CN101427131B - Device for measuring magnetic particles and corresponding method - Google Patents
Device for measuring magnetic particles and corresponding method Download PDFInfo
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- CN101427131B CN101427131B CN2007800143569A CN200780014356A CN101427131B CN 101427131 B CN101427131 B CN 101427131B CN 2007800143569 A CN2007800143569 A CN 2007800143569A CN 200780014356 A CN200780014356 A CN 200780014356A CN 101427131 B CN101427131 B CN 101427131B
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Abstract
The invention concerns a device (10) for the qualitative or quantitative measurement of a magnetically labelled analyte (12). The device (10) includes a coil arrangement (13, 18) for measuring the analyte (12) from a sample absorbed in a test base (11). The coil arrangement includes at least one measuring coil (13) and a reference coil arranged in connection with it. From the signal of the coil arrangement (13, 18) a change in inductance correlating to the content of the magnetically labelled analyte (12) is arranged to be detected. The change in inductance is arranged to be detected from a change (delatA, delataf) in amplitude and/or phase appearing in the output signal (32) of the coil arrangement (13, 18), which is arranged to be measured at the frequency of the input signal (31). In addition, the invention also relates to a corresponding method.
Description
Technical field
The present invention relates to be used for the device of the qualitative and quantitative measurment of magnetic labelled analyte; This device comprises coil configuration; This coil configuration is measured coil by at least one and is formed about the reference coil of measuring coil configuration; Be used for measuring analyte, and be arranged to from the inductance variation relevant of the input of this coil configuration with the content (content) of magnetic labelled analyte from the sample that is absorbed in test base (test base).In addition, the invention still further relates to corresponding method.
Background technology
Prior art becomes known in analytical test for example, measuring many method and apparatus of magnetic particle.For example, fi patent numbers 113297 discloses about following design: use so-called astatic coil to dispose the analyte of measuring from being absorbed in the sample in the test base.In this patent, use coil configuration to detect the inductance relevant and change with the content of magnetic labelled analyte.
Yet the conventional coil technology is applied to this configuration can relate to for example relevant with the sensitivity of equipment major issue.Some examples of these problems are the electric capacity parasitic currents in the coil loop.Another problem serve as reasons manual coiling and the asymmetry of the coil that causes of coil for example.
It is very unconspicuous that the magnetic of magnetic particle and magnetic particle thereby the inductance variation that in coil system, produces are compared with the error signal that is for example caused by environment or test base itself.Therefore, the measurement result of using this equipment to obtain leaves much to be desired.
In addition, owing to the test base according to prior art, for example because of reagent is more expensive, the analyte on the test base reacts very on a small scale.Therefore, test base for example can produce challenge with respect to the location of device, and wrong simultaneously location can make the test result distortion.In addition, test base needs the loop construction of winding especially.
Disclosed technical scheme also makes the application of coil device in analyzing the speed survey become known in PCT communique WO-2005111614 and WO-2005111615.These technical schemes detect inductance based on the variation from resonant frequency and change.When measuring the variation of resonant frequency, when the electric capacity of the inductance of coil or capacitor changed, the resonance peak of lc circuit was changed into different frequencies.Yet the low inductance of coil has produced a problem.All types of parasiticss can easily connect with the coil with low inductance, and therefore, these parasiticss also can be separated with the signaling zone that records with frequency form.
PCT communique WO03/076931A1 is also open from another kind metering system well known in the prior art.This metering system is also based on the variation that detects frequency.
Also known multiple so-called SQUID type method.Yet the principle of operation of these methods need be operated under very low even temperature near absolute zero.This makes the complex equipments in for example POCT (point of care testing, floor inspection) uses.
Summary of the invention
The present invention is intended to create and is used for improved device and corresponding method qualitative or that measure the magnetic labelled analyte quantitatively; With compare when the known device that for example uses based on the coil configuration of at room temperature working, can produce basically metrical information more accurately by means of these apparatus and method.Characteristic according to this device of the present invention is explained in accompanying claims 1, and characteristic explanation in claim 15 of the method corresponding with this device.
In device according to the present invention, be arranged to and detect inductance from the variation of the amplitude that the output signal of coil configuration, shows and/or phase place and change, and the variation of this amplitude and/or phase place is arranged to the frequency measurement with input signal.
According to an embodiment, increase greatlyyer in order to make induction reactance than resistance, the survey frequency of using in the device is arranged at 10
5-10
9Hz is preferably 10
6-10
8Hz.The use of this very high survey frequency will greatly improve the accuracy of using the measurement result that this device obtains.
According to an embodiment who more optimizes, this device can comprise the coil configuration of the error signal that compensation can form with several kinds of different modes extraly.This device for example can be used to compensate by environment and/or does not confirm to be bound to the error signal that the magnetic particle of test base causes.Reference coil also can be used for this compensation purpose.This reference coil can be used to compensate error signal that is caused by test base etc. at least.Certainly, should be noted in the discussion above that reference coil also has other function in device according to the present invention, thereby the compensate function that relates at this aspect will not repel other function.According to an embodiment, can collocation structure be embodied as for example differential coil system.An example of this differential coil system can be an impedance bridge.In this situation, it is relevant with collocation structure with reference coil to measure coil.
By means of device according to the present invention, even under the situation of very weak magnetic analytes, also can obtain measurement result very accurately.High measurement frequency and the differential winding structure in measurement, used mean, aspect temperature conditions, this device be highly suitable in addition room temperature under use.Compare with the frequency measurement of prior art; Apparatus and method according to the present invention are less sensitive for parasitics; Because parasitics can not easily be come out from measured output signal distinguishing, wherein, should export the phase differential and/or the amplitude of signal with the frequency measurement of input signal.
