WO2008145813A1

WO2008145813A1 - Device and coil arrangement for measuring magnetic particles and corresponding method

Info

Publication number: WO2008145813A1
Application number: PCT/FI2008/050297
Authority: WO
Inventors: Jarmo Verho
Original assignee: Magnasense Oy
Priority date: 2007-05-25
Filing date: 2008-05-23
Publication date: 2008-12-04
Also published as: FI20085009A0; FI20085009L

Abstract

The invention relates to device for the qualitative or quantitative measurement of magnetic particles, which device (10) includes a coil arrangement (20 - 23), arranged to form an inductance bridge (19), of which coils (20, 21) at least two are arranged to operate as a measuring part (17), on which the magnetic particles (12) to be measured are arrangeable to act simultaneously, and part of which coil arrangement (20 - 23) is arranged to operate as a reference/compensation part (18), and from the signal of which coil arrangement (20 - 23) a change of inductance correlating to the number of magnetic particles is arranged to be detected. The coils of the measuring part are arranged in an axial arrangement relative to each other.

Description

DEVICE AND COIL ARRANGEMENT FOR MEASURING MAGNETIC PARTICLES AND CORRESPONDING METHOD

The present invention relates to a device for the qualitative or quantitative measurement of magnetic particles, which device includes a coil arrangement, arranged to form an inductance bridge, of which coils at least two are arranged to operate as a measuring part, on which the magnetic particles to be measured are arrangeable to act simultaneously, and part of which coil arrangement is arranged to operate as a reference/compensation part, and from the signal of which coil arrangement a change of inductance correlating to the number of magnetic particles is arranged to be detected. In addition, the invention also relates to a coil arrangement and a corresponding method.

Numerous methods and apparatuses for measuring magnetic particles, for example, in analytic tests, are known from the prior art. For example, Finnish patent number 113297 discloses an idea concerning the use of a so-called astatic coil arrangement for measuring an analyte from a sample absorbed in a test base. In it, a coil arrangement formed of two coils is used to detect a change in inductance correlating to the content of a magnetically labelled analyte. The coil arrangement in question consists of a measuring coil and a reference coil in galvanic contact with each other. In addition, the system includes a separate magnetic-field source, which can be a coil. The magnetic-field source does not belong to the actual coil arrangement, but instead forms its own component, which is essentially separate from the actual coil arrangement. Magnetic particles that are brought into the vicinity of the measuring coil are magnetized using the magnetic field induced with the aid of the magnetic-field source. The application of traditional technology to such an arrangement, however, is associated with significant problems relating, for example, to the sensitivity of the apparatus. One example of these is the capacitive coupling between the coil loops. A second problem that can be referred to is the asymmetry of the coils, which is caused, for example, by the manual winding of the coils. The very small output signal is also problematic.

The seminar article Makiranta, J.; Lekkala, J, 2005: Modelling and Simulation of a Magnetic Nanoparticle Sensor. Engineering in Medicine and Biology Society, 2005, EMBC 2005, 27^th Annual International Conference of the IEEE Engineering in Medicine and Biology Society. Shanghai, China presents a possibility of implementing the aforementioned invention on a circuit board. The driver coils, which are essentially separate from the actual measuring-coil arrangement, can be wound on top of the measuring coil and reference coil, in order to increase the density of the magnetic flux. Further, the magnetic particles are arranged to act on a single measuring coil. Though this solution eliminates, for example, the problem caused by the manual winding of the coils, the problems of the capacitive coupling and the small output signal still remain.

A manner of measurement, which is based on a so-called inductance bridge, is also known. The seminar article Makiranta, J.; Verho, J.; Lekkala, J; Matintupa, N.; 2006. A Novel Magnetic Particle Sensor. Engineering in Medicine and Biology Society, 2006, EMBC 2006, 28^th Annual International Conference of the IEEE Engineering in Medicine and Biology Society. New York, USA presents one example of a manner of measurement based an inductance bridge. The magnetic particles are made to act on a single measuring coil, the presence of the magnetic particles being detected through a change in the self inductance of the coil. As such, the idea of an inductance bridge is very old. The coil elements belonging to the bridge are clearly separate from each other. One way to bring the coils of the bridge as close to each other as possible, and thus reduce the size of the bridge and improve the matching between the coils and possibly their mutual interaction, is to implement the bridge, for example, in the same way as strain-gauge bridges. Locating the coils forming the bridge close to each other improves several problems relating to bridge measurement, depending on the implementation. These are, in magnetic-particle measurement, for example, the imbalance of the different branches of the bridge and their sensitivity to ambient factors. If it is wished to make the bridge especially small, the mechanical implementation too can become a problem. In an inductance bridge implemented using coils or solenoids wound from wire, the signal level of the output can be raised, for example, by winding twice the turns in the coil arrangement. However, this will increase the size of the coil arrangement and also increase its noise level, which are precisely the undesired properties in sensitive and small-scale measurements performed on magnetic particles .

