EP1919625B1 - Device and method for the separation of magnetic particles from a liquid - Google Patents

Description

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.

Methods based on magnetic separation using specific and / or unspecific binding magnetic particles are becoming increasingly important in the field of sample preparation for diagnostic or analytical studies, in particular for the isolation of nucleic acids. This is especially true for automated processes, since in this way a large number of samples can be prepared within a short time and can be dispensed laborious Zentrifugationsschritte. This will create the conditions for efficient screening with high sample throughput. This is of tremendous importance, since a purely manual handling of very large sample numbers is practically unmanageable. Another important application of magnetic particles are pharmaceutical screening methods for the identification of potential drugs.

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. Furthermore, 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.

In known separation processes, 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.

Typically, the immobilized magnetic particles are then resuspended. In this case, 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. Before the elution step, one or more washing steps can be carried out.

Various devices have been described for carrying out such magnetic particle separation processes. So describes US 2001/0022948 an apparatus in which a magnetic rod is immersed in a first reaction vessel containing magnetic particles suspended in liquid. There, the magnetic rod attracts the magnetic particles so that the magnetic particles adhere to the rod. 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, the magnetic force of the rod is then reduced or switched off, so that the magnetic particles detach from the rod and are suspended in a liquid present in the second reaction vessel. Similar procedures are also from the US 6,065,605 and the WO 2005/005049 known.

On the other hand is from the EP 0 965 842 a device is known in which the magnetic particles together with the liquid in which they are suspended in 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. As a result, the magnetic particles are immobilized as a pellet on the inside of the pipette tip. Subsequently, 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 similar method and apparatus are in the US 6,187,270 described.

Another principle for the separation of magnetic particles describes the EP 0 905 520 , In this case, the magnetic particles remain in the same reaction vessel while the liquid is exchanged in this vessel. In this case, the pellets can be immobilized at a desired height on the side wall of the reaction vessel for adaptation to a respective process step. This is done by providing magnets which are arranged on different arms of a rotatably mounted carrier at a different distance from the axis of rotation. 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.

It is therefore an object of the present invention to at least partially overcome the above-described problems in the prior art.

From the document FR 2858688 A1 For example, a method and apparatus are known in which magnetic microspheres contained in a sample liquid to be moved through interconnected containers. The movement of the magnetic microspheres takes place here by means of magnets guided along the outside of the device.

In contrast, the present invention provides an apparatus according to claim 1 and a method according to claim 27. Further details, advantages and aspects of the present invention will become apparent from the dependent claims, the description and the accompanying drawings.

According to an embodiment of the present invention, there is provided 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 the magnetic field along one side of the connection surface is feasible, comprises.

By such a device, magnetic particles suspended in a liquid in the first vessel can be separated from this liquid without the need 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.

Depending on the application, 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.

According to the embodiment of the present invention, the connection surface is formed by a first side wall of the first vessel, a second side wall of the second vessel, and a connection region connecting the first and second side walls.

This eliminates the need to provide a separate interface. In particular, the first and the second vessel could thus be formed as depressions (wells) in a microtiter plate. As an alternative to this embodiment, of course, the first and the second vessel as well as the bonding surface can be provided as separate elements. In this case, for example, the connection surface could be formed as a bridge or hose.

According to an embodiment of the present invention, a permanent magnet is used. In this way, the magnetic field can be provided inexpensively. The guide means is then to be designed such that the magnet can be guided mechanically along the connection surface. Alternatively, the at least one magnet may also be designed as an electromagnet. Also in this case, the electromagnet can be guided mechanically along the connection surface. In addition, however, 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.

According to a further embodiment of the present invention, the guide means is designed so that the at least one magnet can be guided at a fixed predetermined distance from the connection surface. In particular, the fixed predetermined distance may be zero so that the magnet is in contact with the bonding surface as it is passed past it.

In this way, it can be ensured that a substantially constant magnetic force is always exerted on the magnetic particles formed into a pellet along the path from the first vessel to the second vessel. On This way, it is possible to effectively prevent magnetic particles from being released from the pellet due to a weakening of the magnetic force.

According to another exemplary embodiment of the present invention, at least one heating and / or cooling element, for example a heating wire and / or Peltier element, is provided on the connecting surface. By using heating and / or cooling elements, the magnetic particles can be kept on their way to a predetermined temperature.

