance change, to produce a measurable voltage signal.
  • In prior studies and patents, several detection schemes were used. One commonly used scheme is to apply a magnetic field in the transverse direction [4-10, 12-13], e.g. along the X axis as in FIG. 1. Super-paramagnetic beads are also used. When a super-paramagnetic bead is bound to the top surface of the MR sensor, this applied field can magnetize the bead magnetization along the field direction. The bead magnetic moment in turn will produce a magnetic field in the MR sensor below and partially cancel the original applied magnetic field acting on the MR sensor. Therefore, the voltage across the sensor when a bead is present is different than when there is no bead attached at the same applied field condition and the presence of the bead is detected by this voltage amplitude difference.
  • It is important to note that these prior art methods use applied magnetic fields oscillating at frequencies less than 100 kHz (often much less) whereas the present invention requires frequencies in the MHZ (and higher) region.
  • A reference sensor to which beads will not attach to at any time is normally used for comparison of this voltage difference. During the detection, the applied field can also be a modulated by an AC field that will induce a same frequency AC voltage across the sensor. By utilizing a lock-in technique, the signal to noise ratio can be enhanced.
  • Another bead sensing scheme, also known as BARC [1-3,11], is to apply a DC field perpendicular to the film plane, i.e. along the Z axis direction in FIG. 1, with no bias field at all being present. This DC field serves to magnetize the super-paramagnetic bead moment vertically. The in plane component of the field generated by the vertical bead moment will rotate the free layer magnetizations in the upper XY plane and low XY plane towards or away from the Y axis at the same time. If the reference layer magnetization is aligned along the Y axis, or a multi-layer MR structure is used, this rotation will produce a resistance change. It is also called “scissoring mode” [11]. This scheme also needs a reference sensor for detection.
  • A potential problem common to all the previously published or patented bead-MR sensor detection methods is that they are prone to fluctuations in the magnetic signal. Since all these detection methods are mainly practiced in the low frequency region from several Hertz to several kHertz, 1/f noise is very significant. Although the lock-in technique can successfully suppress the noise from the electrical sources by its narrow bandwidth, the noise from magnetic sources, for example Barkhausen noise, popcorn noise and telegraph noise cannot be prevented from affecting the locked-in signal. These magnetic noise sources are related to domain and local magnetization switching of MR sensors and are always most predominant in the low frequency region and usually show up as signal level random fluctuations. For the scheme that requires a reference sensor for detection, this combined noise effect from both the detection sensor and the reference sensor will at least double this parasitic fluctuation of the signal level.
  • Besides the fluctuations from the sensor, the bead itself will always have shape, size and magnetic content variations as well as binding site variations. These variations will also cause fluctuations of the amount of the bead magnetic field going into the sensor. With all the noise sources added together, these can be quite large and can cause significant signal fluctuations to inhibit practical binding assay applications that are based on the detection of the absolute field strength.
  • Another problem specifically for the field cancellation method is that a magnetic field needs to be applied in the sensing direction, i.e. X axis, to magnetize the magnetic beads and thus generate the cancellation field. However, this relatively large amplitude field will rotate the MR sensor free layer magnetization to the place where its sensitivity is not the highest. In other words, when the bead field is highest, the sensor sensitivity is lowest. By proper design of the MR sensor film structure and by using a vertical AC field to mimic the scissoring mode, second harmonic detection [7] can minimize the sensitivity loss. But the signal generated by the cancellation effect from the bead field is significantly decreased because it is only operating with a single bead field polarity and not a full reversal of the bead field direction in the transverse direction.
  • For the scissoring mode, where the bead is magnetized vertically, there is no sensitivity concern. However, this mode requires a relatively large sensor size. For a sub-micron or deep submicron size sensor, the exchange energy within the free layer will degrade the amount of rotation achievable for the two regions of the sensor rotating against each other. A low bias field, Hbias, or no bias field may be needed, which can easily lead to instability in a micron size sensor because of weak or no free layer domain control. In addition, for a GMR or TMR sensor with a single free layer, since this scheme only utilizes the sensor free layer magnetization rotation between 0 and 90 degrees, half of the sensor sensitivity region is not used.
  • For a multilayer GMR sensor, the rotation of magnetization can theoretically reach maximum or 0 to 180 degrees. A current-in-plane (CIP) multilayer GMR sensor usually has a lower dR/R, i.e. lower signal, than the state-of-the-art TMR or carefully designed spin valve GMR sensors. The current-perpendicular-to-plane (CPP) multilayer GMR sensors although possessing a much higher dR/R than the CIP ones, have also shown extraordinary magnetically related 1/f type noise in previous studies.
  • This noise can be more than 10 dB over the sensor's Johnson noise level in a micron size multilayer device and it will severely degrade the SNR of the sensor. To overcome the above problems, what is needed is, first, a scheme that can avoid having the bead magnetizing field affect the sensor free layer as well as utilizing the full reversal of the bead magnetization to gain maximum signal. Second, to avoid fluctuation of the bead magnetic field or the sensor resistance due to various magnetic sources, the method should not rely on detection of the absolute bead field magnitude. Third, signal detection at much higher frequencies than currently being explored (<100 kHz), for example beyond 1 MHz, is preferred in order to reduce low frequency noise effects.
  • A routine search of the prior art was performed with the following references of interest being found:
    • [1] D. R. Baselt et al., “A biosensor based on magnetoresistance technology,” Biosens. Bioelectron., vol. 13, pp. 731-739, October 1998.
    • [2] R. L. Edelstein et al., “The BARC biosensor applied to the detection of biological warfare agents,” Biosens. Bioelectron., vol. 14, pp. 805-813, January 2000.
    • [3] M. M. Miller et al., “A DNA array sensor utilizing magnetic microbeads and magnetoelectronic detection,” J. Magn. Magn. Mater., vol. 225, pp. 138-144, April 2001.
    • [4] D. L. Graham, H. Ferreira, J. Bernardo, P. P. Freitas, and J. M. S. Cabral, “Single magnetic microsphere placement and detection on-chip using current line designs with integrated spin valve sensors: Biotechnological applications,” J. Appl. Phys., vol. 91, pp. 7786-7788, May 2002.
    • [5] H. Ferreira, D. L. Graham, P. P. Freitas, and J. M. S. Cabral, “Biodetection using magnetically labeled biomolecules and arrays,” J. Appl. Phys., vol. 93, pp. 7281, May 2003.
    • [6] G. Li et al., “Detection of single micron-sized magnetic bead and magnetic nanoparticles using spin valve sensors for biological applications,” J. Appl. Phys., vol. 93, pp. 7557-7559, May 2003.
    • [7] G. Li, S. X. Wang and S. Sun, “Model and experiment of detecting multiple magnetic nanoparticles as biomolecular labels by spin valve sesnors,” IEEE Trans. Magn., vo 1.40, pp. 3000, 2004
    • [8] S. X. Wang et al., “Towards a magnetic microarray for sensitive diagnostics,” J. Magn. Magn. Mater., vol. 293, pp. 731-736, 2005.
    • [9] W. Shen, X. Liu, D. Mazumdar and G. Xiao, “In situ detection of single micron-sized magnetic beads using magnetic,” Appl. Phys. Lett., vol. 86, pp. 253901, 2005.
    • [10] H. Ferreira, N. Feliciano, D. L. Graham and P. P. Freitas, “Effect of spin-valve sensor magnetostatic fields on nanobead detection,” J. Appl. Phys., vol. 97, pp. 10Q904, 2005.
    • [11] D. R. Baselt, “Biosensor using magnetically detected label,” U.S. Pat. No. 5,981,297 (1999) teaches that a change in output of MR sensors indicates the presence of magnetic particles.
    • [12] M. C. Tondra, “Magnetizable Bead Detector,” U.S. Pat. No. 6,743,639 B1 (2004)
    • [13] M. C. Tondra, “Magnetizable Bead Detector,” U.S. Pat. No. 6,875,621 B2 (2005); this, and ref. 12 above, shows an MR sensor in a bridge circuit which may comprise interconnected individual sensors adjacent to the binding molecule layer.
