EP1843854B1 - Procede et dispositif pour separer des particules magnetiques ou magnétisables d'un liquide - Google Patents

Procede et dispositif pour separer des particules magnetiques ou magnétisables d'un liquide Download PDF

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Publication number
EP1843854B1
EP1843854B1 EP06706463A EP06706463A EP1843854B1 EP 1843854 B1 EP1843854 B1 EP 1843854B1 EP 06706463 A EP06706463 A EP 06706463A EP 06706463 A EP06706463 A EP 06706463A EP 1843854 B1 EP1843854 B1 EP 1843854B1
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EP
European Patent Office
Prior art keywords
bars
magnetizable
head piece
liquid
particles
Prior art date
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Application number
EP06706463A
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German (de)
English (en)
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EP1843854A1 (fr
Inventor
Lothar A Brassard
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PerkinElmer Chemagen Technologie GmbH
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Chemagen Biopolymer Technologie AG
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Publication of EP1843854A1 publication Critical patent/EP1843854A1/fr
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    • 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
    • B03C1/286—Magnetic plugs and dipsticks disposed at the inner circumference of a recipient, e.g. magnetic drain bolt
    • 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
    • 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
    • B03C1/04—Magnetic separation acting directly on the substance being separated with the material carriers in the form of trays or with tables
    • B03C1/06—Magnetic separation acting directly on the substance being separated with the material carriers in the form of trays or with tables with magnets moving during operation
    • 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
    • B03C1/30—Combinations with other devices, not otherwise provided for
    • 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
    • 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
    • B03C2201/22—Details of magnetic or electrostatic separation characterised by the magnetic field, e.g. its shape or generation
    • 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
    • B03C2201/26—Details of magnetic or electrostatic separation for use in medical or biological applications

Definitions

  • the invention relates to devices for separating and resuspending magnetic or magnetizable particles from liquids by means of a magnetic field generated by one or more permanent magnets.
  • the invention further relates to methods for separating magnetic or magnetizable particles from liquids and mixing and resuspending magnetic or magnetizable particles in liquids by means of a magnetic field generated by one or more permanent magnets.
  • the devices and methods are, for example, suitable for applications in pharmaceutical development, biochemistry, molecular genetics, microbiology, medical diagnostics and forensic medicine.
  • the basic principle of the magnetic separation of substances from complex mixtures is based on the fact that magnetic particles (magnetizable or magnetically attractable particles) are specifically functionalized for the intended separation process, d. H. they are provided by chemical treatment with specific binding properties for the target substances to be separated.
  • the size of such magnetic particles is generally in the range of about 0.05 to 500 microns.
  • Magnetic particles which have specific binding properties for certain substances and are suitable for separating these substances from complex mixtures are described, for example, in US Pat DE 195 28 029 A1 and are commercially available (eg, Chemagen Biopolymer-Technologie AG, DE-52499 Baesweiler).
  • the functionalized magnetic particles are added in a first step ("binding step") to a mixture to be purified, which contains the target substance (s) in a liquid which favors the binding of the target substance molecules to the magnetic particles (binding buffer).
  • binding step a first step
  • these magnetic particles are immobilized by application of magnetic forces or a magnetic field, for example by means of a permanent magnet, at a location of the reaction vessel inner wall ("pellet").
  • pellet the liquid supernatant is separated and discarded, for example by suction or decantation. Since the magnetic particles are immobilized in the aforementioned manner, it is largely prevented that these particles are separated with the supernatant.
  • the immobilized magnetic particles are resuspended again.
  • an elution liquid or an elution buffer is used, which is suitable for dissolving the bond between the target substance (s) and the magnetic particles, so that the target substance molecules are released from the magnetic particles and can be separated with the elution liquid, while the magnetic particles are immobilized by the action of a magnetic field.
  • one or more washing steps can be carried out.
  • the magnetic particles can also be used directly for diagnostic or analytical studies.
  • the functionalization allows specific binding, e.g. of pathogenic substances.
  • all impurities must be removed in suitable solutions. This requires the most efficient possible mixing (washing) of the analyte-containing particles. Such a process facilitates the present invention, especially if the number of simultaneously processed samples is large or must be worked in small volumes (384 or 1536 format).
  • DE 296 14 623 U1 discloses a magnetic separator equipped with movable permanent magnets. Alternatively, it is proposed to move the magnetic particles containing reaction vessel by mechanical drive means relative to a permanently installed permanent magnet. In the DE 296 14 623 U1 described device has no magnetizable rods that dip into the sample liquid; rather, the permanent magnets each positioned next to the individual reaction vessels.
  • the magnetic particles are immobilized or collected on the inner wall or at the bottom of a reaction vessel as a "pellet".
