EP2536507A1

EP2536507A1 - Device, centrifuge and method for fluidic coupling 0f cavities

Info

Publication number: EP2536507A1
Application number: EP11710769A
Authority: EP
Inventors: Felix Von Stetten; Marion Finkbeiner; Roland Zengerle; Nils Paust; Günter Roth
Original assignee: Hann-Schickard-Gesellschaft fuer Angewandte Forschung eV; Albert Ludwigs Universitaet Freiburg
Current assignee: Hann-Schickard-Gesellschaft fuer Angewandte Forschung eV; Albert Ludwigs Universitaet Freiburg
Priority date: 2010-03-24
Filing date: 2011-03-23
Publication date: 2012-12-26
Anticipated expiration: 2031-03-23
Also published as: US20130252796A1; EP2536507B1; US9457359B2; DE102010003223A1; CN102905794B; CN102905794A; WO2011117327A1; DE102010003223B4

Abstract

A device for insertion into a rotor of a centrifuge has at least two bodies stacked one above the other in a stacking direction in a housing. The housing (130) is constructed in order to be inserted into a holder of the rotor of the centrifuge. In the case of correct reception of the device in the rotor of the centrifuge and in the case of rotation of the rotor, a spacing of one of the at least two bodies from an axis of rotation of the rotor is less than a spacing of another of the at least two bodies from the axis of rotation of the rotor. A first (110) of the at least two bodies has at least one first cavity (150a) and a second cavity (150b) and a second (120) of the at least two bodies has at least one first cavity (160a). The two bodies are arranged in the housing so as to be movable with respect to one another in order, responding to a rotation of the rotor, in a first phase, to couple the first cavity of the first body to the first cavity of the second body fluidically, and in a second phase, to couple the second cavity of the first body to the first cavity of the second body fluidically.

Description

description

Background of the Invention Exemplary embodiments of the invention relate to a device for insertion into a rotor of a centrifuge, for example a standard laboratory centrifuge. Further exemplary embodiments relate to a method for the fluidic coupling of cavities. Further exemplary embodiments relate to a centrifuge. The performance of (bio) chemical processes requires the handling of liquids. This is done on the one hand manually with the help of pipettes, reaction vessels and other process aids such as columns or magnetic particles and laboratory equipment and on the other hand automated, usually based on pipetting robots or other specialized equipment. So-called lab-on-a-chip (laboratory on a micro device) systems have an automation of individual process steps, a simplified handling of process fluids and a development of low-cost compact systems as a goal. In lab-on-a-chip systems, miniaturization is in the foreground. In most cases, the lab-on-a-chip systems are an arrangement consisting of two main components. Typical lab-on-a-chip systems have a passive fluidic in-use cartridge (also called a test carrier), which contains channels, reaction chambers and upstream reagents, and moreover contains an active instrument, the actuator components and detection and control units. This active instrument is usually tailored to the requirements of the fluidic cartridge. Such instruments are therefore associated with development, production and acquisition at high costs. For this reason, there are efforts to automate (bio-) chemical processes that do without or with minimal instrumentation. Examples include test strips (also called lateral flow test). Such approaches often have the disadvantage that the processes automatable thereby can only comprise a few steps and the sensitivity of these methods is limited. In many (bio) chemical processes (such as synthesis, analysis and purification), centrifuging is an essential part of processing. A centrifugal force generated by the centrifuging becomes either for the transport of liquids from a radially inner process stage to a radially used in the external process stage, or for the purpose of material separation by density differences. Centrifuges are therefore an essential part of laboratories in which (bio-) chemical processes are carried out.

In the following, automated systems will be demonstrated, which allow an automated execution of several process steps in (bio-) chemical processes.

Pipetting robots with integrated centrifuge are already known. Such systems have a pipetting robot with a gripper and an integrated centrifuge, with which, for example, the purification of DNA, RNA and proteins can be carried out automatically. With certain systems, up to 12 samples per run can be cleaned simultaneously.

A disadvantage of such an automated system for a customer is the high cost of acquiring the specialized equipment, the extra space required in the laboratory and the required training time of the qualified personnel.

Other specialized equipment uses a non-centrifugal automation alternative for handling liquids. In such so-called fluidically integrated systems, samples can be separated (nucleic acid extraction) and analyzed (for example for a so-called real-time PCR). To carry out the tests, special packages adapted to the fluidic integrated systems are required. These containers or reaction vessels consist of a flexible tube which is separated by septa. The compartments separated by the septa are preceded by the required reagents. The handling of the liquids is done by plungers, which press on the hose and act in this way on the one hand as a valve, on the other hand as a pump.

