EP1919625A1 - Dispositif et procede de separation de particules magnetiques d'un liquide - Google Patents

Dispositif et procede de separation de particules magnetiques d'un liquide

Info

Publication number
EP1919625A1
EP1919625A1 EP06792895A EP06792895A EP1919625A1 EP 1919625 A1 EP1919625 A1 EP 1919625A1 EP 06792895 A EP06792895 A EP 06792895A EP 06792895 A EP06792895 A EP 06792895A EP 1919625 A1 EP1919625 A1 EP 1919625A1
Authority
EP
European Patent Office
Prior art keywords
vessel
guide means
magnet
magnetic field
magnetic particles
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.)
Granted
Application number
EP06792895A
Other languages
German (de)
English (en)
Other versions
EP1919625B1 (fr
Inventor
Thomas Rothmann
Thomas Deutschmann
Christian Lenz
Cordula Leurs
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.)
Qiagen GmbH
Original Assignee
Qiagen 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 Qiagen GmbH filed Critical Qiagen GmbH
Publication of EP1919625A1 publication Critical patent/EP1919625A1/fr
Application granted granted Critical
Publication of EP1919625B1 publication Critical patent/EP1919625B1/fr
Active legal-status Critical Current
Anticipated expiration legal-status Critical

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
    • B03C1/025—High gradient magnetic separators
    • B03C1/031—Component parts; Auxiliary operations
    • B03C1/033—Component parts; Auxiliary operations characterised by the magnetic circuit
    • B03C1/0332—Component parts; Auxiliary operations characterised by the magnetic circuit using permanent magnets
    • 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
    • B03C1/029—High gradient magnetic separators with circulating matrix or matrix elements
    • B03C1/03—High gradient magnetic separators with circulating matrix or matrix elements rotating, e.g. of the carousel type
    • 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 present invention relates to a device for separating magnetic particles from a liquid and to a method for separating magnetic particles from a liquid.
  • the device and method are suitable for applications in biochemistry, molecular genetics, microbiology, medical diagnostics or forensic medicine, for example.
  • the basic principle of the magnetic separation of substances from complex mixtures is based on the fact that magnetic particles, for example by chemical treatment of their surface with specific binding properties are equipped 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 so as to provide a large surface area for the binding reaction.
  • the magnetic particles may have a density similar to the density of the liquid in which they are suspended. In this case, sedimentation of the magnetic particles can take several hours.
  • the magnetic particles are immobilized by applying magnetic forces or a magnetic field, for example by means of a permanent magnet, at one point. This accumulation of magnetic particles is also referred to as pellet. Subsequently, the liquid supernatant is separated, for example, by suction or decantation and discarded. Since the magnetic particles are immobilized by the magnetic forces, it is largely prevented that magnetic particles are separated together with the supernatant.
  • the immobilized magnetic particles are then resuspended.
  • an elution liquid or an elution buffer is used, which is suitable for dissolving the bond between the target substance and the magnetic particles, so that the target substance molecules are released from the magnetic particles.
  • the target substance molecules can then be separated together 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.
  • Submerged reaction vessel containing suspended in liquid magnetic particles.
  • the magnetic rod attracts the magnetic particles, so that the
  • the magnetic rod is then pulled out of the first reaction vessel together with the magnetic particles adhering thereto and introduced into a second reaction vessel. There will then be the
  • EP 0 965 842 discloses a device in which the magnetic particles are mixed with the liquid in which they are suspended be pulled up with a pipette.
  • the pipette tip has a special separation area, which can be acted upon by a magnet with a magnetic field.
  • the magnetic particles are immobilized as a pellet on the inside of the pipette tip.
  • the pipetted liquid is removed from the pipette tip by the pipetting function. Thereafter, the magnetic field in the separation region can be removed again, whereby the immobilized in the pellet magnetic particles are released again.
  • a particular arm By rotating the carrier, a particular arm can be brought into the vicinity of the side wall of the reaction vessel, and thus a specific magnet. At this point, the magnetic particles are then immobilized as a pellet.
  • the said conventional devices and methods all have the common feature that they are designed as so-called open systems, since according to their respective principle of action magnetic rods or pipettes must be inserted one or more times in the reaction vessel. As a result, these conventional devices and methods run the risk of cross-contamination of other reaction vessels by aerosol and / or droplet formation. As a result, examination results can be falsified or even rendered unusable.
