EP2192987B1 - Apparatus and method for the treatment of liquids with magnetic particles - Google Patents

Description

Field of the Invention

The present invention relates to an apparatus and a method for treating liquids with magnetic particles. The device and the method are suitable, for example, for applications in biochemistry, clinical chemistry, molecular biology, microbiology, medical diagnostics or forensic medicine.

Technical background

A large number of methods for treating liquids with magnetic particles are known in the prior art, these mostly relating to the separation of nucleic acids or other biologically or biochemically relevant substances from a solution.

Methods based on magnetic separation using specific and / or non-specific binding magnetic particles have become increasingly important in the field of sample preparation for diagnostic or analytical investigations, especially for the isolation of nucleic acids, proteins and cells.

This applies in particular to automated processes, since in this way a large number of samples can be prepared within a short time and for labor-intensive ones Centrifugation steps can be dispensed with. This creates the conditions for efficient and high sample throughput. This is of enormous importance, since the purely manual handling of very large numbers of samples is practically impossible.

The basic principle of magnetic separation of substances from complex mixtures is based on the fact that magnetic particles e.g. by chemical treatment of their surface with specific binding properties for the target substances to be separated. The size of such magnetic particles is generally in the range from approximately 0.05 to 500 μm, so that they provide a large surface for the binding reaction. Depending on their size and nature, the magnetic particles can have a density that is similar to the density of the liquid in which they are suspended. In this case, sedimentation of the magnetic particles can take a few hours.

In known separation processes, the magnetic particles are immobilized at one point by using magnetic forces or a magnetic field, for example by means of a permanent magnet. This accumulation of magnetic particles is also referred to as a pellet or magnetic sediment. The liquid supernatant is then separated off and discarded, for example by suction or decanting. Since the magnetic particles are immobilized by the magnetic forces, magnetic particles are largely prevented from being separated off together with the supernatant.

The immobilized magnetic particles are typically subsequently resuspended. An elution liquid or an elution buffer is used to enrich the bound target substances. The bond between the target substance and the magnetic particles are released and 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. By reducing the volume of elution liquid in relation to the primary starting volume for binding, the target substance molecules can not only be enriched, but also concentrated. One or more washing steps can be carried out before the elution step.

Various types of devices have been described for carrying out such separation processes using magnetic particles. So describes US 2001/0022948 a device 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, together with the magnetic particles adhering to it, is then pulled out of the reaction vessel 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 in the reaction vessel. Similar procedures are also out of the US 6,065,605 and the WO 2005/005049 known.

On the other hand, is from EP 0 965 842 a device is known in which the magnetic particles are drawn up together with the liquid in which they are suspended in a pipette. The pipette tip has a special separation area that can be acted upon by a magnet with a magnetic field. This turns the magnetic particles into pellets or magnetic sediments immobilized on the inside of the pipette tip. The aspirated liquid is then removed from the pipette tip by the pipetting function of the device.

The magnetic field in the separation area can then be removed again, as a result of which the magnetic particles immobilized in the pellet are released again. A similar method and a similar device are in the US 6,187,270 described.

Another principle for the separation of magnetic particles describes the EP 015 905 520 . The magnetic particles remain in the same reaction vessel while the liquid in this vessel is exchanged. The magnetic sediments can be immobilized at a desired height on the side wall of the reaction vessel in order to adapt to a respective process step. This is done by providing magnets which are arranged on different arms of a rotatably mounted carrier at different distances from the axis of rotation. By rotating the carrier, a specific arm - and thus a specific magnet - can be brought near the side wall of the reaction vessel. At this point, the magnetic particles are then immobilized as a pellet.

WO 2007/063174-A describes an enrichment unit for biological components in which a magnetic rod is inserted through an opening into a bag.

WO 99/42832-A describes a method for transferring magnetic particles with the aid of a magnet inserted into a vessel from the outside.

WO 2004/035217-A describes a method for metering magnetic particles with the aid of a magnet inserted into a vessel from the outside. WO 03/072531-A1 describes an apparatus and a method for obtaining magnetic particles in a slurry phase reactor, in which the magnetic particles suspended in a liquid are guided past magnetic bars.

The conventional devices and methods mentioned all have the common property that they are designed as so-called “open systems”, since magnetic rods or pipettes have to be introduced into the reaction vessel one or more times according to their respective functional principle. As a result, with these conventional devices and methods there is a risk of cross-contamination of other reaction vessels by aerosol and / or Drop formation. Test results can be falsified or even unusable.