With this automated system different (bio-) chemical processes can be automated, but in turn a specialized and expensive device is necessary. This system therefore has the same disadvantages as the aforementioned system.

Furthermore, so-called special centrifuges for the processing of liquids already exist. The document US 4190530 (also published as DE 2912676 AI) shows a specially developed centrifuge with various collecting containers in a radial arrangement. The collecting container are arranged at different distances from a rotational axis of a rotor of the centrifuge in Schwenkbecherhaltern. The centrifuge shown in the document thus allows the processing of several fluids via different paths from a location closer to the axis of rotation located to another location with a greater distance to the axis of rotation. A fluid flows through a separation column in a first radially inner collecting container. At the radially outer location there are a plurality of collecting containers in which the fluid which has flowed over the separation column can flow. The fluid is conducted via acceleration forces in different directions of rotation via different paths to the outside. As a result, the fluid can get into different receptacle. With this system, different fluidic paths in the centrifuge can be realized by an exit cavity at the radially inner location. In particular, the fluid is introduced via valves and lines in the centrifuge and nozzles in the radially inner receptacle. A disadvantage of the device is that fluids of different output cavities are not routed through the same path. Furthermore, the device must be specially designed and manufactured, which is associated with high costs.

The document US 5045047 shows a centrifuge apparatus with a rotor with an inner and an outer ring. On the inner ring so-called inner container are arranged and on the outer ring so-called outer container are arranged. Furthermore, the centrifuge apparatus described in the document has a mechanism for preventing centrifugally generated radial alignment of the inner containers. This allows partial alignment of the inner containers with the outer containers so that fluid from an inner container can flow into an associated outer container due to centrifugal force generated by rotation of the rotor of the centrifuge apparatus. The script describes this condition as aligned. In an unoriented state, ie, when the inner containers are held so that they can not radially align, the inner containers can be unloaded. A disadvantage of this centrifuge apparatus shown is that fluids from different inner containers can not be routed into a common outer container. A particular disadvantage is that the centrifuge apparatus, as already described above, is a special device, which has only a limited field of application and is associated with very high costs. The document US 5087369 (also published as DE 68923835 T2) describes a method for separating and recovering proteins present in liquids by a rotating column. Based on a rotation of a column, the fluid is directed from an inner cylinder to an outer cylinder space. Another disadvantage here is that fluids from different outlet cavities can not be directed into a common end cavity.

A major disadvantage of automated systems are in particular the high additional fixed costs associated with the purchase of special equipment. The result is a more difficult market entry for such systems.

An alternative to the automated handling of liquids to perform chemical and (bio) chemical processes is manual handling of the liquids. Disadvantages of manual handling are the very many individual, to be carried out by professionals and extremely time-consuming steps, such as those incurred in a DNA extraction. Furthermore, the risk of cross-contamination of the handled liquids is always given.

Summary of the invention

It is an object of the present invention to provide a concept which enables a more cost-effective automated handling of liquids, especially in (bio-) chemical processes.

This object is achieved by an apparatus according to claim 1, a centrifuge according to claim 22, a method according to claim 23 and a method according to claim 24. Embodiments of the present invention provide an apparatus for insertion into a rotor of a centrifuge. The device has at least two superimposed bodies and a housing. The housing is designed to be inserted into a holder of the rotor of the centrifuge. The at least two bodies are arranged in the housing in a stacking direction such that, when the device is properly accommodated in the rotor of the centrifuge and when the rotor rotates, a distance of one of the at least two bodies from an axis of rotation of the rotor is less than a distance of another of the at least two bodies to the axis of rotation of the rotor. A first of the at least two bodies has at least a first and a second cavity on and a second of the at least two body has at least a first cavity. The at least two bodies are movably disposed within the housing to fluidly couple the first cavity of the first body to the first cavity of the second body in response to rotation of the rotor, in a first phase, and in a second phase to fluidly couple the second cavity of the first body to the first cavity of the second body.

