U.S. patent application number 11/719953 was filed with the patent office on 2009-09-10 for means and method for sensing a magnetic stray field in biosensors.
This patent application is currently assigned to KONINKLIJKE PHILIPS ELECTRONICS, N.V.. Invention is credited to Bart Michiel De Boer, Josephus Arnoldus Henricus Maria Kahlman.
Application Number | 20090224755 11/719953 |
Document ID | / |
Family ID | 36440968 |
Filed Date | 2009-09-10 |
United States Patent
Application |
20090224755 |
Kind Code |
A1 |
Kahlman; Josephus Arnoldus Henricus
Maria ; et al. |
September 10, 2009 |
MEANS AND METHOD FOR SENSING A MAGNETIC STRAY FIELD IN
BIOSENSORS
Abstract
A magnetic sensor (MS) comprising a magneto-resistive element
(GMR) for sensing a magnetic stray field (SF) generated by a
magnetizable object (SPB) when magnetized and for generating an
electrical object signal (UOB) which depends on the sensed magnetic
stray field (SF), the sensor (MS) comprising a magnetic field
generator (WR.sub.1, WR.sub.2) for generating a magnetic field (H,
H.sub.ext) having a first frequency (.omega..sub.1) for magnetizing
the magnetizable object (SPB), a current source (AC.sub.2) for at
least generating an AC-current (I.sub.2 sin .omega..sub.2t) having
a second frequency (.omega..sub.2t) through the magneto-resistive
element (GMR), and electronic means for generating an electrical
output signal (U.sub.0) derived from the electrical object signal
(U.sub.OB), the electronic means comprising stabilization means for
stabilizing the amplitude of the electrical output signal
(U.sub.0), 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 (U.sub.OB) during
operation, which is linearly dependent on the steepness of the
magneto-resistive element (GMR), the steepness being defined as the
derivative of the resistance of the magneto-resistive element (GMR)
as a function of the magnetic field through the magneto-resistive
element in a magnetically sensitive direction of the
magneto-resistive element (GMR).
Inventors: |
Kahlman; Josephus Arnoldus Henricus
Maria; (Eindhoven, NL) ; De Boer; Bart Michiel;
(Eindhoven, NL) |
Correspondence
Address: |
PHILIPS INTELLECTUAL PROPERTY & STANDARDS
P.O. BOX 3001
BRIARCLIFF MANOR
NY
10510
US
|
Assignee: |
KONINKLIJKE PHILIPS ELECTRONICS,
N.V.
EINDHOVEN
NL
|
Family ID: |
36440968 |
Appl. No.: |
11/719953 |
Filed: |
November 28, 2005 |
PCT Filed: |
November 28, 2005 |
PCT NO: |
PCT/IB2005/053935 |
371 Date: |
May 23, 2007 |
Current U.S.
Class: |
324/252 |
Current CPC
Class: |
G01R 33/093 20130101;
G01R 33/1269 20130101; B82Y 25/00 20130101 |
Class at
Publication: |
324/252 |
International
Class: |
G01R 33/09 20060101
G01R033/09 |
Foreign Application Data
Date |
Code |
Application Number |
Nov 30, 2004 |
EP |
04106194.6 |
Claims
1. A magnetic sensor (MS) comprising a magneto-resistive element
(GMR) for sensing a magnetic stray field (SF) generated by a
magnetizable object (SPB) when magnetized and for generating an
electrical object signal (UOB) which depends on the sensed magnetic
stray field (SF), the sensor (MS) comprising a magnetic field
generator (WR.sub.1, WR.sub.2) for generating a magnetic field (H,
H.sub.ext) having a first frequency (.omega..sub.1) for magnetizing
the magnetizable object (SPB), a current source (AC.sub.2) for at
least generating an AC-current (I.sub.2 sin .omega..sub.2t) having
a second frequency (.omega..sub.2) through the magneto-resistive
element (GMR), and electronic means for generating an electrical
output signal (U.sub.0) derived from the electrical object signal
(U.sub.OB), the electronic means comprising stabilization means for
stabilizing the amplitude of the electrical output signal
(U.sub.0), 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 (U.sub.OB) during
operation, which is linearly dependent on the steepness of the
magneto-resistive element (GMR), the steepness being defined as the
derivative of the resistance of the magneto-resistive element (GMR)
as a function of the magnetic field through the magneto-resistive
element in a magnetically sensitive direction of the
magneto-resistive element (GMR).