  • these devices are not suitable for removing the magnetic particles from a reaction vessel. Therefore, to separate the liquid from the magnetic particles in each case the liquid must be sucked from the individual reaction vessels. This is disadvantageous because it involves a high material consumption (disposable pipette tips). Furthermore, it can not be prevented that individual magnetic particles are sucked with; This results in a high error rate. Further errors can be caused by dripping liquids, which lead to cross contamination.
  • a magnetic separator which has a plurality of rotatable rods that can be magnetized by an electromagnetic exciter coil. By immersing the rod in the magnetic particles containing liquid and pulling out the rod in the magnetized state, the magnetic particles can be removed from the liquid and optionally transferred to another reaction vessel. There they can be released by switching off the excitation coil back into a liquid, for example in a washing or elution liquid.
  • the excitation coil has a relatively large amount of space, resulting in constructive limitations.
  • the geometry and geometry of the electromagnet are constrained in terms of the arrangement and number of rods, which may include limitations on sample processing.
  • the geometry of the electromagnet can not be changed arbitrarily, since then inhomogeneities of the magnetic field must be taken into account.
  • the known devices are not suitable for the simultaneous treatment of larger numbers of samples, as required for high-throughput applications (eg 364 or 1536 well plates).
  • the design effort would be immense and in addition a significantly higher susceptibility of the mechanics used would have to be accepted.
  • the known devices are also disadvantageous because they are only suitable for individual sample vessels or only for a specific, fixed predetermined arrangement of the sample vessels, for example in the form of a 96-well microtiter plate.
  • a magnetic separator apparatus be suitable or capable of being adapted for various types of sample vessels or for various types of sample vessels (e.g., 96, 364 or 1536 well plates).
  • the invention therefore an object of the invention to provide devices and methods with which the separation of magnetic particles from liquids and the transfer of magnetic particles from a liquid is made possible in another liquid, without causing the aforementioned disadvantages occur.
  • the devices and methods should be suitable for use in high throughput processes.
  • the devices should be multi-sided can be used and in particular suitable for different types of reaction vessels.
  • the operation of the device is based on the fact that the / the permanent magnet (s) over the head piece (with the rods attached thereto) can be positioned. This causes the magnetization of the rod (s). This state of the device is referred to as "on".
  • the magnetizable rods When the magnetizable rods are immersed with their lower end or portion, for example, in a sample liquid having magnetic particles therein, the magnetic particles will adhere to the lower end of the rods due to the magnetic forces. The sticks with the adhered magnetic particles can then be dipped in another liquid (e.g., a reagent or wash solution).
  • the permanent magnets are / are movably arranged relative to the head piece, so that the magnetization of the magnetizable bars attached to the head piece can be alternately switched on and off by movement of the magnet (s).
  • the magnet (s) is / are moved over the head piece or away from the head piece.
  • the magnetization or demagnetization can also be achieved by moving the head piece under the magnet (s) or away from the magnet, in which case the magnet (s) are preferably arranged stationary.
  • the head piece By the movement of the head piece (with the magnetizable bars attached thereto), it can assume a first position, in which the head piece is located below the area of the permanent magnet (switched-on state), or it can assume a second position in which it is located is outside the specified range (switched off state).
  • the device can be used to remove magnetic particles using the magnetizable rods from a first liquid and transferred to a second or more liquid and release there again.
  • the arrangement of a permanent magnet which may also be composed of a plurality of individual magnets, a substantially homogeneous magnetic field is generated.
  • a substantially homogeneous magnetic field is generated.
  • the devices according to the invention also have the advantage that the magnetic particles - in the magnetized state - accumulate substantially at the top of the rods whereby the adhering substances to be separated can be absorbed in comparatively small elution volumes. This guarantees - for diagnostic or analytical investigations essentially high concentrations of the substances to be separated.
  • all hard magnetic materials known to the person skilled in the art can be used for producing the permanent magnets, in particular ferrites, Al-Ni-Co alloys and rare earth magnets (preferably NdFeB); Such magnetic materials and magnets are commercially available from various manufacturers.
  • the number of magnetizable rods attached to the header depends on the number of samples or the number of wells in liquid containers that are to be treated simultaneously at most.
  • Microtiter plates in particular with 96, 384 or 1536 depressions ("wells") are preferably used as containers, so that corresponding numbers of magnetizable bars are provided for these cases.
  • sample tubes or reaction vessels having a volume of, for example, 0.015 to 100 ml, which can be treated individually or in groups, in each case in combination with magnetizable bars adapted thereto.
  • the magnetizable rods are preferably made of a soft magnetic material, for example of soft iron (in particular Fe-Ni alloys) or magnetizable steel. Their length and diameter depend on the intended application, in particular on the dimensions of the containers and the volumes of liquid, and can be varied accordingly. If a group of multiple rods (for example 96, 384 or 1536) is used, then these rods each have the same length, thickness and material condition.
  • the rods may optionally be hollow inside, ie be formed as tubes, wherein the lower end is preferably closed. In particular, the rods may be shaped as sleeves, as described below.
