WO2010026551A1 - Rotating magnetic field for improved detection in cluster assays - Google Patents
Rotating magnetic field for improved detection in cluster assays Download PDFInfo
- Publication number
- WO2010026551A1 WO2010026551A1 PCT/IB2009/053868 IB2009053868W WO2010026551A1 WO 2010026551 A1 WO2010026551 A1 WO 2010026551A1 IB 2009053868 W IB2009053868 W IB 2009053868W WO 2010026551 A1 WO2010026551 A1 WO 2010026551A1
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- WO
- WIPO (PCT)
- Prior art keywords
- clusters
- magnetic field
- particles
- cluster
- rotating magnetic
- Prior art date
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Classifications
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- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
- G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
- G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
- G01N33/53—Immunoassay; Biospecific binding assay; Materials therefor
- G01N33/543—Immunoassay; Biospecific binding assay; Materials therefor with an insoluble carrier for immobilising immunochemicals
- G01N33/54313—Immunoassay; Biospecific binding assay; Materials therefor with an insoluble carrier for immobilising immunochemicals the carrier being characterised by its particulate form
- G01N33/54326—Magnetic particles
- G01N33/54333—Modification of conditions of immunological binding reaction, e.g. use of more than one type of particle, use of chemical agents to improve binding, choice of incubation time or application of magnetic field during binding reaction
-
- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N27/00—Investigating or analysing materials by the use of electric, electrochemical, or magnetic means
- G01N27/72—Investigating or analysing materials by the use of electric, electrochemical, or magnetic means by investigating magnetic variables
- G01N27/74—Investigating or analysing materials by the use of electric, electrochemical, or magnetic means by investigating magnetic variables of fluids
- G01N27/745—Investigating or analysing materials by the use of electric, electrochemical, or magnetic means by investigating magnetic variables of fluids for detecting magnetic beads used in biochemical assays
Definitions
- the present invention is directed to a method of performing a cluster assay and to an apparatus for performing such a cluster assay.
- Cluster assays are a class of assays in which the amount of formed particle clusters is indicative of the presence and/or concentration of biological components in the sample. Cluster assays are attractive because of the rapid bulk kinetics, ease of fabrication and low costs.
- the main issue with cluster assays is the lack of sensitivity.
- One way to improve the sensitivity is by performing cluster assays with magnetic particles.
- An advantage of using magnetic particles is that field-induced chains can be formed during incubation. This has, e.g., been shown by Baudry et al. "Acceleration of the recognition rate between grafted ligands and receptors with magnetic forces", Proc. Natl. Acad. Sci. p. 16076).
- One important challenge when performing cluster assays is to detect very low concentrations of clusters in a background of other magnetic particles. Another challenge is to avoid the formation of clusters of non-biological origin, and preferably to even break weakly bound clusters. These challenges are particularly important when magnetic actuation is used during the detection.
- a method is provided of performing a cluster assay comprising the steps of : a) providing a suspension of superparamagnetic particles in a fluid to be analyzed, wherein the superparamagnetic particles are coated with a bio active agent; b) allowing the particles to form clusters due to an analyte present within the fluid; c) selectively actuating clusters of superparamagnetic particles by applying an at least partially rotating magnetic field (B), and d) detecting the selectively actuated clusters.
- an apparatus for performing a cluster assay comprising: e) means (12, 15) for accommodating a sample (14); f) means (1 to 4; 11) for applying an at least partially rotating magnetic field (B), the magnetic field being adapted for selectively actuating clusters of superparamagnetic particles; and g) means for detecting the selectively actuated clusters.
- the present invention is based on the finding that a rotating magnetic field with a generally varying field amplitude can couple selectively to bound clusters 20. If the field characteristics are chosen properly, the field does not rotate larger clusters 20 and it does not generate novel clusters 20 during the actuation.
- the wiggling rotation appears at frequencies of the magnetic field higher than a critical frequency as described below. At even higher frequencies, the beads are able to rotate again due to the presence of nanometric grains of ferromagnetic material within the superparamagnetic beads.
- the present invention is directed to a method of performing a cluster assay using the above-mentioned finding.
- a suspension of superparamagnetic particles in a fluid to be analyzed is provided, wherein the superparamagnetic particles are coated with a bioactive agent.
- the particles are then allowed to form clusters 20 due to an analyte present within the fluid.
- the binding of superparamagnetic particles to an analyte is known in the state of the art.
- clusters 20 of superparamagnetic particles are selectively actuated by applying an at least partially rotating magnetic field, wherein the amplitude of the magnetic field varies over time.
- the magnetic field can be designed having completely rotating properties or alternatively having partly common properties and partly rotating properties.
- the superparamagnetic particles are preferably superparamagnetic beads with a diameter in the range between 10 nm and 10 ⁇ m, preferably between 100 nm and 3 ⁇ m.