Object of the present invention

The present invention is based on the object of overcoming the disadvantages arising from the prior art and, in particular, of creating a device and a method for a wide range of applications in which the treatment of liquids with magnetic particles is possible in a simple manner is.

beträgt, wobei sich das Zentralelement vollständig im Inneren des Gefäßes befindet, wobei die Vorrichtung zusätzlich mindestens einen externen Magneten umfasst, der zur Interaktion mit dem mindestens einen Zentralelement ausgebildet ist, so dass das Zentralelement durch den externen Magneten bewegbar ist.The object is achieved by a device according to claim 1 of the present invention. Accordingly, a device for treating a liquid with magnetic particles is claimed, comprising a vessel containing the liquid and a multiplicity of magnetic particles arranged in the liquid and at least one rod-shaped, dumbbell-shaped and / or ellipsoid-shaped magnetic and / or magnetizable central element , wherein the ratio of the longest diameter d2 of the at least one central element to the ratio of the average diameter dl of the magnetic particles at least $$\mathrm{d}\mathrm{2nd}\left(\mathrm{mm}\right)\ge 15\ast \mathrm{d}1\left(\mathrm{mm}\right)$$

, the central element being located completely inside the vessel, the device additionally comprising at least one external magnet which is designed to interact with the at least one central element, so that the central element can be moved by the external magnet.

For the purposes of the present invention, the term “central element” is understood in particular to mean any object which is capable of acting through the action of a magnetic field - possibly under the action of a further “external” magnet (as described below) - to bind at least the majority of the magnetic particles to itself in the idle state.

According to a preferred embodiment of the invention, the at least one central element comprises a magnet, preferably a permanent magnet; According to an alternative, preferred embodiment of the invention, the at least one central element comprises a magnetizable material, such as e.g. Iron.

For the purposes of the present invention, the term “liquids” is understood to mean, but not limited to, in particular aqueous solutions, suspensions and / or two-phase emulsions with water as a phase which contain biomolecules.

The term "treatment" in the sense of the present invention means in particular that certain biomolecules can attach to the magnetic particles in a separation step; however, the present invention is expressly not limited to this.

The term "diameter" of the magnetic particles means in particular if the magnetic particles are not spherical or essentially spherical, the longest diameter of the magnetic particles in each case.

The term "average diameter" means in particular the arithmetic mean of the diameter of the magnetic particles, which can be measured in particular (but not limited to) on a sample basis.

• Dadurch, dass mindestens ein Zentralelement vorgesehen ist, ist eine Homogenisierung der Magnetpartikel wie auch eine Separierung der Magnetpartikel von der Lösung auf einfache Weise möglich, wie u.a. nachfolgend beschrieben.
• Die Vorrichtung erlaubt den Einsatz in "geschlossenen" Systemen;
• Es sind keine weiteren Mittel (wie ein Stabmagnet etc.) notwendig, die direkt in die Flüssigkeit eintauchen und somit eine potentielle Kontaminationsquelle darstellen.
• Es ergibt sich für die meisten Anwendungen eine sehr schnelle und leichte Homogenisierung der Magnetpartikel.
• Weiterhin ist meist eine sehr schnelle Separation der Magnetpartikel möglich.
• Neben dem einfachen Aufbau der Vorrichtung ist gleichzeitig der zu betreibende technische Aufwand meist sehr gering.

Such a device offers at least one of the following advantages for a wide range of applications within the present inventions:

• Because at least one central element is provided, homogenization of the magnetic particles as well as separation of the magnetic particles from the solution is possible in a simple manner, as described below, among others.
• The device allows use in "closed"systems;
• No other means (such as a bar magnet, etc.) are necessary that are immersed directly in the liquid and thus represent a potential source of contamination.
• For most applications, the magnetic particles are homogenized very quickly and easily.
• Furthermore, very fast separation of the magnetic particles is usually possible.
• In addition to the simple construction of the device, the technical effort to be operated is usually very low.

The ratio of the longest diameter d2 of the at least one central element to the ratio of the average diameter d1 of the magnetic particles is advantageously d2 (mm) 50 50 ^∗ d1 (mm), more preferably d2 (mm) ≥ 100 ^∗ d1 (mm), further preferably d2 (mm) ≥ 200 ^∗ d1 (mm), and most preferably d2 (mm) ≥ 300 ^∗ d1 (mm).