  • an apparatus for separating magnetic particles from a liquid comprising a first vessel, a second vessel, a bonding surface connecting the interior of the first vessel to the interior of the second vessel, at least one magnet for providing a magnetic field, and a guide means by means of which the magnetic field is guided along one side of the connection surface, provided.
  • the magnetic particles suspended in a liquid in the first vessel can be separated from this liquid without having to insert a magnetic rod or a pipette tip into the first vessel. Rather, the magnetic particles can be formed into a pellet by the magnetic field, and this pellet can be transferred to the second vessel along the joint surface by the guide means located outside the vessel. In this way, the risk of cross-contamination, for example, by dripping the liquid from the magnetic rod or the pipette tip, significantly reduced or even excluded. Furthermore, the device can be provided as a closed system, further reducing the risk of cross-contamination.
  • the length of the connection surface can be chosen so that an influence of the particles, for example, the drying of the particles, is supported or reduced.
  • the connecting surface is formed by a first side wall of the first vessel, a second side wall of the second vessel and a connecting region connecting the first and the second side wall. This eliminates the need to provide a separate interface.
  • first and the second vessel could thus be formed as depressions (wells) in a microtiter plate.
  • first and the second vessel as well as the bonding surface can be provided as separate elements.
  • the connection surface could be formed as a bridge or hose.
  • a permanent magnet is used.
  • the magnetic field can be provided inexpensively.
  • the guide means would then be designed such that the magnet could be guided mechanically along the connection surface.
  • the at least one magnet could also be designed as an electromagnet.
  • the electromagnet can be guided mechanically along the connection surface.
  • a plurality of electromagnets for example, on an underside of the connecting surface, be arranged one behind the other. The guide means would then sequentially energize and turn the electromagnets on and off so that the magnetic field generated by the electromagnets travels along the interface from the first to the second vessel.
  • Guide means is designed so that the at least one magnet can be guided in a fixed predetermined distance from the connection surface.
  • the fixed predetermined distance may be zero so that the magnet is in contact with the bonding surface as it is passed past it.
  • At least one heating and / or cooling element is at the connecting surface Heating wire and / or Peltier element provided.
  • the magnetic particles can be kept on their way to a predetermined temperature.
  • connection surface along the path of the at least one magnet is formed as a circular arc.
  • guide means is formed so that the at least one magnet is guidable on a circular path, the radius of the circular path being less than or equal to the radius of the arc formed by the connection surface.
  • the guide means can be mounted on a rotation axis, whereby the drive and the control of the guide means can be designed particularly simple. This also allows easy automation of the machining operations.
  • At least a third vessel is further provided, which is connected via a second connection surface with the first and the second vessel, and a second guide means on which at least one further magnet is arranged.
  • the first and the second vessel together with the third vessel, the second connection surface, the second guide means and the further magnet form a further device for separating magnetic particles as described above.
  • At least one of the vessels has a functional element, in particular an outlet opening and / or a filter.
  • a functional element for example, subsequent analysis steps, such as a PCR step (Polymerase Chain Reaction), can be prepared.
  • the outlet opening preferably has fastening possibilities with the aid of which, for example, reaction stubs can be fastened to the outlet opening.
  • the vessels are formed in a cartridge.
  • a so-called lab-on-a-chip can be realized in this way.
  • all devices necessary for carrying out an examination are integrated on a chip or a cartridge.
  • a method of separating magnetic particles from a liquid comprising the steps of:
  • Such a method can, for example, in a device according to a
  • Embodiment of the present invention can be carried out in a simple manner in an automated form. With such a separation method, the risk of cross-contamination compared to the prior art is considerably reduced, since it is not necessary to introduce a magnetic rod or a pipette tip into the vessel. Therefore, here the risk of dripping liquid from the magnetic rod or the pipette tip is excluded.
  • FIGS. IA to IE a schematic representation of a device and a
  • FIGS. 2A to 2E a schematic representation of a device and a