    • [14] U.S. Pat. No. 6,518,747 (Sager et al) discloses applying an AC signal to excite Hall sensors in a DC field to detect magnetic particles.
    • [15] U.S. Patent Application 2006/0020371 (Ham et al) discusses FMR detection of magnetic beads.
    SUMMARY OF THE INVENTION
  • It has been an object of at least one embodiment of the present invention to provide a sensor for the detection of magnetic beads together with a method for utilizing said sensor.
  • Another object of at least one embodiment of the present invention has been that said sensor be relatively insensitive to the precise location of a bead relative to the sensor as well as to the exact size of the bead.
  • Still another object of at least one embodiment of the present invention has been that said sensor be relatively insensitive to the presence of other nearby beads.
  • A further object of at least one embodiment of the present invention has been that said method not require the measurement of the absolute value of a magnetic field generated by the bead.
  • These objects have been achieved by exciting FMR (ferromagnetic resonance) in the bead and then detecting the rotating magnetic field that the bead emits while in the resonance state. Our preferred means for detecting said rotating field has been a magneto-resistive detector such as a GMR (giant magnetic resistance) or TMJ (tunneling magnetic junction) device, though the method can be effectively used with any device capable of detecting magnetic fields as low as 1 Oe that are oscillating at frequencies in the MHz to GHz range. As a practical matter, the lowest field that can be used will be determined by the intrinsic noise discrimination and detection sensitivity of the sensor. Additionally, the detection sensitivity can usually be improved by narrowing the band width of the signal that is being detected.
  • The oscillating magnetic field used to excite the bead to FMR may be generated in a number of ways including external means and in-situ generation.
  • BRIEF DESCRIPTION OF THE DRAWINGS
  • FIG. 1 shows a prior art magnetic bead detector.
  • FIG. 2 illustrates the basic method of the invention, including the various magnetic fields that are needed to bring about FMR.
  • FIG. 3 is FIG. 2 viewed along the Y direction.
  • FIG. 4 plots the X component of the bead magnetization vs. time after the AC field is applied in the Y axis direction for three different values of hAC.
  • FIGS. 5A-5D show four embodiments of the invention that have the following features in common: HDC in the Z direction and hAC in the Y direction.
  • FIGS. 6A-6F show five embodiments of the invention that have the following features in common: HDC in the Z direction and hAC in the X direction.
  • FIGS. 7A-7D show four embodiments of the invention that have the following features in common: HDC in the Y direction and hAC in the Z direction.
  • FIGS. 7E-7F show two embodiments similar to FIGS. 7A and 7B respectively, but with Hbias provided by external magnets as in FIG. 5A.
  • FIGS. 8A-8B are similar to FIGS. 5 thru 6 and FIG. 7, respectively, except that the overlapping field generating stripes are not required to be orthogonal to one another.
  • FIG. 9 illustrates a method for determining the spatial location of any particular bead that is part of an array of beads.
  • DESCRIPTION OF THE PREFERRED EMBODIMENTS
  • In the detection schemes to be described below, a uniform magnetization of the magnetic bead is assumed. The bead is only required to have a magnetic moment, either spontaneous or induced, when in the field. FIG. 2A shows a schematic view of the detection of FMR in an excited magnetic bead by a MR sensor. Free layer 2 of the MR sensor is in the XY plane. A Y axis direction DC field Hbias (applied or anisotropy driven) in the sensor serves to maintain the free layer magnetization along the Y axis direction when there is no transverse X axis field applied. Note that, although we refer to a free layer when we describe the invention, we do so as a matter of convenience rather than to exclude other methods for detecting magnetic fields such as normal (i.e. not giant) magnetoresistance.
  • Magnetic bead 1 lies above the top surface of the sensor. An externally applied static field HDC perpendicular to the sensor film plane orients the bead magnetization in the Z axis direction. Since the sensor only responds to X axis direction transverse fields, this DC field will not cause sensor resistance to change. Then, a low amplitude, high frequency, sinusoidal AC field hAC is applied in the Y axis direction to induce ferromagnetic resonance of the bead magnetization. This Y axis sinusoidal field does not itself cause the free layer magnetization to rotate as long as it is much smaller than Hbias.
  • Basis of the Invention:
  • In FIG. 2 we illustrate the basic effect of FMR on the magnetic moment of a bead excited by an AC magnetic field hAC in the presence of a DC magnetic field HDC. MR sensor magnetization is oriented in the Y axis direction by a bias DC field Hbias. The magnetic field generated by the resonating bead's magnetic moment is sensed by the MR sensor's free layer below. The X component of the resonating bead's moment generates a transverse field in the sensor free layer which leads to an AC voltage across the sensor at the FMR frequency.
  • As shown in FIG. 3, this causes the free layer magnetization to rotate. Since mx has the same frequency, the free layer magnetization will be modulated at this frequency by the bead field. This modulation further leads to a voltage alternating at the same frequency as that of the sensor (which usually implies the free layer). Thus, by tuning the structure so as to achieve resonance, one can be certain that any modulation of the sensor's output derives from the bead(s).
  • FIG. 4 shows simulation of the X component of the magnetic bead's moment as a function of time for the detection structure shown in FIG. 2. HDC for the simulation was 100 Oe, a damping constant of about 0.02 was used, with the Y axis AC field (hAC) frequency being that of the bead resonance frequency ωr, for a 100 Oe field (279.73 MHz). Results for three different values of hAC are shown. Curve 41 is for 1 Oe, curve 42 is for 2 Oe, and curve 43 is for 5 Oe. These show that, for a 0.02 damping constant, a 5 Oe AC field is already enough to generate a full amplitude resonance of the bead moment, i.e. mx=mbead, at the given condition.
  • In first order calculations, the super-paramagnetic effect is not considered. For super-paramagnetic beads, a hAC field beyond 10 Oe may not be trivial for an HDC=50 Oe or 100 Oe. The AC field can also cause the bead moment to vary in magnitude instead of just direction.
  • Besides the comparison of the oscillation amplitude of bead moment at different frequencies or different DC fields, another way to detect the presence of a magnetic bead is to check the existence of an mx component at an AC field near or at a bead's resonant frequency at the given DC field. When there is no bead, no mx component is present. This method is an absolute signal level detection method so it is susceptible to bead field strength variations from various sources as in the prior art. However, it still has the advantage of detection at the bead FMR that produces the largest mx amplitude, i.e. highest detectable signal, using a relatively small excitation AC field.
  • The mx component of the bead magnetic moment will linearly influence the sensor's resistance change. Several previous studies [7,10] demonstrated a straightforward way to estimate the signal level from a GMR or TMR sensor with a given magnetic bead that has a magnetic moment in the X axis direction. The MR signal from the bead moment was reported to usually be a small portion of the entire dynamic range of the MR sensors, i.e. less than 1% to several percent of the dR/R. The signal of the bead FMR at the resonance frequency should be high enough to be picked up by available RF electronics with an applicable signal-to-noise-ratio (SNR). For example, in thermally excited FMR in GMR sensors, usually in the several GHz region and corresponding to less than 0.1% resistance fluctuation, has already been successfully measured with relatively simple RF circuitry [25]. Therefore, FMR detection schemes proposed for monitoring the mx component of the bead magnetic moment should be achievable by measuring the MR sensor voltage output.
  • In summary, use of FMR to detect the presence of beads offers the following advantages:
  • 1. The MR sensor responds to only the bead field during detection. The DC field for magnetizing super-paramagnetic beads and the AC excitation field can be applied in other than the sensing direction of the MR sensor. Thus there is no tradeoff needed between sensitivity and bead magnetic signal. In addition, it allows for adjustment of the sensor bias field towards lower values to enhance the sensor sensitivity to transverse fields.