According to another embodiment of the present invention, the connection surface along the path of the at least one magnet is formed as a circular arc. Typically, then, the 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.

In this way, a particularly simple form of the guide can be done by the magnet is guided on a circular path or along a circular arc with a constant radius. 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.

According to yet another embodiment of the present invention, 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. In this case, 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.

In this way, after the first separation of the magnetic particles from the liquid in the first vessel one or, if several vessels and Guide devices are interposed, several washes of the magnetic particles take place before the magnetic particles are transferred to an elution solution.

According to yet another exemplary embodiment of the present invention, at least one of the vessels has a functional element, in particular an outlet opening and / or a filter. With this functional element, for example, subsequent analysis steps, such as a PCR step (Polymerase Chain Reaction), can be prepared. In this case, the outlet opening preferably has fastening possibilities with the aid of which, for example, reaction stubs can be fastened to the outlet opening.

According to yet another embodiment of the present invention, the vessels are formed in a cartridge. This allows a compact design, in particular, a so-called lab-on-a-chip can be realized in this way. In such a lab-on-a-chip, all devices necessary for carrying out an examination are integrated on a chip or a cartridge.

1. (a) Bereitstellen eines ersten Gefäßes, eines zweiten Gefäßes, einer Verbindungsfläche, die das Innere des ersten Gefäßes mit dem Inneren des zweiten Gefäßes verbindet, und eines Führungsmittels zum Führen mindestens eines Magnetfelds;
2. (b) Bereitstellen einer Suspension magnetischer Partikel in einer ersten Flüssigkeit in dem ersten Gefäß;
3. (c) Bereitstellen des mindestens einen Magnetfelds mittels des Führungsmittels an einen im Inneren des ersten Gefäßes angeordneten Bereich der Verbindungsfläche, so dass sich ein Pellet aus magnetischen Partikeln an diesem Bereich ausbildet;
4. (d) Führen des mindestens einen Magnetfelds mittels des Führungsmittels entlang einer Seite der Verbindungsfläche zu einem im Inneren des zweiten Gefäßes angeordneten Bereich der Verbindungsfläche, so daß das Pellet aus magnetischen Partikeln entlang der Verbindungsfläche zu einem im Inneren des zweiten Gefäßes angeordneten Bereich der Verbindungsfläche geführt wird;
5. (e) Entfernen des mindestens einen Magnetfelds mittels des Führungsmittels von dem im Inneren des zweiten Gefäßes angeordneten Bereich der Verbindungsfläche, so dass die das Pellet bildenden magnetischen Partikel wieder freigegeben werden.

According to another aspect of the present invention, there is provided a method of separating magnetic particles from a liquid according to claim 27. Also disclosed is a method comprising the following steps:

1. (A) providing a first vessel, a second vessel, a connection surface, which connects the interior of the first vessel with the interior of the second vessel, and a guide means for guiding at least one magnetic field;
2. (b) providing a suspension of magnetic particles in a first liquid in the first vessel;
3. (C) providing the at least one magnetic field by means of the guide means to a arranged in the interior of the first vessel Area of the bonding surface, so that a pellet of magnetic particles is formed at this area;
4. (D) guiding the at least one magnetic field by means of the guide means along one side of the connection surface to a region of the connection surface arranged inside the second vessel so that the pellet of magnetic particles is guided along the connection surface to a region of the connection surface arranged inside the second vessel becomes;
5. (E) removing the at least one magnetic field by means of the guide means of the arranged in the interior of the second vessel portion of the connecting surface, so that the pellets forming magnetic particles are released.

Such a method can for example be carried out in an automated manner in a device according to an embodiment of the present invention in a simple manner. 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.

Fign. 1A bis 1E

eine schematische Darstellung einer Vorrichtung und eines Verfahrens gemäß einem Ausführungsbeispiel.

Fign. 2A bis 2E

eine schematische Darstellung einer Vorrichtung und eines Verfahrens gemäß einem weiteren Ausführungsbeispiel.

Fign. 3A bis 3C

eine schematische Darstellung einer Vorrichtung und eines Verfahrens gemäß noch einem weiteren Ausführungsbeispiel.