  • FIGS. 3A to 3C a schematic representation of a device and a
  • FIGS. 4A and 4B is a schematic illustration of a washing process according to an embodiment of the present invention.
  • FIG 5 shows a guide means according to an exemplary embodiment of the present invention.
  • Fig. 6 shows a guide means according to another embodiment of the present invention.
  • connection portion 7 is a cross-sectional view of a connection portion according to an embodiment of the present invention.
  • Fig. 9 shows another embodiment of the present invention.
  • Fig. 10 is a schematic representation of another embodiment of the present invention, in which the invention is implemented in a cartridge.
  • FIGS. IIA to HF a schematic representation, as an inventive
  • Fig. 12 is a schematic representation of a variant of the embodiment of the present invention shown in Fig. 10.
  • FIG. 13 shows a schematic illustration of a variant of the embodiment shown in FIG.
  • Fig. 14 is a schematic representation of another variant of in
  • FIG. 10 embodiment shown.
  • Fig. 15 is a schematic representation of a development of the in Fig.
  • Fig. IA shows a schematic representation of a device according to an embodiment of the present invention.
  • a first vessel 10 is a liquid 15 in which magnetic particles 60 are suspended.
  • a second vessel 20 is shown in which a second liquid 25, e.g. a wash solution or an elution solution.
  • the first vessel 10 has a first side wall 11, which is connected to a second side wall 21 of the second vessel 20 via a connection region 30.
  • the first side wall 11, the second side wall 21 and the connection portion 30 form a connection surface extending from the interior of the first vessel 10 to the inside of the second vessel 20.
  • connection surface could also be provided as a bridge formed in the form of a reverse Us separately from the first and the second vessel, which is inserted into the first and the second vessel.
  • connection surface could also be formed by a tube, one end of which is arranged in the interior of the first vessel and the other end is arranged in the interior of the second vessel.
  • a magnet 40 is provided, which may be embodied for example as a neodymium permanent magnet or as an electromagnet.
  • the magnet 40 is arranged on a guide means 50.
  • the guide means 50 is arranged so that it can guide the magnet 40, and thus the magnetic field generated by it, along the connection surface from the interior of the first vessel 10 into the interior of the second vessel 20.
  • a guide means 50 for example, a cylindrical roller or a rotary arm can be used, as will be explained later in this application.
  • the magnet 40 on a flexible band which is guided along the side walls 11, 21 and the underside of the connecting portion 30.
  • the guide means 50 is designed to hold the magnet 40 at a fixed predetermined distance from the connecting surface, ie the side walls 11, 21 and the underside of the connecting region 30.
  • the fixed predetermined distance is selected so that the magnetic attraction, the magnet 40 exerts on the suspended magnetic particles 60 when it is guided to the side wall 11, sufficient that the suspended particles are immobilized in a pellet 61 on the side wall 11 (see Fig. IB).
  • the distance between the magnet 40 and the side walls 11, 21 and the underside of the connection region 30 may be zero.
  • the magnet 40 is in contact with the sidewalls 11, 21 as well as the underside of the connecting portion 30 when it is passed therethrough.
  • connection surface can be channel-shaped.
  • FIG. 7 shows a cross-section of the connecting region 30, which is formed on its upper side between the first vessel 10 and the second vessel 20 in the form of a groove-shaped depression.
  • FIGS. IA to IE describes a method according to an embodiment of the present invention.
  • Fig. IA the initial state is seen in which the magnetic particles 60 are suspended in the liquid 15 in the first vessel 10.
  • the magnet 40 is arranged outside the region of the side wall 11 of the first vessel 10.
  • the magnet 40 is then brought by the guide means 50 to the side wall 11 of the first vessel 10.
  • the magnet 40 is guided by the guide means 50 along the side wall 11 via the connecting portion 30 to the side wall 21 of the second vessel 20, see Fign. IC and ID.
  • the magnetic particles formed by the magnetic force to the pellet 61 follow due to the magnetic attraction of the movement of the magnet 40. In this way, the pellet 61 along the connecting surface, ie along the inside of the side wall 11 over the top of the connecting portion 30 to the inside of the side wall 21 of the second vessel 20, out. Finally, as shown in FIG. IE, the magnet 40 is led away from the side wall 21 of the second vessel 20, so that the magnetic particles forming the pellet 61 are released again. The magnetic particles 60 resuspend in the liquid 25 in the second vessel 20, eg a washing or elution solution.
  • FIGS. 2 A to 2E Another embodiment of the present invention will now be described with reference to FIGS. 2 A to 2E described. Again, a first and a second vessel 10,