It is a core idea of the present invention that an improved concept for the automated handling of liquids, for example in (bio-) chemical processes can be created, if for the automatic processing of the liquids no special equipment has to be used, but a standard laboratory equipment, such as a standard centrifuge, which is typically part of a (bio) chemical laboratory, can be used, and the processing inside the centrifuge, controlled by a rotation of the rotor of the centrifuge, is automated. Since such a centrifuge is an integral part of almost every laboratory, there are no additional fixed costs for the acquisition of a special device, in contrast to the special devices shown in the prior art. Embodiments of the present invention are designed so that they can be used in a holder of a rotor, for example in a swivel cup holder of the rotor.

By way of example, exemplary embodiments of the present invention make it possible to process different fluids in a closed device (for example a container), wherein the various fluids may already be upstream of the device (eg in the first cavity and in the second cavity of the first body). , In a first phase, a fluid from the first cavity of the first body based on a centrifugal force generated by the rotor of the centrifuge in the first cavity of the second body (due to the fluidic coupling of the first cavity of the first body with the first cavity of the second body) flow. In a second phase, in which the second cavity of the first body is fluidically connected to the first cavity of the second body, then a fluid from the second cavity of the first body due to the centrifugal force generated by the rotation of the rotor, in the first cavity of second body flow. The device may remain in the centrifuge during this process, and in particular, no interaction with a user is necessary. Exemplary embodiments thus make possible an automation process for handling liquids, which does not depend on the acquisition of expensive special appliances, but with a standard appliance available in typical (bio) chemical laboratories. is feasible. A particularly widespread standard device, which is also used for the manual processing of many processes, is the laboratory centrifuge.

Embodiments of the invention can thus be used for the automated handling of liquids in a laboratory centrifuge, with the aim of automating chemical and (biochemical processes, such as, for example, DNA extraction.

In contrast to the already known special devices, embodiments have no significant fixed costs, but may be comparable in their kind substantially with the plastic disposable articles used anyway for carrying out laboratory protocols.

In addition, operator interaction with the device is kept to an absolute minimum, with the result that specialist personnel are not necessarily required to use the device.

According to embodiments of the present invention, required processing aids, such as. B. Reaction vessels, reagents or solid phases already part of the device (for example, within the cavities of the device) be.

Embodiments of the present invention thus enable an automated implementation of processes such as DNA extraction, immunoassay or the synthesis of radiopharmaceuticals in a centrifuge, for example a laboratory centrifuge. According to some embodiments of the present invention, a transition of the first phase to the second phase may change a position of the two bodies relative to each other. A position of the first body with respect to the second body is different in the first phase from a position of the first body with respect to the second body in the second phase. In the first phase, the first cavity of the first body is thus coupled to the first cavity of the second body, and in the second phase, the second cavity of the first body is coupled to the first cavity of the second body. The transition from the first phase to the second phase may be effected in response to a change in the angular velocity of the rotor with respect to an angular velocity of the rotor in the first phase. Embodiments thus enable a fluidic coupling of different cavities within the device, based on an angular velocity, that is to say a rotational speed of the rotor of a centrifuge. In other words, a fluidic coupling of the cavities can be initiated by a centrifugation protocol of the centrifuge. According to some embodiments, the transition from the first phase to the second phase may occur without a change in the direction of rotation of the rotor of the centrifuge. Moreover, in the transition from the first phase to the second phase, an amount of the angular velocity of the rotor may always be greater than zero. In other words, embodiments of the present invention can also be applied in centrifuges in which only a movement in a predetermined direction is possible. Embodiments of the present invention thus make no higher demands on a centrifuge than do already known (manual) processing methods.

According to some embodiments of the present invention, the bodies may be cylindrical bodies, each of the bodies having a top side and a bottom side opposite in the stacking direction. A base side of the first body may be disposed opposite to a top side of the second body. The first and second cavities of the first body may adjoin the base of the first body and the first cavity of the second body may be adjacent to the top of the second body. The device can be designed such that one of the two bodies (for example, the second body) with respect to the other body (for example with respect to the first body) rotates about an axis of rotation of the two bodies extending in the stacking direction. In other words, in the first phase, the second body may be disposed in a first position with respect to the first body, and in the second phase, the second body may be disposed in a position rotated with respect to the first position with respect to the first body. Furthermore, the housing may have a circular cross-section, at least in one area, so that it corresponds, for example, in its outer shape to a standard centrifuge tube. A volume of such a standard centrifuge tube may be, for example, 2 ml, 12-18 ml, 50 ml or 500 ml.