Measurement from a measuring inductance bridge using a single coil, known from the prior art, consumes a considerable part

(typically, for example, one half) of the supply current of the bridge, to produce a reference voltage for the measuring branch of the bridge. If attempts are made to remove this drawback by bringing the two coils of the bridge close to the magnetic particles, it will often be necessary to make a compromise with the size of the coils. This, in turn, leads to a smaller output signal, unless the frequency, input current, or gain of the preamplifier is correspondingly increased. In the case of inductance bridges, the problem also arises from the fact that, even though an attempt would be made to bring adjacent coils as close as possible to each other in the input direction, they will still be, however, clearly separate from each other. Therefore, for example, manufacturing-process errors, temperature gradients, external magnetic fields, and other disturbance factors affect the different branches of the bridge differently, thus producing a distorted output signal. It is then possible to speak of an imbalance in the different branches of the bridge, as well as sensitivity to various ambient effects.

The permeability of the magnetic particles, and thus the change they create in the inductance in the coil arrangement is very small, for example, compared to the error signals caused by the environment or the test base itself. Thus, the measurement results obtained using a device based on bridge measurement leave much to be desired in their implementation. In addition, due to the known test bases according to the prior art, the reactions of the analyte on the test base take place on a notably small scale, due, for example, to the expensiveness of the reagents.

The present invention is intended to create an improved device, a coil arrangement to be fitted to the device, and a corresponding method for measuring a magnetic particles qualitatively or quantitatively, in which a new way to implement the arrangement of the coil arrangements relative to each other is applied, and thus to obtain, using a coil arrangement made to be compact, substantially more accurate measurement data, compared to devices based on known coil arrangements . The characteristic features of the device according to the invention are stated in the accompanying

Claim 1, the characteristic features of the coil arrangement are stated in the accompanying Claim 12, and the characteristic features of the corresponding method are stated in Claim 13.

In the invention, the coils of the measuring part of the inductance bridge are arranged in an axial arrangement relative to each other. The measuring magnetic particles acting simultaneously on the measuring part of the coils can also be in this axial arrangement with the measuring part of the coils.

According to a first embodiment, the two coils of the measuring part of the inductance bridge can be wound inside each other, in such a way that the measuring magnetic particles act on the two coils of the measuring part of the bridge simultaneously. Thus the coils of the measuring part can be wound horizontally entirely inside each other, being thus in a common layer. One way to implement this embodiment is to wind the coils as a double spiral on top of a substrate.

According to a second embodiment, at least the two coils of the measuring part of the inductance bridge can be at least partly, or even entirely on two different layers, but further, however, in such a way that the measuring magnetic particles act simultaneously on the two coils of the bridge and, in the measuring arrangement, are possibly in an axial formation with the coils of the measuring part. The coil pair can also be in a double spiral, for example, in two, or even more layers, for example, on different surfaces of a printed circuit board.

According to one embodiment, the coils of the measuring part, arranged concentrically, or at least very close to each other in an axial coil arrangement, can be the opposing coils of the adjacent branches of the inductance bridge, so that they will also act in opposite directions. This feature allows the device according to the invention to be used to obtain very precise measurement results, even in the case of analytes that are very weakly magnetic. The magnetic particles will then give a double reading compared to a normal inductance bridge, i.e. the output signal of the inductance bridge will be substantially amplified already in the coil arrangement itself. Through the invention, a coil arrangement fitted into a surprisingly small space can be used to create a double output signal, the noise level remaining, however, essentially the same, relative to, for example, a solution according to the prior art.

Also the printed circuit-board implementation of the device according to the invention can be quite varied. One part of the bridge can be implemented on one printed circuit board, or surface of a board, and the other part of the bridge on another printed circuit board, or surface of a board. If the coils are implemented, for example, by etching, their physical proximity will give them mutually considerably more equal quality. In addition, the simpler construction of the bridge permits the achievement of greater symmetry. These factors lead to greater imbalance in the bridge. This is an important advantage, as normally the imbalance of the bridge is considerably greater than the measuring signal and this places limitations on the performance of the measuring device.

In addition, greater thermal coupling is achieved between the different branches of the bridge, particularly as a structure etched onto a circuit board. The imbalancing of the different branches of the bridge, and its sensitivity to various ambient factors can then be eliminated, or at least minimized. Because the bridge can be etched onto one surface, or different layers of the same circuit board, the mechanical implementation of the bridge can be made extremely small. This is advantageous in applications, in which the magnetic particles are in a very small area, or in a very small volume. The use of the invention achieves several other important additional advantages. One of these is the qualitative and quantitative measurement of magnetic particles by means of two coils, with no significant compromise in the size of the coils. Because the invention also permits the coils to be placed in considerably closer contact/interaction with each other, the arrangement is also more immune to external disturbances. As the invention allows the inductance bridge to be implemented in a smaller space, the invention is also preeminently suitable for use in so-called multiplex analysis, in which there can be several inductance bridges in the same device, in order to perform several determinations simultaneously. The surface-area efficiency of a bridge also reduces manufacturing costs.

Other characteristic features of the device and method according to the invention are stated in the accompanying

Claims while additional advantages achieved are itemized in the description portion.