  • connection surface is in turn formed by a first side wall 11, a second side wall 21 and a connection region 30. It is the
  • the guide means 50 is formed as a four-armed turnstile, as shown enlarged in Fig. 5.
  • the guide means on four rotating arms 51, 52, 53, 54 which are rotatably mounted about an axis 55.
  • At the ends remote from the axis of rotation 55 of the pivot arms 51, 52, 53, 54 are each magnets 40, 41, 42, 43 are arranged.
  • the total length r of the rotating arms 51, 52, 53, 54 including the magnets 40, 41, 42, 43 is less than or equal to the radius R of the circular arc, so that the magnets 40, 41, 42, 43 at a distance Rr on the side walls 11th , 21 and the connection area 30 can be passed.
  • the surfaces of the magnets 40, 41, 42, 43, which are in contact with the side walls 11, 21 and the connection region 30, are advantageous are curved, wherein the radius of curvature is smaller than the circular arc radius R.
  • the four pivot arms are integrally formed, but they could also be formed as a single pivot arms and individually secured to the axis of rotation 55.
  • the number of four rotating arms is merely exemplary, because depending on the application, fewer or more rotating arms can be provided. In particular, it is possible to provide only a single rotary arm.
  • the four pivot arms in Fig. 5 are each offset by 90 °, i. evenly distributed over the circumference covered by the turnstile 2 ⁇ r.
  • the two or more rotating arms can also be arranged offset to one another in arbitrarily adjustable angular distances.
  • a guide means 50 usable in the apparatus shown in Fig. 2A is shown in Fig. 6.
  • the guide means 50 is formed as a cylindrical roller or wheel with a radius r, which is less than or equal to the circular arc radius R.
  • the magnets are arranged on the surface of the cylindrical guide means, in which case the radius r together with the thickness of the magnets must be less than or equal to the circular arc radius R.
  • the number and mutual position of the magnets can be varied according to the requirements of a particular application accordingly.
  • the magnets 40, 41, 42 can be removed from the receptacles 56, 57, 58, so that the number of magnets between one and the number of receptacles can be varied.
  • Figs. 2A to 2E reproduced.
  • the magnet 40 is moved to the side wall 11 of the first vessel 10, where then the magnetic particles form a pellet 61 ( Figure 2B).
  • the magnet 40 is then passed along the circular arc, followed by the pellet 61 ( Figures 2C and 2D).
  • the pellet 61 is then introduced into the second vessel 20 (FIG. 2E) and finally the magnet 40 is led away from the second side wall 21 so that the magnetic particles are in the second vessel Resuspend fluid (not shown). In this way, the pellet is guided from inside the first vessel along the bonding surface to the interior of the second vessel.
  • FIGS. 3 A to 3C Another embodiment of the present invention is shown in FIGS. 3 A to 3C shown.
  • a third vessel 70 is provided, which is connected to the second vessel 20 via a second connection region 80.
  • the interconnected side walls of the second and the third vessel and the second connection region form a second connection surface, which is formed as a circular arc with radius R '.
  • the circular arc radius R ' is equal to the circular arc radius R between the first and second vessels, but may be selected differently from R depending on the nature of the application.
  • a second guide means 100 is arranged between each opposite side walls of the second and the third vessel, which has at least one further magnet 90.
  • the magnetic particles transferred from the first vessel 10 into the second vessel 20 and resuspended there can be combined in a second pellet 62 on the side wall of the second vessel.
  • the pellet 62 can now be transferred from the second vessel to the third vessel 70 via the second connecting surface.
  • the magnetic particles may be resuspended in the liquid 75 contained in the third vessel 70.
  • a washing solution can be provided in the second vessel and an elution solution in the third vessel.
  • the eluted magnetic particles could be transported back by opposite rotation of the second guide means in the second vessel and disposed of there.
  • further vessels and interposed connecting surfaces and guide means may be provided with magnets, wherein in the respective vessels for a particular method required liquids are provided.
  • the apparatus shown in Fig. 3A may also be used to carry out a washing process as follows. First, the first pellet 61 from the first vessel 10th in the filled with washing solution second Gelledge 20 transferred. There, the magnet 40 is then led away from the side wall of the second vessel along a first direction of rotation, so that the magnetic particles are resuspended in the washing solution. Then, the magnet 90 arranged on the second guide means 100 is guided along a first rotational direction to the opposite side wall of the second vessel, so that the magnetic particles form a second pellet 62 there. In this case, the first direction of rotation of the first guide means 50 is opposite to the first direction of rotation of the second guide means 100.
