EP2129469A1 - Procédé et appareil permettant le transport magnétique ou magnétisable de microbilles - Google Patents

Procédé et appareil permettant le transport magnétique ou magnétisable de microbilles

Info

Publication number
EP2129469A1
EP2129469A1 EP08716225A EP08716225A EP2129469A1 EP 2129469 A1 EP2129469 A1 EP 2129469A1 EP 08716225 A EP08716225 A EP 08716225A EP 08716225 A EP08716225 A EP 08716225A EP 2129469 A1 EP2129469 A1 EP 2129469A1
Authority
EP
European Patent Office
Prior art keywords
poles
electromagnets
capillary tube
magnetic
row
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Pending
Application number
EP08716225A
Other languages
German (de)
English (en)
Inventor
Olivier Elsenhans
Goran Savatic
Martin Gijs
Amar Rida
Victor Fernandez
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
F Hoffmann La Roche AG
Roche Diagnostics GmbH
Original Assignee
F Hoffmann La Roche AG
Roche Diagnostics GmbH
Boehringer Mannheim GmbH
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by F Hoffmann La Roche AG, Roche Diagnostics GmbH, Boehringer Mannheim GmbH filed Critical F Hoffmann La Roche AG
Priority to EP08716225A priority Critical patent/EP2129469A1/fr
Publication of EP2129469A1 publication Critical patent/EP2129469A1/fr
Pending legal-status Critical Current

Links

Classifications

    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B03—SEPARATION OF SOLID MATERIALS USING LIQUIDS OR USING PNEUMATIC TABLES OR JIGS; MAGNETIC OR ELECTROSTATIC SEPARATION OF SOLID MATERIALS FROM SOLID MATERIALS OR FLUIDS; SEPARATION BY HIGH-VOLTAGE ELECTRIC FIELDS
    • B03C—MAGNETIC OR ELECTROSTATIC SEPARATION OF SOLID MATERIALS FROM SOLID MATERIALS OR FLUIDS; SEPARATION BY HIGH-VOLTAGE ELECTRIC FIELDS
    • B03C1/00—Magnetic separation
    • B03C1/02—Magnetic separation acting directly on the substance being separated
    • B03C1/23—Magnetic separation acting directly on the substance being separated with material carried by oscillating fields; with material carried by travelling fields, e.g. generated by stationary magnetic coils; Eddy-current separators, e.g. sliding ramp
    • B03C1/24—Magnetic separation acting directly on the substance being separated with material carried by oscillating fields; with material carried by travelling fields, e.g. generated by stationary magnetic coils; Eddy-current separators, e.g. sliding ramp with material carried by travelling fields
    • B03C1/253—Magnetic separation acting directly on the substance being separated with material carried by oscillating fields; with material carried by travelling fields, e.g. generated by stationary magnetic coils; Eddy-current separators, e.g. sliding ramp with material carried by travelling fields obtained by a linear motor
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B03—SEPARATION OF SOLID MATERIALS USING LIQUIDS OR USING PNEUMATIC TABLES OR JIGS; MAGNETIC OR ELECTROSTATIC SEPARATION OF SOLID MATERIALS FROM SOLID MATERIALS OR FLUIDS; SEPARATION BY HIGH-VOLTAGE ELECTRIC FIELDS
    • B03C—MAGNETIC OR ELECTROSTATIC SEPARATION OF SOLID MATERIALS FROM SOLID MATERIALS OR FLUIDS; SEPARATION BY HIGH-VOLTAGE ELECTRIC FIELDS
    • B03C1/00—Magnetic separation
    • B03C1/02—Magnetic separation acting directly on the substance being separated
    • B03C1/025—High gradient magnetic separators
    • B03C1/031—Component parts; Auxiliary operations
    • B03C1/033—Component parts; Auxiliary operations characterised by the magnetic circuit
    • B03C1/0335—Component parts; Auxiliary operations characterised by the magnetic circuit using coils
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B03—SEPARATION OF SOLID MATERIALS USING LIQUIDS OR USING PNEUMATIC TABLES OR JIGS; MAGNETIC OR ELECTROSTATIC SEPARATION OF SOLID MATERIALS FROM SOLID MATERIALS OR FLUIDS; SEPARATION BY HIGH-VOLTAGE ELECTRIC FIELDS
    • B03C—MAGNETIC OR ELECTROSTATIC SEPARATION OF SOLID MATERIALS FROM SOLID MATERIALS OR FLUIDS; SEPARATION BY HIGH-VOLTAGE ELECTRIC FIELDS
    • B03C1/00—Magnetic separation
    • B03C1/02—Magnetic separation acting directly on the substance being separated
    • B03C1/28—Magnetic plugs and dipsticks
    • B03C1/288—Magnetic plugs and dipsticks disposed at the outer circumference of a recipient
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B03—SEPARATION OF SOLID MATERIALS USING LIQUIDS OR USING PNEUMATIC TABLES OR JIGS; MAGNETIC OR ELECTROSTATIC SEPARATION OF SOLID MATERIALS FROM SOLID MATERIALS OR FLUIDS; SEPARATION BY HIGH-VOLTAGE ELECTRIC FIELDS
    • B03C—MAGNETIC OR ELECTROSTATIC SEPARATION OF SOLID MATERIALS FROM SOLID MATERIALS OR FLUIDS; SEPARATION BY HIGH-VOLTAGE ELECTRIC FIELDS
    • B03C2201/00—Details of magnetic or electrostatic separation
    • B03C2201/18—Magnetic separation whereby the particles are suspended in a liquid