- the superparamagnetic particles may be coated with any bioactive agent, which is suitable for performing a cluster assay. Typical examples for such a bioactive agent are: antibodies, proteins, cells, DNA, RNA, small molecules, tissues, viruses.
- the particles are bound to each other by means of an analyte, which is present within the fluid, which selectively binds to the bioactive agent provided on the surface of the superparamagnetic particles.
- the step is provided by simply setting a predetermined delay time, during which the analyte may interact with the bioactive agent.
- the particles are actively supported to form clusters 20, e.g., by means of applying a magnetic field.
- clusters 20 of superparamagnetic particles are selectively actuated by applying a rotating magnetic field.
- "Selectively actuating clusters 20" in the context of the present application means to actuate only clusters 20 of certain predetermined characteristics. It is, e.g., preferred to actuate clusters 20 up to a predetermined size only. It is particularly preferred to actuate clusters 20 consisting of two particles only. According to a preferred embodiment, actuating the clusters 20 comprises rotating the clusters 20. Thus, if the characteristics of the rotating magnetic field are chosen properly, one may achieve that only clusters 20 consisting of two particles are rotating, whereas larger clusters 20 do not rotate at all or rotate with another frequency and/or other characteristics.
- the process of selectively actuating, i.e. rotating, clusters 20 of superparamagnetic particles is controlled by applying a rotating magnetic field with a varying field amplitude.
- the rotating magnetic field may consist of two components, wherein the two components differ in amplitude and phase.
- the ratio between the maximum and minimum amplitudes of the magnetic field is between 1.1 and 10, preferably between 2 and 8, and most preferably between 4 and 6.
- the angular frequency of the rotating magnetic field is below a critical frequency, wherein the critical frequency is defined as
- ⁇ is the magnetic susceptibility
- B MAX is the amplitude
- the selectively actuated clusters 20 have to be detected. This is preferably done using an optical technique. Since the clusters 20 are rotating any light scattering, transmission or reflection is modulated. This modulation may be used to optically detect the rotating clusters 20 only.
- the present invention is further directed to an apparatus for performing a cluster assay, in particular for performing a cluster assay according to the above- described method.
- the apparatus comprises means for accommodating a sample and means for applying a rotating magnetic field, the magnetic field being adapted for selectively actuating clusters of superparamagnetic particles.
- the apparatus further comprises means for detecting the selectively actuated clusters.
- the means for applying a rotating magnetic field preferably comprises several magnetic coils, in particular a quadrupole configuration of four magnetic coils. It is preferred that the ratio between the maximum and minimum amplitudes of the rotation magnetic field is between 1.1 and 10, preferably between 2 and 8 and most preferably between 4 and 6. It is further preferred that the angular frequency of the rotating magnetic field is below the critical frequency, wherein the critical frequency is defined as
- the means for detecting the selectively actuated clusters preferably comprises an optical detector (not shown). It is further preferred that the means for detecting comprises a central processing unit adapted to analyze modulations in the detected signal.
- Figure Ia shows the rotational behaviour of a cluster consisting of two magnetic particles.
- Figure Ib schematically depicts the phase-lag ⁇ of the cluster rotation with respect to the rotation of the external magnetic field.
- Figure 2a shows a schematic representation of a quadrupole configuration.
- Figure 2b schematically illustrates the driving signals used to drive the coils of the quadrupole configuration of Figure 2a.
- Figure 3 a is a graph showing the cumulative angle versus time in case of a rotating external field with non-uniform amplitude.
- Figure 3b is a graph showing the cumulative angle versus time in case of a non-uniform angular velocity of the external field.
- Figure 4 is a graph showing the cumulative angle versus time for a cluster consisting of two particles in an external field above the critical frequency.
- Figure 5 is a graph illustrating the frequency of particle rotation versus rotational frequency of the external magnetic field.
- Figure 6 is a graph showing the numerical derivative of the data shown in Figure 3a.
- Figure 7a shows a portion of an apparatus according to a preferred embodiment of the present invention.
- Figure 7b shows a photograph of the apparatus of Figure 7a.
- Figure 8 shows a schematic side view of a cluster of two magnetic beads indicating a magnetic moment induced at the beads, and the resulting forces creating attractive and repulsive areas around the cluster .
- the graph depicted in Figure Ia shows the angular frequency of a cluster consisting of two particles versus the angular frequency of an externally applied magnetic field.
- the angular frequency of the cluster initially increases with an increase of the angular frequency of the external magnetic field B generated by means of driving signals Ia through 4a applied to coils 1 to 4 of the quadrupole, respectively, as shown in Figs. 2a and 2b.