  • the magnet 90 is then led away from the side wall of the second vessel again along a second direction of rotation.
  • the second pellet 62 dissolves and the magnetic particles are resuspended in the wash solution.
  • the magnet 40 arranged on the first guide means 50 is guided along a second rotational direction to the opposite side wall of the second vessel, so that the magnetic particles again form a first pellet 61 there.
  • the second direction of rotation of the first guide means 50 is opposite to the second direction of rotation of the second guide means 100.
  • the first and second rotational direction of the first guide means may be the same or opposite.
  • the first and second rotational direction of the second guide means may be the same or opposite. The process can be repeated until the washing process is completed successfully.
  • connection surface 200 is formed as a bridge in the form of an inverted Us, wherein a first end of the connection surface 200 is arranged in the first vessel 10 and a second end of the connection surface 200 in the second vessel 20 is arranged.
  • the connecting surface 200 is formed on its upper side groove-shaped.
  • a plurality of electromagnets 40 are arranged in the connection surface 200, arranged one behind the other from the first vessel 10 to the second vessel 20.
  • the connecting surface 200 could be formed as an injection molded part, in which the electromagnets are embedded.
  • the electromagnets are individually controllable by a guide means 50, that is individually switched on and off.
  • the separation of the magnetic particles is as follows: First, all of the electromagnets 40 under the connection surface 200 are turned off, and the connection surface is placed in the first and second vessels as shown. Then, the guide means 50 controls the lowermost solenoid (s) at the first end of the interface located in the first vessel. There then forms a pellet of magnetic particles due to the magnetic attraction. Now adjacent electromagnets, which are arranged closer to the end located in the second vessel along the connection surface 200, are switched on one after the other and the electromagnets are switched off again from the first end of the connection surface.
  • the magnetic field travels from the first end of the bonding surface to the second end of the bonding surface, and the pellet retraces this motion due to the magnetic attraction.
  • the electromagnets are switched off and the magnetic particles forming the pellet resuspend in a liquid 25 in the second vessel 20. In this way separation of the magnetic particles can take place without the device moving parts must have. In this way, the device is particularly reliable and low maintenance.
  • a first and a second vessel 10, 20 are provided, which are connected to each other via a connecting surface 11, 21, 30.
  • the connection surface is in turn formed by a first side wall 11, a second side wall 21 and a connection region 30.
  • heating elements 110 are provided on the connecting surface 11, 21, 30. Through these heating elements, the temperature of the magnetic particles can be increased, so that, for example, the drying of the particles is supported.
  • cooling elements for example Peltier elements
  • Peltier elements can also be provided on the connecting surface 11, 21, 30 in order to provide a
  • the vessel 20 has additional functional elements 120, 130 which serve to prepare subsequent analysis steps.
  • the vessel 20 has at the bottom of the vessel an outlet opening 120, on the inside of a filter 130 is attached.
  • the connecting surfaces may be designed channel-shaped.
  • the guide means may be formed so that the
  • the speed with which they lead the magnetic field or along the connecting surfaces is controllable.
  • the speed can be set to zero so that the pellet can be immobilized at the current position.
  • the guide means may be formed so that the direction in which they or the magnetic fields to the
  • Run along connecting surfaces is controllable. In particular, then one
  • FIG. 10 yet another embodiment of the present invention is shown schematically.
  • This is a so-called lab-on-a-chip, in which a first and a second vessel 1010, 1020 are integrated in a cartridge 1000.
  • the first and second vessels 1010, 1020 are interconnected by a connection area 1030.
  • Both vessels 1010, 1020 are formed as chambers in the cartridge 1000 and filled with liquid.
  • the second passage 1020 could contain an elution liquid.
  • Fig. 10 is merely a schematic representation in which the first and the second vessel are the same size. Of course, the sizes of the individual vessels may differ. In particular, typically the volume of an elution vessel will be less than that of a wash vessel.
  • closure 1100 prevents mixing of the liquids.
  • closure 1100 may be removed using the cartridge.
  • closure 1100 is designed so that it can be brought into the closed position after removal and again serves as a closure.
  • the cartridge 1000 is provided with a lid in which two access openings 1012, 1022 are located.