In the following, the invention, which is not restricted to the embodiments described in the following, is examined in greater detail with reference to the accompanying drawings, in which

Figure 1 shows a rough schematic diagram of the basic principle of bridge measurement,

Figure 2 shows a first embodiment of the coil arrangement according to the invention,

Figure 3 shows an embodiment, in the coil pairs are etched on different layers of a board,

Figure 4 shows an embodiment, in which the coils are wound on top of each other, Figure 5 shows an embodiment , in which several bridges are fitted to a printed circuit board.

Figure 1 shows a rough schematic diagram of the basic principle of bridge measurement. In Figure 1 there is an inductance bridge 19, into contact with which the magnetic particles 12 to be measured are brought and the operation of which they then influence in the desired manner (Figures 2 - 4) . The inductance bridge 19 belonging to the device 10 is formed by a coil arrangement 20 - 23, which can have two branches and be implemented as two double spirals. The principle of bridge measurement is that, in the rest state, the ratio of the impedances of the coils 23, 21 of the first branch and of the coils 20, 22 of the second branch is the same. In that case, irrespective of the magnitude of the supply voltage brought to the input 14, 16 of the bridge 19, the output voltage measured from the output 28, 29 of the bridge 19 will be zero.

If the impedance of any of the coils 20 - 23 of the bridge 19 changes, a signal proportional to the change in impedance and the supply voltage of the input 14, 16 will be obtained from the output 28, 29 of the bridge 19. If the impedances of two the coils 20 - 23 of the bridge 19 change suitably, a two times higher signal will be obtained, in contrast to a traditional inductance bridge, in which the coils are separate from each other and in which essentially the impedance of only a single coil is changed. A first way to double the output signal is to change the impedances of the opposite coils 22 and 23 in the different branches of the bridge 19 to the same direction. A second way to double the output signal is to change the impedances of the parallel coils 20, 23 of the different branches of the bridge 19 to the opposite directions or the impedances of the coils 21, 23 of the same branch of the bridge 19 to the opposite directions. The impedances of three or all four coils can also be changed simultaneously.

If some disturbance, for example, temperature, or an inaccuracy in the manufacturing process, causes an equal relative change in the impedances of all the coils 20 - 23 of the bridge 19, this will not appear significantly in the signal measured from the output 28, 29. This will also occur, if the disturbance affects only the coils 21, 23, or 20, 22 of the same branches of the bridge 19. Also, if the electromagnetic disturbance field is coupled evenly over the entire bridge 19, it will not appear in the signal measured from the output 28, 29.

A sufficiently high-frequency alternating current is, or at least sufficiently fast pulses are fed to the input 14, 16 of the inductance bridge 19 by a signal generator 31, for an output signal to be obtained from its output 28, 29. The inductance change can be detected from the change in amplitude or phase appearing in the output signal of the coil arrangement 20 - 23.

The suitable values for the input frequency and pulse rate of the bridge 19 depend on many factors. According to one embodiment, the most practical frequency range is 1 - 20 MHz and more specifically 5 - 20 MHz, when using coil bridges 19, the inductances of which are typically located in the range 20 - 300 nH, particularly 50 - 150 nH. The input voltage provided by the signal source 31 can vary, for example, from 0,1 to 10 V, more particularly from 0,5 to 2,5 V, and the input current (in the impedance) from 0,001 to 10 A, more particularly from 0,05 - 1 A. In addition to the inductances of the actual coils 20 - 23, parasitic capacitances (C_p) and resistances (R) appear in the inductance bridge 19 (Figure 1) . Figure 1 shows the coils 20 - 23 by showing them by a general equivalent circuit (coil L, series resistance R, and parallel capacitor Cp). The signal source is marked with the reference number 31. Some possible ways of locating the resonance capacitor (C_Ri - C_R6) are also included in Figure 1.

Figure 2 shows, on a schematic level, a first embodiment for implementing in practice the coil arrangement of the device according to the invention. It will be obvious to one skilled in the art that only the coil arrangement 20 - 23, together with its connection points 14, 16, 28, 29, is shown in Figures 2 - 4, in order to simplify the basic principle of the coil arrangement according to the invention. For reasons of simplification, Figures 2 - 4 do not show at all, for example, the insulation possibly required on the printed circuit board 26, or other equipment relating to the measuring electronics, which the practical implementation of the device 10 requires/may demand. It is obvious that, in order to function, the device will require all kinds of auxiliary electronics, which will be obviously realized by one skilled in the art, and which has been omitted from the schematic diagrams. Figure 1 shows the basic principle of a bridge measurement circuit, which will be referred to in this connection.

Qualitative and quantitative measurements of- magnetic particles 12 can be performed by means of the device according to the invention, to which the inductance bridge 19 is fitted.

One application for this is in medical, veterinary, foodstuffs, and environmental diagnostics, in which magnetically labelled samples are measured. Measurement is based on the use of a coil arrangement 20 - 23, in the operation of which the presence of magnetic particles 12 will cause a detectable deviation.

At least two of the coils 20, 21 of the inductance bridge 19 belonging to the device 10 operate as the measuring part 17 of the coil arrangement, with which the magnetic particles 12 being measured are made to act upon simultaneously. For their part, some of the coils 22, 23 of the coil arrangement operate on the measuring part 17, to function as an, as such, known reference/compensation part 18. Its main purpose is to compensate, for example, for the error signals caused by the environment and/or magnetic particles bound unspecifically to the test base 11, and/or error signals caused by the test base 11 itself.