  • the magnetic bars are substantially perpendicular and parallel to each other, and the individual bars of a group or array are preferably equidistant from adjacent bars.
  • Particularly preferred is a grid-like arrangement of the rods, which corresponds to the arrangement of the wells in conventional microtiter plates.
  • the invention therefore also extends to arrangements of magnetizable bars in which a plurality of magnetizable bars (4) are mounted on a base plate (9), the bars being substantially parallel to one another and preferably arranged in one, two or more rows are, each row comprising two or more rods.
  • the magnetizable rods whether fixed or detachably connected to the head piece, preferably have a thickness of 0.5 mm to 10 mm, in particular 1 to 5 mm.
  • the length of the rods is preferably 1 to 20 cm, in particular 5 to 10 cm.
  • conventional means may be used (eg glued connection, screw connection, welding).
  • the head piece (without rods) may be wholly or partly made of a non-magnetic or non-magnetizable material.
  • the magnetizable rods are preferably connected by means of a clamping connection to the head plate.
  • the head piece may be provided on its underside with corresponding recesses or holes into which the rods can be inserted.
  • rods may be used which are tubular or at least have a recess at their upper end and which can be plugged onto corresponding pins or protrusions provided on the underside of the header.
  • the head piece is provided with a mechanism which releases the clamping connection between the bars and the head piece, thus causing the bars to be pushed off or thrown off when they are to be replaced by unused bars after use.
  • This may preferably be accomplished by electromotive drive, or by pneumatic, electromagnetic or hydraulic means, or by a combination thereof.
  • the magnetizable rods are attached to a base plate and form a unit with this.
  • the base plate can be detachably connected to the header.
  • the base plate and the rods located thereon can optionally also be made in one piece.
  • base plates with rods attached thereto can be carried out by means of known materials and processes for the production of molded parts, for example by deep-drawing, extrusion, welding, gluing, etc.
  • the units consisting of Base plate and connected rods, manufactured and used as Disposables.
  • the base plate is provided with a plurality of magnetizable bars arranged in one or more rows, each row containing a plurality of bars.
  • the rods are preferably arranged in a regular matrix, for example in accordance with the arrangement of the wells of a microtiter plate (in particular a microtiter plate with 96, 384 or 1536 wells).
  • the base plate generally has a rectangular or square outline.
  • the releasable connection between said baseplate and the header may be effected in a manner known to those skilled in the art, e.g. by clamping, clamping or clamping devices, levers, springs, etc ..
  • the device has means by which the rods, or the base plate with the rods located thereon, can be detachably connected to the head piece and / or removed from the head piece.
  • Said means will preferably be actuated by electromotive drive, or by pneumatic, electromagnetic or hydraulic means, or by a combination thereof. In this way, the picking up, attaching and dropping of the base plate can be done automatically, and these operations can be controlled by, for example, a program.
  • the said rod (s) - regardless of whether they are fixed or detachable, with or without base plate, are connected to the head piece - each with a strippable, replaceable Sleeve are provided.
  • the sleeves are - depending on the dimensions of the rods - dimensioned so that they can be fixed by means of clamping connection to the rods.
  • the group of sleeves is provided on a dispensing device, wherein the arrangement of the sleeves on the dispenser device corresponds to the respective arrangement of the magnetizable bars (eg arrangement corresponding to the distances between the individual Wells of a microtiter plate).
  • the number and arrangement of the sleeves on such a unit corresponds to the respective number and arrangement of the magnetizable bars.
  • the invention also extends to arrays of sleeves suitable for use with any of the devices of the invention; in particular to arrangements with a plurality of sleeves (8) which are attachable to the magnetizable bars of said device and are arranged substantially parallel to each other.
  • the sleeves are in one, two or more rows arranged, wherein each row comprises two or more rods.
  • the sleeves mentioned can be made of known materials, for.
  • plastics such as polyethylene, polypropylene, Teflon, polyethylene terephthalate, nylon, polyvinyl chloride, etc., or from metallic materials such as stainless steel, tinplate, aluminum foils, etc., or combinations of such materials, in a manner known in the art are made (in particular by injection molding or deep drawing).
  • the sleeves or the sleeves connected to a common unit of a magnetizable material (as mentioned above).
  • the magnetizable sleeves or the unitized magnetizable sleeves assume the function of the above-described magnetizable rods or the magnetizable rods connected to a base plate.
  • the units formed from groups of sleeves are manufactured as disposables and used to eliminate contamination.
  • the device according to the invention comprises means by which the interchangeable sleeves or the sleeves forming a common unit on the rods - or at the head of the device - recorded, held and / or by the rods (or of the head piece ) can be removed or discarded.
  • Said means are preferably operated by electromotive drive, or by pneumatic, electromagnetic or hydraulic means, or by a combination thereof. In this way, the recording, attaching and dropping the sleeves can be done automatically or automatically, in particular programmatically.