  • the access openings 1012, 1022 serve to bring magnetic particles into and out of the vessels.
  • the access openings 1012, 1022 may be provided with lids.
  • the cartridge has a magnet 1040 which can be moved by a guide means 1050 along a wall of the first vessel 1010, the connection region 1030 to a wall of the second vessel 1020.
  • the magnet 1040 may not only be attached to a sidewall but also along the ceiling wall, i. the lid, or the bottom of the cartridge 1000 be feasible.
  • FIG. 1A magnetic particles 1060 are first introduced into the first vessel 1010 through the access opening 1012. If these particles 1060 are now to be removed from the liquid present in the first vessel 1010, then the magnet 1040 is brought in by means of the guide means 1050. This forms a pellet 1061 immobilized on the sidewall of the first vessel 1010 (see FIG. 1B). Pellet 1061 is then fed to closure 1100 (see Figure 1 IC). Now, the shutter 1100 is opened and the path for the pellet 1061 is released into the connection area 1030 (see Fig. HD).
  • the pellet 1061 is then inserted into the second vessel 1020 by means of the magnet 1040 (see Fig. HE), where it can subsequently be released (see Fig. HF). Should the magnetic particles 1060 from the second vessel 1020 through the second Access opening 1022 are removed, it is advisable to form the magnetic particles 1060 again by means of the magnet 1040 into a compact pellet 1061, which can be easily seen through opening 1022. Via the second access opening 1022 it is likewise possible to remove the liquid without the magnetic particles 1060. Typically, the magnet 1040 would hold the pellet 1061 at a distance from the access port 1022 during liquid withdrawal, thus allowing removal of the liquid without entrainment of the magnetic particles.
  • FIG. 10 Another embodiment of the present invention is shown in FIG. In essence, the structure is the same as that shown in Fig. 10, but a magnet arrangement similar to the embodiment shown in Fig. 8 is provided. In this case, a plurality of electromagnets 1040 - from the first vessel 1010 to the second vessel 1020 extending successively arranged - in the cartridge
  • the cartridge 1000 could be formed as an injection-molded part, in which the electromagnets 1040 are embedded.
  • Electromagnets are individually controllable by a guide means 1050, i. individually switched on and off. In this way, a magnetic field extending from the first vessel 1010 via the connection region 1030 to the second vessel 1020 can be generated. Pelleting and transport of the pellet from the first vessel 1010 to the second vessel 1020 is then similar to that shown in FIG.
  • Fig. 13 shows a perspective view of another embodiment of the present invention.
  • the interior of the cartridge 1000 corresponds substantially to the construction shown in FIG.
  • the magnet 1040 is disposed outside of the cartridge 1000. It can be guided along the surface of the cartridge 1000 by means of a guide means 1050 such that a pellet moves under the influence of the magnetic force from the first vessel via the connection region to the second vessel.
  • the magnet 1040 may be directed away from or toward the surface by the guide means 1050. In this way, for example, a pellet may be formed by lowering the magnet 1040 above the first vessel onto the surface of the cartridge. Likewise, those in a pellet bonded magnetic particles are released by the magnet 1040 is lifted off the surface of the cartridge again.
  • FIG. 10 Another embodiment of the present invention is shown in FIG.
  • the cartridge 1000 is arranged on a guide means 1050, which is designed as a movable support.
  • the carrier 1050 is movable in its plane, but preferably also perpendicular thereto, so that it can move the cartridge 1000 mounted thereon along a predeterminable path.
  • a magnet 1040 is held substantially stationary by a retaining means 1045.
  • the carrier 1050 By raising or lowering the carrier 1050, the surface of the cartridge 1000 can be brought to the magnet 1040.
  • the cartridge 1000 is then moved on a predeterminable path under the magnet 1040.
  • the embodiment shown in Fig. 14 represents a reversal of the principle shown in Fig. 13.
  • FIG. 15 shows a development of that shown in FIG
  • Embodiment in addition to the first and the second vessel 1010, 1020 still a third vessel 1070 on the cartridge 1000 is arranged.
  • This third vessel 1070 is separated from the third vessel 1070 by a second closure 1200.
  • the second vessel 1020 could contain a washing liquid and the third vessel 1070 an elution solution. It should be understood that, of course, any number of other vessels can be integrated on a cartridge and the exact number of vessels and the liquids contained in them are tailored to the specific application.
  • the invention enables a separation of magnetic particles from a liquid which significantly reduces or even eliminates the risk of cross-contamination.
  • the devices according to the above embodiments of the present invention may be configured and operated as closed systems.
  • the devices and methods according to the embodiments of the present invention are simple and to a considerable extent automation friendly.

