U.S. patent application number 11/719954 was filed with the patent office on 2008-02-14 for method for calibrating a transfer function of a magnetic sensor.
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 | 20080036450 11/719954 |
Document ID | / |
Family ID | 36440968 |
Filed Date | 2008-02-14 |
United States Patent
Application |
20080036450 |
Kind Code |
A1 |
Kahlman; Josephus Arnoldus Henricus
Maria ; et al. |
February 14, 2008 |
Method for Calibrating a Transfer Function of a Magnetic Sensor
Abstract
A method for calibrating a transfer function of a magnetic
sensor (MS) on a substrate (SBSTR) in which sensor (MS) the
presence of magnetizable objects (SPB) can be detected by
magnetizing the objects (SPB) by a magnetic field (H) delivered by
a magnetic field generator (WR.sub.1, WR.sub.2) and in which the
transfer function is defined as the transfer from an electrical
input signal (I.sub.in) for generating the magnet field H, via
magnetic stray field (SF) radiated by the objects (SPB) when
magnetized, to an electrical output signal (I.sub.out) delivered by
the sensor (MS), comprising the steps of: putting sample fluid on
the substrate (SBSTR), the sample fluid comprising a large amount
of the magnetizable objects (SPB), attracting part of the
magnetizable objects (SPB) towards the magnetic sensor (MS),
activating the electrical input signal (I.sub.in), thereby
generating the magnet field (H), measuring the electrical output
signal (I.sub.out) as a response to the electrical input signal
(I.sub.in), calculating the transfer function from the electrical
input and output signals (I.sub.in, I.sub.out).
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.
GROENEWOUDSEWEG 1
EINDHOVEN
NL
5621 BA
|
Family ID: |
36440968 |
Appl. No.: |
11/719954 |
Filed: |
November 28, 2005 |
PCT Filed: |
November 28, 2005 |
PCT NO: |
PCT/IB05/53930 |
371 Date: |
May 23, 2007 |
Current U.S.
Class: |
324/202 |
Current CPC
Class: |
G01R 33/1269 20130101;
B82Y 25/00 20130101; G01R 33/093 20130101 |
Class at
Publication: |
324/202 |
International
Class: |
G01R 35/00 20060101
G01R035/00 |
Foreign Application Data
Date |
Code |
Application Number |
Nov 30, 2004 |
EP |
04106194.6 |
Claims
1. A method for calibrating a transfer function of a magnetic
sensor (MS) on a substrate (SBSTR) in which sensor (MS) the
presence of magnetizable objects (SPB) can be detected by
magnetizing the objects (SPB) by a magnetic field (H) delivered by
a magnetic field generator (WR.sub.1, WR.sub.2) and in which the
transfer function is defined as the transfer from an electrical
input signal (I.sub.in) for generating the magnet field H, via
magnetic stray field (SF) radiated by the objects (SPB) when
magnetized, to an electrical output signal (I.sub.out) delivered by
the sensor (MS), comprising the steps of: putting sample fluid on
the substrate (SBSTR), the sample fluid comprising magnetizable
objects (SPB), attracting part of the magnetizable objects (SPB)
towards the sensor (MS), activating the electrical input signal
(I.sub.in), thereby generating the magnet field (H), measuring the
electrical output signal (I.sub.out) as a response to the
electrical input signal (I.sub.in), and calculating the transfer
function from the electrical input and output signals (I.sub.in,
I.sub.out).
2. A method as claimed in claim 1, characterized in attracting the
part of magnetizable objects (SPB) by a force acting on the part of
magnetizable objects (SPB) which is caused by a gradient in the
magnetic field (H).
3. A method as claimed in claim 1, characterized in applying a
further magnetic field causing a force acting on the part of
magnetizable objects (SPB) caused by a gradient in the further
magnetic field.
4. A method as claimed in claim 3, characterized in that a current
is flowing through a wire in the neighborhood of, or integrated in,
the sensor (MS), thereby generating the further magnetic field.