  • the apparatus may further comprise means by which individual envelopes, arrays of envelopes, or interconnected envelopes are automatically or programmatically provided (e.g., disposed in a stand or dispenser) so that they can be received by the bars.
  • the sleeves In order to enable the replacement of the sleeves, or the sleeves forming a common unit, they can - as mentioned - be clamped on the rods; alternatively or additionally, the sleeves on the specialist z. B. by clamping, clamping or clamping devices, levers, springs, etc. are attached to the rods and / or with the top plate or other parts of the device.
  • the head piece of the device is arranged to be movable and can be set in motion by a drive device.
  • Electromotive, pneumatic, electromagnetic or hydraulic drive means, or a combination thereof, are particularly suitable for the drive device.
  • the vertical direction corresponds substantially to the longitudinal direction of the substantially vertically oriented magnetizable rods.
  • the vertical movements serve to effect the immersion of the rods into the sample liquid and the withdrawal of the rods from the liquid.
  • the horizontal movements may be used in particular for performing shaking or vibrating movements (e.g., circular or orbital shaker movements). Suitable mechanisms by which the mentioned types of movement can be effected are known to the person skilled in the art.
  • At least one holding device is provided which can be positioned below the bars, so that the bars are aligned with the openings of the container.
  • This holding device can be configured for example in the form of a holding plate.
  • the holding device is preferably arranged to be movable and can be set in motion by a drive device so that the sample containers can be alternately positioned in a region below the bars or outside this region.
  • Electromotive, pneumatic, electromagnetic or hydraulic drive means, or combinations thereof, are preferably used as drive means of the holding device.
  • the holding devices and their drive means may also be designed in such a way that they are suitable for carrying out shaking or vibrating movements.
  • the design measures required for this purpose are generally known to the person skilled in the art.
  • both the head piece and the holding device is movable and in particular are capable of carrying out shaking movements. In this way, a particularly effective mixing of the sample liquid is possible if the rods are immersed therein.
  • the device is equipped with a movable holding device, the head piece, however, arranged immovable.
  • the holding device is part of a program-controlled laboratory robot system.
  • it is arranged so that a plurality of individual ones of the said containers or groups of such containers, in particular microtiter plates, are alternately brought into a position below said bars and then returned to a position after a predetermined time interval, which is outside the below Bars located area lies. In this way, a high sample throughput is possible.
  • control or regulating device by means of which the vertical movement of the holding device (s) is adjustable or controllable in such a way that the rods are immersed in the liquid-filled upon upward movement Container is effected.
  • the operation of the device according to a preferred embodiment is based on the fact that the / the permanent magnet (s) can be positioned over the head piece, and then can be moved out of this position again / can.
  • the magnet In order to allow movement of the permanent magnet (s) for turning on and off the magnetic field, the magnet, or a group of a plurality of magnets, may be slidably mounted, rotatable or tiltable in a dedicated device. By moving, turning or tilting the magnet can be brought into a position in which its poles or its magnetic field point in the direction of the bars (switched-on state, maximum field strength on the bars), or the magnet can be moved to another position, in which the magnetic field emitted by it does not magnetize the rods of the head piece (switched-off state).
  • the magnet (s) may also be slid, rotated or tilted in intermediate positions to cause the field strength at the magnetizable bars to be less than the maximum value.
  • the movement of the permanent magnet (s) is made possible according to a preferred embodiment in that the / the permanent magnet (s) is slidably arranged so that the / the magnet (s) from the outside by shifting (or by pulling forces) into the region lying above the head piece and can be moved out of this area again / can.
  • the permanent magnet can be mounted for example on rails, rollers or racks.
  • the movement of the / the permanent magnet (s) is made possible by the / the permanent magnet (s) (1) on a rotatable or tiltable device is / are arranged, by means of which the / the permanent magnet (s) via the head piece and can be moved away from this again / can.
  • the movement (eg, tilting, turning, shifting) of the permanent magnet (s) can be done either directly or indirectly by hand or by means of a drive device, which preferably has electromotive, pneumatic, electromagnetic or hydraulic drive means, or a combination thereof.
  • drive means are generally known to those skilled in the art, as well as other components (e.g., gears, linkages) that may be needed for the drive means.
  • a device according to the invention is preferably equipped in such a way that the extent of the movement of the permanent magnet (s) is predictable (eg turning angle or tilting angle, displacement distance).
  • the devices of the invention may be advantageously combined with other devices for the automated treatment of sample material. Furthermore, two or more of the devices according to the invention can be arranged side by side and combined.
  • the devices and methods of the invention may be advantageously used to separate and / or mix a target substance from / in a liquid mixture or solution.
  • the magnetizable rods are immersed in a liquid which contains a target substance which is specific but reversible the particle is bound.
  • the target substances may be, for example, antibodies, enzymes, receptors, ligands, pharmaceutical agents, nucleic acids. These can also be present in the form of complex mixtures with other substances, the target substances, depending on the binding properties of the magnetizable particles, are specifically bound to them.