This has proven to be advantageous for a wide range of applications within the present invention, since the desired inventive effects can often be achieved in a simple manner.

According to a preferred embodiment of the invention, the ratio of the volume V2 of the at least one central element to the ratio of the average volume V1 of the magnetic particles $$\mathrm{V}\mathrm{2nd}\left({\mathrm{mm}}^{\mathrm{3rd}}\right)\ge \mathrm{10th}\ast \mathrm{V}1\left({\mathrm{mm}}^{\mathrm{3rd}}\right).$$

This has also turned out to be favorable, since it can in particular be ensured that after homogenization (resuspension) of the magnetic particles, they again attach to the magnets.

Advantageously, the ratio of the volume V2 of the at least one central element to the ratio of the average volume V1 of the magnetic particles V2 (mm ³ ) ≥ 100 ^∗ V1 (mm ³ ), more preferably V2 (mm ³ ) ≥ 1000 ^∗ V1 (mm ³ ) and most preferably V2 (mm ³ ) ≥ 10 ^{5 ∗} V1 (mm ³ ).

According to a preferred embodiment of the invention, the number of magnetic particles per central element is ≥10 ⁴ , advantageously up to ≤10 ⁸ , preferably ≥5 x 10 ⁵ to ≤ 5 x 10 ⁶ .

According to a preferred embodiment of the invention, the magnetic particles contain a material selected from the group consisting of paramagnetic materials, superparamagnetic materials, ferromagnetic materials, ferrimagnetic materials and mixtures thereof.

The average saturation magnetization of the magnetic particles is advantageously ≥1 Am ² / kg and 250 Am ² / kg, preferably ≥10 Am ² / kg and 240 Am ² / kg, and most preferably ≥20 Am ² / kg and 235 Am ² / kg kg. This has been found to be advantageous for many applications of the present invention.

The at least one central element is rod-shaped, dumbbell-shaped and / or ellipsoid-shaped and the ratio of the longest diameter a to the ratio of the shortest diameter b is advantageously from a / b ≥ 1.1 to a / b ≤10.

This has proven to be particularly advantageous for simple homogenization of the magnetic particles in many applications. The ratio of the longest diameter a to the ratio of the shortest diameter b is advantageously from a / b 1.5 1.5 to a / b 8 8, preferably a / b 2 2 to a / b 5 5.

The magnetic particles and the at least one central element are advantageously arranged in a closed vessel.

According to a preferred embodiment of the invention, the added volume V _{m of} the magnetic particles and that of the at least one central element are 0 0.25% to 50 50% of the total volume V _{G of} the vessel. This has proven to be favorable for many applications.

The added volume V _{m of} the magnetic particles and that of the at least one central element are preferably 0 0.5% to 20 20%, even more preferably 1 1% to 15 15%, of the total volume V _{G of} the vessel.

The device according to the invention further comprises at least one external magnet which is designed to interact with the at least one central element. In the event that the central element is a permanent magnet, the ratio of the magnetic strength H _{3 of} the at least one external magnet to the magnetic strength H _{2 of} the at least one central element is according to a preferred embodiment of the invention
H ₃ ≥ 1.1 ^∗ H ₂ to H ₃ ≤ 10 ^∗ H ₂

This has turned out to be favorable, since the at least one central element can often be influenced very well according to the invention on the one hand, and the homogenization or attachment of the magnetic particles to the at least one central element is not unnecessarily influenced on the other hand.

The ratio of the magnetic strength H _{3 of} the at least one external magnet to the magnetic strength H _{2 of} the at least one central element is advantageously H ₃ 1.5 1.5 ^∗ H ₂ to H ₃ 8 8 ^∗ H ₂ , even more preferably H ₃ 2 2 ^∗ H ₂ to H ₃ ≤ 5 ^∗ H ₂ .

According to a preferred embodiment of the invention, the at least one external magnet is and / or comprises an electromagnet (s) which is operated under alternating voltage for the homogenization of the magnetic particles. In this embodiment, the central element is then preferably a (permanent) magnet.

According to a preferred embodiment of the invention, the at least one external magnet is and / or comprises a permanent magnet (s).