According to further embodiments, the cavities (for example, the first and the second cavity of the first body) may comprise closure means, wherein the apparatus may be configured to open a closure means of the first cavity of the first body in the first phase, and in the second phase to open a closure means of the second cavity of the first body. Exemplary embodiments of the present invention thus make it possible, for example, to precopper certain reagents in the cavities which are opened in a phase in which the reagents are required. Just as a coupling of the various cavities takes place in response to a rotation of the rotor, an opening of the closure means of the cavities can also take place in response to a rotation of the rotor. For example, according to some embodiments, the closure means may be membranes, and the second body may, for example, have on its cover side at least one mandrel which is designed to puncture at least one of the membranes in response to rotation of the rotor.

According to further embodiments, a distance of the two bodies to each other can be variable, so that, for example, in a transition from the first phase to the second phase, a distance of the two bodies is greater than a distance of the two bodies to each other in the first phase and in the second Phase. For example, a change in the distance between the two bodies can be used to open closure means of the cavities or to be able to move the bodies to each other in the transition from the first phase to the second phase, but also in the first phase and in the second phase to allow a dense fluidic coupling of the cavities of the two bodies.

According to some exemplary embodiments, the housing may have at least two housing parts that can be separated from one another, such that at least one of the at least two body can be removed from the device when the at least two housing parts are separated. Thus, for example, after completion of the automated processing of the liquids, the device can be removed from the centrifuge, and then removed by separating the two housing parts of the housing one of the two bodies from the housing, for example, the second body, with a, in a cavity the second body, eluate, which is needed for further use.

According to some embodiments of the present invention, the at least two bodies may be configured as microtiter plates, i. H. as plates with a field of channels or cavities. The plates are displaceable to each other. Embodiments of the present invention will be described below in detail with reference to the accompanying drawings. Show it:

1a is a schematic representation of a device according to an embodiment of the present invention in a first phase;

FIG. 1b shows a schematic representation of the device from FIG. 1a in a second phase; FIG. a schematic representation of a device according to an exemplary embodiment of the present invention; schematic representations of various closure means, as may occur in devices according to embodiments of the present invention for the closure of cavities; schematic representations of various inserts as may occur in cavities of bodies of devices according to embodiments of the present invention; schematic representations of various Eluatsammelbehäl- tern, as may occur in devices according to embodiments of the present invention; a schematic representation of a device according to an exemplary embodiment of the present invention; a schematic representation of a device according to an exemplary embodiment of the present invention; schematic representations of individual components of the device of Fig. 7; schematic representations for explaining a ballpoint pen principle, as it can be used in a device according to an embodiment of the present invention; a diagram between time and angular velocity of a rotor of a centrifuge; schematic representations of two bodies of a device according to an embodiment of the present invention, in dependence on the angular velocity of a rotor shown in Figure 10 over a time. schematic representations for explaining a ratchet principle and a schematic representation of a device according to an embodiment of the present invention with the ratchet principle; a flowchart of a method according to an exemplary embodiment of the present invention; a diagram between time and angular velocity of a rotor of a centrifuge in a method for fluidly coupling a plurality of cavities according to an exemplary embodiment of the present invention; schematic representations of bodies of a device according to an embodiment of the present invention, as they occur in carrying out the method of Fig. 14; and a schematic representation of a possible embodiment of a column, which can be formed in a cavity of a body of a device according to an exemplary embodiment of the present invention.

Detailed description of exemplary embodiments

Before the present invention is explained in more detail below with reference to the figures, it is pointed out that the same elements or functionally identical elements in the figures are given the same reference numerals and that a repeated description of these elements is omitted. A description of elements with the same reference numerals is therefore interchangeable and / or applicable to each other in the various embodiments.

FIGS. 1 a and 1 b show a device 100 according to an exemplary embodiment of the present invention in two different phases of the device 100. The device 100 for insertion into a rotor of a centrifuge has two bodies 110, 120 stacked one above the other. In addition, the device 100 comprises a housing 130, which is designed to be inserted in a holder of the rotor of the centrifuge. The two bodies 110, 120 are in the housing 130 in a Stacking arranged so that when a proper recording of the device 100 in the rotor of the centrifuge, and with a rotation of the rotor, a distance of one of the two bodies 110, 120 to a rotation axis 140 of the rotor is less than a distance 1 ₂ of another of two bodies 110, 120 to the axis of rotation 140 of the rotor. A first body 110 of the two bodies 110, 120 has a first cavity 150a and a second cavity 150b. A second body 120 of the two bodies 110, 120 has a first cavity 160a. The two bodies 110, 120 are movably disposed in the housing 130 to fluidly couple the first cavity 150a of the first body 110 with the first cavity 160a of the second body 120 in response to rotation of the rotor in a first phase second phase, to fluidically couple the second cavity 150b of the first body 110 with the first cavity 160a of the second body 120.