More particularly, one of the first functions of the reference/compensation part 18 can be to compensate the self- inductance, resistance, resistance temperature dependence, and capacitance of the measuring part 17 of the inductance bridge 19. In other words, the reference/compensation part 18 is used to compensate for the signal (impedance of the coils 20, 21 and ambient disturbances) of the empty measuring part 17 in the measured signal 32. Indeed, it is possible to refer in general the compensation of the electrical variables caused by the measuring part 17 itself and the changes in them caused by the magnetic particles. Particles unspecifically bound to the test base 11, a possible capacitive coupling between the windings of a coil and the test base 11, and a capacitive coupling between the medium (sample solution, etc.) transporting the samples and particles 12 and the windings of a coil, for example, can be classified as errors caused by the test base 11.

Error sources caused by the environment can be, for example, a change in resistance caused by temperature variations, error signals induced from the excitation electronics 31, the magnetic field of the Earth when using a ferromagnetic coil core, and other disturbances. One way to eliminate the effect of the Earth's magnetic field is to use a perfect magnetic conductor (PMC) in the device 10. In the device, the coils 20, 21 of the measuring part 17 are surprisingly arranged axially relative to each other. In addition, the magnetic particles 12 to be measured, and arranged to act upon both coils 20, 21 of the measuring part simultaneously, can also be arranged axially relative to the coils. Thus compromises need not be made in terms of the size or placing of the coils 20 - 23, because, due to such placing, the magnetic particles 12 act in the same way on both coils 20, 21 of the measuring part 17. The axial setup of the coils 20, 21 and of the magnetic particles 12 to be arranged in connection with them can be implemented, surprisingly, in several different ways.

In the terms of reference of the invention, the term axial arrangement refers to at least the measuring part 17 of the coil arrangement 20 - 21 being formed in such a way that it is in an axial arrangement. When performing a measurement, the magnetic particles 12 can also be in an axial arrangement with the coils 20, 21. The coils 20, 21 of the measuring part 17, and possible also the magnetic particles 12, are then all in the same axial rising line from the plane of the circuit board 26, in other words, at the normal to the surface 27. The coils 20, 21 can also be either separate from each other or in an axial line, in such a way that the coils 20, 21 of the measuring part 17, which are wound as spirals, are wound concentrically, either partly or entirely, to form, in both cases, a double spiral. In Figure 2 and 3, the axial line is depicted from the measuring part 17 by a rising arrow, thus being, in other words, the normal of the surface 27 of the printed circuit board 26.

In a first embodiment according to Figure 2, the coils 20, 21 of the measuring part 17 of the inductance bridge 19, and in this case also the coils 22, 23 of the reference/compensation part 18, are wound to form a double spiral entirely inside each other. In other words, the inductance bridge 19 belonging to the device 10 is formed of a coil arrangement 20 - 23, which can be implemented as two double spirals 17, 18. Being concentric, both coils forming the relevant part, are also on the same plane. Now the reference/compensation part 18 too includes two coils 22, 23. By winding concentrically, the coil arrangement is implemented in a considerably smaller space than in the prior art, as two coils have been surprisingly fitted into a space on the circuit board that is in principle taken by a single coil.

The coils 20, 21 of the measuring part 17, which are wound concentrically inside each other on the same plane, are on the left side in Figure 2, while the coils 22, 23 of the reference/compensation part 18 are on the right side. The measuring part 17 and the reference/compensation part 18 can be galvanically connected to each other and in a mirror-image arrangement and symmetrical relative to each other, in order to improve the noise immunity of the coil arrangement 20 - 23. The distance between the parts 17, 18 is arranged to be such that they are sufficiently close to each other in terms of the measurement, but, on the other hand, in such a way that the magnetic fields of the parts 17, 18 do not significantly mutually interact in terms of the measurement.

Instead on being wound entirely concentrically, the coils 20, 21 of the measuring part 17 and/or also the coils 22, 23 of the reference/compensation part 18 can be wound at least partly concentrically. Partial concentric winding can be implemented, for example, in such a way that the coil pairs 17, 18 are on the same line in the axial direction, but on slightly different planes relative to each other. This too improves the surface-area efficiency of the coil arrangement. The measuring part 17 and the reference/compensation part 18 of the coil arrangement 20 - 23 can be formed of the coils 20, 21; 22, 23, which are, relative to each other, surprisingly in adjacent branches 24, 25 of the inductance bridge 19 and now in addition to this are the opposite coils 20, 21; 22, 23 of the adjacent branches 24, 25. In the embodiment of Figure 2, the measuring part 17 of the bridge 19, by means of which the particles 12 on the test base 11 are detected, can be formed by the opposing coils 20, 21, i.e. the coils acting in opposite directions, of the different branches 24, 25 of the bridge 19. In that case, not only is a double output signal 32 is obtained from the symmetrical output 28, 29 of the parts 17, 18 forming the bridge 19, but also better noise immunity, the noise level remaining, however, substantially the same. The double signal is obtained using the same amount of particles, without the magnitude of the input signal needing to be increased, relative to the input signals known from measurement procedures known from the prior art. In addition, the importance of the non-idealities of the manufacturing process and ambient effects decreases.