1. a) Verteilen der magnetischen Partikel in der Flüssigkeit sowie nachfolgend
2. b) Anlagern der magnetischen Partikel an das mindestens eine Zentralelement.

According to claim 9, the present invention further relates to a method for treating liquids with magnetic particles with a device according to one of claims 1 to 8, comprising the steps

1. a) Distribution of the magnetic particles in the liquid and subsequently
2. b) attaching the magnetic particles to the at least one central element.

The central element remains in the container throughout the process.

• Dadurch, dass mindestens ein Zentralelement vorgesehen ist, ist eine Homogenisierung der Magnetpartikel wie auch eine Separierung der Magnetpartikel von der Lösung auf einfache Weise möglich, wie u.a. nachfolgend beschrieben.
• Das Verfahren erlaubt den Einsatz in "geschlossenen" Systemen.
• Es sind keine weiteren Mittel (wie ein Stabmagnet etc.) notwendig, die in die Flüssigkeit eintauchen und somit eine potentielle Kontaminationsquelle darstellen.
• Es ergibt sich für die meisten Anwendungen eine sehr schnelle und leichte Homogenisierung der Magnetpartikel.
• Weiterhin ist meist eine sehr schnelle Separation der Magnetpartikel möglich.
• Neben dem einfachen Aufbau des Verfahrens ist gleichzeitig der zu betreibende technische Aufwand meist sehr gering.

Such a method offers at least one of the following advantages for a wide range of applications within the present inventions:

• Because at least one central element is provided, homogenization of the magnetic particles and also separation of the magnetic particles from the solution are possible in a simple manner, as described below, among others.
• The method allows use in "closed" systems.
• No other means (such as a bar magnet, etc.) are necessary that are immersed in the liquid and thus represent a potential source of contamination.
• For most applications, the magnetic particles are homogenized very quickly and easily.
• Furthermore, very fast separation of the magnetic particles is usually possible.
• In addition to the simple structure of the method, the technical effort to be operated is usually very low.

According to a preferred embodiment of the invention, step a) comprises resuspending the magnetic particles in the liquid.

According to a preferred embodiment of the invention, prior to step a), the magnetic particles were at least partially, preferably almost completely, attached to the at least one central element, and step a) takes place by the action of an external force on the at least one central element, which during the entire process the container remains.

Step b) is advantageously supported by means of a further, external permanent magnet. This is preferably done in such a way that an external permanent magnet is brought into the vicinity of the vessel in which the magnetic particles and the at least one central element are located. In many embodiments of the present invention, this allows the magnetic particles to be deposited on the at least one central element much more quickly. This embodiment has also proven to be particularly advantageous when the at least one central element is not a permanent magnet.

According to claim 12, the present invention also relates to the use of a device according to the invention and / or a method according to the invention for at least partial separation of biomolecules from / in a preferably aqueous solution.

Under the term "biomolecules", all biomolecules, such as, for. B understood lipids, carbohydrates, metabolites, metabolic products, all types of nucleic acids, all types of peptides and proteins, also substituted or functionalized peptides and / or proteins.

For the purposes of the present invention, the term “biomolecules” is further understood - but not limited to this - to mean all molecules which occur naturally or are artificially introduced in biological samples.

The device according to the invention and / or the method according to the invention is advantageously used for at least partial separation of nucleic acids from / in a preferably aqueous solution.

The term "nucleic acid" in the sense of the present invention is particularly - but not limited to - natural, preferably isolated, linear, branched or circular nucleic acids such as RNA, in particular mRNA, siRNA, miRNA, snRNA, tRNA, hnRNA or ribozymes, DNA and Similar, synthetic or modified nucleic acids, for example oligonucleotides, in particular primers, probes or standards used for the PCR, nucleic acids labeled with digoxigenin, biotin or fluorescent dyes or so-called PNAs ( "peptide nucleic acids ") are understood.

The size, shape, material selection and technical conception of the above-mentioned components as well as those claimed and described in the exemplary embodiments, which are to be used according to the invention, are not subject to any special exceptional conditions, so that the selection criteria known in the field of application can be used without restriction.