According to an embodiment, this device also can be made very terminal user close friend.Ground is integrated if test base and coil configuration interact, and then need test base be set to the link of coil device separately.So, this is enough to sample is placed on the test base and measures.As device embodiment, this just in time can be especially in the coil of micro-dimension scale and be to be considered during PoCT uses for example in floor inspection.
Further feature according to apparatus and method of the present invention is explained in accompanying claims, and other advantage that realizes specifies in the instructions part.
Description of drawings
Hereinafter, will study the present invention in greater detail with reference to the attached drawings, and the invention is not restricted to hereinafter illustrated example, in the accompanying drawings,
Fig. 1-3 illustrates some possible examples that are used in according to the coil structure in the device of the present invention,
Fig. 4 illustrates first embodiment according to device of the present invention, and wherein, it is right to have used differential winding,
Fig. 5 illustrates second embodiment according to device of the present invention, and wherein, it is right to have used differential toroid winding,
Fig. 6 illustrates the embodiment with the circuit component modeling according to device of the present invention, wherein, has used bridge measurement principle,
Fig. 7 illustrates the example of the measurement configuration of the bridge measurement principle of having used Fig. 6,
Fig. 8 illustrates the 3rd embodiment according to device of the present invention, wherein, has used coil bridge measurement at grade,
Fig. 9 illustrates the embodiment according to device of the present invention, wherein, has used bridge measurement and at least some coils on different plane,
Figure 10 illustrates the embodiment according to device of the present invention, wherein, has used bridge measurement and coil and has become a row at grade.
Figure 11 illustrates the application examples of figure, and wherein, the inductance of measuring the coil that is caused by magnetic particle through amplitude measurement changes,
Figure 12 illustrates the example of the standard drawing of the process of measurement acquisition of using Figure 11,
Figure 13 illustrates the application examples of use according to the measuring principle measurement sample of Figure 11, and
Figure 14 illustrates the application examples of figure, and wherein, the inductance of measuring the coil that is caused by magnetic particle through phase difference measurement changes.
Embodiment
By means of device 10 according to the present invention with based on the measuring method of this device, can detect amount from the magnetic particle of test base 11.This is measured based on using coil configuration 13,18-20, and in the operation of this measurement, the existence of magnetic particle will cause detectable dispersing.
Fig. 1-3 illustrates the example that is suitable for use in according to some simplification of the coil 21 in the device 10 of the present invention, and this coil 21 is used for the qualitative or quantitative measurement of magnetic labelled analyte 12.
Fig. 1 illustrates first example of the coil 21 that can be used in the device 10.In this case, loop construction forms the planar rectangular spiral, and the number of turns of this spiral is two now.The test base 11 of elongation can quite freely be located, but under any circumstance all with respect to coil 21, more briefly, with respect to the coil configuration of device, is asymmetric.In this case, test base 11 crosses coil 21, and the vertical and direction that is limited contact terminal 14,15 of this test base meets at right angles, and coil loop 21 can be connected with this contact terminal 14,15.The example of the inductance interval of this coil 21 generally can be 1pH-1mH, more specifically, is 1nH-1000nH, and resistance interval generally is 1-100 Ω, more specifically, is 10m Ω-10 Ω (depending on used survey frequency).Usually, we can say that the main efficiency factor of resistance value and inductance value is the size of coil.In this case, the read value of being given adapts with the coil dimension that the back literary composition is mentioned.
Fig. 2 illustrates second example of the coil 21 that is used in the device 10.Shown in embodiment, the structure of coil 21 really can be very simple.Now, coil is formed by single conductor loops only, thereby is the simple version of loop construction shown in Figure 1.Conductor loops forms single around planar coil 21, configurablely is connected with the mutual of this conductor loops from the test base 11 with magnetic particle 12.In this situation, same, nowadays the contact terminal 14 in the same side is connected with coil loop 21 with 15.An example of inductance interval that is used for the coil loop 21 of this loop construction can be 1nH-20nH, and resistance interval can be 1m Ω-100m Ω.
Fig. 3 illustrates the 3rd example of the structure of single coil 21.In this case, coil 21 is by forming than the also simple structure of the structure in above-mentioned two kinds of situation.This example illustrate coil 21 in addition can be by straight conductor structure, the conductor rods (conductor beam) that promptly crosses the stretching of test base 11 forms.Although this is simple in structure, this structure is still thought coil equally beyond all doubtly, and this is because the coil component that this conductor rods 21 forms in the circuit when conductor rods 21 is connected to electronic installation.Equally, can contact terminal 14,15 be connected with conductor 21.An example for the inductance interval of this structure can be 100pH-3nH, and resistance interval is 0.1m Ω-10m Ω.
Fig. 4 and Fig. 5 illustrate some embodiment according to device 10 of the present invention, wherein, but the loop construction shown in the application drawing 1-3.In device 10 according to the present invention; The citation form of coil configuration comprises at least two coils 13,18 that formed by conductor structure; By means of the sample analyte 12 of this coil configuration from absorbing at test base 11, the conductor structure of this coil configuration can be for example the plane and mutual electric current connection.Should be noted in the discussion above that in order to simplify, Fig. 1-10 do not illustrate the insulator that possibly need on the circuit board 22, or install that 10 actual enforcement requires/possibly need with measure the relevant equipment of electronic installation.Fig. 6 illustrates this all of full details that have.
Should be noted that; Measure the integral body that coil 13 and reference coil form single compactness; Make by measuring coil configuration that coil 13 and reference coil form and test base 11 interactions that are provided with about their; And output is single measuring-signal 32; Variation according to the amplitude that records from this output with the frequency of input signal 31 and/or phase delta A,
(delta A, delta phi) can draw the necessary conclusion about the analyte in the inspection.This has simplified the structure and the operation of sensor 10.