  • the particles following the step b) or d) may be advantageous to release the particles following the step b) or d) by switching off the magnetic field in the liquid to mix them, and then collect again by turning on the magnetic field on the rods.
  • the mixing can be effected, for example, by shaking the holding device and / or the head part.
  • the said methods can be carried out in a particularly simple and rapid manner.
  • the devices and methods of the invention are particularly suitable for the application areas mentioned above, in particular for high-throughput methods.
  • Fig. 1A and 1B show an embodiment of a device (10) according to the invention in a side view, wherein Fig. 1A the switched on, Fig. 1B illustrates the off state.
  • the device (10) comprises a permanent magnet (1) which is slidably mounted on rails (2) and can be moved in the direction of the arrow (a) in a horizontal plane.
  • a fixed frame of the device (not shown) carries a head piece (3) with magnetizable bars or rods (4) attached thereto. Below the bars is a vertically displaceable holding device (6).
  • a sample container (7) On the holding device is a sample container (7) arranged with a plurality of wells for receiving liquid samples, for example, removably fixed on the holding device (6).
  • the head piece (3) is connected to a drive unit (5), which makes it possible to move the head piece with the rods attached thereto in movement, preferably in a shaking movement in the horizontal plane, as indicated by arrow (b).
  • the holding device (6) is equipped with a drive unit (not shown), which allows an upward and downward movement of the holding device (arrow c).
  • sleeves (8) are attached or clamped. The rods are firmly connected to the head piece; Alternatively, they can also be releasably connected to the head piece.
  • the magnet (1) is in Fig. 1A in a position substantially above the header or magnetizable bars so that the bars can be magnetized by the magnet. As a result, a magnetic field is generated at the ends of the rods (7) which can be used to attract magnetic particles.
  • Fig. 1B off state
  • the magnet has been moved out of this position and is no longer above the bars (4).
  • Fig. 1C shows a modification of the in Fig. 1A and 1B shown apparatus (10), wherein the sleeves (8 ') are connected together at their upper ends and form a common unit.
  • Fig. 2A to 2C show a further embodiment of the device (10), in which a plurality of bars (4) are connected in a regular arrangement with a base plate (9) and form a unit with this.
  • the plate (9) is releasably attached to the head piece (3).
  • the header is then preferably equipped with a holding and dropping device which allows automatic picking and dropping of the plate through the header (not shown).
  • a holding and dropping device which allows automatic picking and dropping of the plate through the header (not shown).
  • Fig. 2A shows the switched on
  • Fig. 2B the off state.
  • Fig. 2C shows a further advantageous embodiment of the invention (in the on state), wherein the entire unit comprising the head piece and the magnet, can be moved up and down, preferably by drive means of the type mentioned above. In this case, can on a vertical mobility the holding device (6) are dispensed with.
  • Fig. 2D shows a further advantageous embodiment of the invention, in which instead of a base plate (9) with bars (4) attached thereto, a group of sleeves or hollow bars (8 ") joined together in one unit is used, in which case the sleeves are made of a magnetizable one Material produced.
  • Fig. 3 shows a further embodiment of the device according to the invention, in which the holding device (6) for the sample vessels with a drive unit (5 ') in the horizontal direction (arrow d) can be moved.
  • Fig. 4 shows a further embodiment of the invention, wherein two units, each with a head piece (3), magnetizable bars (4), holding device (6), are combined, wherein the magnet (1) via a rail (2) alternately over the one or the other header (3) can be positioned.

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  • Physical Or Chemical Processes And Apparatus (AREA)
  • Automatic Analysis And Handling Materials Therefor (AREA)
  • Investigating Or Analyzing Materials By The Use Of Magnetic Means (AREA)
  • Soft Magnetic Materials (AREA)
  • Sampling And Sample Adjustment (AREA)
  • Apparatus Associated With Microorganisms And Enzymes (AREA)
  • Mixers With Rotating Receptacles And Mixers With Vibration Mechanisms (AREA)

Claims (31)

  1. Dispositif pour séparer des particules magnétiques ou magnétisables d'un liquide en utilisant un champ magnétique, le dispositif (10) présentant
    - une pièce supérieure (3) avec une ou plusieurs barres (4) magnétisables, laquelle (lesquelles) est (sont) reliée(s) de façon fixe ou amovible à la pièce supérieure (3) ;
    - un ou plusieurs aimants permanents (1) dont la position relative par rapport à la pièce supérieure est modifiable par un déplacement pouvant être prédéterminé de l'aimant/des aimants et/ou par un déplacement pouvant être prédéterminé de la pièce supérieure en ce sens que l'aimant/les aimants permanent(s) occupe(ent) une première position se trouvant au-dessus de la pièce supérieure ou une seconde position, qui se trouve à l'extérieur de ladite première position.