Definitions

  • the invention concerns a method for transporting magnetic or magnetisable microbeads being capable of binding a biological probe and/or a biological analyte, said magnetic or magnetisable microbeads being immersed in a liquid comprising a biological probe and/or a biological analyte, said liquid being contained in a capillary tube having a length symmetry axis which defines an axial direction, said transporting being effected in the absence of a static magnetic field in said capillary tube.
  • the invention further concerns an apparatus for transporting magnetic or magnetisable microbeads being capable of binding a biological probe and/or a biological analyte, said magnetic or magnetisable microbeads being immersed in a liquid comprising a biological probe and/or a biological analyte, said liquid being contained in a capillary tube.
  • magnetic microbeads may be used, as non- limiting examples, for generically binding a biological probe or a biological analyte.
  • This method can be used to separate a biological analyte from a liquid sample.
  • magnetic microbeads having a biological probe molecule immobilized on their surface may bind to a biological analyte comprised in a liquid.
  • said biological analyte is RNA or DNA.
  • said biological probe is an oligonucleotide which is complementary to a target RNA or DNA.
  • the biological probe can be immobilized on the magnetic particles and hybridized to the target RNA or DNA. A specific target RNA or DNA can thus be separated from a complex liquid.
  • the separated biological analyte can then be quantitated.
  • One method known in the art for quantitating a target RNA or DNA is amplification, such as, as non-limiting example, real time PCR.
  • the advantage of using magnetic particles in a method according to the present invention is that magnetic particles can be manipulated using magnetic fields independently from any flow pattern of the solution.
  • magnetic particles can be manipulated using magnetic fields independently from any flow pattern of the solution.
  • an important relative motion of the magnetic particles with respect to the fluid and thereby with respect to the target molecules can be created, and this effect strongly increases the probability of capturing a biological probe or a biological analyte with the magnetic particles, or to bind a biological analyte to a biological probe immobilized on the magnetic particles.
  • Magnetic particles can then be separated and the bound analyte eluted for further processing, or directly processed.
  • transport of magnetic particles means that the magnetic particles are effectively moved, that is displaced along a transport path by a magnetic force, and not just retained by a magnetic force at a given place and thereby separated from a liquid solution which flows close to a magnet .
  • Manipulation of magnetic particles in general, and in particular transport of magnetic particles is a difficult task, because the magnetic particles used are usually superparamagnetic microbeads which have a rather weak effective relative magnetic susceptibility ⁇ eff (typically Xeff ⁇ 1/ due to demagnetization effects of the mostly spherical particles) and because the volume of a magnetic particle is small.
  • a very small microbead has thus no effective magnetization when there is no external magnetic field applied to it, i.e. it is superparamagnetic.
  • the magnetic force on an induced moment in a magnetic induction field is given by
  • Junho Joung et al . IEEE Transactions on Magnetics, Vol. 36, No. 4, July 2000, pages 2012-2014, describes an arrangement for displacing clusters of magnetic particles.
  • This arrangement comprises an array of uniformly spaced electromagnetic posts, wherein each post has one electromagnet pole the end of which faces one side of a straight pipe which contains a solution in which magnetic particles are immersed.
  • the poles of the electromagnetic posts are positioned close to, on opposite sides the pipe and are uniformly spaced in an axial direction defined by the length symmetry axis of the pipe.
  • the first pole is located on a first side of the pipe
  • the second pole is located on a second side of the pipe opposite to the first side thereof, and further from the first end of the pipe than the first pole
  • the third pole is located on the first side of the pipe and further from the first end of the pipe than the second pole
  • the fourth pole is located on the second side of the pipe and further from the first end of the pipe than the third pole, and so on.
  • the electromagnetic post are activated one after the other and one at a time by a simple driving circuit which turns them on and off in sequence starting from the electromagnetic post whose pole is the one nearest to the first end of the pipe.
  • a first aim of the invention is to provide a method and an apparatus of the above mentioned kind which do not require the use of large magnets or electromagnets which have to be mechanically moved.
  • aims are achieved by means of a method defined by claim 1.
  • Claims 2 to 5 define preferred embodiments of this method.
  • the above aims are achieved by using an apparatus defined by claim 6 for transporting microbeads having a non-spherical shape.
  • the above aims are achieved by using an apparatus defined by claim 6 for transporting microbeads having a spherical shape.
  • the apparatus comprises a miniaturized and low-price electromagnetic arrangement made by using coils made on simple printed circuit boards and ferrite microstructures patterned from ferrite wafers using a batch-type powder blasting micro-erosion technology,
  • the magnetic particles can be displaced back and forth within one or more liquids contained in a capillary tube.
  • the efficient transport of magnetic microbeads achieved with instant invention is particularly useful in biochemical reactions wherein as many as possible interactions between magnetic microbeads which may interact with probe molecules or analytical target molecules, or which carry e.g. probe molecules (e.g. single stranded DNA) on their surface and which specifically interact with complementary target molecules (e.g. a complementary target DNA) .