In device according to the present invention, the reference coil configuration that in this situation, comprises single reference coil 18 has several different but meanings of not repelling each other.First function of reference coil is the temperature dependency of compensation self-induction, resistance, resistance and the electric capacity of measuring coil 13.Substantially, we can say electrical quantity that compensation self causes by coil 13 and can't help the variation that those magnetic particles cause.When the self-induction of coil 13,18 is identical, in the output of measuring coil 13, will occur and the proportional difference of particle weight, owing to this difference, this measurement can be called as differential.In addition, reference coil 18 also can be used to compensate the error that is caused by test base 11 and/or environment, and this is also relevant with the differential character of this configuration.For example; The particle of confirming constraint in the test base 11, the possible electric capacity between the material of multiturn coil and test base 11 are connected and carry the medium (sample solution or analog) of sample to be connected with electric capacity between particle and the multiturn coil, can be classified as the error that is caused by test base 11.Error signal, magnetic field of the earth and other interference that the source of the error that is caused by environment is the resistance variations that for example caused by temperature variation, import from input electronic installation 23.
Use and measure the particle 12 that coil 13 detects on the test base 11.Can carry out this measurement from coil 13, contact 15 between 18, promptly so-called in the middle of output measure.If test base 11 does not have particle, the AC signal of then supplying with from contact 14,16 on the coil 13,18 adds up to zero centre output 15.The magnetic field that belongs to the measurement coil 13 of coil configuration is used to magnetize particle to be detected, and these particles to be detected are interacted with the measurement coil 13 that installs 10 at least.The particle that is magnetized has strengthened the magnetic field of measuring coil 13 self, regards this variation as variation inductance thereby measure coil 13.As the magnetic field enhanced results of measuring coil 13, the voltage with the proportional ground with respect to input signal of population appears in centre output 15.Aspect this, can mention differential connection really, that is, be output as two differences between the signal.
Therefore; Coil configuration 13, the 18-20 of device 10 can be used to detect with the corresponding inductance of the content of magnetic labelled analyte 12 and change; In device 10 according to the present invention and method; From variation, measure this inductance and change with the amplitude that the output signal 32 of coil configuration 13,18, occurs of the frequency measurement of input signal 31 and/or phase delta A,
.According to an embodiment, can from measure coil 13 and reference coil 18 in the middle of the variation of amplitude and/or phase delta A,
of output 15 measure this inductance and change.This metering system has been realized the special advantage that literary composition will be mentioned behind this instructions.The quantity and the position of variation inductance and particle are proportional, and the quantity of this particle and position are the measurement results of wanting, and can draw the conclusion about test result from the quantity and the position of particle.In situation according to device of the present invention, can mention impedance/inductance sensor really, wherein measured the characteristic of coil-conductor.
In Fig. 4, test base 11 is placed in only to be measured on the coil 13.Selectively, shown in the embodiment of Fig. 5, test base 11 can be configured in the two top of path of winding 13,18.Has electrical connection from contact terminal 14-16 to the measurement configuration that forms by coil 13,18.
Fig. 5 illustrates the second right embodiment of differential pick-up-ring, and nowadays this differential pick-up-ring to being formed around planar coil ring 13,18 by two lists that are parallel to each other.The structure of the embodiment that this texture ratio is shown in Figure 4 is slightly simple, thereby is easier to make.In the present embodiment, the test base 11 that has a magnetic particle 12 is laterally placed on two coils 13,18.Make test base 11 improve elimination to the measuring error that causes by test base 11 etc. on the two at coil 13,18.Be connected to this measuring system from contact terminal 14-16, wherein, contact terminal 15 is to be used for output in the middle of the two common of coil 13,18 once more.Should be noted in the discussion above that to be independent of this embodiment ground, each coil 13,18 also can have the contact terminal 14-16 of self.
In two embodiment, the reference coil 18 of measuring coil 13 and the collocation structure that is formed for this measurement coil 13 so forms the differential winding configuration now.Can be used to the amplitude A and/or the phase place
of the variate output signal 32 relevant with the inductance variation of measuring coil 13 about the reference coil 18 of measuring coil 13 configurations.This makes and disturbs the error signal that is especially caused by the too much magnetic particle of not confirming the location to minimize on every side.
Fig. 6 illustrates the embodiment with the device 10 of circuit component modeling, wherein, uses four coils 13,18-20 to use bridge measurement principle.In this situation, compensation additional structure 19,20 or structure and placement thereof (for example, symmetry, overlapping) can mainly be used to eliminate the error signal that is caused by environment.Can and also cause these error signals by for example electromagnetic machine and calutron by the magnetic field of the earth.In addition, the bridge measurement permission " is floated and is measured ", in the measurement of floating, signal and earth potential is not compared, otherwise may cause error.
In this case, collocation structure not only comprises reference coil 18, also comprises at least two interpole coils 19,20.In this case, measuring coil 13, reference coil 18 and collocation structure 19,20 relative to each other is configured in the impedance bridge.In addition, also relative to each other configuration symmetrically of coil 13,18-20.In this case, coil 13,18-20 for example can be identical copy or the mirror images of measuring coil 13, improve the anti-interference of configuration with the characteristic of identical copy or mirror image.Thereby inductance, resistance and/or the electric capacity of measuring coil 13, reference coil 18 and collocation structure 19,20 can be for example identical sizes.Therefore, at least some electrical quantitys of measurement coil 13, reference coil 18 and collocation structure 19,20 can be identical sizes.The application of same coil makes the sensitivity of bridge measurement increase greatly, and this is because all impedances will be roughly identical size.