    2. For a bead of low damping material, only a relatively small AC field is needed to excite full amplitude resonance in the bead so as to produce the maximum AC field in the sensing direction of the MR sensor.
    3. The method is minimally affected by low frequency parasitic magnetic fluctuations. The excited FMR of the bead magnetic moment, under moderate magnetic fields. is usually at a frequency beyond the Barkhausen noise, popcorn noise, telegraph noise, and 1/f noise active regions. For example, the FMR frequency at a DC field of 100 Oe is about 280 MHz.
    4. A reference sensor is not needed for signal detection. Measurement of the relative amplitude or phase of the FMR signal at different AC field frequencies at a constant DC field, or at the same AC field frequency but varying DC fields, will indicate the presence of a magnetic bead. For example, by keeping the DC and AC field amplitudes constant while sweeping the AC field frequency from a value lower than ωr to a frequency higher than ωr, while simultaneously measuring the sensor signal at the same frequency. When a magnetic bead is present the sensor signal peaks at ωr but if there is no bead, the signal vs. AC field frequency will stay flat. Peak detection of the swept curve can thus be used as an indicator of a bead's presence.
    5. The method is insensitive to the precise location of the binding site of the bead on the MR sensor. In absolute field level detection methods the magnetic field level that the sensor sees (due to the bead) will be different for different binding sites. However, as discussed in the preceding paragraph, the frequency dependence of the signal on the AC field frequency will stay the same for a given bead. Therefore, if detection is achieved by sweeping the AC field frequency, local binding site variations will not affect the peaking of the AC signal at ωr.
    6. The method is relatively insensitive to bead size distribution. Field cancellation methods are strongly affected by the beads' physical size distribution because each bead's magnetic moment is proportional to its volume. With a large bead size distribution, the magnetic field from the beads will fluctuate substantially. For FMR detection, however, although bead size variations will still cause the absolute signal level to fluctuate, as long as the beads' composition and shape are the same, the frequency dependence of the AC signal from each bead still stays the same. As long as this frequency dependence is used for detecting the beads' presence (and assuming sufficient bead field strength) the scheme that is taught by this invention will be insensitive to the bead size distribution.
    7. The method is insensitive to the bead-sensor distance (see d in FIG. 3). Longer biological or chemical binding pair lengths will lead to longer distances between bead and sensor, which will decrease the absolute level of the bead magnetic field at the sensor. However, for the FMR detection scheme, as long as the bead-sensor distance is within a range that is low enough to show a dependence of the FMR signal on the AC field frequency, this physical distance variation can be tolerated. This insensitivity results in having greater flexibility when choosing biological and chemical binding pairs.
    8. The method enables field effects from neighboring beads to be minimized. The AC field needed to evoke full amplitude FMR in a bead with a relatively small damping constant is usually small (several Gauss). An AC field of this magnitude can be generated by passing an AC current through a conductive stripe that runs beneath a row or column of sensors or even by an individual line underneath each sensor, which excites only the beads directly above the stripe lines. Neighboring beads not over the stripe line will not contribute to the signal generated by the sensor.
  • This feature may be used as the basis for a method to determine the spatial location of a single bead which may, or may not, be part of an array of similar, or identical, beads. Se feature (g) below.
  • 9. Since the resonance frequency is a function of the shape anisotropy of the magnetic beads and their damping constants, the method facilitates the simultaneous use of multiple beads whose resonance frequencies are not necessarily all the same, even in the same DC field. Examples include, but are not limited to, elongated magnetic beads and beads with a magnetic shell and a non-magnetic core. These structures will have different FMR frequencies from a spherical magnetic bead because of the shape anisotropy. It is also possible to vary the damping constant of the bead through control of its composition in order to shift the FMR frequency. In addition, magnetic beads formed from magnetic particles suspended in a nonmagnetic matrix will also exhibit different FMR resonance behavior, depending on the densities of the particles in the matrix.
    10. The method offers a way to quantify the number of beads attached to a given sensor from the resonance frequency shift caused by the magneto-static interaction between beads attached to the same sensor. From the FMR frequency shift of the ensemble of the beads, the number and formation of the beads on the sensor surface is obtainable after careful characterization and calculation.
  • Features of the Method
  • All necessary layers, coatings and structures that enable the MR sensor to function in the relevant biological or chemical environments are assumed in the embodiments.
  • The magnetic beads used in the embodiments vary in shape, structure and composition as needed to obtain different bead FMR frequencies under the same DC field to enable bead labeling. The applied DC magnetic field in the following embodiments is also the field used to magnetize the beads should they be super-paramagnetic.
  • The MR sensor for FMR detection is not limited to GMR and TMR sensors, but rather any thin film sensing device that can show a measurable change in the presence of a magnetic field. The excited FMR of the bead moment produces an AC magnetic field in the MR sensor and subsequently an AC voltage signal across the sensor when a sensing current is applied. The detection of the presence of the bead can be achieved by the following methods (list not intended to be exhaustive):
  • (a) Sensor signal amplitude dependence on the AC field frequency when DC field is fixed. The amplitude is preferably measured at the same frequency as the AC field.
    (b) Sensor signal amplitude dependence on the DC field when AC field frequency is fixed. The amplitude is preferably measured at the same frequency as the AC field.
    (c) Sensor signal phase dependence on the AC field frequency when DC field is fixed. The phase should be measured at the same frequency as the AC field.
    (d) Sensor signal phase dependence on the DC field when AC field frequency is fixed. The phase should be measured as close to the AC field frequency as possible.
    (e) The existence of an AC signal from the sensor at the frequency of the driving AC field, preferably near or at bead's resonant frequency.
    (f) Cancellation of the driving AC field on the sensor at a frequency preferably near or at bead's resonant frequency.
    (g) Determining the precise location of a bead. In a conventional MRAM (magnetic random access memory), two non-parallel sets of conductive wires are used to form an array in which the intersection of any two wires (from opposing sets) is made to be unique by providing the same input to each wire, namely slightly more than half the magnetic field needed to trigger a single device. Consequently, it is only at the intersection of the two wires that the local field becomes strong enough to trigger a device.
  • In the present invention, the inputs provided to the two intersecting differ from one another. Referring now to FIG. 9, HDC is provided by external means and IAC (to generate hAC) is sent down one of the lines which we will (arbitrarily) designate as line 92. A DC current IDC is sent down one of the non-parallel lines which we will (arbitrarily) designate as line 93, thereby generating a static magnetic field hDC All beads on lines that run parallel to line 92 (e.g. line 96) are powered so that they ‘see’ hAC and HDC while all beads on lines that run parallel to line 93 (e.g. line 94), except at the intersection, will see only HDC+hDC Thus, only bead 91, located at the intersection, will also see hAC so it will exhibit FMR, but at a different frequency from any beads lying along line 92, 96, etc.
  • Comments:
  • For methods (a) through (d), when a bead is present, the mentioned frequency or DC field dependence is observed. When there is no bead, no dependence is seen.