  • probe molecules e.g. single stranded DNA
  • complementary target molecules e.g. a complementary target DNA
  • the magnetic or magnetisable microbeads transported are electrically non- conductive microbeads.
  • Such microbeads are e.g. non-metallic magnetic or magnetisable particles having a resistivity larger than 2 milliohm.cm.
  • Fig. Ia shows a first embodiment of a first electromagnet of a first row of electromagnets in a first polarity state.
  • Fig. Ib shows the first electromagnet of Fig. Ia in a second polarity state.
  • Fig. 2a shows a first embodiment of a first electromagnet of a second row of electromagnets in a first polarity state.
  • Fig. 2b shows the first electromagnet of Fig. 2a in a second polarity state.
  • Fig. 3 shows a cross-sectional view of a portion of a first embodiment of an apparatus according to the invention comprising a capillary tube located between a first row of electromagnets and a second row of electromagnets.
  • Figures 4a to 4g illustrate transport of beads along the capillary tube shown in Fig. 3 achieved by successively actuating the electromagnet arrangements so that these are successively in the states represented in Figures 4a to 4g.
  • Fig. 5 shows direct current intensities applied to the electromagnet arrangements represented in Figures 4a to 4g in order that these are successively in the states shown by Figures 4a to 4g.
  • Fig. 6 shows current pulses formed by multiplication of the current pulses shown in Figure 5, with an alternating current signal .
  • Fig. 7 a schematic representation of the circuit used for applying direct current voltages and alternating current voltages to the electromagnet arrangements shown in Figures 4a to 4g.
  • Fig. 8a shows a second embodiment of a first electromagnet of a first row in a first polarity state.
  • Fig. 8b shows the first electromagnet of Fig. 8a in a second polarity state.
  • Fig. 9a shows a second embodiment of a first electromagnet of a second row in a first polarity state.
  • Fig. 9b shows the first electromagnet of Fig. 9a in a second polarity state.
  • Fig. 10 shows a cross-sectional view of a portion of a second embodiment of an apparatus according to the invention comprising a capillary tube located between a first row of electromagnets of the type shown in Fig. 8a and a second row of electromagnets of the type shown in Fig. 9a.
  • Figures 11a to Hh illustrate transport of beads along the capillary tube shown in Fig. 10 achieved by successively actuating the electromagnet arrangements so that these are successively in the states represented in Figures Ha to Hh.
  • Fig. 12 shows direct current intensities applied to the electromagnet arrangements represented in Figures Ha to Hh in order that these are in the states shown by Figures Ha to Hh.
  • Fig. 13 shows additional alternating current intensities applied to the electromagnet arrangements shown in Figures Ha to Hh.
  • Fig. 14 shows a schematic representation of the circuit used for applying direct current voltages and alternating current voltages to the electromagnet arrangements shown in Figures Ha to Hh.
  • Fig. 15 shows a perspective exploded view showing the components of an embodiment the apparatus shown by Fig. 10.
  • Fig. 16 shows an enlarged view of a portion of Fig. 15.
  • Fig. 17 shows a cross-sectional view of an apparatus according to Figures 15 and 16.
  • Fig. 18 shows a cross-sectional view along plane XVIII- XVIII represented in Fig. 17.
  • Fig. 19 shows a perspective view of a coil arranged on both sides of a printed circuit board.
  • Fig. 20 illustrates a first step of the fabrication of pole tips on a ferrite wafer.
  • Fig. 21 illustrates a second step of the fabrication of pole tips on a ferrite wafer.
  • Fig. 22 shows a ferrite wafer with pole tips fabricated according to the steps shown by Figures 20 and 21.
  • Fig. 23 shows an enlarged view of a cut-out XXIII in Fig. 22.
  • the magnetic force exerted in the direction X (e.g. along the length axis of the capillary tube 3 in the examples described hereinafter) on a magnetic microbead in a magnetic field is given by: 3 H
  • ⁇ Q is the permeability in vacuum
  • Vj b is the volume of the microbead
  • X b is the magnetic susceptibility of the microbead H is the vector of the external magnetic field.
  • the magnetic microbead in motion with a velocity vector v experiences a hydrodynamic drag force. If there is no macroscopic motion of the liquid solution containing the microbeads, the hydrodynamic viscous force acting on a spherical particle of radius R b , is given by:
  • Micromer ® -M microbeads are monodisperse particles which consist of magnetite in an organic matrix from a styrene- maleic acid-copolymer .
  • Type 2 microbeads are of similar size as the microbeads of type 1, but differ from them by a non-spherical 'corn flake' -like shape. They are characterized by a product v b ⁇ b , which is estimated from transport experiments to be about a factor 30 higher than the corresponding product for the microbeads of type 1.
  • a capillary tube 3 is used as chamber within which the transport of the magnetic microbeads takes place.
  • the capillary tube is e.g. a glass capillary having an inner diameter of 0.58 millimeter and an outer diameter of 1 millimeter.
  • a first embodiment of an apparatus according to the invention for transporting electrically non-conducting, magnetic or magnetisable microbeads immersed in a liquid contained in a capillary tube is described hereinafter with reference to Figures Ia to 3 and 7.
  • Fig. Ia shows a first electromagnet 1.1 comprising a coil 10 wound around magnetic core 9 having poles 11 and 12.
  • Fig. Ia shows this electromagnet in a first polarity state designated by 1.1+ and indicated by the sense of the excitation current applied to coil 10 and by the corresponding direction of the magnetic flux indicated by arrows in poles 11 and 12.
  • electromagnet 1.1 belongs to a first row 1 of electromagnets which are arranged on a first side of a capillary tube 3 having a length axis A as represented in the arrangement shown by Fig. 3.