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  • Automatic Analysis And Handling Materials Therefor (AREA)

Abstract

L'invention concerne un dispositif permettant de séparer des particules magnétiques d'un liquide. Ce dispositif comprend un premier récipient (10), un deuxième récipient (20), une surface de liaison (11, 21, 30; 200) qui s'étend de l'intérieur du premier récipient (10) jusqu'à l'intérieur du deuxième récipient (20), au moins un aimant (40) délivrant un champ magnétique et un moyen de guidage (50) qui permet de guider le champ magnétique le long d'une face de la surface de liaison (11, 21, 30; 200).
EP06792895.2A 2005-08-18 2006-08-18 Dispositif et procede de separation de particules magnetiques d'un liquide Active EP1919625B1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
DE102005039175A DE102005039175A1 (de) 2005-08-18 2005-08-18 Vorrichtung und Verfahren zum Abtrennen von magnetischen Partikeln aus einer Flüssigkeit
PCT/EP2006/065451 WO2007020294A1 (fr) 2005-08-18 2006-08-18 Dispositif et procede de separation de particules magnetiques d'un liquide

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EP1919625A1 true EP1919625A1 (fr) 2008-05-14
EP1919625B1 EP1919625B1 (fr) 2019-12-11

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US (1) US8323507B2 (fr)
EP (1) EP1919625B1 (fr)
JP (1) JP5027128B2 (fr)
DE (1) DE102005039175A1 (fr)
WO (1) WO2007020294A1 (fr)

Families Citing this family (18)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20070207272A1 (en) * 2006-03-03 2007-09-06 Puri Ishwar K Method and apparatus for magnetic mixing in micron size droplets
JP2009066476A (ja) * 2007-09-11 2009-04-02 Tamagawa Seiki Co Ltd 液体中の磁性粒子の集合／分散方法及び装置
US20090181359A1 (en) * 2007-10-25 2009-07-16 Lou Sheng C Method of performing ultra-sensitive immunoassays
DE102008057317A1 (de) 2007-11-13 2009-09-10 Stratec Biomedical Systems Ag Vorrichtung und Verfahren zur Aufreinigung von Biomolekülen
EP2068143A1 (fr) * 2007-12-07 2009-06-10 Roche Diagnostics GmbH Manipulation de microparticules magnétiques dans un système de liquide à haute pression et processus d'extraction
EP2072133A1 (fr) * 2007-12-20 2009-06-24 Koninklijke Philips Electronics N.V. Dispositif à plusieurs compartiments doté de particules magnétiques
US8337705B2 (en) 2008-12-04 2012-12-25 Roche Diagnostics Operations, Inc. Manipulation of magnetic microparticles in a high pressure liquid system and extraction process
DE102008062662B4 (de) * 2008-12-16 2010-08-19 H2 Ag Verfahren zum Erzeugen von Wasserstoff, Anlage zur Durchführung dieses Verfahrens sowie Schüttkörper zur Verwendung in dieser Anlage
US20100158646A1 (en) * 2008-12-23 2010-06-24 Lynntech, Inc. Method and Apparatus for Handling Magnetic Particles
EP2485844B1 (fr) * 2009-10-06 2020-07-22 Koninklijke Philips N.V. Purification magnétique d'échantillon
ATE542136T1 (de) * 2010-03-15 2012-02-15 Boehringer Ingelheim Int Vorrichtung und verfahren zur manipulation oder untersuchung einer flüssigen probe
JP5573335B2 (ja) * 2010-04-28 2014-08-20 株式会社島津製作所 磁性体粒子操作デバイス及び磁性体粒子操作方法
US9593589B2 (en) 2014-02-28 2017-03-14 General Electric Company System and method for thrust bearing actuation to actively control clearance in a turbo machine
JP6987756B2 (ja) * 2015-07-24 2022-01-05 ノベル マイクロデバイシズ, エルエルシー (ディービーエー ノベル デバイシズ)Novel Microdevices, Llc (Dba Novel Devices) 直線又は回転運動を行う磁気式及び機械式アクチュエータ要素を含む試料処理デバイス及びその使用方法
JP6956166B2 (ja) * 2016-08-30 2021-10-27 シスメックス株式会社 試料分析用カートリッジ及びその製造方法、並びにその利用
US11673134B2 (en) * 2017-06-06 2023-06-13 Northwestern University Trans-interfacial magnetic separation
EP3642624A1 (fr) 2017-06-19 2020-04-29 Lab-on-a-Bead AB Séparation combinatoire
GB201711804D0 (en) * 2017-07-21 2017-09-06 Mast Group Ltd Apparatus for conducting an assay