Therefore, impedance bridge is formed by the reference coil 18 of measuring coil 13, measurement coil 13 and the compensating coil 19,20 of measurement coil 13 and reference coil 18.Test base 11 can for example be configured in the top of measuring coil 13 at least with the mode shown in Fig. 8-10, and in this situation, test base 11 also is configured in the top of reference coil 18.All the other coils 19,20 are used for compensation.In Fig. 6, coil 13,18-20 are shown as and draw equivalent electrical circuit (coil L, resistors in series R and shnt capacitor C as the one of which
p).Mark signal source with Reference numeral 23.
Fig. 6 also comprises some possible mode (C that place resonating capacitor
R1-C
R6).An example that disposes the mode of this resonating capacitor can be: make the capacitor at the input side of circuit be connected in series, be connected in parallel at the capacitor of measuring side.These capacitors also can be made with coil 13, the 18-20 on the shared pedestal 22.The advantage of doing like this is to reach first amplification stage that increases signal easily.
In electric bridge connects, two coils that separate between measuring-signal 32.To compare to exporting 17 in the middle of 19,20 from measuring signal 32 that coil obtains output 15 in the middle of 13,18 and the corresponding compensating coil that does not have a particle, thereby also can be called variate.Equally, also can be called " floating " and measure, this is because actual output is that measuring-signal 32 is compared with the earth potential that does not have electric current to contact, and for example, compares with the earth potential of input media 23.
Fig. 8-10 illustrates the coil 13 of 4 coil bridge measurements, some the possible modes of 18-20 of being used for of placing.Fig. 8 illustrates an embodiment, and in this embodiment, coil 13,18-20 all are positioned at the par height, become rectangular structure.Wherein, measuring coil 13 aligns about measuring- signal conductor 15 and 17 with reference coil 18 symmetrically.Compensating coil 19,20 is adjacent one another are on the par height, and as square.In addition, compensating coil 19,20 and measuring- signal conductor 15,17 and first coil are symmetrical about at least one axis to 13,18.To get into the electric current of input- signal conductor 14,16 much little because leave the current ratio of measuring- signal conductor 15,17, so this balanced configuration has realized extra remarkable advantage, for example, aspect interference compensation.The continuous performance of symmetry extends to the range of influence of coil 13,18-20.When interference on every side occupied ascendancy, the range of influence of coil 13,18-20 we can say and is through with.
Fig. 9 illustrates another embodiment of bridge measurement.In this embodiment, coil is overlapped to 13,18,19,20.Substantially, can be referred to as layered configuration, in this configuration, at least some coils are compared with other coil and are in the different horizontal height.13,18 of coils on the par height can be parallel to each other, and are for example, symmetrical in couples.If there be very little not confirming to fetter, these coils 13,18-20 can be independent (singly), will illustrate in greater detail like the back literary composition.
Measuring coil 13 aligns about measuring- signal conductor 15,17 with reference coil 18 once more symmetrically.Input- signal conductor 14 and 16 arrives sidepiece.Be different from embodiment shown in Figure 8, compensating coil 19,20 is positioned at now measures coil 13 and reference coil 18 belows.In the present embodiment, the test base 11 that has a magnetic particle 12 laterally is configured on two " coil stacks ".In this case, this stacked geometry of coil 13,18-20 is than making minimize interference in the embodiment shown in fig. 8 better.In addition, present embodiment allows the better placement of coil on test base 11.This is an advantage, especially when using the effluent test.
Figure 10 illustrates the 3rd embodiment of bridge measurement, and in this embodiment, coil 13,18-20 still become the structure of delegation in this example once more at the par height.Measuring coil 13 aligns about measuring- signal conductor 15,17 with reference coil 18 once more symmetrically.Equally, in this example, input- signal conductor 14,16 is from sidepiece.Compensating coil 19,20 is positioned at the either side of two ends, measurement coil 13 and the reference coil 18 of coil column now.Test base 11 with magnetic particle 12 once more landscape configuration on all coils 13,18-20.An advantage of this structure is better to align with respect to test base 11.
According to another bridge measurement embodiment, coil 13,18-20 also can go up at post (post) and concentrate.In this situation, can be with reference to figure 9.Different with Fig. 9 is that the signal conductor of measurement coil 13 and reference coil 18 mode as follows is provided with: if necessary, can for example around coil, remove insulating material through milling (milling).With this mode, for example other conductor is obviously higher than around it with reference coil 18 can to make measurement coil 13.For example, can make the conductor 17 of Fig. 9 be arranged on the back and the below of conductor 15.The advantage of this structure is better to align for some test bases.
According to an embodiment, test base 11 also can be integrated with sensor construction 13,18-20 on the independent matrix abandoned (disposablebase) 22 (Figure 10).In this case, measure at least in the proximate portion that coil 13 will be integrated in test base 11, promptly be coupled to test base 11 or at least very near test base 11 (distance < diameter of coil 13 1/>10).Under any circumstance, be independent of configuration, all can mention test base 11 and coil configuration, at least with mutual connection of measuring between the coil 13.Configuration testing matrix 11 also is fine in this device with the corresponding method that is connected of coil 13,18, connects relevant ground with this, can make test base 11 be in dismountable mode.Abandon on the matrix 22 coil (reference coil 18, compensating coil 19,20) that can also be more integrated or all and/or at least a portion or even whole measurement electronic installation same.The matrix abandoned that is integrated 22 can be connected to the remainder of electronic installation by for example electric current connection, electric capacity connection or inductance.
Shown in above-mentioned embodiment, test base 11 not only can dispose (XY plane) with coil plane abreast, and can vertically pass coil plane (Z axle).Test zone also can cross measures coil 13 (in the XY plane).