- the configuration according to Fig. 2a comprises four poles 1, 2, 3, 4 arranged at a ring as shown. By activating the four coils 1, 2, 3, 4 of the corresponding poles in a certain manner, for instance as shown in the signal curve in Fig. 2b, a rotational field is generated.
- This rotating magnetic field is depicted by the arcuate arrow in the middle of the quadrupole. While the amplitudes of the signals characterizing the voltage applied actuating the coils 1, 2, 3, 4 vary in a controlled way the generated magnetic field within the quadrupole rotates.
- sinusoidal signal curves Ia, 2a, 3 a, 4a describing activation signals are shown corresponding to the four coils 1, 2, 3, 4.
- the signal curves can be changed resulting in a different magnetic field.
- This different magnetic field is referred to as partly rotating magnetic field consisting of a weak component and a strong component.
- the weak component is either a constant magnetic field, a magnetic field generated by sinusoidal signals, or generated by square wave signals.
- the strong component is either a magnetic field generated by a sinusoidal signal, or generated by a sequence of pulses. In the contrary the completely rotating magnetic field is a magnetic field generated by sinusoidal signals.
- the strong component has a signal amplitude up to 10 times higher than the weak component.
- the signal frequency of the strong component can be different from the signal frequency of the weak component. Up to a first peak, the clusters can rotate at the same frequency as the external field. However, a phase-lag ⁇ , which depends on the frequency, arises between the rotation of the cluster and the rotation of the external magnetic field as is schematically shown in Figure Ib.
- the phase-lag ⁇ reaches 90 degrees.
- the cluster experiences the maximum torque available.
- the coupling between the external field and the cluster becomes more and more inefficient which leads to a slowdown of the clusters. In this regime, a wiggling of the clusters is superimposed to the rotation of the clusters.
- the clusters are able to rotate again due to the presence of nanometric grains of ferromagnetic material within the supermagnetic particles.
- the clusters are of major interest, in particular in a low concentration limit. The clusters all qualitatively behave in the same way as described in Figure Ia when exposed to an external, uniformly rotating field.
- FIG. 4 An example for the cumulative angle versus time a cluster consisting of two particles experiences in an external magnetic field above the critical frequency is shown in Figure 4.
- the critical frequency according to the formula above is 2.87 Hz.
- Curve 7 in Figure 4 represents the rotational behaviour of a cluster in an external field rotating with a frequency of 5 Hz
- Figure 7a represents a cluster in an external frequency of 6.5 Hz.
- the clusters consisting of two particles can still rotate, but they behave quite irregular due to the superposition of the wiggling oscillation with the oscillations due to the time dependent factor.
- Well above that limit none of the clusters is rotating, but just shacking.
- Figure 5 shows a graph of the rotational frequency of the rotating cluster versus the frequency of the external magnetic field.
- a clear peak at 2 Hz representing the breakdown frequency is visible. Beyond said breakdown frequency the response decreases rapidly.
- the breakdown frequency itself is dependent on the size of the beads used.
- the lower component seems to be the most important since it must be at least high enough to guarantee the rotation of the smaller clusters and on the same time small enough to prevent the bigger clusters from rotating.
- the lower component fixes the maximum dimension of the clusters that can be rotated by such a low field. Since the bigger the clusters the bigger must be the field to actuate them, it is indeed possible to tune the value of the lower component so that they do not respond to the field. This tuning process is dependent on a lot of experimental conditions such as the actual implementation of the coils (dimensions, type of magnetic core, number of windings%), the size of the particles used, the hydrodynamic properties of the liquid and the magnetic content of the beads.
- FIG 7a shows a schematic sketch of a part of an apparatus according to a preferred embodiment of the present invention.
- the means 10 for applying a rotating magnetic field comprises twelve circularly arranged magnetic coils 11 and a central hole 13 for accommodating a sample cell.
- the sample cell 12 made e.g. from PMMA, has a hole 15 of 1 mm diameter for accommodating a sample fluid 14 with the analyte and the superparamagnetic particles.
- the sample cell 12 exactly fits into the hole 13.
- twelve magnetic coils are shown in Figure 7a, only four of them were used in the actual experiment. However, it should be apparent that other actuation schemes may be applied by using more or less magnetic coils.
- Figure 7b shows a photograph of the apparatus schematically sketched in Figure 7a.
- superparamagnetic beads of 1 ⁇ m in diameter, covered with streptavidin (Dynabeads MyOnesTM from Invitrogen) have been used. They have been incubated with biotinylated BSA (a protein covered with biotin, which is specifically recognized by streptavidin).
- the buffer liquid used was PBS (a solution containing different salts and water).
- Fig. 8 shows a schematic side view of a cluster 20 consisting of two magnetic beads next to each other.