  • For method (e), the absolute value of the bead field is detected i.e. if there is no bead there is no field. This method is susceptible to bead field strength fluctuations caused by various sources. However, it still has the advantages that when detection is in the high frequency region, the MR sensor is at its maximum sensitivity and maximum bead magnetic field at a small FMR excitation field. Note that, for method (e) the AC field is not to be applied in the sensing direction of the MR sensor.
  • For method (f), the absolute combined total field of the applied AC field and the bead field is detected. When there is no bead, there is no bead field acting against the AC field effect on the sensor. This method is thus similar to (e) and enjoys the same advantages as (e) over the field cancellation methods of the prior art. In (f), however, the AC field is applied in the sensing direction of MR device.
  • For method (g), HDC is typically in the range of from about 1 and 1,000 Oe while hDC is typically in the range of from about 1 to 100 Oe. For example, for Hn=100 Oe and hn=20 Oe, FMR for beads on line 1 will occur at about 280 MHz while for a bead at the intersection of lines 92 and 93 it will occur at about 285.6 MHz.
  • Structural Embodiments of the Invention
  • Listed below are the preferred structural embodiments of this invention. Note that, although each of these depicts only a single bead over each sensor, it is clear that extension to multiple beads per sensor is readily implemented.
  • 1. Embodiment 1A
  • Referring to FIG. 5A, the magnetic bead 1 is attached to the MR sensor 2 through biological or chemical binding pair 5 following a recognition process. Two permanent magnets 6 on the sides of the sensor provide a biasing field in the MR sensor to orient the sensing layer magnetization in the Y axis direction. A static field HDC is applied perpendicular to the sensor plane in the Z axis direction. This static field determines the FMR frequency of the bead magnetic moment. It also magnetizes the bead when the bead is super-paramagnetic. A stripe line (or lines) 7 exists underneath the sensor or between the sensor and the bead, where an AC current IAC is used to produce an AC magnetic field hAC in the Y axis direction to excite the FMR of the bead magnetic moment. The bead FMR then produces a rotating component in the XY plane. The MR sensor 2 detects the oscillating magnetic field
  • 2. Embodiment 1B
  • Referring to FIG. 5B, every other aspect is the same as embodiment 1A except that the AC magnetic field hAC in the Y axis direction is generated not by stripe line (or lines), but externally by other means. For example, RF coils or electromagnetic waves in a microwave cavity.
  • 3. Embodiment 1C
  • Referring to FIG. 5C, every other aspect is the same as embodiment 1A except that biasing DC field Hbias is applied externally or generated by the anisotropy field of the sensor. HDC (and Hbias as well if applied externally) determines the FMR frequency of the bead magnetic moment.
  • 4. Embodiment 1D
  • Referring to FIG. 5D, every other aspect is the same as embodiment 1C except that the AC magnetic field hAC is generated not by stripe line (or lines), but externally by other means. For example, RF coils or electromagnetic waves.
  • 5. Embodiment 2A
  • Referring to FIG. 6A, every other aspect is the same as embodiment 1A except that the stripe line (or lines) 7 that is underneath the sensor or between the sensor and the bead, is now used to produce an AC magnetic field hAC in the X direction to excite the FMR of the bead magnetic moment when an AC current IAC flows through it. The MR sensor 2 detects both hAC and the field generated by the bead moment. The difference of the bead field cancellation of hAC in the MR sensor at different driving frequencies can be used as the mechanism for detection. The cancellation of hAC is preferably measured in the same phase as hAC. Since mx has the maximum amplitude and is the exact same phase as hAC when the frequency of hAC is the same as the FMR frequency of the magnetic bead in the DC field HDC, the dependence of the cancellation effect on the AC field frequency will be more pronounced when measured at the same phase as hAC
  • 6. Embodiment 2B
  • Referring to FIG. 6B, every other aspect is the same as embodiment 2A except that the AC magnetic field hAC in the X axis direction to excite the FMR of the bead magnetic moment is generated not by a stripe line (or lines), but externally with other means. For example, RF coils or electromagnetic waves.
  • 7. Embodiment 2C
  • Referring to FIG. 6C, every other aspect is the same as embodiment 2A except that the biasing DC field Hbias is applied externally or generated by the anisotropy field of the sensor. HDC (and Hbias as well if applied externally) determines the FMR frequency of the bead magnetic moment.
  • 8. Embodiment 2D
  • Referring to FIG. 6D. every other aspect is the same as embodiment 2C except that the AC magnetic field hAC in the X axis direction to excite the FMR of the bead magnetic moment is generated not by a stripe line (or lines), but externally by other means. For example, coils or electromagnetic waves.
  • 9. Embodiment 2E
  • Referring to FIG. 6E. every other aspect is the same as embodiment 2A except that the DC field HDC is applied in the Y axis direction, which also serves as a biasing field to orient the sensor layer magnetization of the MR sensor in the Y axis direction.
  • 10. Embodiment 2F
  • Referring to FIG. 6F every other aspect is the same as embodiment 2E except that the AC magnetic field hAC in the X axis direction to excite the FMR of the bead magnetic moment is generated not by a stripe line (or lines), but externally by other means. For example, RF coils or electromagnetic waves.
  • 11. Embodiment 3A
  • Referring to FIG. 7A, bead 1 is attached to the MR sensor 2 through biological or chemical binding pair 5 after the recognition process. A DC field HDC is applied in the sensor plane in the Y axis direction. HDC determines the FMR frequency of the bead magnetic moment and can also serve as a bias field to orient the sensor layer magnetization of the MR sensor in the Y axis direction. It also magnetizes the bead when the bead is super-paramagnetic. An AC magnetic field hac is applied in the Z direction to excite the FMR of the bead magnetic moment. This AC field is generated by a pair of stripe lines 7 on the sides or over the top or underneath the MR sensor. The AC currents flowing in the lines are constantly in the opposite direction to produce a net vertical AC field in the sensor. The MR sensor 2 detects the field generated by the bead moment during the excited FMR.
  • 12. Embodiment 3B
  • Referring to FIG. 7B, every other aspect is the same as embodiment 3A except that the pair of stripe lines 7 that produce the AC magnetic field hAC in the Z direction is now oriented in the X direction. As a matter of fact, this pair of lines can be oriented in any direction in the XY plane as the Z axis field is not affected by their orientation.
  • 13. Embodiment 3C
  • Referring to FIG. 7C, every other aspect is the same as embodiment 3A except that the AC magnetic field hAC in the Z axis direction to excite the FMR of the bead magnetic moment is generated by coil 7 (single or mufti turn) around, below or above the top of the sensor. The AC current flowing in the coil produces a vertical AC field.
  • 14. Embodiment 3D
  • Referring to FIG. 7D, every other aspect is the same as embodiment 3A except that the AC magnetic field hAC in the Z direction to excite the FMR of the bead magnetic moment is applied externally with RF coils or electromagnetic waves. This leads to a voltage signal of the same frequency being generated by the sensor when there is a DC current flowing through the sensor. Because mx magnitude is a function of frequency, the voltage signal generated by the MR sensor at the same AC field amplitude but different AC field frequencies will have different output amplitudes as well. This amplitude dependence of the sensor's voltage output on frequency can be used as the mechanism for the detection of the presence of the magnetic beads. When a bead is not present, the sensor will theoretically have no output dependence on the AC field frequency because of the absence of the bead mx component.
  • 15. Embodiments 3E and 3F
  • Referring to FIGS. 7E and 7F, these are the same as embodiments 3A and 3B respectively, except that the longitudinal bias is supplied by permanents as shown, for example, in FIG. 5A.
  • 16. Embodiments 4A and 4B
  • Referring to FIGS. 8A and 8B, these relate to embodiments 1A-2F and 3A, 3B, 3E, 3F respectively but show that the field generating stripes and the free layer's long axis do not have to be orthogonal to one another but, rather, are required only to be as close to coplanar as their thickness permits.
  • In addition, the phase of m, relative to hAC, will also show frequency dependence. With the MR sensor free layer resistance closely following the field from the mx, this phase dependence on the hAC frequency will also show up in the sensor's AC voltage signal and can be used as a detectable physical quantity as well.