  2. Dispositif selon la revendication 1, caractérisé en ce que les barres (4) magnétisables sont placées sur une plaque de base (9) et forment avec celle-ci une unité, sachant qu'on préfère que la plaque de base soit reliée de façon amovible à la pièce supérieure (3).
  3. Dispositif selon la revendication 2, caractérisé en ce que la plaque (9) est dotée d'une pluralité de barres (4) magnétisables, qui sont disposées dans une ou plusieurs rangées, chaque rangée contenant une pluralité de barres (4).
  4. Dispositif selon la revendication 2 ou 3, caractérisé en ce qu'il présente des moyens, par lesquels les barres (4) ou la plaque de base (9) peut/peuvent être reliée(s) aux barres (4) se trouvant dessus de façon amovible sur la pièce supérieure et/ou être enlevée(s) de la pièce supérieure, lesdits moyens étant actionnés de préférence par un entraînement électromoteur ou par des moyens pneumatiques, électromagnétiques ou hydrauliques, ou par une combinaison de ces moyens.
  5. Dispositif selon l'une quelconque des revendications précédentes, caractérisé en ce que ladite/lesdites barre(s) sont dotées chacune d'une douille (8) pouvant être enlevée et remplacée.
  6. Dispositif selon la revendication 5, caractérisé en ce qu'il présente plusieurs douilles qui forment une unité (8') commune.
  7. Dispositif selon la revendication 5 ou 6, caractérisé en ce qu'il présente des moyens par lesquels les douilles (8) amovibles ou les douilles (8') formant une unité commune peut/peuvent être fixée(s) sur les barres (4) ou sur la pièce supérieure (3) et/ou enlevée(s) des barres (4) ou de la pièce supérieure (3), lesdits moyens étant actionnés de préférence par un entraînement avec moteur électrique ou par des moyens pneumatiques, électromagnétiques ou hydrauliques, ou par une combinaison de ces moyens.
  8. Dispositif selon l'une quelconque des revendications précédentes, caractérisé en ce que la pièce supérieure est disposée de façon mobile et peut être mise en mouvement par un dispositif d'entraînement, le dispositif d'entraînement présentant de préférence des moyens d'entraînement électromoteurs, pneumatiques, électromagnétiques ou hydrauliques, ou une combinaison de ces moyens.
  9. Dispositif selon la revendication 8, caractérisé en ce que la pièce supérieure (3) est disposée de façon mobile en ce sens qu'elle peut exécuter un ou plusieurs des types de mouvement mentionnés ci-dessous :
    - mouvements de translation dans un plan horizontal ;
    - déplacements le long d'une trajectoire circulaire, d'une trajectoire elliptique ou d'une trajectoire irrégulière. à chaque fois dans un plan horizontal
    - déplacements dans le sens vertical ;
    le sens vertical correspondant sensiblement au sens longitudinal des barres (4') magnétisables.
  10. Dispositif selon l'une quelconque des revendications précédentes, caractérisé en ce qu'il présente un dispositif de retenue (6) pour un ou plusieurs récipients d'échantillons (7).
  11. Dispositif selon la revendication 10, caractérisé en ce que le dispositif de retenue (6) est disposé de façon mobile et peut être mis en mouvement par un dispositif d'entraînement, de sorte que les récipients d'échantillons (7) peuvent être positionnés dans une zone située au-dessous des barres (4) ou à l'extérieur de cette zone, le système d'entraînement du dispositif de retenue (6) présentant de préférence des moyens d'entraînement électromoteurs, pneumatiques, électromagnétiques ou hydrauliques, ou une combinaison de ces moyens.
  12. Dispositif selon la revendication 10 ou 11, caractérisé en ce que le dispositif de retenue (6) est disposé de façon mobile en ce sens qu'il peut exécuter un ou plusieurs des types de mouvement cités ci-dessous
    - mouvements de translation dans un plan horizontal ;
    - mouvements le long d'une trajectoire circulaire, d'une trajectoire elliptique ou d'une trajectoire fermée irrégulière, à chaque fois dans un plan horizontal ;
    - mouvements dans le sens vertical ;
    le sens vertical correspondant sensiblement au sens longitudinal des barres (4) magnétisables.
  13. Dispositif selon l'une quelconque des revendications 10 à 12, caractérisé en ce que le dispositif de retenue (6) est un composant d'un système de robot de laboratoire commandé par programme et est aménagé de telle sorte qu'une pluralité de certains desdits récipients ou de groupes de tels récipients (7), en particulier des plaques de microtitrage, sont amenés alternativement dans une position au-dessous desdites barres (4) et sont amenés ensuite, après un intervalle de temps pouvant être prédéfini, à nouveau dans une position qui se situe en dehors de la zone se trouvant au-dessous des barres.