5. A method as claimed in claim 1, characterized in having an
additional step after the step of attracting part of the
magnetizable objects towards the sensor (MS), the additional step
being: washing away a free moving part of the objects (SPB).
6. A method as claimed in claim 5, characterized in that the
washing away of the free moving part of the objects (SPB) is being
carried out by magnetically washing away the free moving part of
the objects (SPB).
7. A method for calibrating a transfer function of a magnetic
sensor (MS) on a substrate (SBSTR) in which sensor (MS) the
presence of magnetizable objects (SPB) can be detected by
magnetizing the objects (SPB) by a magnetic field (H) delivered by
a magnetic field generator (WR.sub.1, WR.sub.2) and in which the
transfer function is defined as the transfer from an electrical
input signal (I.sub.in) for generating the magnet field, via
magnetic stray field (SF) radiated by the objects (SPB) when
magnetized, to an electrical output signal (I.sub.out) delivered by
the sensor (MS), comprising the steps of: shooting part of the
magnetizable objects (SPB) towards the sensor (MS), activating the
electrical input signal (I.sub.in), thereby generating the magnet
field (H), measuring the electrical output signal (I.sub.out) as a
response to the electrical input signal (I.sub.in), and calculating
the transfer function from the electrical input and output signals
(I.sub.in, I.sub.out).
8. A method for calibrating a transfer function of a reference
magnetic sensor (MS) on a substrate (SBSTR) whereby during the
fabrication process of the reference sensor (MS) magnetizable
objects (SPB) are attached and in which reference sensor (MS) the
presence of the magnetizable objects (SPB) can be detected by
magnetizing the objects (SPB) by a magnetic field (H) delivered by
a magnetic field generator (WR.sub.1, WR.sub.2) and in which the
transfer function is defined as the transfer from an electrical
input signal (I.sub.in) for generating the magnet field (H), via
magnetic stray field (SF) radiated by the objects (SPB) when
magnetized, to an electrical output signal (I.sub.out) delivered by
the reference sensor (MS), comprising the steps of: activating the
electrical input signal (I.sub.in), thereby generating the magnet
field (H), measuring the electrical output signal (I.sub.out) as a
response to the electrical input signal (I.sub.in), and calculating
the transfer function from the electrical input and output signals
(I.sub.in, I.sub.out).
9. A magnetic sensor (MS) on a substrate (SBSTR) in which the
presence of magnetizable objects (SPB) can be detected, and
presented by an electrical output signal (I.sub.out), by
magnetizing the objects (SPB) by a magnetic field (H) delivered by
a magnetic field generator (WR.sub.1; WR.sub.2), comprising
calibration means for calibrating a transfer function which is
defined as the transfer from an electrical input signal (I.sub.in)
for generating the magnet field (H), via magnetic stray field (SF)
radiated by the objects (SPB) when magnetized, to the electrical
output signal (I.sub.out), for executing the method steps as
defined in claim 1.
10. A biochip (BCP) comprising a plurality of magnetic sensors (MS)
wherein at least one of the sensors is a sensor as defined in claim
9.
Description
[0001] The invention relates to a method for calibrating a transfer
function of a magnetic sensor in which sensor the presence of
magnetizable objects can be detected by magnetizing the objects by
a magnetic field delivered by a magnetic field generator and in
which the transfer function is defined as the transfer from an
electrical input signal for generating the magnet field, via
magnetic stray field radiated by the objects when magnetized, to an
electrical output signal delivered by the sensor.
[0002] The invention further relates to a magnetic sensor which
performs said calibrating and to the use of such a sensor in a
biochip for e.g. molecular diagnostics, biological sample analysis
or chemical sample analysis.
[0003] 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.
[0004] 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
analysed can bind if they are matched. 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 analysed. As an alternative to fluorescent markers
magnetizable objects can be used as magnetic markers that are
coupled to the molecules to be analysed. 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 analyse 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.
[0005] 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 molecules (e.g. protein, DNA, drugs of abuse, hormones)
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.