Claims (15)

1. A method to detect the presence of a magnetic bead, comprising:
providing a detector that signals the presence of a magnetic field through a change in its electrical resistance, said detector having an upper surface that is parallel to a free layer of the detector;
causing said free layer to be magnetized in a bias direction;
attaching said magnetic bead to said upper surface at a binding site;
providing a static magnetic field, having a value, in a direction normal to said upper surface;
providing an alternating magnetic field having a frequency, a first amplitude, and a direction parallel to said upper surface; and
varying said frequency and said static field value until ferromagnetic resonance (FMR) occurs, whereby said magnetic bead emits a magnetic field that rotates at said FMR frequency at a second amplitude, thereby causing said detector signal to peak and to signal the presence of said magnetic bead.
2. The method of claim 1 wherein said direction of said provided alternating magnetic field is a first direction that is parallel to said bias direction or a second direction that is perpendicular to said first direction.
3. The method of claim 1 wherein said magnetization in said bias direction is achieved through shape anisotropy or through a magnetic field provided by a pair of permanent magnets or by a pair of exchange-coupled magnets.
4. The method of claim 1 wherein said bead is ferromagnetic or super-paramagnetic or ferrimagnetic.
5. The method of claim 1 wherein FMR occurs at a frequency not lower than about 1 MHz, at which frequency parasitic effects, including Barkhausen noise, popcorn noise, telegraph noise, and 1/f noise are minimal, whereby magnetization along said bias direction may be limited to generating a detectable signal of no more than 1 Oe, thereby increasing said detector's sensitivity.
6. The method of claim 1 wherein said magnetic bead has a damping constant of 0.2 or less, whereby said provided alternating magnetic field need be no greater than about 50 Oe, thereby increasing sensitivity of said sensor and detectability of said bead.
7. The method of claim 1 further comprising canceling any component of said provided alternating magnetic field in the free layer whereby any AC signal generated by said sensor will be closely related to FMR of said bead.
8. The method of claim 1 wherein local binding site variations do not affect the peaking of the AC signal emitted by said sensor.
9. The method of claim 1 wherein differences in relative bead size in a range of about 0.01 to 1 micron will not affect the peaking of the AC signal emitted by said sensor.
10. The method of claim 1 wherein variations in bead distance from said upper surface that are less than or equal to said bead's diameter will not affect the peaking of the AC signal emitted by said sensor.
11. The method of claim 1 wherein said sensor is a member of an array of GMR or MTJ devices and there is present a plurality of magnetic beads.
12. The method of claim 11 wherein FMR frequencies of at least two of said beads are different from one another, said differences being due to variations in shape and composition of said beads, and then utilizing said differences in FMR frequency to determine a spatial distribution of the beads.
13. The method of claim 1 wherein said beads are used as magnetic labels in all applications where successful detection of a label corresponds to the presence of an object selected from the group consisting of molecules, chemicals, compounds, viruses, bacteria, and biological cells.
14. The method of claim 1 wherein the presence of said magnetic bead is detected through of a change of phase of said detector's output signal.
15-44. (canceled)
US11/528,878 2006-09-28 2006-09-28 Detection of magnetic beads using a magnetoresistive device together with ferromagnetic resonance Active 2028-12-18 US7729093B1 (en)