Fign. 4A und 4B

eine schematische Darstellung eines Waschvorgangs gemäß einem Ausführungsbeispiel.

Fig. 5

ein Führungsmittel gemäß einem Ausführungsbeispiel.

Fig. 6

ein Führungsmittel gemäß einem anderen Ausführungsbeispiel.

Fig. 7

eine Querschnittsansicht eines Verbindungsbereichs gemäß einem Ausführungsbeispiels.

Fig. 8

ein anderes Ausführungsbeispiel.

Fig. 9

ein weiteres Ausführungsbeispiel.

Fig. 10

eine schematische Darstellung eines weiteren Ausführungsbeispiels, bei dem die Erfindung in einer Kartusche verwirklicht ist.

Fign. 11A bis 11F

eine schematische Darstellung, wie ein erfindungsgemäßes Verfahren in dem in Fig. 10 gezeigten Ausführungsbeispiel ausgeführt wird.

Fig. 12

eine schematische Darstellung einer Variante des in Fig. 10 gezeigten Ausführungsbeispiels.

Fig. 13

eine schematische Darstellung noch einer Variante des in Fig. 10 gezeigten Ausführungsbeispiels.

Fig. 14

eine schematische Darstellung einer weiteren Variante des in Fig. 10 gezeigten Ausführungsbeispiels.

Fig. 15

eine schematische Darstellung einer Weiterbildung des in Fig. 10 gezeigten Ausführungsbeispiels.

In the following, the details of the invention will be explained with reference to various embodiments with reference to the accompanying drawings. Objects not covered by the claims are merely illustrative. In the drawings shows:

FIGS. 1A to 1E

a schematic representation of an apparatus and a method according to an embodiment.

FIGS. 2A to 2E

a schematic representation of an apparatus and a method according to another embodiment.

FIGS. 3A to 3C

a schematic representation of an apparatus and a method according to yet another embodiment.

FIGS. 4A and 4B

a schematic representation of a washing process according to an embodiment.

Fig. 5

a guide means according to an embodiment.

Fig. 6

a guide means according to another embodiment.

Fig. 7

a cross-sectional view of a connection region according to an embodiment.

Fig. 8

another embodiment.

Fig. 9

another embodiment.

Fig. 10

a schematic representation of another embodiment in which the invention is implemented in a cartridge.

FIGS. 11A to 11F

a schematic representation of how a method according to the invention in the in Fig. 10 shown embodiment is executed.

Fig. 12

a schematic representation of a variant of in Fig. 10 shown embodiment.

Fig. 13

a schematic representation of yet another variant of in Fig. 10 shown embodiment.

Fig. 14

a schematic representation of another variant of in Fig. 10 shown embodiment.

Fig. 15

a schematic representation of a development of in Fig. 10 shown embodiment.

In the following description of various embodiments, functionally similar features of the various embodiments are provided with the same reference numerals.

Fig. 1A shows a schematic representation of a device according to an embodiment. In a first vessel 10 is a liquid 15 in which magnetic particles 60 are suspended. Furthermore, a second vessel 20 is shown in which a second liquid 25, for example a washing solution or an elution solution, is located. 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. In this embodiment, 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. However, such a 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. Furthermore, the 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.

Furthermore, 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. In the present exemplary embodiment, this means that the guide means 50 can guide the magnet 40 along the first side wall 11 and along an underside of the connection region 30 to the second side wall 21. As a guide means 50, for example, a cylindrical roller or a rotary arm can be used, as will be explained later in this application. However, it is also possible, for example, 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. In this case, 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 (please refer Fig. 1B ). In particular, the distance between the magnet 40 and the side walls 11, 21 and the underside of the connection region 30 may be zero. In this case, 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.

According to a further embodiment, the connection surface may be channel-shaped. Fig. 7 shows a cross section of the connecting portion 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. In this way, it is possible to prevent the first liquid 15, which possibly adheres to the pellet 61, from detaching laterally in the upper region of the connection region 30 and possibly leading to cross contamination. Should liquid actually detach on movement of the pellet 61 from the first to the second vessel, this liquid is returned via the channel into the first or the second vessel.