The term the branches 24, 25 of the bridge 19 refers, in this case, to two parallel routes, along which the input current of the bridge travels from point 14 to point 16 (Figure 1) . In Figure 1, the first branch 24 of the bridge 19 is thus formed of the pair of coils 21, 23 and correspondingly the second branch 25 of the pair of coils 20, 22. For its part the oppositeness of the coils refers to the fact that the coils that are in an axial arrangement relative to each other are coils of the opposite ends of the bridge 19, in which the term end refers to the feed points 14, 16 of the bridge 19. Even more specifically, the first coil 21 of the coils forming the measuring part 17 is the coil on the side of the first feed point 14 of the branch 24 of the bridge 19 and the second coil 20 of the branch 25 of the bridge 19 is the coil on the side of the second feed point 16, in which the feed points 14, 16 are opposite to each other.

The concentrically wound pairs of coils 20, 21; 22, 23 can be, for example, etched into the circuit board 26 on the same plane, or printed using a desired method, onto some other suitable substrate. The physical proximity of the coils 20 - 23 helps to compensate for disturbances factors. In addition, the physical proximity of the coils 20 - 23 permits, for example, a compact device suitable for multiplex analysis to be manufactured, using the coil arrangement according to the invention.

Because the invention also permits the coils 20 - 23 of the bridge 19 to be placed in considerably closer contact/interaction with each other, the arrangement is more immune to external disturbances. For example, in a circuit- board solution, the coils 20 - 23 can overlap at a distance of, for example, 50 - 200 μm, preferably 75 - 150 μm, such as about 100 μm from each other.

In terms of manufacturing technique and disturbances, it advantageous to etch all the coils 20 - 23 on the same surface, as closely as possible to each other. In this way too, the solution according to the invention is advanced, because the formation of the parts 17, 18 as concentric double spirals the coil arrangement surprisingly to be implemented even on a single circuit board 26. The concentric coils can be typically at an insulating distance of 75 - 150 um from each other and the different branches of the bridge 19 1 - 5 mm from each other. If necessary, the different halves 17, 18 of the bridge 19 can also be moved farther from each other. This can be implemented by arranging the halves 17, 18 of the bridge 19, for example, on different layers of the same board 26, for example, on the upper and lower surfaces 27.1, 27.2 according to Figure 3 (for example, at a distance of 1,6 mm from each other), or also on completely separate boards.

In the device 10 according to the invention, at least one dimension of the conductor structure in at least one of the coil structures 20 - 23 is in the order of magnitude of a few micrometres to a few hundred micrometres. Thus, for example, the insulating gap and the pitch can be in the range 50 ... 200 urn, preferably 75 ... 150 urn, for example, 100 μm. The height, i.e. thickness of the conductor can be in the range 10 um ... 40 μm, for example, 35 μm. In this case, the terms height and thickness of the conductor refer to the direction at right angles to the base 26 and the term width to the direction parallel to the plane of the base 26.

The plane direction scale (plane direction cross-section and/or length and/or width) of the coil 20 - 23 belonging to the device 10 can be, for example, 10^"7 - 10^"2 m, more particularly 10^"5 - 10^"3 m. This is particularly in a coil structure formed of several conductors. Depending on the manufacturing technique, some examples of the plane direction dimensions are 3 mm x 3 mm, or 300 um x 300 um.

The dimensions of the coils 20 - 23 can be used to affect significantly the sensitivity of the measurement arrangement.

The embodiments shown in Figures 2 - 4 show the basic geometries for planar coils. The number of windings, and the lengths, thicknesses, and widths of the coils 20 -23 of the embodiments of Figures 2 - 4 can differ relative to each other. The electrical properties of the coils are determined by their geometry and dimensions.

The size of the test base 11 and the reaction area in it depend on the application being used and the number of particles. A lateral flow test suitable for the transportation of larger numbers of particles can be, for example, 3 -mm wide, 50-mm long, and some few hundreds of micrometres thick. The surface area of the test area of a lateral flow test can be, for example 3 mm x l mm or 5 mm x l mm. The particle distribution in such a test can be, for example, quite homogeneously distributed over the entire thickness of the strip 11. The channel diameter of microfluidics more suitable for the transportation of smaller numbers of particles can be, for example, about 100 μm and the surface area of the test area can be, for example, about 300 μ x 300 μm. In test implemented using microfluidics, the particle distribution is, for example, on the surface of the test area, or in its immediate vicinity.

Once a sample labelled with magnetic particles 12 has been absorbed into the test base 11, the magnetic particles 12 can then be brought on top of the coils 20, 21 forming the measuring part 17, or stated more generally, into interaction with both of them, in which case the magnetic field of the measuring part 17 magnetizes the detected particles 12. As a result, the magnetized particles 12 reinforce the measuring part's 17 own magnetic field and thus the inductance of both coils 20, 21 of the measuring part 17 increases and, in addition, the coupling coefficient between them also changes. A voltage, from which the output signal is obtained, proportional to the number of magnetic particles 12, appears from the output 28, 29, which is, for example, an intermediate output, of the coil arrangement 20 - 23, a result of the strengthening of the magnetic field of the measuring part 17. In other words, a change in inductance correlating with the number of magnetic particles 12 and thus the amount of the sample labelled with them, can be detected from the sample. By magnetizing the particles 12 using the coils 20, 21 of the measuring part 17, the structure remains simple, because the arrangement operates without separate exciter coils and the external magnetic field created by them.