  • Fig. Ib shows the same first electromagnet 1.1 as in Fig. Ia, but when this electromagnet is in a second polarity state designated by 1.1- which is opposite to the first polarity state designated by 1.1+ and shown by Fig. Ia.
  • Fig. 2a shows a second electromagnet 2.1 comprising a coil 10 wound around magnetic core 9 having poles 11 and 12.
  • Fig. 2a shows this electromagnet in a first polarity state designated by 2.1+ and indicated by the sense of the excitation current applied to coil 10 and by the corresponding direction of the magnetic flux indicated by arrows in poles 11 and 12.
  • electromagnet 2.1 belongs to a second row 2 of electromagnets which are arranged on a second side of the capillary tube 3, the second side being opposite to the first side thereof.
  • Fig. 2b shows the same second electromagnet 2.1 as in Fig. 2a, but when this electromagnet is in a second polarity state designated by 2.1- which is opposite to the first polarity state designated by 2.1+ and shown by Fig. 2a.
  • an apparatus comprises the following components: a capillary tube 3, a first row 1 of uniformly spaced, stationary electromagnets forming a first linear array of poles 11, 12 located on a first side of the capillary tube 3, a second row 2 of uniformly spaced, stationary electromagnets forming a second linear array of poles 11, 12 located on a second side of the capillary tube 3, the second side being opposite to the first side.
  • Capillary tube 3 has a length symmetry axis A and is adapted for receiving a liquid containing an amount of electrically non-conducting, magnetic magnetic or magnetisable microbeads to be transported.
  • the first linear array of poles 11, 12 and the second linear array of poles 11, 12 extend in an axial direction defined by the length symmetry axis A of the capillary tube 3.
  • Each of the electromagnets has an electromagnetic circuit which comprises a magnetic core 9 which has two poles 11, 12, which are neighboring poles in the first or the second linear array of poles, and a coil 10 coupled with that magnetic core 9.
  • Magnetic core 9 is e.g. a ferrite core or any other suitable soft magnetic material. The dimensions of each magnetic core are in the millimeter-centimeter-range.
  • At least two successive poles 11, 12 of the first array of poles are portions of a first one-piece magnetic core 9 and at least two successive poles 11, 12 of the second array of poles are portions of a second one-piece magnetic core 9.
  • Each of poles 11, 12 has an outer end surface that faces capillary tube 3, and each of poles 11, 12 defines a magnetic axis which is perpendicular to the length symmetry axis A of the capillary tube 3.
  • the magnetic axis of all poles lie in a common plane which passes through the length symmetry axis A of capillary tube 3.
  • the poles 11, 12 of the first row 1 of electromagnets and the poles 11, 12 of the second row 2 of electromagnets are axially offset with respect to each other.
  • Fig. 3 which shows that B is the center-to- center distance between neighbor electromagnets of the same row, and that the electromagnets of rows on opposite sides of capillary tube 3 are shifted of a distance B/2 with respect to each other.
  • This feature is important for achieving the desired effect, i.e. the transport of the magnetic microbeads in the axial direction.
  • Fig. 7 shows a schematic representation of an electrical circuit which is adapted for applying to the coils 10 of the electromagnetic circuits of the first row 1 of electromagnets, and to the coils 10 of the electromagnetic circuits of the second row 2 of electromagnets, periodical electrical current pulses of uniform duration.
  • the electrical circuit represented therein comprises a DC current source 15, an AC current source 16 and switches 13 and 14 actuated by a control circuit 17.
  • AC current source 16 optionally comprises a phase shifter which introduces a phase shift ⁇ .
  • the electrical circuit just described has output terminals which are connected with the input terminals of the electromagnets of the first and the second row of electromagnets in such a way that periodical electrical current pulses delivered at the output terminals of the electrical circuit are applied to the coils 10 of the electromagnets in the order of their position in the axial direction.
  • switches 13 and 14 change the polarity of the current pulses applied to the coils 10 of the electromagnets.
  • Successive current pulses delivered at the output terminals of the electrical circuit shown by Fig. 7 extend over overlapping time intervals and the phase difference between successive pulses is constant and is comprised between 90 and 180 degrees.
  • a first embodiment of a method according to the invention for transporting electrically non-conducting, magnetic or magnetisable microbeads immersed in a liquid contained in a capillary tube is described hereinafter with reference to Figures 4a to 6.
  • the method according to this first embodiment is carried out e.g. with an apparatus of the type described above with reference to Figures Ia to 3 and 7 and comprises:
  • step (c) the electrical current pulses of uniform duration are applied to the coils 10 in the order of the position of the corresponding electromagnets in the axial direction, successive pulses extend over overlapping time intervals, and the phase difference between successive pulses is constant and is comprised between 90 and 180 degrees.
  • the application of the electrical current pulses to the coils 10 of the electromagnets generates a magnetic field within capillary tube 3. The amplitude, polarity and position of this magnetic field varying so with time that the magnetic field moves forward in the axial direction, and thereby causes transport of the microbeads in the axial direction.
  • the magnetic microbeads introduced into capillary tube 3 comprise magnetic microbeads having a non-spherical shape.
  • the magnetic microbeads introduced into capillary tube 3 comprise magnetic microbeads having a spherical shape.
  • the electrical current pulses applied to the coils 10 have a frequency in the range of 0.01 to 5 cycles per second.
  • an alternating current signal having a frequency in the range of 1 to 2000 cycles per second is superposed onto the electrical current pulses.