[0006] In the current patent application focus is on a biochip
based on (integrated) 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.
[0007] In order to get an unambiguous relation between the number
of immobilized beads and the detected signal from the GMR sensors,
the total transfer function of the biochip should be calibrated.
Said transfer function depends on the device geometry, the
properties of the superparamagnetic beads, the properties of the
GMR sensor and the signal processing electronics (e.g.
pre-amplifier).
Parameters like
[0008] Geometry tolerances
[0009] Magnetic properties of the superparamagnetic beads
[0010] GMR stack tolerances, e.g. thickness, magnetic
properties
[0011] External magnetic fields
[0012] IC (Integrated Circuit) tolerances in signal processing
circuitry
[0013] Aging effects
[0014] Temperature
[0015] may have a strong influence on the transfer function.
Furthermore the common practice of applying a calibration fluid
(usually a liquid) for calibration will complicate the design of
the biochip, especially the design of the micro fluids part. The
calibration fluid is for instance artificial blood which should be
kept in a refrigerator or a freezer until it is needed for
calibrating one of the sensors on the biochip which can then serve
as a reference sensor for the other sensors during the analysis of
for instance (real) blood samples. Furthermore the calibration
fluid may be stored in a dedicated container integrated in the
biosensor cartridge. Prior to the actual assay the calibration
fluid is guided over the sensor surface. This requires a
complicated cartridge design. Thus the use of a calibration fluid
prior to the actual measurement is both complicate and expensive.
There is thus a general need to develop methods for analyzing the
sample fluids without the need of an additional fluid which
function as a calibration fluid.
[0016] It is therefore an object of the invention to provide a
method for calibrating the magnetic sensor without the need of a
calibration fluid. In order to achieve this object the invention
provides a method for calibrating a transfer function of a magnetic
sensor on a substrate in which sensor the presence of magnetizable
objects can be detected by magnetizing the objects by a magnetic
field delivered by a magnetic field generator and in which the
transfer function is defined as the transfer from an electrical
input signal for generating the magnet field, via magnetic stray
field radiated by the objects when magnetized, to an electrical
output signal delivered by the sensor, comprising the steps of:
[0017] putting sample fluid on the substrate, the sample fluid
comprising magnetizable objects, [0018] attracting (at least) part
of the magnetizable objects towards the sensor, [0019] activating
the electrical input signal, thereby generating the magnet field,
[0020] measuring the electrical output signal as a response to the
electrical input signal, and [0021] calculating the transfer
function from the electrical input and output signals.
[0022] The sample fluid is for instance a blood or a saliva sample,
comprising a target particle (molecule), taken from a human or
animal body which is supplemented by magnetizable objects, e.g.
superparamagnetic beads, which bind to the target particles.
Usually there is a plurality of sensors integrated on the same
substrate of a single biochip. Although possible, it is not
necessary to calibrate all these sensors by the abovementioned
method. Basically it is only necessary to calibrate a single
(reference) magnetic sensor. The thus acquired transfer function of
this reference sensor can then also be used as the transfer
function for the other sensors. This is because of the fact that
all sensors are fabricated on the same substrate, and thus
electronic parameters of the sensors match with each other.
Alternatively it is also possible to determine the transfer
functions of a multiple of sensors and use the outcome to determine
an average transfer function of the multiple of sensors, which
average transfer function can then also serve as the transfer
function for the remaining sensors. Hereby the overall accuracy
(average accuracy of all sensors on the same substrate) of the
calibration is increased. Of course in this situation the part
(amount) of the attracted magnetizable objects should be large
enough to at least partly cover the active areas (probe areas) of
the multiple of magnetic sensors. Said transfer function is used as
a reference for the bio-measurements to be performed after the
calibration. It is also possible to only use a single sensor which
is first calibrated by the inventive method, thus with the use of
the sample fluid, and after calibration the bound target molecules
are released (e.g. by (magnetically) washing it away), and then
putting a sample fluid (which can be from the same sample fluid
batch, thus no additional human intervention is needed) on the
single sensor.