Fig. 1

zeigt eine sehr schematische Ansicht einer erfindungsgemäßen Vorrichtung gemäß eines Ausführungsbeispiels der Erfindung vor "Homogenisierung" der Magnetpartikel;

Fig. 2

zeigt die Vorrichtung aus Fig. 1 nach "Homogenisierung"; sowie

Fig. 3

eine UV-Kurve einer DNA-Elutionslösung nach Durchführung einer Präparation von genomischer DNA gemäß Beispiel I.

Further details, features and advantages of the subject matter of the invention emerge from the subclaims and from the following description of the associated figures and examples, in which - by way of example - several exemplary embodiments and possible uses of the present invention are illustrated.

Fig. 1

shows a very schematic view of a device according to the invention according to an embodiment of the invention before "homogenization" of the magnetic particles;

Fig. 2

shows the device Fig. 1 after "homogenization"; such as

Fig. 3

a UV curve of a DNA elution solution after performing a preparation of genomic DNA according to Example I.

Fig. 1 shows a very schematic view of a device according to the invention according to an embodiment. It should be noted that 1 and 2 are highly schematic and in most applications of the inventors the actual ratios (be it size ratios such as the number of magnetic particles) will be different.

The device comprises a plurality of first magnetic particles 10 which are attached to a central element 20 in the “idle state”. Magnetic particles 10 and central magnet 20 are arranged in a (preferably closed) vessel 100, which can optionally have inlets and outlets 110 or 120 (indicated schematically in dashed lines). The vessel 100 is preferably filled with a liquid 150 to such an extent that the magnetic particles 10 and the central element 20 are in the liquid.

In the present embodiment, the central element 20 is a permanent magnet; however, this is not limitative. As already described, the central element 20 can also contain a magnetizable material such as iron.

By moving the central element 20 (for example by rotating in the direction of arrow A or alternatively by shaking), which is preferably carried out by means of a further magnet (not shown in the figure), it is possible to "detach" the magnetic particles from the central element 20 (quasi "shake off") and distribute in the vessel, so that (depending on the specific application) eg Can attach biomolecules to the magnetic particles.

It should be noted at this point that, in many applications of the present invention, it has been found beneficial that when a circular (or circular) movement of the central element 20 takes place, the center of this "imaginary" circle is not nearby the center of the vessel 100 is located. This arrangement often has the effect that the magnetic particles 10 are literally “flung” away from the central element 20 during the homogenization, which further simplifies the homogenization step. Thus, this is a preferred embodiment of the present invention.

Another embodiment for moving the at least one central element is a one-dimensional oscillating movement. Due to the effect of a magnetic field that moves back and forth on a line, the at least one central element is alternately “hewn” against the opposite vessel walls, as a result of which the magnetic particles are also effectively shaken off the central element 20.

A shaking movement of the at least one central element can also take place by means of an electromagnet when it is operated under alternating voltage and the magnetic field polarity changes alternately, insofar this also represents a preferred embodiment of the invention. If the operating mode is changed to direct current, a magnetic separation takes place.

The state after this "homogenization" is very schematic in Fig. 2 shown.

If the movement of the central element 20 is stopped, the magnetic particles 10 attach themselves to the central element 20 again, so that (essentially) the state of the Fig. 1 is reached again. The liquid 150 can now be removed from the vessel, for example, or additional reagents can be added, depending on the specific application.

The invention is also explained below using examples. It goes without saying that these are to be considered purely for illustrative purposes and are not intended to represent a restriction of the present invention, which is defined exclusively by the claims.

In particular, it should be explicitly noted that the present example is also to be understood in a purely illustrative manner with regard to the size / volume / quantity information described or the geometric design of the reaction vessel. As has been shown in many applications and exemplary embodiments, the present invention can be applied within a wide range and a person skilled in the art will accordingly choose other dimensions or arrangements. In addition to the advantage of operating the process as a closed system, there is of course the option to design this as an open system (see example I). In particular, it has been shown that the present invention also applies to Microsystems, such as micromixers etc., can be used very well in many applications, which is a preferred embodiment of the present invention.

Example I: Preparation of genomic DNA from 5 ml whole blood

Genomic DNA was isolated from 5 ml of whole blood using the following protocol:
5 ml of blood was placed in a 30 ml beaker with a central element (standard Teflon-coated stirring fish; length 2 cm; diameter 7 mm).

5 ml of Buffer AL (branded product from QIAGEN) and 500 μl of Proteinase K (QIAGEN) were then added. There was an incubation for 30 min at 60 ° C on a magnetic heating stirrer at a slow stirring speed.