2. A sensor as claimed in claim 1 characterized in that the signal
component is the second harmonic component, in relation to the
second frequency (.omega..sub.2), in the AC-current through the
magneto-resistive element (GMR).
3. A sensor as claimed in claim 1 characterized in that the
stabilization means comprises means (AC.sub.3) for generating a
further AC-current (I.sub.3 sin .omega..sub.3t), having a third
frequency (.omega..sub.3), through the magneto-resistive element
(GMR), and in that the signal component is either a harmonic
component in the current through the magneto-resistive element
(GMR) having a frequency which is equal to the third frequency
(.omega..sub.3), or to the difference (.omega..sub.3-.omega..sub.2)
of the third and the second frequency, or to the sum
(.omega..sub.3+.omega..sub.2), of the third and the second
frequency.
4. A sensor as claimed in claim 3 characterized in that the sensor
comprises a further magnetic field generator (WR.sub.3) for
generating a further magnetic field (H.sub.3 sin .omega..sub.3t),
having the third frequency (.omega..sub.3), for causing the
generation of the further AC-current.
5. A sensor as claimed in claim 1 characterized in that the
stabilization means comprises steepness adaptation means for
adapting the steepness of the magneto-resistive element.
6. A sensor as claimed in claim 5, characterized in that the
adaptation of the steepness is performed by changing the value of a
DC-current through the magneto-resistive element.
7. A sensor as claimed in claim 4 characterized in that the
stabilization means comprises steepness adaptation means for
adapting the steepness of the magneto-resistive element wherein the
adaptation of the steepness is performed by changing a DC value
component in the further magnetic field.
8. A sensor as claimed in claim 6, characterized in that the
steepness adaptation means comprises a synchronous detector
(MP.sub.1) for synchronously detecting the signal component, and
means for comparing the detected signal component with a target
value (s.sub.TR) for the steepness of the magneto-resistive element
and for delivering an error signal as a result of the comparison,
and in that the error signal forms a basis for the changing of the
value of the DC-current through the magneto-resistive element or
the DC value component in the further magnetic field.
9. A sensor as claimed in claim 1, characterized in that the
stabilization means comprises gain adaptation means (G.sub.ADPT)
for adapting a gain value in the electronic transfer from the
electrical object signal to the electrical output signal.
10. A sensor as claimed in claims 9, characterized in that the gain
adaptation means comprises a synchronous detector (MP.sub.1) for
synchronously detecting the signal component, and means for
comparing the detected signal component with a target value
(s.sub.TR) for the steepness of the magneto-resistive element and
for delivering a control signal as a result of the comparison which
forms a basis for the changing of the gain value.
11. A sensor as claimed in claim 1 characterized in that the
electronic means comprises a further synchronous detector
(MP.sub.2) for synchronously detecting the object signal
(U.sub.OB), or a gain adapted version of the object signal
(U.sub.OBG), 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 (LPF.sub.1) for
filtering the resulted signal from the further detector (MP.sub.2)
and for delivering the electrical output signal (U.sub.0) as a
result of the filtering.
12. A biochip (BCP) comprising a magnetic sensor as claimed in
claim 1.
13. A biochip comprising a multiple of magnetic sensors wherein at
least one sensor as claimed in claim 1 is used as a reference
sensor (RFS) 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 (BSA) is performed by using information derived from
the reference sensor (RFS).
14. A method for stabilizing the steepness of a magneto-resistive
element in a magnetic sensor 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 steepness being defined as 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,
comprising the steps of: generating a magnetic field, having a
first frequency, for magnetizing the magnetizable object,
generating an AC-current, having a second frequency, through the
magneto-resistive element, generating an electrical output signal
from the electrical object signal, and stabilizing the amplitude of
the electrical output signal by detecting a signal component which
is present in the object signal and which is linearly dependent on
the steepness of the magneto-resistive element.
Description
[0001] 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.