[0023] Thus the transfer function is calibrated prior, or during
the actual bio-measurement without the use of a calibration fluid.
The transfer function may be calibrated for a large frequency range
in order to characterize the complete biochip system like
capacitive crosstalk, bead properties (magnetic susceptibility
.chi., relaxation time .tau..sub.nee1, rotational parameters),
pre-amplifier gain etceteras.
[0024] In an embodiment the beads are attracted in a well-defined
way to a sensor surface. For this purpose the surface of at least
one reference-sensor (comprising GMR plus field generating wires)
in an array of sensors on a biochip is not (in contrast as
indicated in FIGS. 1 and 4) covered by anti-bodies, hence no target
molecules will immobilize to said reference-sensor. After applying
magnetic beads to the sample fluid, said beads are attracted in a
well-defined way towards the reference-sensor by field generating
wires near the reference sensor. The GMR response from the
reference sensor is indicative to the transfer function of the
sensor system. If the reference-sensor surface is sufficiently
covered by beads, then the reference sensor is shielded from free
moving beads, that is to say the not attracted beads, near the
sensor, which may influence the measurement of the transfer
function. Alternatively, free moving beads above the
reference-sensor may (magnetically) be washed away. In this
embodiment it is assumed that the GMR stack, the geometry and the
magnetic beads are equal for every sensor on the biochip. An
advantage of this method is the fact that beads from the same
`micro-batch` are used for calibration as for the actual
bio-measurement.
[0025] In another embodiment a high affinity binding takes place
between beads in the sample volume and at least one sensor surface.
In this way a high areal bead density, which saturates the sensor,
is realized at a sensor surface. As an example steptavidine coated
beads and biotine on the sensor surface.
[0026] 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.
[0027] 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.
[0028] The invention will be further elucidated with reference to
the accompanying drawings, in which:
[0029] FIG. 1 shows a biochip comprising a substrate and a
plurality of magnetic sensors,
[0030] FIG. 2 shows an embodiment of a magnetic sensor with
integrated magnetic field excitation;
[0031] FIG. 3 shows the resistance of the GMR as a function of the
magnetic field component in the direction in which the layer of the
GMR is sensitive to magnetic fields; and
[0032] FIG. 4 shows a method for calibrating the transfer function
of the magnetic sensor as shown in FIG. 2.
[0033] 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.
[0034] 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 is preferably 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. 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.
[0035] 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 suspended in a (polymer) binder or
matrix 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
.times. exp .times. - KV kT ##EQU1## where KV (with K the magnetic
anisotropy energy density and V the particle volume) is the energy
barrier that has to be overcome, and v.sub.0 is the reversal
attempt frequency (typical value: 10.sup.9 s.sup.-1).
[0036] 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 (that
is to say not internal in the GMR) field for which the GMR is
sensitive is indicated by H.sub.ext in FIG. 2.
[0037] With the assumption that the biochip BCP is horizontally
positioned (thus perpendicular to the force of gravity) the GMR is
positioned in a manner that it is only or mainly sensitive to
magnetic fields having a horizontal component. Therefore the GMR is
not sensitive to the magnetic field H because if it passes
perpendicular to the GMR and has thus no horizontal component. In
contrast the stray field SF does have a horizontal component 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.
[0038] 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 = d R GMR d H ext ##EQU2## is not constant but
depends on H.sub.ext.
[0039] 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.
[0040] 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, which 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.
[0041] 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.
[0042] 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.
[0043] FIG. 4 shows a method for calibrating the transfer function
of the magnetic sensor (MS). Sample fluid is put on the substrate
SBSTR. The sample fluid comprises superparamagnetic beads SPB. It
is a major advantage of the application of the current inventive
method that calibration can be applied with only using sample
fluid, thus no need for the use of for instance artificial blood as
a calibration fluid. Thus the sample fluid from the same batch can
be used for both the calibration and the biomeasurements after the
calibration.