Priority Applications (5)

Application Number Priority Date Filing Date Title
US11/528,878 US7729093B1 (en) 2006-09-28 2006-09-28 Detection of magnetic beads using a magnetoresistive device together with ferromagnetic resonance
US12/800,322 US7835118B2 (en) 2006-09-28 2010-05-12 Detection of magnetic beads using a magnetoresistive device together with ferromagnetic resonance
US12/800,324 US7978444B2 (en) 2006-09-28 2010-05-12 Detection of magnetic beads using a magnetoresistive device together with ferromagnetic resonance
US12/800,323 US7835117B2 (en) 2006-09-28 2010-05-12 Detection of magnetic beads using a magnetoresistive device together with ferromagnetic resonance
US12/800,321 US7898777B1 (en) 2006-09-28 2010-05-12 Detection of magnetic beads using a magnetoresistive device together with ferromagnetic resonance

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
US11/528,878 US7729093B1 (en) 2006-09-28 2006-09-28 Detection of magnetic beads using a magnetoresistive device together with ferromagnetic resonance

Related Child Applications (4)

Application Number Title Priority Date Filing Date
US12/800,321 Division US7898777B1 (en) 2006-09-28 2010-05-12 Detection of magnetic beads using a magnetoresistive device together with ferromagnetic resonance
US12/800,323 Division US7835117B2 (en) 2006-09-28 2010-05-12 Detection of magnetic beads using a magnetoresistive device together with ferromagnetic resonance
US12/800,322 Division US7835118B2 (en) 2006-09-28 2010-05-12 Detection of magnetic beads using a magnetoresistive device together with ferromagnetic resonance
US12/800,324 Division US7978444B2 (en) 2006-09-28 2010-05-12 Detection of magnetic beads using a magnetoresistive device together with ferromagnetic resonance

Publications (2)

Publication Number Publication Date
US20100117641A1 true US20100117641A1 (en) 2010-05-13
US7729093B1 US7729093B1 (en) 2010-06-01

Family

ID=42174397

Family Applications (5)

Application Number Title Priority Date Filing Date
US11/528,878 Active 2028-12-18 US7729093B1 (en) 2006-09-28 2006-09-28 Detection of magnetic beads using a magnetoresistive device together with ferromagnetic resonance
US12/800,322 Active US7835118B2 (en) 2006-09-28 2010-05-12 Detection of magnetic beads using a magnetoresistive device together with ferromagnetic resonance
US12/800,321 Expired - Fee Related US7898777B1 (en) 2006-09-28 2010-05-12 Detection of magnetic beads using a magnetoresistive device together with ferromagnetic resonance
US12/800,324 Expired - Fee Related US7978444B2 (en) 2006-09-28 2010-05-12 Detection of magnetic beads using a magnetoresistive device together with ferromagnetic resonance
US12/800,323 Active US7835117B2 (en) 2006-09-28 2010-05-12 Detection of magnetic beads using a magnetoresistive device together with ferromagnetic resonance

Family Applications After (4)