[0002] The introduction of micro-arrays or biochips is
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.
[0003] 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.
[0004] The term "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. The term "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.sub.2 or an Si.sub.3N.sub.4 layer in
addition to a semiconductor substrate portion. Thus the term
"substrate" also includes glass, plastic, ceramic,
silicon-on-glass, silicon-on-sapphire substrates. The term
"substrate" is thus used to define generally the elements for
layers that underlie a layer or portions of interest. Also the
"substrate" may be any other base on which a layer is formed, for
example a glass or metal layer.
[0005] For example, 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. As an
alternative to 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. In a biochip 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. It is expected that the usefulness of
information that can become available from the use of biochips will
increase rapidly during the coming decade, as a result of projects
such as the Human Genome Project, and follow-up studies on the
functions of genes and proteins. A general explanation of the
functioning of the biochip has already been described in the
international patent application of the present applicant published
as WO 03/054523 A2.
[0006] 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.
[0007] In the current patent application focus is for a biochip
based on excitation of superparamagnetic nanoparticles. However
also the application in other magneto resistive sensors like
Anisotropic Magneto Resistor (AMR) and Tunnel Magneto Resistor
(TMR) is part of the invention. 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.
[0008] For further explanation of the background of the invention
reference is made to FIGS. 1 and 2.
[0009] 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.sub.1. It may also comprise a second (or even
more) current conducting wire WR.sub.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. In 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.
[0010] The functioning of the magnetic sensor MS or more generally
of the biochip BCP is as follows. 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
v = v 0 exp - KV kT ##EQU00001##
where KV (with K the magnetic anisotropy energy density and V the
particle volume) is the energy barrier that has to be overcome, and
.nu..sub.0 is the reversal attempt frequency (typical value:
10.sup.9 s.sup.-1), k is the Boltzmann constant, and T is the
absolute temperature (in Kelvin).
[0011] 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. Although not necessary 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.sub.ext in FIG.
2.
[0012] 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. By this 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)
can be delivered by the sensor MS which is a measure for the amount
of targets TR.
[0013] Not only the amount of superparamagnetic beads but also 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.
[0014] It is therefore an object of the invention to stabilize the
sensitivity of a GMR present in a magnetic sensor.
[0015] In order to achieve this object 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.
[0016] 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. By 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.
[0017] 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. Thus 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. However 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.
[0018] 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. Sometimes 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. By the addition of
the further magnetic field, 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.
[0019] 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).
[0020] Another way of stabilizing the sensitivity of the GMR is by
adding gain adaptation means for adapting a gain value in the
electronic transfer from the electrical object signal to the
electrical output signal. Since now there is no negative feedback
loop in which the GMR is incorporated, it is easier to design than
the previous mentioned way because undesired oscillations or
overshoot can not occur. 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.
[0021] In another embodiment, 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.
[0022] 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.
[0023] In another embodiment 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.
[0024] 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. By this 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.
[0025] As an alternative 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.
[0026] If desired, after attracting beads to the surface, beads
near the surface are removed by (magnetically) washing it away. As
an alternative 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. As an alternative 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. having frequency
.omega..sub.3 above the magnetic response frequency of the beads,
perpendicular to the sensitive direction of the GMR. This field
saturizes the beads, as a consequence only the magnetic cross-talk
from the current wires are measured. This signal is indicative for
the gain, and can thus be used to keep the gain constant. It can
also be done by applying beads with hysteresis (with the aid of an
additional magnetic field). The beads are adjusted to their linear
region, which is necessary for detection. If then the additional
field is taken away, the beads will no longer respond to the
magnetic field, and thus only cross-talk is then measured.
[0027] The invention also provides a method for stabilizing the
steepness of a magneto-resistive element in a magnetic sensor 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 comprising the
steps of:
[0028] generating a magnetic field, having a first frequency, for
magnetizing the magnetizable object,
[0029] generating an AC-current, having a second frequency, through
the magneto-resistive element,
[0030] generating an electrical output signal from the electrical
object signal, and
[0031] stabilizing the amplitude of the electrical output signal by
detecting a signal component which is present in the object signal
and which is linearly dependent on the steepness of the
magneto-resistive element.