  14. Dispositif selon l'une quelconque des revendications 10 à 13, caractérisé en ce que le déplacement vertical du dispositif de retenue (6) peut être commandé ou réglé par une unité de commande ou de réglage en ce sens que, lors d'un mouvement ascendant, une immersion des barres (4) dans les récipients (7) remplis de liquide est occasionnée.
  15. Dispositif selon l'une quelconque des revendications précédentes, caractérisé en ce que la pièce supérieure et/ou le dispositif de retenue est apte à exécuter des mouvements de secousse ou de vibration.
  16. Dispositif selon l'une quelconque des revendications 1 à 14, caractérisé en ce que la pièce supérieure est disposée de façon fixe.
  17. Dispositif selon l'une quelconque des revendications précédentes, caractérisé en ce que l'aimant permanent/les aimants permanents (1) est/sont disposé(s) de façon coulissante, de sorte que l'aimant/les aimants peut/peuvent être déplacé(s) par l'extérieur à l'intérieur de la zone située au-dessus de la pièce supérieure (3) et être enlevé(s) à nouveau de cette zone.
  18. Dispositif selon l'une quelconque des revendications précédentes, caractérisé en ce que le (les) aimant(s) permanent(s) (1) est/sont disposé(s) de façon rotative ou basculante
  19. Dispositif selon l'une quelconque des revendications précédentes, caractérisé en ce que le mouvement de l'aimant/des aimants permanent(s) s'effectue au moyen d'un dispositif d'entraînement qui présente de préférence des moyens d'entraînement électromoteurs, pneumatiques, électromagnétiques ou hydrauliques, ou une combinaison de ces moyens.
  20. Dispositif selon l'une quelconque des revendications précédentes, caractérisé en ce qu'un ordinateur commandé par programme est attribué au dispositif et est relié à celui-ci, ordinateur par lequel au moins l'une des fonctions suivantes du dispositif peut être commandée ou réglée, ou par lequel au moins deux des fonctions citées ci-dessous peuvent être coordonnées l'une avec l'autre :
    - mouvement de l'aimant/des aimants permanent(s) (1), en particulier les intervalles de temps à l'intérieur desquels l'aimant/les aimants sont positionnés au-dessus des barres (4) magnétisables ;
    - déplacement de la pièce supérieure (3) dans le sens horizontal et/ou le sens vertical, en particulier durée, fréquence et amplitude d'un mouvement de secousse ou de vibration ;
    - actionnement des moyens pour la fixation amovible de la plaque de base (9) sur la pièce supérieure (3) et pour l'enlèvement de la plaque de base de la pièce supérieure ;
    - actionnement des moyens pour le maintien des douilles (8) sur les barres (4) et pour l'enlèvement des douilles (8) des barres (4) ;
    - déplacement du dispositif de retenue (6), pour positionner des récipients (7) ou des groupes de récipients alternativement au-dessous des barres (4) et les enlever ensuite à nouveau de cette position, en particulier vitesse et fréquence des mouvements, ainsi que durée de séjour du dispositif de retenue au-dessous des barres ;
    - déplacement vertical du dispositif de retenue (6) pour immerger la barre/les barres (4) dans le liquide du récipient/des récipients (7) et l'enlever/les enlever à nouveau du liquide, en particulier profondeur d'immersion, durée et fréquence ;
    - si prévu, mouvement de rotation, de secousse ou de vibration du dispositif de retenue (6), en particulier vitesse de rotation, amplitude de rotation et intervalle entre des phases de travail individuelles.
  21. Dispositif selon l'une quelconque ou plusieurs des revendications précédentes, caractérisé en ce qu'un ou plusieurs des dispositifs cités ci-dessous, dont les fonctions sont coordonnées par une commande commune avec les fonctions du dispositif, sont attribués à ce dispositif ;
    - un ou plusieurs dispositifs de chauffage ou de refroidissement thermostatisables ;
    - une ou plusieurs stations de pipettage pour l'ajout dosé de liquides, en particulier de réactifs ;
    - un ou plusieurs dispositifs d'aspiration pour l'aspiration de liquide hors des récipients ;
    - un ou plusieurs dispositifs pour secouer ou mélanger les liquides contenus dans les récipients ;
    - appareils analytiques, en particulier pour des mesures photométriques ou détection de luminescence.
  22. Agencement de barres magnétisables destiné à une utilisation dans un dispositif pour la séparation de particules magnétiques ou magnétisables selon l'une quelconque des revendications 1 à 21, caractérisé en ce qu'une pluralité de barres (4) magnétisables sont placées sur une plaque de base (9), les barres étant orientées sensiblement parallèlement entre elles et étant disposées de préférence dans une, deux ou plusieurs rangées, chaque rangée comprenant deux ou plusieurs barres.
  23. Agencement selon la revendication 22, caractérisé en ce que les barres (4) magnétisables forment avec la plaque de base (9) une unité qui est fabriquée de préférence d'une seule pièce, en particulier par emboutissage.