Application Number Title Priority Date Filing Date
US12/800,322 Active US7835118B2 (en) 2006-09-28 2010-05-12 Detection of magnetic beads using a magnetoresistive device together with ferromagnetic resonance
US12/800,321 Expired - Fee Related US7898777B1 (en) 2006-09-28 2010-05-12 Detection of magnetic beads using a magnetoresistive device together with ferromagnetic resonance
US12/800,324 Expired - Fee Related US7978444B2 (en) 2006-09-28 2010-05-12 Detection of magnetic beads using a magnetoresistive device together with ferromagnetic resonance
US12/800,323 Active US7835117B2 (en) 2006-09-28 2010-05-12 Detection of magnetic beads using a magnetoresistive device together with ferromagnetic resonance

Country Status (1)

Country Link
US (5) US7729093B1 (en)

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20100156406A1 (en) * 2007-07-09 2010-06-24 Canon Kabushiki Kaisha Magnetic detection element and detecting method
WO2013059692A1 (en) * 2011-10-19 2013-04-25 Regents Of The University Of Minnesota Magnetic biomedical sensors and sensing system for high-throughput biomolecule testing
US9927431B2 (en) 2011-09-14 2018-03-27 Regents Of The University Of Minnesota External field—free magnetic biosensor
US20180356473A1 (en) * 2017-06-08 2018-12-13 Tdk Corporation Magnetic sensor and camera module
CN113242979A (en) * 2019-11-22 2021-08-10 西部数据技术公司 Magnetic gradient concentrator/magnetoresistive detector for molecular detection

Families Citing this family (22)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20090206825A1 (en) * 2004-11-30 2009-08-20 Koninklijke Philips Electronics, N.V. Excitation and measurement method for a magnetic biosensor
DE102006016334B4 (en) * 2006-04-06 2018-11-15 Boehringer Ingelheim Vetmedica Gmbh Method and device for detecting magnetizable particles
US8289019B2 (en) * 2009-02-11 2012-10-16 Infineon Technologies Ag Sensor
JP5250109B2 (en) 2009-06-12 2013-07-31 アルプス・グリーンデバイス株式会社 Magnetic balanced current sensor
WO2011111648A1 (en) 2010-03-12 2011-09-15 アルプス電気株式会社 Magnetism sensor and magnetic-balance current sensor using same
JP5594915B2 (en) * 2010-03-12 2014-09-24 アルプス・グリーンデバイス株式会社 Current sensor
CN103069282B (en) 2010-08-23 2015-06-03 阿尔卑斯绿色器件株式会社 Magnetic-balance current sensor
WO2012068146A1 (en) 2010-11-15 2012-05-24 Regents Of The University Of Minnesota Search coil
US10222438B2 (en) * 2012-11-01 2019-03-05 The Trustees Of Dartmouth College System and apparatus for combined magnetic resonance imaging with magnetic spectroscopy of brownian motion and/or magnetic nanoparticle imaging
US9244134B2 (en) * 2013-01-15 2016-01-26 Infineon Technologies Ag XMR-sensor and method for manufacturing the XMR-sensor
US9841469B2 (en) 2016-01-26 2017-12-12 Nxp Usa, Inc. Magnetic field sensor with multiple sense layer magnetization orientations
US9897667B2 (en) * 2016-01-26 2018-02-20 Nxp Usa, Inc. Magnetic field sensor with permanent magnet biasing
US10545196B2 (en) 2016-03-24 2020-01-28 Nxp Usa, Inc. Multiple axis magnetic sensor
US10145907B2 (en) 2016-04-07 2018-12-04 Nxp Usa, Inc. Magnetic field sensor with permanent magnet biasing
US9933496B2 (en) 2016-04-21 2018-04-03 Nxp Usa, Inc. Magnetic field sensor with multiple axis sense capability
US11579217B2 (en) 2019-04-12 2023-02-14 Western Digital Technologies, Inc. Devices and methods for frequency- and phase-based detection of magnetically-labeled molecules using spin torque oscillator (STO) sensors
US11609208B2 (en) 2019-04-12 2023-03-21 Western Digital Technologies, Inc. Devices and methods for molecule detection based on thermal stabilities of magnetic nanoparticles
US11738336B2 (en) 2019-04-12 2023-08-29 Western Digital Technologies, Inc. Spin torque oscillator (STO) sensors used in nucleic acid sequencing arrays and detection schemes for nucleic acid sequencing
US11112468B2 (en) 2019-04-12 2021-09-07 Western Digital Technologies, Inc. Magnetoresistive sensor array for molecule detection and related detection schemes
US11327073B2 (en) 2019-04-12 2022-05-10 Western Digital Technologies, Inc. Thermal sensor array for molecule detection and related detection schemes
US11208682B2 (en) 2019-09-13 2021-12-28 Western Digital Technologies, Inc. Enhanced optical detection for nucleic acid sequencing using thermally-dependent fluorophore tags
JP7106591B2 (en) * 2020-03-18 2022-07-26 Tdk株式会社 Magnetic field detector and current detector

Citations (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5981297A (en) * 1997-02-05 1999-11-09 The United States Of America As Represented By The Secretary Of The Navy Biosensor using magnetically-detected label
US6057982A (en) * 1997-03-31 2000-05-02 Seagate Technology, Inc. Disc drive head disc assembly and printed circuit board connected with flexible connectors
US6518747B2 (en) * 2001-02-16 2003-02-11 Quantum Design, Inc. Method and apparatus for quantitative determination of accumulations of magnetic particles
US6743639B1 (en) * 1999-10-13 2004-06-01 Nve Corporation Magnetizable bead detector
US6875621B2 (en) * 1999-10-13 2005-04-05 Nve Corporation Magnetizable bead detector
US20060020371A1 (en) * 2004-04-13 2006-01-26 President And Fellows Of Harvard College Methods and apparatus for manipulation and/or detection of biological samples and other objects
US20080221432A1 (en) * 2007-03-05 2008-09-11 Headway Technologies, Inc. Low temperature method to enhance detection of magnetic beads
US7502200B2 (en) * 2004-12-27 2009-03-10 Kabushiki Kaisha Toshiba Information recording and reproducing unit

Family Cites Families (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2882989B2 (en) * 1993-12-29 1999-04-19 株式会社ケンウッド Optical disk recording and playback device
DE4418116A1 (en) * 1994-05-24 1995-11-30 Nsm Ag Playback and / or recording and / or output device for disks designed as information carriers
JP3822989B2 (en) * 1998-12-28 2006-09-20 クラリオン株式会社 Disc player