[0032] 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.
[0033] Preferably 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. Optionally the
sensor may comprise a so called Wheatstone bridges or
half-Wheatstone bridges in which one or more GMRs are
incorporated.
[0034] The invention will be further elucidated with reference to
the accompanying drawings, in which:
[0035] FIG. 1 shows a biochip comprising a substrate and a
plurality of magnetic sensors,
[0036] FIG. 2 shows an embodiment of a magnetic sensor with
integrated magnetic field excitation;
[0037] 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;
[0038] 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;
[0039] FIG. 5 shows a schematic of an inventive embodiment in which
means are present for adapting the DC-current through the GMR;
[0040] FIG. 6 shows a cross-section of a GMR stack in which the
current through the stack is schematically indicated;
[0041] 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;
[0042] FIG. 8 shows a schematic of an alternative inventive
embodiment for adapting the gain value;
[0043] FIG. 9 schematically shows an example of an advantageous
location for a wire for generating the further magnetic field
having the third frequency;
[0044] 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;
[0045] 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;
[0046] 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; and
[0047] 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.
[0048] The drawings are only schematic and non-limiting. In the
drawings the size of some of the elements may be exaggerated and
not drawn on scale and serve only for illustrative purposes. The
description to the Figures only serve to explain the principles of
the invention and may not be construed as limiting the invention to
this description and/or the Figures.
[0049] FIG. 3 shows the resistance of the GMR as a function of the
magnetic field component H.sub.ext. It is to be noted that the GMR
sensitivity
s GMR = R GMR H ext ##EQU00002##
is not constant but depends on H.sub.ext. It is also depends on any
internally generated magnetic field caused by asymmetric current
distribution in the GMR stack.
[0050] In the sensor MS as shown in FIG. 2, in stead of the giant
magnetoresistive GMR 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. In an AMR, GMR or TMR
material, the electrical resistance changes when the magnetization
direction of one or more layers changes as a result of the
application of a magnetic field. GMR is the magnetoresistance for
layered structures with conductor interlayers in between so-called
switching magnetic layers, and TMR is the magneto-resistance for
layered structures comprising magnetic metallic electrode layers
and a dielectric interlayer.
[0051] In GMR technology, structures have been developed in which
two very thin magnetic films are brought very close together. 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.
[0052] 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. This is a
quantum-mechanical transport process. 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.
[0053] 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.
[0054] FIG. 4 shows part of a magnetic sensor in which besides the
magnetic field H.sub.ext (coming from the beads) also the
internally generated field H.sub.int generated by the GMR itself is
indicated. A current source I.sub.BIAS which supplies a DC-current
I.sub.DC and an AC-current source AC.sub.2 which supplies an
AC-current I.sub.2 sin .omega..sub.2t having a second frequency
.omega..sub.2 are coupled to the magneto-resistive element GMR.
Thus the sum of these two currents flow through the GMR and is
indicated with the sense current i.sub.s. The sense current i.sub.s
causes a signal (voltage) U.sub.GMR across the GMR. The voltage
U.sub.GMR is amplified by an amplifier AMP which delivers an object
signal U.sub.OB. The sense current is generates the internal
magnetic field H.sub.int=.alpha.i.sub.sense in the GMR. Therefore
by choosing the appropriate value for the sense current i.sub.s the
curve shown in FIG. 3 can be "moved" horizontally and a suitable
sensitivity of the GMR can be chosen. The effect of the internal
magnetic field H.sub.int can be interpreted as internal magnetic
cross talk and will give rise to a voltage component
e.sub.int=s.sub.GMR.alpha.i.sub.s.sup.2 in the signal U.sub.GMR, in
which s.sub.GMR is the sensitivity of the GMR and .alpha. is a
constant value. As a result the GMR voltage contains a second
harmonic signal, which is utilized to stabilize the GMR
sensitivity. This is illustrated as follows. The total in-plane
magnetization H.sub.x in the sensitive layer of the GMR equals
H.sub.x=H.sub.ext+H.sub.int=H.sub.ext+.alpha.i.sub.s
[0055] The signal U.sub.GMR can be expressed by:
u.sub.GMR=i.sub.s(R.sub.GMR+s.sub.GMR(H.sub.ext+.alpha.i.sub.s))=i.sub.s-
(R.sub.GMR+s.sub.GMRH.sub.ext)+i.sub.s.sup.2s.sub.GMR.alpha..