  • Figures 4a to 4g illustrate transport of microbeads along the capillary tube shown in Fig. 3. This transport is achieved by successively actuating the electromagnet arrangements so that these are successively in the polarity states represented in Figures 4a to 4g.
  • the polarity states of the electromagnets are indicated in the same way as in Figures Ia to 2b, that is by a + or a - sign on the right of the reference number which designates the electromagnet, e.g. 1.1+, 2.2-, etc.
  • Fig. 5 shows direct current intensities I 1 . (t), I 2 . (t), I 3 . (t) applied to the electromagnet arrangements represented in Figures 4a to 4g in order that these are successively in the polarity states shown by Figures 4a to 4g.
  • the letters a, b, c, d, e, f_ and g designate time intervals.
  • Fig. 5 shows three direct current intensities which have a phase difference of 120° with respect to each other.
  • four direct current intensities which have a phase difference of 90° with respect to each other are applied to the electromagnets. This embodiment provides a more efficient transport.
  • Fig. 4a show the polarity states of the electromagnets during time interval a in Fig. 5.
  • Figures 4b to 4g show the polarity states of the electromagnets during each of the time intervals b, c, d, e, f_ and g respectively.
  • Fig. 4a shows a cluster 5 of distributed magnetic microbeads formed by the magnetic fields generated by the current intensities I 1 . (t), I 2 . (t), I 3 . (t) applied to the electromagnets during time interval a in Fig. 5.
  • Figures 4b to 4g show the position of the cluster 5 of distributed magnetic microbeads formed by the magnetic fields generated by the current intensities Ii . (t) , I 2 . (t) , I 3 . (t) applied to the electromagnets during each of the time intervals b, c, d, e, f_ and g respectively.
  • the cluster 5 of distributed magnetic microbeads shown in each of Figures 4a to 4g is composed of magnetic microbeads distributed over a the cross-section of the capillary tube 3 and over a short segment thereof.
  • the cluster 5 of distributed magnetic microbeads has approximately the shape of a column or a disk.
  • the cluster 5 is not a compact mass of magnetic microbeads, but a swarm of magnetic microbeads spaced from each other and moving as a group.
  • the current intensities applied to the electromagnets are not the direct current pulses shown in Fig. 5, but current pulses formed by multiplication of the current pulses shown in Fig. 5 with an alternating current signal.
  • Fig. 6 shows current pulses I 1 . (t) , I 2 . (t) , I 3 . (t) which are the result of this multiplication.
  • a second embodiment of an apparatus according to the invention for transporting electrically non-conducting, magnetic or magnetisable microbeads immersed in a liquid contained in a capillary tube is described hereinafter with reference to Figures 8a to 10, 14 and 15 to 23.
  • Fig. 8a shows a first electromagnet 1.1 comprising a planar coil 20 wound around a magnetic core element 19.
  • Fig. 8a shows this electromagnet in a first polarity state designated by 1.1+ and indicated by the sense of the excitation current applied to planar coil 20 and by the corresponding direction of the magnetic flux indicated by arrows in pole 21.
  • electromagnet 1.1 belongs to a first row 1 of electromagnets which are arranged on a first side of a capillary tube 3 having a length axis A as represented in the arrangement shown by Fig. 10.
  • Fig. 8b shows the same first electromagnet 1.1 as in Fig. 8a, but when this electromagnet is in a second polarity state designated by 1.1- which is opposite to the first polarity state designated by 1.1+ and shown by Fig. 8a.
  • Fig. 9a shows a second electromagnet 2.1 comprising a planar coil 20 wound around a magnetic core element 19.
  • Fig. 9a shows this electromagnet in a first polarity state designated by 2.1+ and indicated by the sense of the excitation current applied to planar coil 20 and by the corresponding direction of the magnetic flux indicated by arrows in pole 21.
  • electromagnet 2.1 belongs to a second row 2 of electromagnets which are arranged on a second side of the capillary tube 3, the second side being opposite to the first side thereof.
  • Fig. 9b shows the same second electromagnet 2.1 as in Fig. 9a, but when this electromagnet is in a second polarity- state designated by 2.1- which is opposite to the first polarity state designated by 2.1+ and shown by Fig. 9a.
  • an apparatus comprises the following components: a capillary tube 3, a first linear array of uniformly spaced poles 21 of a first row 1 of stationary electromagnets located on a first side of the capillary tube 3, a second linear array of uniformly spaced poles 21 of a second row 2 of stationary electromagnets located on a second side of the capillary tube 3, the second side being opposite to the first side.
  • Capillary tube 3 has a length symmetry axis A and is adapted for receiving a liquid containing an amount of electrically non-conducting, magnetic or magnetisable microbeads to be transported.
  • the first linear array of poles 21 and the second linear array of poles 21 extend in an axial direction defined by the length symmetry axis A of the capillary tube 3.
  • Each one of the electromagnets has an electromagnetic circuit which comprises a magnetic core element 19 and a planar coil 20 coupled therewith.
  • At least two successive poles 21 of the first row 1 of electromagnets are portions of a first one-piece magnetic core 23, and at least two successive poles 21 of the second row 2 of electromagnets are portions of a second one-piece magnetic core 23.
  • Each of poles 21 has an outer end surface that faces capillary tube 3, and each of poles 21 defines a magnetic axis which is perpendicular to the length symmetry axis A of the capillary tube 3.
  • the magnetic axis of all poles lie in a common plane which passes through the length symmetry axis A of capillary tube 3.