No matter integrated degree how, can typically on insulator or semiconductor, make according to coil configuration of the present invention.This insulator can be, for example, and glass (quartz), plastics (FR4) or conductor oxidate (silicon dioxide).Employed insulating material depends on manufacturing technology.Compensating coil/ structure 19,20 of measuring coil 13, reference coil 18 and possibly existing can also be processed by for example other electric conductor such as electric conductive polymer or doped semiconductor by processing such as conductive metal such as copper, aluminium, gold or silver.In order to make this structure, can use for example little processing (micro-machining) method, for example, photoetching, wet etching or dry ecthing, doping, metallization, printing electronics and/or thick film technology.Also can use and process this structure such as machining process such as millings.
According to an embodiment, in order to increase the induction reactance of the coil configuration of for example measuring coil 13, the survey frequency of device 10 can adopt the frequency higher than the known survey frequency of prior art.An example of this survey frequency can be 10
5-10
9Hz more particularly, is 10
6-10
8Hz.Small size 10 for device 10 coil 13
-7-10
-1M, more particularly, 10
-5-10
-3M, and in high measurement frequency 10
5-10
9Hz, more particularly, 10
6-10
8Hz is with the bigger sensitivity of sensitivity that obtains than early stage inductance measure of the change apparatus and method.In the method according to the invention, use with the input signal that supplies to coil configuration 10 31 identical frequencies and measure.Though in some cases or in some measurement configuration, frequency possibly change, this variation can not be detected, because in situation of the present invention, do not measure this variation.Export amplitude A and/or the phase rather than the survey frequency variation of signal 32 with the frequency measurement of input signal 31.
According to the present invention, test base 11 also can have many forms.Some examples wherein are so-called effluent test, pothole (pit) test, kapillary, microfluid passage, microarray, or will particle to be detected take near some alternate manners of device 10 to.For the conveying of a large amount of particles, can use the effluent test, this is because this mode is simple, reliable and inexpensive.For more a spot of particle and less sensor transfer scheme, expect specific bearing accuracy (with the distance of coil 13).Microfluid is more suitable than side direction test, and can will allow the very high bearing accuracy about the mutual position of coil 13 and test base 11 about coil 13 permanent integrated test bases 11.
The diameter that can use each particle that limits according to device according to the present invention 10 can be for example in the scope of 1nm-10 μ m.Special concern Particle Cluster, the diameter of this Particle Cluster depend on that test base can be the scope of for example 30nm-10 μ m or more particularly be 100-600nm, and this Particle Cluster is formed by the littler particle of for example 5-30nm.The amount of magnetite or corresponding magnetic material can be for example at the order of magnitude of 1ng-1mg, and corresponding sample size is for example in the scope of 1nl-1ml.In this case, the number of particles on test base can be at 1-10
12In the scope of particle, more particularly, 10
3-10
10Scope (for example, effluent test) or at 1-10
8The scope of (for example, the diagnosis of miniaturization).The size of particle and the minimum value of quantity and maximal value generally depend on the application and the size of used coil configuration.
Measure the shape of coil 13; And the shape that can belong to other coil device 18-20 of device 10; Can be polygon (for example, square, rectangle, triangle, hexagon) for example, perhaps circular (for example; Circle, ellipse, omega shape), possibly be spiral, the plane, continuous, conduction, current structure.
In device 10 according to the present invention, at least one size of the conductor structure at least one loop construction 13 is several microns orders of magnitude to the magnitude range of hundreds of micron.Therefore, for example, the height of conductor, promptly thickness (insulation spacing and winding spacing simultaneously) can be 10
-7-10
-4M, the width of conductor can be 10
-6-10
-4M.Here, term " height of conductor and thickness " refers to the direction vertical with matrix 22, and term " width " refers to the parallel plane direction with matrix 22.
With the parallel yardstick in plane (planar cross-sectional and/or length and/or width) of each coil 13 that belongs to device 10,18-20 can be for example 10
-7-10
-2M, particularly 10
-5-10
-3M.This is especially true in the loop construction that is formed by several conductors.Depend on manufacturing technology, with the example of parallel plane size can be 3mmx3mm or 300 μ mx300 μ m.Correspondingly, the spacing of the circle circle of coil 13,18-20 can be for example 100 μ m or 10 μ m.In the loop construction of using bridge structure, coil 13,18-20 distance each other can be 1-5mm, for example 1-3mm.Therefore can be called big coil or small coil substantially.
Conversion zone in the size of test base 11 and the test base 11 depends on the quantity of purposes and particle.Being suitable for carrying the effluent test of a large amount of particles can be that for example 3mm is wide, and 50mm is long, the hundreds of micron thick.The surface area of the test zone of effluent test can be for example 3mmx1mm, perhaps 5mmx1mm.In this test, distribution of particles can be the for example distribution relatively uniformly on the whole thickness of bar (strip) 11.Being more suitable in the channel diameter of the microfluid of carrying less particle can be for example about 100 μ m, and the surface area of this test zone is for example about 300 μ mx300 μ m.In the test of carrying out using microfluid, distribution of particles is in the surface of for example test zone, perhaps its next-door neighbour.
The size of coil 13,18-20 has remarkable influence for the sensitivity of measuring system.Embodiment shown in Fig. 1-3 illustrates the basic geometry that is used for planar coil.In order to simplify, rectangular loop shaped only is shown in this example.With reference to other possible coil shape.The number of turn of the coil of the embodiment of Fig. 1-3, length, thickness and width can be different each other.The electrical characteristics of coil are confirmed by its geometry and size.Preceding text have provided based on the approximate evaluation value (being not limited to these values) of measuring and simulating for various variations, and for inductance and resistance, the cross-sectional area of the coil that is made of copper approximately is 36 μ mx100 μ m, and the xsect in X and Y direction of coil is 2-4mm.Depend on employed frequency by these impedances of confirming.