[0056] By substituting i.sub.s=I.sub.DC+I.sub.2 sin
.omega..sub.2t:
u.sub.GMR=(I.sub.DC+I.sub.2 sin
.omega..sub.2t)(R.sub.GMR+s.sub.GMRH.sub.ext)+(I.sub.DC.sup.2+2I.sub.DCI.-
sub.2 sin .omega..sub.2t+I.sub.2.sup.2 sin
.omega..sub.2t)s.sub.GMR.alpha.
[0057] The magnetic field from the beads equals: H.sub.ext=H.sub.1
sin .omega..sub.1t
[0058] The following expression can then be derived for the signal
U.sub.GMR:
u GMR = I DC ( R GMR + s GMR .alpha. I DC ) + 1 2 I 2 2 s GMR
.alpha. + I 2 sin .omega. 2 t ( R GMR + s GMR .alpha. 2 I DC ) + I
DC s GMR H 1 sin .omega. 1 t + 1 2 I 2 s GMR H 1 [ cos ( .omega. 1
- .omega. 2 ) t - cos ( .omega. 1 + .omega. 2 ) t ] - 1 2 I 2 2 s
GMR .alpha. cos 2 .omega. 2 t ##EQU00003##
[0059] The last term in the latter expression for the signal
U.sub.GMR equals
- 1 2 I 2 2 s GMR .alpha. cos 2 .omega. 2 t ##EQU00004##
and is thus a second harmonic component in relation to the second
frequency .omega..sub.2. Further the sensitivity s.sub.GMR of the
GMR is linearly present in this last term. Thus with the aid of
this last term the sensitivity can be stabilized. this can be
performed by synchronously demodulating the object signal U.sub.OB,
which is an amplified version of the signal U.sub.GMR.
[0060] The result of this demodulation is a DC component which is
proportional to s.sub.GMR and independent from H.sub.1.
[0061] FIG. 5 shows a schematic of an inventive embodiment in which
means are present for adapting the DC-current through the GMR. In
addition to the schematic of FIG. 4 the following elements are
present: a first multiplier MP.sub.1, a second multiplier MP.sub.2,
a (first) frequency low pass filter LPF.sub.1, a subtracter DFF,
and an integrating filter INT. The first multiplier MP.sub.1
synchronously demodulates the object signal U.sub.OB by multiplying
the object signal U.sub.OB with a signal cos 2.omega..sub.2t. (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.sub.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.sub.DC of
the current source IBIAS. Note that the elements "AMP", "MP.sub.1",
DFF, "INT", "IBIAS" form a negative feedback loop. Therefore, if
the gain of the feedback loop is sufficiently high, the error
signal at the output of the subtracter DFF (=the input of the
integrating filter INT) will be controlled to approximately zero.
Therefore the effective sensitivity of the sensor will be equal to
the target value s.sub.TR (and is thus stabilized). The thus
stabilized object signal U.sub.OB is synchronously demodulated by
the second multiplier MP.sub.2 which multiplies the object signal
U.sub.OB with either cos(.omega..sub.1-.omega..sub.2)t or
cos(.omega..sub.1-.omega..sub.2)t or sin(.omega..sub.1)t, or a
combination of these three signals. The resulted signal UMP.sub.2
at the output of the second multiplier MP.sub.2 is filtered by the
low pass filter LPF.sub.1 and delivers the electrical output signal
U.sub.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.
[0062] FIG. 6 shows a cross-section of a GMR stack in which the
current through the stack is schematically indicated. The previous
mentioned parameter .alpha. and s.sub.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.sub.s
to an optimal position just below the sensitive layer FL, results
in more magnetic field strength being induced by the sense current
i.sub.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.
[0063] The applied magnetic field H.sub.int (see FIG. 5), generated
by the sense current i.sub.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.
[0064] Note that the harmonic distortion components due to the
non-linear GMR characteristic are neglectable because of the small
AC amplitude of the magnetic field induced by the sense current
i.sub.s.