[0044] Accurate calibration can be acquired for instance by putting
a large amount of the sample fluid to completely cover the complete
active area of the magnetic sensor MS with a very thin layer of
superparamagnetic beads SPB. The superparamagnetic beads SPB are
magnetically attracted to the active area (probe elements PE) of
the sensor MS by a magnetic force caused by for instance the
magnetic fields generated by the first and second wires WR.sub.1,
WR.sub.2. Alternatively it is also possible to generate this force
by a further magnetic field (not shown in FIG. 4). It is to be
noted that the exact amount of superparamagnetic beads SPB need not
be known. This is because the amount of detected stray field SF
sensed by the sensor GMR is influenced approximately only by the
superparamagnetic beads SPB close to the surface. This is because
the distance from higher positioned beads SPB is larger and thus
the influence is smaller. This effect is further enhanced by the
fact that the magnetic stray field SF of the higher positioned
superparamagnetic beads SPB is magnetically shielded by the lower
(thus closest to the substrate SBSTR) positioned superparamagnetic
beads SPB.
[0045] Another method for acquiring accurate calibration is
controlling the amount of the superparamagnetic beads SPB. Under
the assumption that the bead volume density is known, the
controlling can be done by performing the magnetically attraction
of the beads for a fixed (and known) amount of time. Alternatively
a controlled amount of superparamagnetic beads SPB can be reached
by sedimentation. In the latter case a fixed (and known) amount of
time should be awaited in which sedimentation occurs. Also in the
latter case it is assumed that the bead volume density is
known.
[0046] The sensor MS comprises an electronic circuit CRT which is
coupled to the GMR to measure its resistance and more specifically
its changes in resistance. By way of example this circuit CRT also
provides an electrical input signal, which may be a current or a
voltage, through or at the first electrical wire WR.sub.1 (and
possibly also through or at the second wire WR.sub.2). In this
example the electrical input signal is represented by an input
current I.sub.in. The input current I.sub.in may also be supplied
by other means for instance means which are positioned outside the
biochip CHP. The input current I.sub.in generates a magnetic field
H (not indicated in FIG. 4, but see FIG. 2). The superparamagnetic
beads SPB of said very thin layer (at the lower side) generates a
stray field (not indicated in FIG. 4) similar to the stray field SF
as indicated in FIG. 2. Thus a horizontal component of this stray
field (see H.sub.ext in FIG. 2) causes a change in resistance of
the GMR. This change is measured by the circuit CRT. As a response
to this the circuit CRT supplies a signal to an amplifier G which
responses by delivering an electrical output signal in the form of
an output signal I.sub.out. The value of the output current
I.sub.out divided by the value of the input current I.sub.in may be
used as the reference transfer function of the sensor. However the
circuit CRT may also be used to tune this transfer function to be
equal to one (for a certain frequency) by supplying a certain gain
adaptation value GAV to the amplifier G so that the gain of the
amplifier G is lowered or increased by the appropriate amount. This
may also be carried out for more than one frequency, e.g. a range
of frequencies, of the input signals I.sub.in. The calibration is
now completed.
[0047] After completion of the calibration a small amount of sample
fluid, e.g. a drop of blood, in which superparamagnetic beads SPB
are attached to the target molecules TR, is put on a magnetic
sensor MS, the input current I.sub.in is activated, an output
current I.sub.out is generated and measured by a measuring system
MRS thereby measuring the amount of immobilized superparamagnetic
beads SPB and thus the amount of target molecules TR. The output
current I.sub.out can be supplied to the measuring system MRS via a
bonding pad PB. Basically numerous sensors (not shown in the
Figures) on the same substrate SBSTR (so in the same biochip BCP)
can be used all having "loaded" the gain adaptation value GAV to
its amplifier G. Thus basically the sensor MS which was previously
calibrated serve as a reference sensor for all the other sensors MS
in the same biochip BCP.
[0048] 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.
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