The change in inductance is proportional to the number of particles 12 and their location in the test base 11, which are measured in the test and from which conclusions can be drawn concerning the final results of the test. Alternatively, a liquid containing the magnetic particles 12 can also flow in a channel 11. It should be noted that the measuring part 17 and the reference/compensation part 18 together form a compact coil entity, in- which case the coil arrangement 20 - 23 formed by them and the test base 11 set in connection with them interact mutually, the output being a single measurement signal 32, from which the necessary conclusions can be drawn concerning the analyte being measured. This simplifies the construction and operation of the device 10.

The elongated test base 11 can be positioned quite freely relative to the measuring part 17, more generally the coil arrangement of the device 10, but in any case, however, asymmetrically, so that the magnetic particles 12 are at different distances from the different parts 17, 18. In the embodiments of Figures 2 - 4, the test base 11 lies transversely across the measuring part 17 and reference/compensation part 18 of the inductance bridge 19, and its longitudinal direction is at right angles to the direction defined by the contact points 14, 16, 28, 29, from which points the measuring system formed by the inductance bridge 19 can be connected. Alternatively, the test base 11 can be set on top of only the measuring part 17.

An example of the inductance range for the coils 20 - 23 can be generally IpH - 1 mH, more specifically 1 nH - 100OnH, and the resistance interval generally 1 mΩ - 100 Ω, more specifically 10 mΩ - 10 Ω (depending on the measuring frequency used) . In can be generally stated that the factor mainly affecting the resistance and inductance values is the dimensions of the coils 20 - 23. For example, the inductance, resistance, and/or capacitance of the coils 20, 21 of the measuring part 17 and coils 22, 23 of the reference/compensation part 18 can be of the same magnitude. Thus, at least some of their electrical variables can be of the same magnitude.

Figure 3 shows a second embodiment for implementing the inductance bridge 19. In it the pairs of coils 17, 18 are etched onto different layers 27.1, 27.2 of a printed circuit board 26. The numbering is as above. The circuit board 26 is now between the pair of coils 20, 21 of the measuring part 17 and the pair of coils 22, 23 of the reference/compensation part 18. Alternatively, the pairs of coils 20, 21; 22, 23 can be even on different boards (not shown) .

Figure 4 illustrates an embodiment, in which the coils 20, 21 of the measuring part 17 are still in an axial arrangement relative to each other, but now the coils 20, 21 of the measuring part 17 are not wound inside each other. In this case, both the coil spirals 20, 21 are essentially on their own plane, i.e. the coils 20, 21 do not interlock in the axial direction. As in some cases it can also be advantageous to wind the coils 20, 21 on top of each other in two very close planes, so that even though they are not, strictly speaking, concentric, the final results and functionality are nearly the same, i.e. both coils 20, 21 of the measuring part 17 see the same magnetic particles 12. When using existing circuit-board technology, this means, for example, a distance of 60 - 120 um, the value being typically 90 urn. It can also be seen from Figure 4 that the magnetic particles 12 need not necessarily be in an axial alignment with the coils 20, 21 of the measuring part 17. The magnetic particles 12 are now slightly offset from the centre line of the coils 20, 21, but, however, still interact with the coils 20, 21 of the measuring part 17.

Additional equalization coils (not shown) can be arranged around the inductance bridge, for example, on each side of it.

They can be used to replace, for example, the ferrite pieces

(not shown) that balance the measurement. The external balancing coils can be controlled using the same frequency as the input to the bridge. Control can take place in such a way that the ratio between two equalization coils can be adjusted to achieve balance.

Figure 5 shows one rough example of a coil arrangement suitable for multiplex analysis, in which there are now four bridges 19.1 - 19.4.

Within the scope of the basic idea of the invention there is also no need to be limited to only matching the opposing pairs of coils 20, 21 and 22, 23 of the adjacent branches 24, 25 of the inductance bridge 19 in an axial manner when forming the measuring part 17 and the reference/compensation part 18. If desired, it is also possible to connect the concentric coils to a traditional solution of separate coils. The selected coil pair is then implemented concentrically and the remaining two coils can be implemented as separate coils. The axial arrangement can be formed, for example, of two coils in the bridge 19 acting in the same direction, in which case the consecutive coils 21, 23 in the same branch 24 of the bridge 19, or the adjacent coils 20, 23 of the adjacent branches 24, 25 of the bridge 19 can be in an axial arrangement. Even though the signal doubling advantage is not achieved in these embodiments, and the coil bridge 19 may, in addition, also be in slight imbalance, it is, however, possible to influence the structure's noise immunity in this manner and at least it achieves a size advantage. The coil arrangement according to the invention can surprisingly be manufactured on a single printed circuit board 26. It can be manufactured, for example, either on the same side 27 of the printed circuit board 26, as shown in Figure 2. In that case, the coil arrangement 20 - 23 can be on the surface 27 of the board 26 and/or in different layers or the same layer, near to the surface 27. On the other hand, it can also be on different sides 27.1, 27.2 of the printed circuit board 26, as shown in the embodiment of Figure 3. In addition, it is also possible to implement one half of the bridge 19 on one printed circuit board, or surface 27.1 of a board, and the other half of the bridge 19 on a second printed circuit board, or surface 27.2 of a board. The printed circuit board of Figure 3 can then be imagined as being cut in two in the planar direction, in which case two printed circuit boards on top of each other are created. There is a separate printed circuit board for the set of coils 18 on the underside and another for the set of coils 17 on the upperside. Another alternative for implementing two printed circuit boards is one in which the set of coils 18 on the underside in Figure 3 has its own printed circuit board.