[0065] 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.sub.OB to
the electrical output signal U.sub.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. Thus also the DC-value I.sub.DC of the current
source IBIAS is not controlled by an error signal. Further the
circuit of FIG. 7 comprises, in addition to the circuit of FIG. 5,
a gain adapter G.sub.ADPT which is with a signal input coupled to
the output of the amplifier AMP for receiving the object signal
U.sub.OB and with a signal output coupled to an input of the second
multiplier MP.sub.2 for delivering the signal U.sub.OBG which is a
gain adapted version of the object signal U.sub.OB. Further the
circuit of FIG. 7 comprises, in addition to the circuit of FIG. 5,
a further frequency low pass filter LPF.sub.2 which is coupled
between the output of the first multiplier MP.sub.1 and a control
input of the gain adapter G.sub.ADPT. The circuit operates as
follows. The object signal U.sub.OB is multiplied (synchronously
demodulated) with a signal cos 2.omega..sub.2t like in the circuit
of FIG. 5. The resulted signal is filtered by the further low pass
filter LPF.sub.2 which delivers a control signal to the control
input of the gain adapter G.sub.ADPT. By the presence of the
further low pass filter LPF.sub.2 this control signal is a pure
DC-signal. The control signal is compared to the target value
s.sub.TR which is present at a reference input of the gain adapter
G.sub.ADPT. The gain of the gain adapter G.sub.ADPT is expressed by
the following equation:
U OB U OBG = s TR G + .delta. ##EQU00005##
in which G is the value of the DC-signal delivered by the further
low pass filter LPF.sub.2, and is thus related to the sensitivity
s.sub.GMR of the GMR, and .delta. determines the maximum possible
gain of the gain adapter G.sub.ADPT. Thus, like in the circuit of
FIG. 5, the effective sensitivity of the sensor is stabilized. The
advantage of the circuit of FIG. 7 over the circuit of FIG. 5 is
that now no feedback loop is present and thus with respect of the
stability (avoiding overshoot and oscillations) this circuit is
easier to design and does not depend on the sense current dependent
gain controlling property of the GMR. In stead of the indicated
location in FIG. 7 the gain adapter G.sub.ADPT may also be located
after the second multiplier MP.sub.2.
[0066] 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. In FIG. 8 a third multiplier MP.sub.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.sub.1 and MP.sub.2. Further in the circuit of FIG. 8
the output of the integrating filter INT is not coupled to the
current source IBIAS but to a second input of the multiplier
MP.sub.3. It is to be noted that although the construction of the
circuit of FIG. 8 shows a large resemblance with the construction
of the circuit of FIG. 5 the principle of operations of these two
circuits are different. The principle of operation of the circuit
of FIG. 8 is similar to the principle of operation of the circuit
of FIG. 7. Basically the (negative) feedback loop formed by the
elements: "MP.sub.3", "MP.sub.1", "DFF", "INT" in FIG. 8 perform a
similar function as the feedforward loop formed by the elements:
"MP.sub.1", "LPF.sub.2", "G.sub.ADPT" in FIG. 7. It is to be noted
that although 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.
[0067] 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.sub.3 sin .omega..sub.3t
having the third frequency .omega..sub.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.sub.3 and a
further wire WR.sub.3. The further AC-current source AC.sub.3
supplies the further AC-current I.sub.3 sin .omega..sub.3t through
the further wire WR.sub.3 which as a response generates the further
magnetic field H.sub.3 sin .omega..sub.3t. Application of the
circuit of FIG. 10 is advantageous in all situations in which the
internally generated magnetic field H.sub.int is so small that it
is difficult (too noisy signal) to accurately detect the second
harmonic component in the object signal U.sub.OB. (Note that the
arrow below H.sub.int=.alpha.i.sub.s intentionally indicated
smaller than in the previous Figures.) So basically an AC-current
having a frequency .omega..sub.3 is induced in the GMR and takes
over the function of the second harmonic component. Thus harmonic
components having frequencies equal to .omega..sub.3-.omega..sub.2
and to .omega..sub.3+.omega..sub.2 occur in the current through the
GMR. As a consequence these components are also present in the
signal U.sub.GMR across the GMR and in the object signal U.sub.OB.