In the following, the basis of the FIGS. 1A to 1E a method according to an embodiment described. In Fig. 1A is the initial state 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. As in Fig. 1B shown, the magnet 40 is then brought by the guide means 50 to the side wall 11 of the first vessel 10. There he attracts the magnetic particles 60, which are immobilized as a pellet 61 on the side wall 11. Subsequently, 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 FIGS. 1C and 1D , The magnetic particles formed by the magnetic force to the pellet 61 follow due to the 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. As in Fig. 1E Finally, the magnet 40 is shown 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.

Another embodiment will now be described with reference to FIGS. 2A to 2E described. Again, 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. Here, the connecting surface, ie here the first side wall 11, the second side wall 21 and the connecting portion 30, is formed so that it forms a circular arc with radius R. Typically, the side walls 11, 21 and the connecting portion 30 are integrally formed as a connecting surface. However, as already stated above, the first and the second vessel as well as the connection surface can also be provided as separate elements. The guide means 50 is formed as a four-armed turnstile, as enlarged in Fig. 5 is shown.

In Fig. 5 is the guide means on four pivot 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. When the total length r is equal to the circular arc radius R, the magnets 40, 41, 42, 43 are in contact with the side walls 11, 21 and the connecting portion 30 as they are passed therethrough. In this case, it is advantageous if 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.

According to Fig. 5 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. Furthermore, 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. Furthermore, the four rotating arms in Fig. 5 each offset by 90 °, ie evenly distributed over the swept by the turntable circumference 2 π r. Depending on the application, however, the two or more rotating arms can also be arranged offset to one another in arbitrarily adjustable angular distances.

Another embodiment of a guide means 50, which in the in Fig. 2A can be used, is shown in Fig. 6 shown. Therein, 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. According to Fig. 6 are three magnets 40, 41, 42 each offset by 120 ° in receptacles 56, 57, 58 are arranged. However, it would also be conceivable that 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. Again, of course, the number and mutual position of the magnets can be varied according to the requirements of a particular application accordingly. In particular, it is conceivable that 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.

The functioning of the in Fig. 2A shown embodiment is in the FIGS. 2A to 2E played. First, the magnet 40 is moved to the side wall 11 of the first vessel 10, where then the magnetic particles form a pellet 61 ( Fig. 2B ). The magnet 40 is then guided along the circular arc with the pellet 61 following it ( FIGS. 2C and 2D ). The pellet 61 is then introduced into the second vessel 20 ( Fig. 2E ) And finally, the magnet 40 led away from the second side wall 21, so that the magnetic particles in the located 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.

Another embodiment is in the FIGS. 3A to 3C shown. In addition, a third vessel 70 is provided, which is connected to the second vessel 20 via a second connection region 80. In this case, 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 '. Typically, 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. Furthermore, 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. With the aid of the magnet 90 and the second guide means 100, 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. In the same way as between the first and the second vessel, the pellet 62 can now be transferred from the second vessel to the third vessel 70 via the second connecting surface. When the magnet 90 is led away from the side wall of the third vessel 70, the magnetic particles may be resuspended in the liquid 75 contained in the third vessel 70. For example, in this device, a washing solution can be provided in the second vessel and an elution solution in the third vessel. In this case, the eluted magnetic particles could be transported back by opposite rotation of the second guide means in the second vessel and disposed of there. Furthermore, of course, 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.

According to a further embodiment, the in Fig. 3A As shown, the apparatus shown also for executing a washing process. First, the first pellet 61 from the first vessel 10 into the washing solution filled second vessel 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. Subsequently, the magnet 90 is then led away from the side wall of the second vessel again along a second direction of rotation. Now the second pellet 62 dissolves and the magnetic particles are resuspended in the wash solution. Then, 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. In this case, 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. Also, 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.

In the following, another embodiment will be described with reference to FIG Fig. 8 described. Therein, the first vessel 10 and the second vessel 20 are provided as separate vessels. A 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. Typically, the connecting surface 200 is formed on its upper side groove-shaped. In this case, 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. For example, 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.

In this embodiment, 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. In this way, 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. When the pellet finally reaches the inside of the second vessel, 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.

In the following, another embodiment will be described with reference to FIG Fig. 9 described. Again, 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. Furthermore, 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.