It below is brief description according to principle of operation with the method for correspondence of device 10 of the present invention.Can magnetic particle 12 be taken to the measured zone of the measurement coil 13 that uses suitable test base 11.When particle arrives under the influence in magnetic field of coil 13, the magnetic field in the environment of particle intensifier coil 13.These effects of coil 13 experience are as the variation (μ of the relative permeability (permeability) of environment
r>1).This causes measuring the inductance (L of coil 13
0) in variation (Δ L).
ΔL＝L
0(μ
r-1)
X
L＝ω
0L
0
Changing (Δ L) with the proportional inductance of the quantity of particle can be detected as by induction reactance (X
L) variation (Δ X
L) variation of the resulting impedance (Z) that causes.This has improved in the performance of high frequency treatment to the measurement of amplitude A and/or phase place
.Lc circuit also can be used for this measurement, but in this case, and is same, measurement be amplitude A (y axle) rather than frequency.
Can through measure high-frequency voltage or be fed into amplitude and/or the phase place of the current signal 31 of measuring coil 13 changes delta A,
and magnetic test coil 13 inductance (for example; 1-100nH) and change (for example, approximately 50fH-50pH).The input voltage that is provided by source of supply 23 can change between 0.1-10V, more particularly, between 0.5-2.5V, change, and input current (impedance) changes between 0.001-10A, more particularly, between 0.05-1A, changes.The frequency of input voltage/electric current can be 10
5-10
9Change between the Hz, more particularly, 10
6-10
8Change between the Hz by (for example, for little coil).As the example of frequency, can with reference at a 5-20MHz, be use in extensive guiding (pilot) device of 7-14MHz more particularly.Before being exposed to magnetic particle, carry out the changes delta A of amplitude and/or phase place, the measurement of
through what coil 13 was measured in monitoring, use the frequency of the input signal 31 that is fed into coil configuration 10 to carry out this monitoring with afterwards the impedance and/or the absolute value of phase place
.Problem maximum in this measurement configuration is an external interference, and this external interference makes the measurement result distortion and reduced measuring reliability, but using compensation structure 18-20 can eliminate the influence of this external interference surprisingly.
Can for example use Fig. 4 and difference structure shown in Figure 5 to compare, wherein, the signal that uses this structure to cause by sky measurement coil 13 (impedance of coil and interference on every side) from measured signal with compensation at reference coil 18 places.Fig. 4 illustrates this difference structure.In this structure, two identical spiral windings 13,18 are connected in series, supply high frequency voltage or current signal 31 on coil, (the typical change interval of top electric current, voltage and frequency).In ideal conditions, can suppose that the two inductance and resistance of coil 13,18 is identical.Therefore, coil 13,18 voltage on the two coil 13, between 18 in the middle of should add up to zero in the output 15.Magnetic particle departs from from this equilibrium state.This is unbalance can be for example as the current/voltage signal 32 of middle output 15 and measured.
Can through make coil 13 or coil 13,18 in suitable frequency (especially 10
6-10
8The scope of Hz) locates to resonate and improve the sensitivity of Fig. 4 and device 10 shown in Figure 5.This can be through such increasing and measurement coil/a plurality of measurement coils from parallel connection of coils of circuit or the suitable capacitor of connecting as shown in Figure 6, for example uses independently lc circuit to realize.The value of such capacitor is confirmed by the inductance of coil and the resonant frequency of expectation at least.For the frequency range of indication, electric capacity can (for example, have the coil of 50nH) between 1fF-1 μ F changes, and more particularly, between 50pF-500nF, changes.
Through using the bridge diagram shown in Fig. 6-10 to can further improve measurement sensitivity, in this circuit, in the middle of two difference structures, export 15, measure between 17.Use this structure will obtain bigger sensitivity and anti-interference.Fig. 6 illustrates generally the describing of impedance bridge, but also can consider the bridge solution of other type.Fig. 6 comprises placement resonating capacitor C
R1-C
R6Some possible methods.Can use in these capacitors at least some or even all.Confirm the electric capacity of capacitor with following known way: this mode uses the resonant frequency of inductance and expectation of coil as the basis.An example of capacitance interval can be 1fF-1 μ F, more particularly, is 50pF-500nF.
Output through electric current and/or voltage signal with opposite phase and same-amplitude supply to system for example, supplies to the output of bridge measurement, perhaps supplies to the output of variate, and the signal level of system can be set to zero.
Fig. 7 illustrates the simplification example of metering circuit, and it can be applied in the coil configuration 10 according to Fig. 6.Those skilled in the art will it is obvious that, and this measurement configuration also is not intended to restricted root according to basic thought of the present invention, but only as an example, can carry out according to measurement of the present invention by means of this measurement configuration.
Can mix with the cosine sinusoidal and that form by DDS oscillator 27 (quadrature Q) of the input signal 31 that forms by DDS oscillator 23 (homophase I) through exporting signal 32, and use mixer 25,26 to carry out quadrature detection.
The output of I and Q mixer 25,26 is exaggerated by low-pass filter 29.1,29.2 filtering, and is fed into 16 ADC30.Dispose the 3rd DDS oscillator 33 and belong to the difference of the coil 13,18,19,20 of electric bridge 10, no matter the symmetry of measuring bridge and manufacturing accuracy how, this difference still occurs with elimination.By means of this feedback, the balanced signal 34 of amplitude and phase controlled is supplied to the output of electric bridge 10.When in the coverage of coil configuration 10, not having magnetic particle, signal 34 is forced to zero with the output of electric bridge 10.
In order to reduce noise level and to prevent the feedthrough between the module, circuit comprises necessary protection and power supply filtrator.In addition, each main modular can have its oneself regulator (not shown).