Family Cites Families (26)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US9610A (en) * 1853-03-08 Improved magnetic machine for washing and separating gold
US2088364A (en) * 1934-09-22 1937-07-27 Edwin E Ellis Electromagnetic separator device
US2604207A (en) * 1949-02-01 1952-07-22 Walter J Scott Apparatus for separating magnetic material
US2661092A (en) * 1950-03-08 1953-12-01 Dings Magnetic Separator Co Endless belt magnetic separator
US2826302A (en) * 1956-02-21 1958-03-11 Walter J Scott Magnetic separator
US3168464A (en) * 1961-12-04 1965-02-02 Eriez Mfg Company Permanent magnetic separator
US3295678A (en) * 1962-07-19 1967-01-03 Reserve Mining Co Magnetic separator flow control
US3985649A (en) * 1974-11-25 1976-10-12 Eddelman Roy T Ferromagnetic separation process and material
US4080760A (en) * 1977-02-18 1978-03-28 Wheelabrator-Frye Inc. Surface treatment device including magnetic shot separator
EP0133869A3 (fr) * 1983-06-30 1985-06-19 International Business Machines Corporation Procédé de séparation de particules magnétiques finement suspendues d'un liquide
JPS63188764A (ja) * 1987-02-02 1988-08-04 Nippon Telegr & Teleph Corp <Ntt> レ−ザ磁気免疫測定方法のための検体容器並びに該検体容器を用いた検体の調製方法
US5536475A (en) * 1988-10-11 1996-07-16 Baxter International Inc. Apparatus for magnetic cell separation
WO1994026414A1 (fr) * 1993-05-17 1994-11-24 Syntex (U.S.A.) Inc. Recipient de reaction pour essai par liaison specifique et procede d'utilisation
DK0925494T3 (da) * 1996-09-04 2002-07-01 Scandinavian Micro Biodevices Mikrostrømningssystem til partikelseparation og analyse
US5942161A (en) * 1997-07-16 1999-08-24 Battelle Memorial Institute Device and process for liquid treatment
DE69839294T2 (de) * 1997-09-29 2009-04-09 F. Hoffmann-La Roche Ag Gerät zur Abscheidung magnetischer Teilchen
EP1712921A2 (fr) * 1997-09-29 2006-10-18 F.Hoffmann-La Roche Ag Appareil de séparation des particules magnétiques
JP2002066375A (ja) * 2000-08-31 2002-03-05 Hitachi Ltd 被除去物の磁気分離装置
FR2817343B1 (fr) * 2000-11-29 2003-05-09 Commissariat Energie Atomique Procede et dispositifs de transport et de concentration d'un analyte present dans un echantillon
JP4407068B2 (ja) * 2001-03-26 2010-02-03 横河電機株式会社 磁気粒子泳動方法および装置
JP4633627B2 (ja) * 2003-07-16 2011-02-16 東洋紡績株式会社 生体成分分離用デバイス、およびそれを用いた生体成分の分離方法
FR2858688A1 (fr) * 2003-08-04 2005-02-11 Gilbert Skorski Methode et dispositif pour mesurer plusieurs parametres biochimiques dans un echantillon
JP4821085B2 (ja) * 2003-10-29 2011-11-24 株式会社日立プラントテクノロジー 磁気分離浄化装置および磁気分離浄化方法
FR2863626B1 (fr) * 2003-12-15 2006-08-04 Commissariat Energie Atomique Procede et dispositif de division d'un echantillon biologique par effet magnetique
JP2005169015A (ja) * 2003-12-15 2005-06-30 Hisayo Ishimaru 適合既製靴教示装置、適合既製靴教示システム及びプログラム
JP4353417B2 (ja) * 2004-04-14 2009-10-28 日立マクセル株式会社 反応装置

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See references of WO2007020294A1 *

Also Published As

Publication number Publication date
US20090206039A1 (en) 2009-08-20
JP5027128B2 (ja) 2012-09-19
DE102005039175A1 (de) 2007-02-22
WO2007020294A1 (fr) 2007-02-22
JP2009505090A (ja) 2009-02-05
EP1919625B1 (fr) 2019-12-11
US8323507B2 (en) 2012-12-04

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