Further, it is also possible to continue the double spirals 17, 18 entirely or at least partly concentric, or even several layers, when using a multi-layer circuit board. The double spiral 17, 18 can also continue to the other side of the printed circuit board. This creates an important advantage in manufacture, for example, as simplified assembly, improved symmetry, and thermal contact. The efficient coil arrangement of the device makes it particularly compact and suitable, for example, for bedside testing, i.e. Point-of-Care Testing (POCT) applications. Irrespective of the degree of integration, the coil arrangement 20 - 23 according to the invention can be manufactured typically on an insulator or a semiconductor. Such an insulator can be, for example, glass, plastic (FR4) , a semiconductor oxide (SiO₂) , or some other insulator suitable for a semiconductor implementation. The insulator material used depends on the manufacturing technique. The coils 20, 21 of the measuring part 17 and the coils 22, 23 of the reference/compensation part 18 can be manufactured not only from an electrically conductive metal, for example, copper, aluminium, gold, or silver, but also from other electrical conductors, for example, electrically conductive polymers, or a compound semiconductor. Micro-machining methods, such as photolithography, wet or dry etching, doping, metallizing, printable electronics, and/or thick-membrane techniques, for example, can be used for the manufacture of the structures. The structures can also be manufactured using mechanical machining methods, for example, milling.

In terms of the invention, the test base 11 itself can be of quite many kinds . Some examples of these are the so-called lateral-flow test, the well plate, capillary, microfluidics channel, the micro-array, or some other known way of bringing the particles 12 to be measured into the vicinity of the device 10, or one that is presently only being developed. The lateral-flow test can be used for the transportation of larger numbers of particles, on account of its reliability and economy. Particular positioning accuracy (distance from the measuring part) can be expected from the transportation formats with smaller numbers of particles and smaller sensors. Microfluidics is better suited to this than a lateral test and a test base 11 permanently integrated in the measuring part 17 will permit a high positioning accuracy relative to the position of the measuring part 17 and the test base 11. The diameter of the individual magnetic particles, which can be determined by means of the device 10 according to the invention, can be, for example, in the range 1 run - 10 μm. Particle clusters formed, for example, of 5 - 30 run particles, the diameter of which can be, for example, in the range 30 run - 10 μm, or particularly 100 - 600 nm, depending on the test base, are particularly interesting. The amount of magnetite or a corresponding material can be, for example, in the order of magnitude of 1 ng - 1 mg and the corresponding sample volume in the order of magnitude of, for example, 1 nl - 1 ml . In that case, the number of particles on the test base can be in the range 1 - 10¹², more particularly 10³ - 10¹⁰ (for example, lateral-flow tests), or 1 - 10⁸ (for example, miniaturized diagnostics) . The upper and lower limits of the size and number of particles generally depends on the application and the dimensions of the coil arrangement used.

In the applications described above, each coil 20 - 23 was a planar square spiral, formed of a conductor structure, the number of windings being, for example, two. The shape of the coils 20, 21 of the measuring part 17 and also the shape of the coils 22, 23 of the reference/compensation part can be, instead of the square described above, for example, a polygon (for example, a rectangle, triangle, hexagon), or round (for example, a circle, oval, omega), spiral, planar, continuous, electrically conductive, live conductor structure.

According to yet another embodiment, four coils, which belong to two separate inductance bridges, can, for example, be set to act of the same particle cluster. In other words, in that case at least two bridges 19 of the types described above are constructed either entirely or at least partly on top of each other, in which case the measuring parts 17 and/or the reference parts 18 of both bridges 19 will be on top of each other and in such a way that the same magnetic flux can travel through both bridges. According to a second embodiment, two bridges 19 can be arranged very close to each other, in such a way that they see the magnetic particles in an area the width of two bridges. According to one embodiment, the bridges can be arranged on different sides of a single thin circuit board. The outputs of the bridges can be placed in parallel (or in series) and can feed input signals to the input of each bridge in turn.

In the aforementioned embodiment, the signals of the bridges can be summed with each other and a stronger signal obtained, though the noise level may increase correspondingly slightly. The reliability of the measurement can be influenced in this way, because the same particles are read from more than one bridge and their signals can then be averaged, even though in this case the bridges measure some of the particles they see in different ways.