  24. Agencement de douilles destiné à une utilisation dans un dispositif pour séparer des particules magnétiques ou magnétisables d'un liquide selon l'une quelconque des revendications 1 à 21, caractérisé en ce qu'une pluralité de douilles (8), qui peuvent être emboîtées sur les barres magnétisables dudit dispositif, sont orientées sensiblement parallèlement entre elles, de préférence dans une, deux ou plusieurs rangées, chaque rangée comprenant deux ou plusieurs barres.
  25. Agencement selon la revendication 24, caractérisé en ce que les douilles (8) sont reliées pour former une unité (8') commune, qui est fabriquée de préférence d'une seule pièce, en particulier par emboutissage.
  26. Procédé pour séparer des particules magnétiques ou magnétisables d'un liquide avec l'utilisation d'un champ magnétique, pouvant être mis en oeuvre au moyen d'un dispositif selon l'une quelconque des revendications 1 à 21, le procédé présentant les étapes suivantes :
    a) immersion d'au moins une barre magnétisable du dispositif dans le liquide contenant des particules ;
    b) enclenchement d'un champ magnétique par variation de la position d'un aimant permanent par rapport à la barre magnétisable en ce sens que l'aimant permanent occupe une position au-dessus de la pièce supérieure, de sorte que la barre est magnétisée et les particules s'accumulent principalement sur l'extrémité inférieure de la barre ;
    c) enlèvement de la barre avec les particules adhérentes du liquide.
  27. Procédé selon la revendication 26, caractérisé en ce que le liquide utilisé à l'étape (a) contient une substance cible qui est liée de façon spécifique, mais réversible aux particules.
  28. Procédé selon la revendication 27, caractérisé par les étapes supplémentaires suivantes :
    d) immersion de la barre avec les particules adhérentes dans un volume prédéfini d'un liquide de lavage ;
    e) mise hors circuit du champ magnétique par variation opposée de la position de l'aimant permanent en ce sens que l'aimant permanent occupe une position qui n'est pas posée au-dessus de la pièce supérieure, de sorte que les particules sont libérées dans le liquide ;
    f) mélange ;
    g) magnétisation des barres par variation de la position du/des aimants permanents en ce sens que l'aimant permanent occupe une position au-dessus de la pièce supérieure, de sorte que les particules s'accumulent principalement sur l'extrémité inférieure de la barre ;
    h) enlèvement de la barre du liquide de lavage.
  29. Procédé selon la revendication 27 ou 28, caractérisé par les étapes supplémentaires suivantes :
    i) immersion de la barre avec les particules adhérentes dans un volume prédéfini d'un liquide d'élution, qui entraîne l'élution de la substance cible des particules ;
    k) enlèvement de la barre du liquide d'élution, les particules restant attachées à la barre et étant séparées ainsi du liquide.
  30. Procédé selon l'une quelconque des revendications 26 à 29, le procédé présentant en supplément au moins l'une des étapes citées ci-dessous:
    l) un premier groupe de barres magnétisables ou plusieurs barres reliées en une unité commune est fixé/sont fixés de façon amovible sur un dispositif qui présente un ou plusieurs aimants permanents (1) mis en place, dont la position relative par rapport aux barres magnétisables est modifiable ;
    m) le premier groupe de barres magnétisables est séparé ou éjecté du dispositif et remplacé par un second groupe de barres magnétisables, qui est fixé de façon amovible sur le dispositif.
  31. Procédé selon l'une quelconque des revendications 26 à 30, le procédé présentant en supplément au moins l'une des étapes citées ci-dessous :
    n) un premier groupe de douilles ou des douilles reliées en une unité commune est emboîté/sont emboîtées sur les barres magnétisables d'un dispositif selon la revendication 1 ;
    o) le premier groupe de douilles est enlevé ou éjecté des barres magnétisables du dispositif et remplacé par un second groupe de douilles qui sont emboîtées sur les barres.
EP06706463A 2005-02-02 2006-01-28 Procede et dispositif pour separer des particules magnetiques ou magnétisables d'un liquide Active EP1843854B1 (fr)

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DE102005004664A DE102005004664B4 (de) 2005-02-02 2005-02-02 Vorrichtung und Verfahren und Verwendung zum Abtrennen von magnetischen oder magnetisierbaren Partikeln aus einer Flüssigkeit sowie deren Verwendungen
PCT/EP2006/000747 WO2006081995A1 (fr) 2005-02-02 2006-01-28 Procede et dispositif pour separer des particules magnetiques et pouvant etre magnetisees d'un liquide

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US9023212B2 (en) 2015-05-05
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TWI294309B (en) 2008-03-11
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DE102005004664B4 (de) 2007-06-21
DK1843854T3 (da) 2011-09-12
CA2595972A1 (fr) 2006-08-10
WO2006081995A1 (fr) 2006-08-10
NO20074217L (no) 2007-08-17
ES2366653T3 (es) 2011-10-24
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