However, instead of heating elements, cooling elements, for example Peltier elements, may also be provided on the connection surface 11, 21, 30 in order to effect cooling of the magnetic particles and of the substances adhering to the magnetic particles. In this way, for example, a drying of the particles could be reduced, if the analysis carried out so required.

Furthermore, the vessel 20 at the in Fig. 9 embodiment shown 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.

Of course, various aspects of the embodiment just described can also be combined with the exemplary embodiments described above. Thus, e.g. Also be arranged along a first side wall, a connecting region and a second side wall individually controllable electromagnets. Likewise, a mechanical guide, e.g. a roller or pivot arms, are guided along a connecting surface formed separately as a bridge.

In all embodiments described above, the connecting surfaces may be designed channel-shaped. Furthermore, in all described exemplary embodiments, the guide means can be designed so that the speed with which they guide the magnetic field (s) along the connecting surfaces is controllable. In particular, the speed can be set to zero so that the pellet can be immobilized at the current position. Furthermore, in all described embodiments, the guide means may be designed so that the direction in which they guide the magnetic field or fields along the connecting surfaces is controllable. In particular, then a reversal of direction in the movement of the pellets is possible. Furthermore, all embodiments mentioned above can be designed as closed systems.

In Fig. 10 Yet another embodiment 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. Typically, the second vessel 1020 could contain an elution liquid. In this context, it should be noted that Fig. 10 is only a schematic representation in which the first and the second vessel are the same size. Of course, the sizes of each Vessels but differ from each other. In particular, typically the volume of an elution vessel will be less than that of a wash vessel.

A closure 1100 prevents mixing of the liquids. However, closure 1100 may be removed using the cartridge. Optionally closure 1100 is designed so that it can be brought into the closed position after removal and again serves as a closure. Typically, 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. Finally, the cartridge has a magnet 1040 which can be guided 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. In particular, 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.

The following is based on the FIGS. 11A to 11F briefly the functioning of the in Fig. 10 described embodiment described. As in Fig. 11A First, magnetic particles 1060 are 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. 11B ). The pellet 1061 is then fed to closure 1100 (see Fig. 11C ). Now, the shutter 1100 is opened and the path for the pellet 1061 is released into the connection portion 1030 (see FIG Fig. 11D ). The pellet 1061 is then inserted into the second vessel 1020 by means of the magnet 1040 (see Fig. 11E ), where it can subsequently be released (see Fig. 11F ). If the magnetic particles 1060 are to be removed from the second vessel 1020 through the second access opening 1022, it makes sense to again form the magnetic particles 1060 by means of the magnet 1040 into a compact pellet 1061, which can be easily removed through the opening 1022. Via the second access opening 1022 it is likewise possible to remove the liquid without the magnetic particles 1060. typically, For example, during the removal of the liquid, the magnet 1040 would keep the pellet 1061 at a distance from the access opening 1022, thus allowing us to remove the liquid without entrainment of the magnetic particles.

Another embodiment is in Fig. 12 shown. Essentially, the structure corresponds to the in Fig. 10 however, a magnet arrangement similar to that shown in FIG Fig. 8 shown embodiment provided. In this case, a plurality of electromagnets 1040-arranged from the first vessel 1010 to the second vessel 1020 running one behind the other-are integrated into the cartridge 1000. For example, the cartridge 1000 could be formed as an injection-molded part, in which the electromagnets 1040 are embedded. The electromagnets can be controlled individually by a guide means 1050, ie 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 in FIG Fig. 8 shown embodiment, which is why a more detailed explanation is omitted here.

Fig. 13 shows a perspective view, wherein the interior of the cartridge 1000 is substantially the in Fig. 10 corresponds shown construction. However, 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. Furthermore, 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, the magnetic particles bound in a pellet can be released again by the magnet 1040 being lifted off the surface of the cartridge again.

In Fig. 14 the cartridge 1000 is arranged on a guide means 1050, which is designed as a movable carrier. The carrier 1050 is movable in its plane, but preferably also perpendicular thereto, so that it supports the ones mounted on it Cartridge 1000 can move along a predetermined path. A magnet 1040 is held substantially stationary by a retaining means 1045. By raising or lowering the carrier 1050, the surface of the cartridge 1000 can be brought to the magnet 1040. By moving the carrier 1050 in its plane, the cartridge 1000 is then moved on a predeterminable path under the magnet 1040. Basically, that's what in Fig. 14 embodiment shown a reversal of in Fig. 13 shown principle.