In the case of the device 100 shown in FIGS. 1 a and 1 b, during a rotation of the rotor, the first body 110 is arranged closer to the rotational axis 140 of the rotor than the second body 120 with the distance 1 ₂ .

According to further embodiments, it is also possible that the two bodies 110 and 120 are arranged in the housing 130, that the distance 1 _{2 of} the second body 120 to the rotation axis 140 during the rotation of the rotor is less than the distance of the body 110 to the rotation axis 140 of the rotor 140.

The device 100 is shown in FIG. 1a in the first phase, i. H. the first cavity 150 a of the first body 110 is fluidically coupled to the first cavity 160 a of the second body 120. A fluid, such as a reagent, located in the first cavity 150a of the first body 110 may be moved from the first cavity 150a of the first body 110 into the first cavity 160a of the first cavity 110, based on a centrifugal force generated by the rotation of the rotor about the rotation axis 140 second body 120 flow.

In Fig. 1b, the device 100 is in the second phase, i. H. the second cavity 150b of the first body 110 is coupled to the first cavity 160a of the second body 120. A fluid, for example a reagent, located in the second cavity can thus flow from the second cavity 150b of the first body 110 into the first cavity 160a of the second body 120, based on a centrifugal force generated by the rotation of the rotor about the rotation axis 140.

In some embodiments, the first cavity 160a of the second body 120 may include a mixing device configured to move from the first cavity 150a of the first body 110 into the first cavity 160a of the second one in the first phase Body 120 fluid having a merged in the second phase of the second cavity 150 b of the first body 110 in the first cavity 160 a of the second body 120 fluid to mix. In particular, the mixing device may be configured to mix the two fluids in response to the rotation of the rotor.

According to further embodiments, in the first cavity 160a of the second body 120, a further reagent may be upstream, which based on a processing protocol first with the fluid from the first cavity 150a of the first body 110 and then with the fluid from the second cavity 150b of first body 110 should come into contact.

Exemplary embodiments thus enable automated processing of liquids, for example for (bio) chemical, chemical or biological processes, in a standard laboratory centrifuge without having to remove the device 100 from the centrifuge during processing.

The two mutually movably arranged in the housing 130 body 110, 120 may be arranged according to some embodiments displaceable (for example, translationally displaceable) to each other or len according to some other Ausfuhrungsbeispie- be arranged rotatable to each other.

According to some embodiments, in a transition from the first phase to the second phase, a position of the two bodies 110, 120 to each other may change so that a position of the first body 110 relative to the second body 120 in the first phase is different from a position of the first Body 110 is relative to the second body 120 in the second phase. Further, the device 100 may be configured to transition from the first phase to the second phase in response to a change in the angular velocity of the rotor with respect to an angular velocity of the rotor in the first phase. In other words, in the first phase, the rotor may have a given angular velocity to allow a fluid in the first cavity 150 a of the first body 110 to flow into the first cavity 160 a of the second body 120. Then, an angular velocity of the rotor may be changed, for example, such that the second body 120 shifts or twists with respect to the first body 110. The device 100 may, for example, have an actuation mechanism which, based on a centrifugal force generated by the rotation of the rotor, alters a position of the two bodies 110, 120 relative to one another. According to some embodiments, the transition from the first phase to the second phase may occur without a change in the direction of rotation of the rotor to the centrifuge, and so that in the transition from the first phase to the second phase, an amount of the angular velocity of the rotor is always greater than zero. In other words, according to some embodiments, the centrifuge can not be stopped to bring the device 100 into the second phase. In contrast, in known manual processes, for example, placing a first fluid in a centrifuge cup, it is centrifuged in the centrifuge, and then the centrifuge is stopped to add a second fluid to this centrifuge cup to supply to it together with the first fluid in the centrifuge centrifuge. Embodiments of the present invention thus allow for easier handling in the processing of different liquids compared to manual methods.