  • the poles 21 of the first row 1 of electromagnets and the poles 21 of the second row 2 of electromagnets are axially offset with respect to each other. This is shown in particular by Fig. 10 which shows that B is the center-to- center distance between neighbor poles of the same row, and that the poles of rows on opposite sides of capillary tube 3 are shifted of a distance B/2 with respect to each other. This feature is important for achieving the desired effect, i.e. the transport of the magnetic microbeads in the axial direction.
  • all magnetic core elements 19 of the first row 1 of electromagnets are portions of a first one-piece magnetic core 23 and all magnetic core elements 19 of the second row 2 of electromagnets are portions of a second one-piece magnetic core 23.
  • Magnetic core 23 is e.g. a ferrite core or any other suitable soft magnetic material. Magnetic core 23 can also be formed by assembling together a ferrite plate and a wafer on which pin-shaped poles have been formed, e.g. by the powder blasting process described hereinafter.
  • each of the magnetic core elements 19 has the shape of a pin that terminates in a sharp pointed tip.
  • the distance between the tip of a pole 21 of the first row of electromagnets and the next tip of a pole 21 of the second row of electromagnets is at most two times the width of the capillary tube 3.
  • each of the electromagnets comprises a planar coil 20 which has a central opening and the pin shaped magnetic core element 19 is inserted through the opening of the planar coil .
  • Fig. 14 shows a schematic representation of an embodiment of the above mentioned electrical circuit which is adapted for applying to the coils 20 of the electromagnetic circuits of the first row of electromagnets 1, and to the coils 20 of the electromagnetic circuits of the second row of electromagnets 2, periodical electrical current pulses of uniform duration.
  • the electrical circuit represented therein comprises a DC current source 15, an AC current source 16 and switches 13 and 14 actuated by a control circuit 17.
  • AC current source 16 optionally comprises a phase shifter which introduces a phase shift ⁇ .
  • the electrical circuit just described has output terminals which are connected with the input terminals of the electromagnets of the first row 1 and the second row 2 of electromagnets in such a way that periodical electrical current pulses delivered at the output terminals of the electrical circuit are applied to the planar coils 20 of the electromagnets in the order of their position in the axial direction. Under the control of control circuit 17, switches 13 and 14 change the polarity of the current pulses applied to the planar coils 20 of the electromagnets.
  • Successive current pulsesdelivered at the output terminals of the electrical circuit extend over overlapping time intervals and the phase difference between successive pulses is constant and is comprised between 90 and 180 degrees.
  • the electrical circuit of Fig. 14 provides direct current pulses or a superposition of direct current pulses and AC current pulses to the planar coils 20 of the electromagnets in the sequences described in detail hereinafter with reference to Figures 11a to 13 in the description of a second example of a method according to the invention.
  • Fig. 15 shows a perspective exploded view showing the components of an embodiment the apparatus shown by Fig. 10.
  • such an embodiment comprises an upper ferrite plate 23 in which a first row 1 of magnetic poles 21 has been formed, an upper printed circuit board 22 having a thickness of 100 micrometer on which a first row of planar coils 20 having each a thickness of 35 micrometer and a pitch of 200 micrometer has been formed, a capillary tube 3, a lower printed circuit board 22 on which a second row of planar coils 20 has been formed, and a lower ferrite plate 23 in which a second row 2 of magnetic poles 21 has been formed.
  • the magnetic poles of each row belong to portions 19 (shown in Figures 8a to 9b) of a ferrite plate 23.
  • Portions 19 are magnetic core elements which have the shape of a pin that terminates in a sharp pointed pole tip 21.
  • Fig. 16 shows an enlarged view of a portion of Fig. 15.
  • Fig. 16 shows the spatial correspondence between the location of the poles 21 and the location of the corresponding planar coils 20.
  • each of the planar coils 20 has a central opening which is aligned with an opening of the printed circuit board and each of the poles 21 having the shape of a pin is inserted through the central opening of the corresponding planar coil 20 and the corresponding opening of the printed circuit board.
  • Fig. 17 shows a longitudinal cross-sectional view of an apparatus comprising components of the type shown in Figures 15 and 16, wherein the planar coils 20 are arranged on both sides of each printed circuit board 22 (the structure of such a planar coil is shown by Fig. 19) in order to generate stronger magnetic fields.
  • capillary tube 3 contains 3 different liquids 4a, 4b and 4c which are e.g. different reagents.
  • Fig. 17 shows a cluster 5 of distributed electrically non-conducting, magnetic microbeads being transported along capillary tube 3 by actuation of the planar coils 20 as described below in a second example of a method according to the invention.
  • Fig. 18 shows a cross-sectional view of the apparatus shown by Fig. 17 along plane XVIII- XVIII represented in Fig. 17.
  • Fig. 19 shows a perspective view of a planar coil arranged on both sides of a printed circuit board.
  • Figures 20 to 23 illustrate various steps of the process used for forming of magnetic poles 21 on a ferrite wafer by- powder blasting micro-erosion technology.
  • Fig. 20 illustrates a first step of the process wherein a first mask 31 having rectilinear web 32 is positioned on a ferrite wafer 30a.
  • the web 32 protects a linear region of the ferrite wafer 30a and after this run a rectilinear ridge 33 results in the wafer now designated as wafer 30b.
  • Fig. 21 illustrates a second step of the fabrication of pole tips 21 on a ferrite wafer.
  • a second mask 34 which has an array of webs parallel to each other and extending in a direction perpendicular to ridge 33, is positioned on ferrite wafer 30b. After powder blasting of wafer 30b with mask 34 on it, the ridge 33 is transformed into an array of ferrite posts or pins 36