Fig. 15 shows a training of in Fig. 10 shown embodiment. In this case, 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. In this case, 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.

By the embodiments described above, a separation of magnetic particles from a liquid is made possible, which significantly reduces the risk of cross-contamination or even excludes. In particular, the devices according to the above embodiments can be designed and operated as closed systems. The devices and methods according to the embodiments are simple and to a considerable extent automation-friendly.

Claims (30)

1. Device for the separation of magnetic particles from a liquid, comprising
   a first vessel (10; 1010),
   a second vessel (20; 1020),
   a connecting surface (11, 21, 30; 200), which runs from the interior of the first vessel (10) to the interior of the second vessel (20), wherein the connecting surface (11, 21, 30; 200) is formed by a first side wall (11) of the first vessel (10), a second side wall (21) of the second vessel (20), which is opposite from the first side wall (11) of the first vessel (10), and a connecting region (30), which connects the first and the second side wall (11; 21) and has an upper side and an underside,
   at least one magnet (40) for providing a magnetic field,
   and a guiding means (50), which is arranged outside the first vessel (10) and the second vessel (20), and by means of which the magnetic field can be guided along a side of the connecting surface (11, 21, 30; 200) comprising the underside of the connecting region (30), so that a pellet (61) of magnetic particles (60) can be guided along the inner side of the first side wall (11) over the upper side of the connecting region (30) to the inner side of the second side wall (21),
   wherein the magnet (40) is arranged on the guiding means (50).
2. Device according to claim 1, wherein the at least one magnet (40) is a permanent magnet.
3. Device according to claim 1, wherein the at least one magnet (40) is an electromagnet.
4. Device according to one of the preceding claims, wherein the guiding means (50) is formed such that the at least one magnet (40) can be guided at a prescribed fixed distance from the side of the connecting surface (11, 21, 30; 200).
5. Device according to claim 4, wherein the prescribed fixed distance is zero, so that the magnet is in contact with the side of the connecting surface (11, 21, 30; 200) as it is guided along on it.
6. Device according to one of the preceding claims, wherein the guiding means (50) has at least one further magnet (41, 42, 43), which is at a distance from the first magnet (40).
7. Device according to one of the preceding claims, wherein at least one heating and/or cooling element (110) is provided at the connecting surface (11, 21, 30; 200).
8. Device according to one of the preceding claims, wherein the connecting surface (11, 21, 30; 200) is formed as an arc.
9. Device according to claim 8, wherein the guiding means (50) is formed such that the at least one magnet (40) can be guided on a circular path, wherein the radius (r) of the circular path is less than or equal to the radius (R) of the arc that is formed by the connecting surface (11, 21, 30; 200).
10. Device according to claim 9, wherein the guiding means (50) has at least one rotary arm (51), one end of which is arranged on an axis of rotation (55) and the other end of which has the at least one magnet (40) arranged on it.
11. Device according to claim 10, wherein the guiding means (50) has one or more further rotary arms (52, 53, 54), one end of which in each case is arranged on the axis of rotation (55) and the other end of which in each case has a further magnet (41, 42, 43) arranged on it.
12. Device according to claim 11, wherein the rotary arms (51, 52, 53, 54) are formed in one piece.
13. Device according to claim 9, wherein the guiding means (50) takes the form of a cylinder, which is mounted rotatably about an axis (55).
14. Device according to claim 13, wherein the at least one magnet (40) and/or the further magnets (41, 42) are arranged on the surface of the cylindrical guiding means (50).
15. Device according to claim 13, wherein the at least one magnet (40) and/or the further magnets (41, 42) are arranged in each case in a receptacle (56, 57, 58) formed in the cylindrical guiding means (50).
16. Device according to one of claims 11, 12, 14 or 15, wherein the at least one magnet (40) and the one or more further magnets (41, 42, 43) are arranged in each case offset by the same angle in relation to one another.
17. Device according to one of the preceding claims, wherein the guiding means (50) is formed such that the speed at which it guides the magnetic field of the one magnet (40) and/or of the number of further magnets (41, 42, 43) along the connecting surface (11, 21, 30; 200) is controllable.
18. Device according to one of the preceding claims, wherein the guiding means (50) is formed such that the direction in which it guides the magnetic field of the one magnet (40) and/or of the number of further magnets (41, 42, 43) along the connecting surface (11, 21, 30; 200) is controllable.
19. Device according to one of the preceding claims, further comprising at least one third vessel (70), which is connected to the first or the second vessel by way of a second connecting surface, and a second guiding means (100) for guiding at least one further magnetic field, wherein the first or second vessel (10, 20) together with the third vessel (70), the second connecting surface, the second guiding means (100) and the further magnetic field form a device according to one of the claims 1 to 17.
20. Device according to claim 19, wherein the first and the second guiding means (50, 100) are arranged on opposite sides of the second vessel (20).
21. Device according to claim 19 or 20, wherein the second vessel (20) contains a wash solution and the third vessel an elution solution.
22. Device according to one of the preceding claims, wherein at least one of the vessels (10, 20, 70) has a functional element, in particular an outlet opening and/or a filter.
23. Device according to one of the preceding claims, wherein the connecting surface (30) takes the form of a groove.
24. Device according to one of the preceding claims, wherein the first and the second vessel (1010, 1020) and/or the third vessel (1070) are formed in a cartridge (1000).
25. Device according to claim 24, wherein in each case adjacent vessels (1010, 1020; 1020, 1070) are separated from one another by a removable closure (1100, 1200).
26. Device according to claim 24 or 25, wherein the cartridge (1000) has a cover, which has a first access opening (1012) to a first vessel (1010) and a second access opening (1022, 1072) to a second vessel.
27. Method for the separation of magnetic particles from a liquid with the following steps:

    (a) providing a device according to one of claims 1 to 26;

    (b) providing a suspension of magnetic particles (60) in a first liquid (70) in the first vessel (10) of the device;

    (c) providing the at least one magnetic field by means of the guiding means (50) of the device at a region (11) of the connecting surface (11, 21, 30; 200) of the device in the interior of the first vessel (10), so that a pellet (61) of magnetic particles forms at this region (11);

    (d) guiding the at least one magnetic field by means of the guiding means (50) along a side of the connecting surface (11, 21, 30; 200) comprising the underside of the connecting region (30), so that the pellet (61) of magnetic particles is guided along an opposite side of the connecting surface (11, 21, 30; 200) comprising the upper side of the connecting region (30) to a region (21) of the connecting surface in the interior of the second vessel (20) of the device;

    (e) removing the at least one magnetic field by means of the guiding means (50) from the region (21) of the connecting surface in the interior of the second vessel (20), so that the magnetic particles (60) forming the pellet (60) are released again.
28. Method according to claim 27, wherein in step (a) a device according to claim 19 is provided,
    wherein after step (e) the magnetic particles (60) are washed in the second vessel (20), and by analogy with steps (a) to (e), the magnetic particles (60) are subsequently transferred by means of the second guiding means (100) and the further magnetic field from the second vessel (20) into the third vessel (70).
29. Method according to claim 28, wherein the step of washing the magnetic particles in the second vessel comprises the following partial steps:

    releasing the magnetic particles (60) forming a pellet (61) by removing the at least one magnetic field by the first guiding means (50),

    forming a pellet (62) by providing the at least one further magnetic field by the second guiding means (100),

    releasing the magnetic particles (60) forming a pellet (62) by removing the at least one further magnetic field by the second guiding means (100),

    forming a pellet (61) by providing the at least one magnetic field by the first guiding means (50).
30. Method according to claim 29, wherein the provision of the at least one magnetic field and the at least one further magnetic field takes place by turning the first and second guiding means (50, 100), respectively, in a first direction of rotation, wherein the first direction of rotation of the first guiding means (50) is counter to the first direction of rotation of the second guiding means (100), and wherein the removal of the at least one magnetic field and of the at least one further magnetic field takes place by turning the first and second guiding means (50, 100), respectively, in a second direction of rotation counter to the first direction of rotation, wherein the second direction of rotation of the first guiding means (50) is counter to the second direction of rotation of the second guiding means (100).

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