According to some embodiments, one of the cavities of the device 100 may include a closure means, wherein the device 100 is configured to open the closure means. For example, the first cavity 150a and the second cavity 150b of the first body 110 may each have a closure means, and the apparatus 100 may be configured to open the closure means of the first cavity 150a of the first body 110 in the first phase and to open in the second phase, the closing means of the second cavity 150 b of the first body 110 to open. In this case, an opening of the closure means can take place, for example, by increasing an angular velocity of the rotor until a fluid located in a respective cavity exerts a high pressure on the closure means such that the closure means breaks. Furthermore, the closure means of the first cavity 150a of the first body 110 may be configured to rupture at a slower angular velocity than the closure means of the second cavity 150b of the first body 110. However, according to other embodiments, a body opposing the cavity may also be used two bodies 110, 120, that is, for example, the second body 120, have a mandrel, which is designed to open at least one of the closure means. The mandrel may, in response to rotation of the rotor (eg, depending on a particular angular velocity of the rotor) pierce at least one of the closure means such that the fluid which is in the cavity closed by the closure means is released. According to further embodiments, the device 100 may be formed so that a distance of the two bodies 110, 120 in the transition from the first phase to the second phase is greater than a distance of the two bodies 120, 130 to each other in the first phase and in the second phase. For example, in the first phase and in the second phase, the two bodies 110, 120 are in direct contact to form a tight fluidic bond between the first cavity 150a of the first body 110 and the first cavity 160a of the second body 120 and the second cavity 150b of the first body 110 and the first cavity 160a of the second body 120 to ensure. Furthermore, in the transition from the first phase to the second phase, a distance of the two bodies 110, 120 may be greater, for example, such that a frictionless displacement of the body is ensured against each other. In addition, a change in the distance between the two bodies can be used to open closure means of the cavities, for example if, as described above, a mandrel is arranged on the second body, which is designed to open at least one closure means of the cavities , Thus, in the transition from the first phase to the second phase, the mandrel can be retracted, for example, into a closure means of the second cavity 150b of the first body 110 and remain there during the second phase. According to a further embodiment, the device 100 may comprise a phase display, wherein the phase indication is adapted to indicate in which phase the device is at a time of dropping. In other words, after performing the processing and after removing the device 100 from a centrifuge, a user may determine whether all necessary processing steps have been performed. The device 100 may have, for example, a counter or a scale.

Fig. 2 shows a device 200 according to an embodiment of the present invention. The device 200 differs from the device shown in FIGS. 1a and 1b in that the first cavity 150a of the first body 110 has a first closure means 210a on a side facing the second body 120 and the second cavity 150b of the first body 110 on the The second body 120 facing side has a second closure means 210b. A closure means can also assume a function of a lid. Furthermore, on a side facing the first body 110, the second body 120 has a mandrel 220, for example a thorn for piercing a lid. In this case, the mandrel 220 can be designed to puncture the first closure means 210a of the first cavity 150a of the first body 110 in the first phase, and to pierce the second closure means 210b of the second cavity 150b of the first body 110 in the second phase. The first cavity 160a of the second body 120 may, as in the embodiment shown in FIG. 2, be open on a side facing away from the first body 110, for example as an outlet channel 160a or closed, for example as a collection container. In the first cavity 150 a of the first body 110 may be a liquid or a fluid 230 a, in The second cavity 150b of the first body 110 may be a second liquid or a second fluid 230b. The two cavities 150a, 150b can therefore also assume a function of a reservoir. Therefore, the first body 110 may also be referred to as a magazine of a unit, that is, as a magazine of the device 100, and the second body 120 may be referred to as a downstream body.

According to some exemplary embodiments, the two bodies 110, 120 may be cylindrical bodies each having a cover side and a base side opposite in the stacking direction. A base side 114 of the first body 110 can be arranged opposite a cover side 122 of the second body 120. As shown in FIG. 2, the first cavity 150 a of the first body 110 and the second cavity 150 b of the first body 110 may adjoin the base side 114 of the first body 110. The first cavity 160 a of the second body 120 may adjoin the cover side 122 of the second body 120. In this case, the device 200 may be configured such that, in the transition from the first phase to the second phase, the second body 120 rotates with respect to the first body 110 about an axis of rotation 250 of the two bodies 110, 120 running in the stacking direction. In other words, in response to rotation of the rotor about the axis of rotation 140, or about the axis of rotation of the centrifuge, the second body 120 may rotate relative to the first body 110. The rotation axis 250 of the two bodies 110, 120 may also form a rotary axis of the unit or device 200.