The operation of the circuit is further similar to that of the
circuit in FIG. 5 except for the fact that the object signal
U.sub.OB is now not synchronously detected on a frequency
2.omega..sub.2 but on either .omega..sub.3-.omega..sub.2,
.omega..sub.3+.omega..sub.2, or .omega..sub.1. This is performed by
the first multiplier MP.sub.1 which multiplies the object signal
U.sub.OB with either cos(.omega..sub.3-.omega..sub.2)t,
cos(.omega..sub.3+.omega..sub.2)t, sin .omega..sub.1t, or a
combination of these three signals.
[0068] FIG. 9 schematically shows an example of an advantageous
location for the further wire WR3 for generating the further
magnetic field H.sub.3 sin .omega..sub.3t. Because the further wire
WR.sub.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.sub.3 to the
superparamagnetic beads SPB is relatively large compared to the
distance from the beads to the GMR.
[0069] As an alternative to the location of the wire WR.sub.3 in
FIG. 9 the wire WR.sub.3 may also be located adjacent to the GMR.
Now the beads SPB are closer to the wire WR.sub.3, so that the
beads SPB may disturb the measurement of the sensitivity S.sub.GMR
of the GMR. This effect can be suppressed by measuring the
sensitivity S.sub.GMR at a frequency well above the response
bandwidth of the magnetic beads SPB, thus at a frequency
.omega. 3 .gtoreq. 1 .tau. neel . ##EQU00006##
[0070] The time constant .tau..sub.neel is the so-called Neel
relaxation time (see for Neel relaxation: "Journal of Magnetism and
Magnetic Materials 194 (1999) page 62 by R. Kotiz et al.)
[0071] Generally speaking: by increasing .omega..sub.3, the
response from the super paramagnetic beads SPB will decrease. By
sweeping .omega..sub.3 over a broad frequency range, information
about the gain and the sensitivity of the magnetic sensor and thus
about the number of beads SPB is retrieved.
[0072] As an alternative a wire WR.sub.3 adjacent (or below the
GMR) generates a DC magnetic field in order to control the
sensitivity s.sub.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.
[0073] As yet another alternative the sensitivity s.sub.GMR is
controlled by varying the strength or the position (translation,
rotation) of an external magnet (permanent or electromagnet) with
respect to the biochip.
[0074] It is also possible that the external magnet also generates
a fluctuating magnetic field in the GMR in order to perform the
measurement of the sensitivity s.sub.GMR.
[0075] 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.sub.OB to
the electrical output signal U.sub.0 and in which the further
magnetic field generator having the third frequency .omega..sub.3
is present. Basically 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.sub.3, and the
AC-current source AC.sub.3. The addition of the further magnetic
field generator is for the same reasons as mentioned earlier with
reference to FIG. 10.
[0076] 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.sub.DC3
through the wire WR.sub.3 in stead of adapting the DC-current
source I.sub.BIAS.
[0077] 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.sub.s of each sensor is
corrected by the same gain correcting value. .beta. represents the
detection of the second harmonic of the sense current i.sub.s in
the reference sensor RFS. The output of loop filter .alpha., 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. As an alternative to the system of FIG. 13 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).
[0078] It should be noted that the above-mentioned embodiments
illustrate rather than limit the invention, and those skilled in
the art will be capable of designing alternative embodiments
without departing from the scope of the invention as defined by the
appended claims. In the claims, any reference signs placed in
parentheses shall not be construed as limiting the claims. The
words "comprising" and "comprises", and the like, do not exclude
the presence of elements other than those listed in any claim or in
the application as a whole. The singular reference of an element
does not exclude the plural reference of such elements. The mere
fact that certain measures are recited in mutually different
dependent claims does not indicate that a combination of these
measures can not be used. Any terms like top, bottom, over, under
and the like in the description and the claims are used for
descriptive purposes and not necessarily for describing relative
positions. It is to be understood that the terms so used are
interchangeable under appropriate circumstances and that the
embodiments of the invention described herein are capable of
operation in other orientations than described or illustrated by
the Figures.
* * * * *