Patent Citations (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5981297A (en) * 1997-02-05 1999-11-09 The United States Of America As Represented By The Secretary Of The Navy Biosensor using magnetically-detected label
US6057982A (en) * 1997-03-31 2000-05-02 Seagate Technology, Inc. Disc drive head disc assembly and printed circuit board connected with flexible connectors
US6743639B1 (en) * 1999-10-13 2004-06-01 Nve Corporation Magnetizable bead detector
US6875621B2 (en) * 1999-10-13 2005-04-05 Nve Corporation Magnetizable bead detector
US6518747B2 (en) * 2001-02-16 2003-02-11 Quantum Design, Inc. Method and apparatus for quantitative determination of accumulations of magnetic particles
US20060020371A1 (en) * 2004-04-13 2006-01-26 President And Fellows Of Harvard College Methods and apparatus for manipulation and/or detection of biological samples and other objects
US7502200B2 (en) * 2004-12-27 2009-03-10 Kabushiki Kaisha Toshiba Information recording and reproducing unit
US20080221432A1 (en) * 2007-03-05 2008-09-11 Headway Technologies, Inc. Low temperature method to enhance detection of magnetic beads

Cited By (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20100156406A1 (en) * 2007-07-09 2010-06-24 Canon Kabushiki Kaisha Magnetic detection element and detecting method
US9927431B2 (en) 2011-09-14 2018-03-27 Regents Of The University Of Minnesota External field—free magnetic biosensor
WO2013059692A1 (en) * 2011-10-19 2013-04-25 Regents Of The University Of Minnesota Magnetic biomedical sensors and sensing system for high-throughput biomolecule testing
CN103987654A (en) * 2011-10-19 2014-08-13 明尼苏达大学董事会 Magnetic biomedical sensors and sensing system for high-throughput biomolecule testing
US9823316B2 (en) 2011-10-19 2017-11-21 Regents Of The University Of Minnesota Magnetic biomedical sensors and sensing system for high-throughput biomolecule testing
US20180356473A1 (en) * 2017-06-08 2018-12-13 Tdk Corporation Magnetic sensor and camera module
US11009567B2 (en) * 2017-06-08 2021-05-18 Tdk Corporation Magnetic sensor and camera module
US11519978B2 (en) 2017-06-08 2022-12-06 Tdk Corporation Magnetic sensor and camera module
CN113242979A (en) * 2019-11-22 2021-08-10 西部数据技术公司 Magnetic gradient concentrator/magnetoresistive detector for molecular detection
EP4062185A4 (en) * 2019-11-22 2023-12-13 Western Digital Technologies Inc. Magnetic gradient concentrator/reluctance detector for molecule detection

Also Published As

Publication number Publication date
US7729093B1 (en) 2010-06-01
US7898777B1 (en) 2011-03-01
US20100231214A1 (en) 2010-09-16
US7835117B2 (en) 2010-11-16
US20100232075A1 (en) 2010-09-16
US7978444B2 (en) 2011-07-12
US7835118B2 (en) 2010-11-16
US20110095751A1 (en) 2011-04-28
US20110043201A1 (en) 2011-02-24

Similar Documents

Publication Publication Date Title
US7729093B1 (en) Detection of magnetic beads using a magnetoresistive device together with ferromagnetic resonance
US11313834B2 (en) Discrete contact MR bio-sensor with magnetic label field alignment
EP2390651B1 (en) GMR biosensor with enhanced sensitivity
Li et al. Detection of single micron-sized magnetic bead and magnetic nanoparticles using spin valve sensors for biological applications
US8432644B2 (en) Spin torque oscillator sensor enhanced by magnetic anisotropy
US9519036B2 (en) Magnetic sensor including magnetic layer of closed loop shape
US6743639B1 (en) Magnetizable bead detector
US20080129286A1 (en) Means and Method for Reducing Magnetic Cross-Talk in Biosensors
US20090278534A1 (en) Magnetic sensor device for and a method of sensing magnetic particles
KR20040068968A (en) Sensor and method for measuring the areal density of magnetic nanoparticles on a micro-array
KR20060127918A (en) Method and device for on-chip magnetic resonance spectroscopy
US20090102465A1 (en) Magneto-resistive sensors with improved output signal characteristics
KR20100104396A (en) System for signal detection of specimen using magnetic resistance sensor and detecting method of the same
KR20060059980A (en) Integrated 1/f noise removal method for a magneto-resistive nano-particle sensor
JP2005527782A (en) Methods and configurations for analyzing substances
Volmer et al. Using permalloy based planar hall effect sensors to capture and detect superparamagnetic beads for lab on a chip applications
US8343777B2 (en) Low temperature method to enhance detection of magnetic beads
Ziętek et al. Rectification of radio-frequency current in a giant-magnetoresistance spin valve
KR20110021429A (en) System for signal detection of specimen using magnetic resistance sensor and detecting method of the same
Mor et al. Planar Hall effect (PHE) magnetometers
JP2008101939A (en) Matter detecting device and matter detection method
WO2001027592A1 (en) Magnetizable bead detector
Biziere et al. Hyper frequency behavior of the GMR effect in a single spin valve sensor

Legal Events

Date Code Title Description
AS Assignment

Owner name: HEADWAY TECHNOLOGIES, INC,CALIFORNIA

Free format text: ASSIGNMENT OF ASSIGNORS INTEREST;ASSIGNOR:ZHOU, YUCHEN;REEL/FRAME:018541/0642

Effective date: 20060816

STCF Information on status: patent grant

Free format text: PATENTED CASE

FPAY Fee payment

Year of fee payment: 4

MAFP Maintenance fee payment

Free format text: PAYMENT OF MAINTENANCE FEE, 8TH YEAR, LARGE ENTITY (ORIGINAL EVENT CODE: M1552)

Year of fee payment: 8

MAFP Maintenance fee payment

Free format text: PAYMENT OF MAINTENANCE FEE, 12TH YEAR, LARGE ENTITY (ORIGINAL EVENT CODE: M1553); ENTITY STATUS OF PATENT OWNER: LARGE ENTITY

Year of fee payment: 12