- a bioactive agent is applied (not shown) which connects to an analyte generating a binding between the analyte and the magnetic bead, as is known in the state of the art.
- a magnetic field is applied as described inducing a magnetic moment at the beads directed in one direction towards above, denoted as m m( j and a corresponding arrow indicating the force direction. This effect is referred to as an alignment of the particles.
- alignment time The time passing until the cluster 20 is oriented in a way described is denoted as alignment time, which is roughly in the order of tens of milliseconds depending on the magnetic field applied.
- the oscillation frequency of the magnetic field is lower than 10 times the inverse of the alignment time of the cluster 20.
- the magnetic particles and therewith the cluster 20 is oriented in the direction facing upwards, and the resulting forces creating attractive and repulsive areas around the cluster, as indicated in Fig. 8 by attractive zones above and below the cluster 20 and repulsive zones besides the cluster 20.
- the method according to the present invention provides several advantages. Only specific clusters respond to the external magnetic field so that these specific clusters can be detected with high sensitivity.
- the actuation does not show magnetic-field-driven formation of clusters during the actuation scheme. Detection can be performed both in the bulk and on a surface. Thus, the biological reactions can be preformed in the bulk of the liquid, which is advantageous for assay simplicity, speed of the assay and costs.
- unspecific clusters are not stable and tend to break.
- the detection of the clusters 20 of beads can be done by different technologies known in the state of the art. One detection technology is optical detection, for example described in the WO2008-072156.
Abstract
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Priority Applications (6)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
BRPI0913469A BRPI0913469A2 (en) | 2008-09-05 | 2009-09-04 | method for conducting a cluster test, apparatus for conducting a cluster test, use of a method and use of apparatus |
RU2011112853/15A RU2528102C2 (en) | 2008-09-05 | 2009-09-04 | Rotating magnetic field for improved detection in cluster analysis |
JP2011525668A JP5685537B2 (en) | 2008-09-05 | 2009-09-04 | A rotating magnetic field for improved detection in cluster assays |
US13/060,804 US8981772B2 (en) | 2008-09-05 | 2009-09-04 | Rotating magnetic field for improved detection in cluster assays |
EP09787103.2A EP2326956B1 (en) | 2008-09-05 | 2009-09-04 | Apparatus and method for detecting supaparamagnetic clusters |
CN200980134594.2A CN102144162B (en) | 2008-09-05 | 2009-09-04 | Rotating excitation field is to improve the detection in cluster analysis |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
EP08105253.2 | 2008-09-05 | ||
EP08105253 | 2008-09-05 |
Publications (1)
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WO2010026551A1 true WO2010026551A1 (en) | 2010-03-11 |
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PCT/IB2009/053868 WO2010026551A1 (en) | 2008-09-05 | 2009-09-04 | Rotating magnetic field for improved detection in cluster assays |
Country Status (7)
Country | Link |
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US (1) | US8981772B2 (en) |
EP (1) | EP2326956B1 (en) |
JP (1) | JP5685537B2 (en) |
CN (1) | CN102144162B (en) |
BR (1) | BRPI0913469A2 (en) |
RU (1) | RU2528102C2 (en) |
WO (1) | WO2010026551A1 (en) |
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WO2011036638A1 (en) | 2009-09-28 | 2011-03-31 | Koninklijke Philips Electronics N.V. | Substance determining apparatus |
WO2012001546A1 (en) | 2010-07-02 | 2012-01-05 | Koninklijke Philips Electronics N.V. | Detection of actuated clusters by scattering |
EP2541230A1 (en) * | 2011-06-30 | 2013-01-02 | Koninklijke Philips Electronics N.V. | Detection of clusters of magnetic particles |
EP2584338A1 (en) * | 2011-10-19 | 2013-04-24 | Koninklijke Philips Electronics N.V. | Detection of clusters of magnetic particles |
WO2013057634A1 (en) * | 2011-10-19 | 2013-04-25 | Koninklijke Philips Electronics N.V. | Detection of clusters of magnetic particles |
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JP2014535060A (en) * | 2011-11-14 | 2014-12-25 | コーニンクレッカ フィリップス エヌ ヴェ | Cluster detection device |
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Also Published As
Publication number | Publication date |
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RU2011112853A (en) | 2012-10-10 |
CN102144162A (en) | 2011-08-03 |
EP2326956A1 (en) | 2011-06-01 |
JP5685537B2 (en) | 2015-03-18 |
US8981772B2 (en) | 2015-03-17 |
BRPI0913469A2 (en) | 2015-12-22 |
JP2012502271A (en) | 2012-01-26 |
RU2528102C2 (en) | 2014-09-10 |
CN102144162B (en) | 2017-11-10 |
US20110156701A1 (en) | 2011-06-30 |
EP2326956B1 (en) | 2019-08-14 |
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