In notion according to the present invention, output signal 32 is construed as for example direct original measured signal from electric bridge 10, perhaps for controlling the original signal of measuring to allow in known manner.In ideal conditions, original signal is directly proportional with the quantity of particle.Because the imperfection of electric bridge 10, the output signal of electric bridge 10 generally has skew.Using calibrating signal 34 to remove should skew.After this, amplifying signal is the measuring-signal 32 that is directly proportional with particle, can measure from this measuring-signal.Yet under the situation that does not change basic thought of the present invention, the signal handling of other kind also will be conspicuous to those skilled in the art.
Shape and size through change measuring coil 13 and reference coil 18 the two and/or compensating coil 19,20 (for example; In the plane of coil) ratio; Can reduce the measuring error that causes by the error of placing sample, therefore can improve the robustness (robustness) of system.
The fact that should further note is that in device 10 according to the present invention, the benchmark of measuring coil 13 is directly from the adjacent reference coil 18 on the current contact.Through this current contact, measuring coil 13 can be same conductor/structure with reference coil 18.Even, do not have intermediate electronics through coil 13, simple directly contact between 18, also will greatly eliminate interference.For example, if basic structure is configured to symmetry and unified as much as possible, then can eliminate the error that causes by element inferior or asymmetry.
Figure 11 illustrates examples of applications, and in this example, the inductance of measuring the coil configuration that is caused by magnetic particle with the mode of amplitude measurement changes.In this case, the measured conduct of the amplitude A of output voltage 32 obtains the amplitude difference DELTA A with respect to input voltage 31 in this case from the function of the frequency of the middle output 15 of measuring coil 13 and reference coil 18.Through measuring the sinusoidal input voltage of supply on coil 13 and the reference coil 18, convert electric signal to and will change by the inductance that amplitude difference DELTA A representes.Confirm output 15 measured voltage in the middle of coil 13, so-called between 18 from the ratio of the impedance (inductance) of coil 13,18, and the quantity of this voltage and magnetic particle is proportional.The frequency of input signal 31, i.e. frequency during measurement output signals 32 can be the resonant frequency of coil system for example, but also can use other frequency.
The illustration of Figure 11 be illustrated in as under the situation of Figure 11 as the input voltage of the function of time.In this is measured, the also frequency of possibility generation signals and/or the variation of phase place.It is sinusoidal to should be noted in the discussion above that signal is not necessary for, but can be for example square wave, triangular wave, impact or more conspicuous other waveform of those skilled in the art.
Figure 12 illustrates the example of the typical standard drawing of the metering system acquisition of using Figure 11.The amplitude variations Δ A that is surveyed illustrates on the longitudinal axis, and the relative populations of particle illustrates on transverse axis.The unit of the longitudinal axis can be volt (V), an electric current (I) for example, perhaps when in signal Processing, using AD converter even be bit (Bit).As visible from Figure 12, actual measurement result is followed the strong linearity of used logarithmically calibrated scale, and the value R of the expression measured deviation that produces from standard drawing
2Be 0.99578.
Figure 13 illustrates the content CRP (high sensitivity, C reactive protein) in the sample that the process of measurement that uses Figure 11 measures.The amplitude variations Δ A that records illustrates on the longitudinal axis, illustrates on transverse axis with CRP content in the proportional sample of the quantity of magnetic particle.
Figure 14 illustrates the examples of applications of figure, in this example, replaces measuring amplitude A, and the phase difference φ between measurement input voltage 31 and the output voltage 32 is in this situation, and is same, measures from (middle output 15) between measurement coil 13 and the reference coil 18.In this situation, same, also maybe occurrence frequency and/or oscillation amplitude change in measurement.Except that sine, signal can also be for example square wave, triangular wave, impact or more conspicuous other signal shape of those skilled in the art.
In device 10 according to the present invention, can use almost desirable reference signal, it measures background (not confirming the magnetic particle of constraint) from sample, eliminate external interference (for example, magnetic field of the earth) in addition.
What it must be understood that is that the explanation of preceding text only is intended to explain the present invention with relevant accompanying drawing.Therefore the invention is not restricted to the embodiment that claim is open or state, many different change and modification possible in the scope of invention thought defined in the appended claims of the present invention will be obvious to those skilled in the art.
Claims (18)
1. device (10) that is used for the qualitative or quantitative measurment of magnetic labelled analyte (12), this device (10) comprise the coil configuration (13,18) by at least one measures coil (13) and the reference coil (18) that disposes about this measurements coil (13) forms; This coil configuration (13; 18) be used for measuring analyte (12), and be arranged to output signal (32) the detection inductance variation relevant that output (15) in the middle of this coil configuration (13,18) is recorded with the content of said magnetic labelled analyte (12) from the sample that is absorbed in test base (11); It is characterized in that; Be arranged to the amplitude and/or the phase change (Δ A, Δ φ) that from the output signal (32) that records in middle output (15), occur and detect said inductance variation by said coil configuration (13,18); This amplitude and/or phase change (Δ A; Δ φ) be arranged to frequency measurement with input signal (31), said device (10) also comprises compensating coil structure (19,20); This compensating coil structure (19,20) is used for compensation by environment and/or be bound to the error signal that the magnetic particle of said test base (11) causes indefinitely.
2. device according to claim 1 (10) is characterized in that, for the induction reactance that makes said measurement coil (13) is increased to greatlyyer than resistance, the survey frequency of said device (10) is configured to 10
6-10
8Hz.
3. device according to claim 1 and 2 (10) is characterized in that, said reference coil (18) is the identical copy or the mirror image of said measurement coil (13).
4. device according to claim 1 (10) is characterized in that, said measurement coil (13), said reference coil (18) and compensating coil structure (19,20) are configured to form the differential winding configuration.