Then 5 ml of isopropanol and 500 μl of MagAttract Suspension G (QIAGEN) were added, which contained the magnetic particles; the average diameter of the particles is 8 µm.

An external magnetic stirrer was used for 5 min. stirred to bind the genomic DNA to the magnetic particles.

The stirrer was then stopped, whereupon the magnetic particles accumulated on the central element. The supernatant was removed, then 15 ml of wash buffer AW1 (QIAGEN) were added. Homogenization was carried out the magnetic particles by stirring for 60 seconds, then again a magnetic separation by stopping the stirring.

The supernatant was removed again and 15 ml of washing buffer AW2 (QIAGEN) were added. The magnetic particles were then homogenized by stirring for 60 seconds. After the stirring had stopped, the magnetic particles were deposited on the central element.

The supernatant was removed, then the magnetic particles were air dried for 20 min.

5 ml of Buffer TE (DNA Elution, QIAGEN) were added to elute the DNA. The magnetic particles were then homogenized by stirring for 5 min. After the stirring had stopped, the magnetic particles were deposited on the central element.

The supernatant, which now contained the DNA, was transferred to a suitable storage tube and the DNA concentration was measured by UV quantification and OD scan.

The UV curve of the supernatant is in Fig. 3 to see. The yield can be estimated on the basis of the UV spectrum, which took place approximately quantitatively in Example 1 (approx. 170 μg genomic DNA from 5 ml whole blood).

Claims (12)

1. Apparatus for the treatment of a liquid with magnetic particles, comprising a vessel (100) containing the liquid (150) and a plurality of magnetic particles (10) arranged in the liquid (150) and at least one magnetic and/or magnetizable central element (20) formed in bar shape, dumbbell shape or ellipsoidal shape, wherein the ratio of the longest diameter d2 of the at least one central element (20) to the ratio of the average diameter d1 of the magnetic particles (10) is at least $$\mathrm{d}2\left(\mathrm{mm}\right)\ge 15*\mathrm{d}1\left(\mathrm{mm}\right)$$

   

   wherein the central element (20) is located completely within the interior of the vessel (100), wherein the apparatus additionally comprises at least one external magnet, which is designed for interaction with the at least one central element (20) such that the central element (20) is movable via the external magnet.
2. Apparatus according to claim 1, wherein the ratio of the volume V2 of the at least one central element (20) to the ratio of the average Volume V1 of one magnetic particle (10) is V2 (mm³) ≥ 10^∗V1 (mm³).
3. Apparatus according to claim 1, wherein the number of magnetic particles (10) per central element (20) is ≥ 10⁴.
4. Apparatus according to one of claims 1 to 3, wherein the magnetic particles (10) include a material selected from the group of paramagnetic materials, superparamagnetic materials, ferromagnetic materials, ferrimagnetic particles and mixtures thereof.
5. Apparatus according to one of claims 1 to 4, wherein the added volume V_m of the magnetic particles (10) and the at least one central element (20) is ≥0.25% to ≤50% of the total volume V_G of the vessel (100).
6. Apparatus according to one of claims 1 to 5, wherein the central element (20) comprises at least one permanent magnet and the ratio of the magnetic strength H₃ of the at least one external magnet to the magnetic strength H₂ of the at least one central element (20) is H₃ ≥ 1.1^∗H₂ to H₃ ≤ 10^∗H₂.
7. Apparatus according to one of claims 1 to 6, wherein the at least one external magnet is an electromagnet.
8. Apparatus according to one of claims 1 to 6, wherein the at least one external magnet is a permanent magnet.
9. Method for treating liquids with magnetic particles (10) with an apparatus according to one of claims 1 to 8, comprising the steps

   a) distributing the magnetic particles (10) in the liquid (150) and subsequently

   b) attaching the magnetic particles (10) to the at least one central element (20).
10. Method according to claim 9, characterized in that step a) comprises resuspending the magnetic particles (10) in the liquid (150).
11. Method according to claim 9 or 10, characterized in that prior to step a) the magnetic particles (10) were at least partially attached to the at least one central element (20) and that step a) occurs due to a force acting on the at least one central element (20).
12. Use of an apparatus according to one of claims 1 to 8 and/or of a method according to one of claims 9 to 11 for at least partially separating biomolecules from/in a preferably aqueous solution.

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