A second advantage, which can be achieved using the aforementioned embodiment, is, for example, multiplex determinations. In that case, the reference parts of the bridges can be arranged on top of each other, in which case the two bridges can be arranged closed to each other and thus take up less space on the printed circuit board. The measuring parts are now not on top of each other, but both measure their own group of magnetic particles for multiplex analysis, in the characteristic manner.

Four combinations of the solution applying two bridges can be obtained, in some of which, for example, transformers will be required to combine the signals of the bridges:

1) the inputs and outputs can be in parallel, in which case the system will behave like a single low-inductance bridge, 2) the inputs and outputs can be in series, in which case a double output will be obtained with a double impedance, in other words, the same as doubling the inductance, 3) the inputs can be in series and the outputs in parallel, in which case the same output will be obtained as with a double inductance, and

4) the inputs can be in parallel and the outputs in series, in which case a double output will be obtained with half the inductance.

If the same space used on the circuit board were to be used for only a single bridge, in other words, only its number of windings being doubled, a double output will also be obtained with a double impedance. Compared to alternative 2, the embodiment has the advantage that there will be less waste surface area.

Through the invention, a double signal is obtained without compromise with the size of the coils. The fact that the coils do not significantly disturb each other is also a significant additional advantage.

It must be understood that the above description and the related figures are only intended to illustrate the present invention. The invention is thus in no way restricted to only the embodiments disclosed or stated in the Claims, but many different variations and adaptations of the invention, which are possible within the scope on the inventive idea defined in the accompanying Claims, will be obvious to one skilled in the art.

Claims

1. Device for the qualitative or quantitative measurement of magnetic particles, which device (10) includes a coil arrangement (20 - 23), arranged to form an inductance bridge

(19), of which coils (20, 21) at least two are arranged to operate as a measuring part (17), on which the magnetic particles (12) to be measured are arrangeable to act simultaneously, and part of which coil arrangement (20 - 23) is arranged to operate as a reference/compensation part (18), and from the signal of which coil arrangement (20 - 23) a change of inductance correlating to the number of magnetic particles (12) is arranged to be detected, characterized in that the coils (20, 21) of the measuring part (17) are arranged in an axial arrangement relative to each other.

2. Device according to Claim 1, characterized in that the coils (20, 21) of the measuring part (17) are wound at least partly concentrically inside each other.

3. Device according to Claim 1 or 2 , characterized in that the said reference/compensation part (18) includes two coils (22, 23) .

4. Device according to Claim 3, characterized in that the coils (22, 23) of the reference/compensation part (18) are wound at least partly concentrically inside each other.

5. Device according to any of Claims 1 - 4, the inductance bridge (19) of which has two branches, characterized in that the measuring part (17) and the reference/compensation part (18) of the coil arrangement (20 - 23) are arranged to be formed of coils (20, 21; 22, 23), which are in branches (24, 25) of the inductance bridge (19) that are adjacent to each other.

6. Device according to Claim 5, characterized in that the measuring part (17) and the reference/compensation part (18) of the coil arrangement (20 - 23) are arranged to be formed of coils (20 - 23), which are opposing coils ( 20, 21; 22, 23) of the adjacent branches (24, 25) .

7. Device according to any of Claims 1 - 6 , characterized in that the coil arrangement (20 - 23) is etched on the same plane (27) of a printed circuit board (26) .

8. Device according to any of Claims 1 - 7, characterized in that the parts (17, 18) of the coil arrangement (20 - 23) are implemented on different surfaces (27.1, 27.2) of the same printed circuit board (26) .

9. Device according to any of Claims 1 - 7, characterized in that the parts (17, 18) of the coil arrangement (20 - 23) are implemented on separate printed circuit boards.

10. Device according to any of Claims 1 - 9, characterized in that the parts (17, 18) of the coil arrangement (20 - 23) are arranged to extend to several layers of the printed circuit board (26) .

11. Device according to any of Claims 1 - 10, characterized in that at least two coil arrangements (19.1 - 19.4) are fitted to the device (10), for multiplex analysis.

12. Coil arrangement for the qualitative or quantitative measurement of magnetic particles, which coil arrangement (20 - 23) is arranged to form an inductance bridge (19), of which coils (20, 21) at least two are arranged to operate as a measuring part ( 17 ) , on which the magnetic particles ( 12 ) to be measured are arrangeable to act simultaneously, and part of which coil arrangement (20 - 23) is arrangeable to operate as a reference/compensation part (18) , characterized in that the coils (20, 21) of the measuring part (17) are arranged in an axial arrangement relative to each other.

13. Method for the qualitative or quantitative measurement of magnetic particles (12), in which the measurement is performed using a coil arrangement (20 - 23), arranged to form an inductance bridge (19), in which there is a measuring part (17), on which the magnetic particles (12) to be measured act simultaneously, and a reference/compensation part (18), from the signal of which coil arrangement (20 - 23) a change in inductance correlating to the number of magnetic particles (12) is detected, characterized in that the magnetic particles (12) are measured using the measuring part (17), the coils (20, 21) of which are in an axial arrangement relative to each other.

14. Method according to Claim 13, characterized in that the coils (20, 21) of the measuring part (17) are opposing coils

(20, 21) of the adjacent branches (24, 25) of the inductance bridge (19), to improve the strength of the output signal of the coil arrangement (20 - 23) .