  • Fig. 22 shows a ferrite wafer 30c with pole tips fabricated according to the steps shown by Figures 20 and 21.
  • Fig. 23 shows an enlarged view of a cut-out XXIII in Fig. 22.
  • a second embodiment of a method according to the invention for transporting electrically non-conducting, magnetic or magnetisable microbeads immersed in a liquid contained in a capillary tube is described hereinafter with reference to Figures 11a to 13.
  • the method according to this first embodiment is carried out e.g. with an apparatus of the type described above with reference to Figures 8a to 10, 14 and 15 to 23 comprises: (a) positioning a capillary tube 3 having a length symmetry axis A in a space which extends between a first linear array of uniformly spaced poles 21 of a first row of stationary electromagnets 1 located on a first side of the capillary tube 3, and a second linear array of uniformly spaced poles 21 of a second row 2 of stationary electromagnets located on a second side of the capillary tube 3 opposite to the first side,
  • step (c) the electrical current pulses of uniform duration are applied to the coils 20 in the order of the position of the corresponding electromagnets in the axial direction, successive pulses extending over overlapping time intervals and the phase difference between successive pulses being constant and comprised between 90 and 180 degrees.
  • the application of the electrical current pulses to the coils 20 of the electromagnets generates a magnetic field within capillary tube 3. The amplitude, polarity and position of this magnetic field varying so with time that the magnetic field moves forward in the axial direction, and thereby causes transport of the microbeads in the axial direction.
  • the magnetic microbeads introduced into capillary tube 3 comprise electrically non-conducting, magnetic microbeads having a non-spherical shape.
  • the magnetic microbeads introduced into capillary tube 3 comprise electrically nonconducting, magnetic microbeads having a spherical shape.
  • the electrical current pulses applied to the coils 20 have a frequency in the range of 0.01 to 5 cycles per second. If the coils 20 are mounted on a printed circuit board with no particular cooling other than unforced air convection the maximum current density that can be applied to the coils is about 150 A/square millimeter and that corresponds to a maximum current intensity of about 0.5 A for the coils 20 of the type described above in the second example of an apparatus according to the invention.
  • an alternating current signal having a frequency in the range of 1 to 2000 cycles per second is superposed onto said electrical current pulses .
  • Figures 11a to Hg illustrate transport of microbeads along the capillary tube shown in Fig. 10. This transport is achieved by successively actuating the electromagnet arrangements so that these are successively in the polarity states represented in Figures Ha to Hg.
  • the polarity states of the electromagnets are indicated in the same way as in Figures 8a to 9b, that is by a + or a - sign on the right of the reference number which designates the electromagnet, e.g. 1.1+, 2.2+, etc.
  • Fig. 12 shows direct current intensities I x . (t), I 2 . (t), I 3 . (t) , I 4 . (t) applied to the electromagnet arrangements represented in Figures Ha to Hg in order that these are successively in the polarity states shown by Figures Ha to Hg.
  • the letters a, b, c, d, e, f_ , g and h designate time intervals.
  • Figure 12 shows four direct current intensities which have a phase difference of 90° with respect to each other.
  • the current intensities I 1 . (t) , I 2 . (t) , I 3 . (t) , I 4 . (t) shown in Figure 12 during time the time interval g are applied to the coils 20 of the corresponding electromagnets.
  • the current intensities I 1 . (t) , I 2 . (t) , I 3 . (t) , I 4 . (t) shown in Figure 12 during time the time interval g are applied to the coils 20 of the corresponding electromagnets.
  • the current intensities I 1 . (t) , I 2 . (t) , I 3 . (t) , I 4 . (t) shown in Figure 12 during time the time interval g are applied to the coils 20 of the corresponding electromagnets.
  • the current intensities I 1 . (t) , I 2 . (t) , I 3 . (t) , I 4 . (t) shown in Figure 12 during time the time interval g are applied to the
  • Figure Ha show the polarity states of the electromagnets during time interval a in Figure 12.
  • Figures Hb to Hg show the polarity states of the electromagnets during each of the time intervals b, £, d, e, f_, g and h respectively.
  • Fig. Ha shows a cluster 5 of distributed magnetic microbeads formed by the magnetic fields generated by the current intensities Ii . (t) , I 2 . (t) , I 3 . (t) , I 4 . (t) applied to the electromagnets during time interval a in Figure 12.
  • Figures Hb to Hh show the position of the cluster 5 of distributed magnetic microbeads formed by the magnetic fields generated by the current intensities I 1 . (t) ,
  • the cluster 5 of distributed magnetic microbeads shown in each of Figures Ha to Hg is composed of magnetic microbeads distributed over a the cross-section of the capillary tube 3 and over a short segment thereof.
  • the cluster 5 of distributed magnetic microbeads has approximately the shape of a column or a disk.
  • the cluster 5 is not a compact mass of magnetic microbeads, but a swarm of magnetic microbeads spaced from each other and moving as a group .
  • the current intensities applied to the electromagnets are not the direct current pulses shown in Fig. 12, but current pulses formed by multiplication of the current pulses shown in Fig. 12 with an alternating current signal.
  • Fig. 13 shows current pulses Ii . (t) , I 2 . (t) , I 3 . (t) , I 4 . (t) which are the result of this multiplication.
  • the magnetic fields generated by the electromagnets induce a dynamic vortex- like motion of the microbeads of the microbead cluster 5 over the entire cross-section of capillary tube 3 and this motion takes place during the transport of cluster 5 in axial direction.
  • the vortex-like motion of the microbeads of the cluster 5 being transported in advantageous in applications where interaction of the microbeads with target particles is desirable.