5. device according to claim 1 (10) is characterized in that, the compensating coil structure comprises at least two coils (19,20), and these two coils dispose with respect to said measurement coil (13) and said reference coil (18) symmetrically.
6. device according to claim 1 (10) is characterized in that, said measurement coil (13), said reference coil (18) and compensating coil structure (19,20) relative to each other dispose with the impedance bridge form.
7. device according to claim 1 (10) is characterized in that, said measurement coil (13), said reference coil (18) and compensating coil structure (19,20) have identical size aspect at least one electrical quantity.
8. device according to claim 6 (10) is characterized in that, form said impedance bridge coil (13,18-20) be two-way array structure.
9. device according to claim 6 (10) is characterized in that, form said impedance bridge coil (13,18-20) be layered struture.
10. device according to claim 1 and 2 (10) is characterized in that, said test base (11) is integrated about said measurement coil (13) and the interactional mode of said reference coil (18) with said test base (11) with said device (10).
11. device according to claim 1 and 2 (10) is characterized in that, (13,18-20) yardstick in in-plane is 10 to said coil
-7-10
-2M.
12. device according to claim 11 (10) is characterized in that, (13,18-20) yardstick in in-plane is 10 to said coil
-5-10
-3M.
13. device according to claim 1 and 2 (10) is characterized in that, and said coil (13,18-20) be configured to form conductor structure, in this conductor structure, the thickness of conductor is 10
-7-10
-4M, width are 10
-6-10
-4M.
14. device according to claim 1 and 2 (10) is characterized in that, said measurement coil (13) and said reference coil (18) align about the conductor (15,17) of measuring-signal symmetrically.
15. a method that is used for the qualitative or quantitative measurment of analyte (12), in the method, use test matrix (11) is measured said analyte (12), and in the method,
Sample is absorbed in the said test base (11), and
Use coil configuration (13,18-20) analyze said test base (11), from this coil configuration (13, detect the inductance variation relevant in the signal (32) of output (15) in the middle of 18-20) with the content of magnetic labelled analyte (12),
It is characterized in that, from (13, amplitude and/or phase change (the Δ A that occurs in the output signal (32) of (15) exported in centre 18-20) in said coil configuration; Δ φ) detecting said inductance changes; This amplitude and/or phase change (Δ A, Δ φ) are measured with the frequency of input signal (31), and; In addition, compensate by environment by coil configuration (18-20) and/or be bound to the error signal that the magnetic particle of said test base (11) causes indefinitely.
16. method according to claim 15; It is characterized in that; Said coil configuration comprises the reference coil (18) that at least one is measured coil (13) and disposes about this measurement coil (13); For the induction reactance that makes said measurement coil (13) is increased to greatlyyer than resistance, use the survey frequency of 106-108Hz to carry out said measurement.
17. method according to claim 16 is characterized in that, uses differential winding to dispose and carries out said compensation.
18., it is characterized in that in said method, said sample is absorbed into test base (11) according to each described method among the claim 15-17, (13, at least a portion interaction ground 18-20) is integrated with said coil configuration for this test base (11).
Applications Claiming Priority (5)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| FI20065257 | 2006-04-21 | ||
| FI20065257A FI20065257A0 (en) | 2006-04-21 | 2006-04-21 | Arrangement and method for measuring magnetic particles |
| FI20065502 | 2006-07-27 | ||
| FI20065502A FI121248B (en) | 2006-04-21 | 2006-07-27 | Device for measuring magnetic particles and the corresponding method |
| PCT/FI2007/050211 WO2007122293A1 (en) | 2006-04-21 | 2007-04-20 | Device for measuring magnetic particles and corresponding method |
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| Publication Number | Publication Date |
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| CN101427131A CN101427131A (en) | 2009-05-06 |
| CN101427131B true CN101427131B (en) | 2012-07-25 |
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| CN2007800143569A Active CN101427131B (en) | 2006-04-21 | 2007-04-20 | Device for measuring magnetic particles and corresponding method |
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| CN (1) | CN101427131B (en) |
| FI (1) | FI20065257A0 (en) |
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| CN105911487B (en) * | 2016-04-14 | 2018-12-14 | 中国科学院上海微系统与信息技术研究所 | A kind of superconducting magnetic sensor search coil and detector |
| CN107257235A (en) * | 2017-06-06 | 2017-10-17 | 中国振华(集团)新云电子元器件有限责任公司(国营第四三二六厂) | A kind of LPF electric bridge for eliminating capacitor parasitic parameter |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5068315A (en) * | 1990-04-12 | 1991-11-26 | University Of Dundee | Composition for the regulation of hair growth |
| CN1317693A (en) * | 2000-04-10 | 2001-10-17 | 兰道克斯实验有限公司 | Magnetic particle analyzing |
| CN1639567A (en) * | 2002-03-08 | 2005-07-13 | 莱夫阿塞斯有限公司 | Drift compensated magnetic permeability detector |
-
2006
- 2006-04-21 FI FI20065257A patent/FI20065257A0/en not_active Application Discontinuation
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Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5068315A (en) * | 1990-04-12 | 1991-11-26 | University Of Dundee | Composition for the regulation of hair growth |
| CN1317693A (en) * | 2000-04-10 | 2001-10-17 | 兰道克斯实验有限公司 | Magnetic particle analyzing |
| CN1639567A (en) * | 2002-03-08 | 2005-07-13 | 莱夫阿塞斯有限公司 | Drift compensated magnetic permeability detector |
Non-Patent Citations (2)
| Title |
|---|
| JP特开平7-248676A 1995.09.26 |
| 殷勇辉，严新平，萧汉梁，王成焘.《磨粒监测电感式传感器设计》.《传感器技术》.2003,第22卷(第7期),第36至37页. * |
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| FI20065257A0 (en) | 2006-04-21 |
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