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  • Physical Or Chemical Processes And Apparatus (AREA)
  • Apparatus Associated With Microorganisms And Enzymes (AREA)

Abstract

La présente invention concerne un procédé et un appareil permettant le transport de microbilles magnétiques ou magnétisables immergées dans un liquide contenu dans un tube capillaire ayant un axe de symétrie longitudinal qui définit une direction axiale, le transport étant effectué en l'absence de champ magnétique statique dans le tube capillaire.
EP08716225A 2007-03-26 2008-03-04 Procédé et appareil permettant le transport magnétique ou magnétisable de microbilles Pending EP2129469A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
EP08716225A EP2129469A1 (fr) 2007-03-26 2008-03-04 Procédé et appareil permettant le transport magnétique ou magnétisable de microbilles

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
EP07006148A EP1974821A1 (fr) 2007-03-26 2007-03-26 Procédé et appareil pour transporter des microbilles magnétiques ou magnétisables
PCT/EP2008/001706 WO2008116543A1 (fr) 2007-03-26 2008-03-04 Procédé et appareil permettant le transport magnétique ou magnétisable de microbilles
EP08716225A EP2129469A1 (fr) 2007-03-26 2008-03-04 Procédé et appareil permettant le transport magnétique ou magnétisable de microbilles

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EP2129469A1 true EP2129469A1 (fr) 2009-12-09

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EP08716225A Pending EP2129469A1 (fr) 2007-03-26 2008-03-04 Procédé et appareil permettant le transport magnétique ou magnétisable de microbilles

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EP2208531A1 (fr) 2008-12-30 2010-07-21 Atonomics A/S Distribution de particules dans un canal capillaire par l'application d'un champ magnétique
DE102009004086A1 (de) * 2009-01-05 2010-07-22 Gottfried Wilhelm Leibniz Universität Hannover Elektromagnetisches Mikrosystem zur Manipulation magnetischer Mikro- oder Nanoperlen
DE102010017957A1 (de) * 2010-04-22 2011-10-27 Siemens Aktiengesellschaft Vorrichtung zum Abscheiden ferromagnetischer Partikel aus einer Suspension
DE102011004958A1 (de) 2011-03-02 2012-09-06 Siemens Aktiengesellschaft Trenneinrichtung zum Separieren von in einer Suspension enthaltenen magnetischen oder magnetisierbaren Teilchen
DE102011076192A1 (de) * 2011-05-20 2012-11-22 Siemens Aktiengesellschaft Filter und Verfahren zum Filtrieren von magnetischen Partikeln
WO2013041983A1 (fr) 2011-09-19 2013-03-28 Centre National De La Recherche Scientifique Système micro-fluidique
FR2995225B1 (fr) 2012-09-07 2014-10-03 Jean-Louis Viovy Systeme microfluidique presentant un lit de particules magnetiques
PL3126053T3 (pl) * 2014-03-31 2023-07-17 Basf Se Urządzenie oddzielające namagnesowany materiał
EP3223953A1 (fr) 2014-11-27 2017-10-04 Basf Se Amélioration de la qualité de concentré
CN107073479A (zh) 2014-11-27 2017-08-18 巴斯夫欧洲公司 用于磁力分离的附聚期间的能量输入
FR3125442A1 (fr) * 2021-07-26 2023-01-27 Airbus Helicopters Procédé et dispositif de captation de particules ferromagnétiques pour un système mécanique, et système mécanique associé

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JPS59196766A (ja) * 1983-04-23 1984-11-08 Japan Atom Energy Res Inst クラツド分離装置
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