According to some embodiments, a distance of the two bodies 110, 120 may change in the transition from the first phase to the second phase. For example, the device 200 may include a pressure mechanism 240 configured to transition the first phase 110 into the second phase with the first body 110 relative to the second body 120 by a stroke 260 of the device 100 from the second body 120 to space. In particular, during the first phase and during the second phase, a distance of the two bodies 110, 120 may be minimal, for example such that the mandrel 220 pierces the closure means 210a, 210b in the respective phase.

As shown in FIG. 2, according to further embodiments, the second body 120 may be formed to have recesses on its top side 122 for at least partially receiving the first body 114.

In other words, exemplary embodiments allow a rotational displacement of a unit or the device 200 by the pressure mechanism 240. In the unit or device 200 are different liquids (the fluids 150a, 150b) upstream. By rotation (about the rotary axis 250 of the apparatus 200), the liquids are fed in sequence over the mandrel 220 and the first body 110 is lowered relative to the mandrel 220. In other words, the distance between the first body 110 and the second body 120 is reduced. In this case, the closure means of the respective cavity, or the membrane of the respective reservoir, pierced and the liquid in the reservoir is released.

Embodiments thus allow all reagents and processing aids required for processing to be combined into a container (for example, to device 100 or 200) with which the rotor of a laboratory centrifuge can be equipped by the user. Such containers are shown as devices 100 and 200 in Figures la, lb and Fig. 2. The container remains in the rotor until the end of the process to be automated and is only then removed again. As already mentioned above, the container has at least two stacked bodies whose stacking direction has a radial directional component during centrifuging. The bodies have one or more chambers (or cavities), which can be equipped with process aids and reagents or fluidic internals. The direction of the chambers or the cavities also has a radial directional component during centrifuging. The channels or cavities can be open, closed on one or both sides with a lid. A lid or closure means of these cavities can be designed so that the lid or the closure means can be opened automatically during the Zentrifugationsprotokolls, z. B. by a mandrel or by pressure. In the channels or cavities contained liquid or solid substances can be transported by means of centrifugal force from a radially further inward cavity in a radially further outward cavity.

According to embodiments, to automate process flows, various combinations of cavities may be sequentially, indirectly, or directly fluidly contacted in sequence. The bodies can be moved against each other, for example, with a tangential directional component. According to embodiments, in a first centrifugation step, a substance (for example a liquid) from a first radially further inwardly located source channel (for example the first cavity 150a of the first body 110) of a body (for example the first body 110) into a radially outer body or in a cavity (for example, the first cavity 160a of the second body 120) of the body. After a relative displacement of the two bodies can in a second centrifugation step from a second radially further inward source channel (for example, the second cavity 150b of the first body 110) of the body, a substance in the same radially outward target channel (for example, the first cavity 160a of the second body 120) are conveyed. In this way, exemplary embodiments enable various substances or process aids involved in a process to be brought into contact sequentially.

A displacement of the two bodies relative to one another can be effected or initiated directly by the centrifugation protocol. A required energy for displacement of the two bodies can be obtained from the centrifuging energy and the time and / or the extent of the displacement can be determined for example by a time-varying centrifugation frequency (or a time-varying angular velocity of the rotor of the centrifuge). The mutual displacement of the body can be carried out linearly or rotationally. As already described above, closing means or covers or valves can be used to close the cavities. The lid or the closure means can be opened, for example, by a mandrel or by pressure, as can be generated for example in the centrifugal field by an overlying liquid column.

Fig. 3 shows two different possibilities for the realization of closure means for the cavities of the bodies of the devices 100 and 200. Fig. 3-A shows a cavity 310, which with a closure means, which is designed as a valve (320) is opened and can be closed. A pressure mechanism 240 already described in FIG. 2 can be used to operate the valve 320 or to open or close it in response to a rotation of the rotor or a change in the angular velocity of the rotor. In FIG. 3-A, on the left, for example, a force generated by the pressure mechanism 240 may be smaller than a centrifugal force generated by the centrifugation of the rotor, so that the valve 320 is opened, so that a liquid located in the cavity 310 or a liquid Liquid flowing through the cavity 310 may leave the cavity 310 via a liquid flow 330. The valve 320 is not disposed in a valve seat 340 in the cavity 310 in FIG. 3-A on the left. FIG. 3-A on the right shows the cavity 310 with the valve 320, which is received by the valve seat 340 of the cavity 310. The valve 320 thus closes the cavity 310, so that a liquid present in the cavity 310 or a liquid flowing into the cavity 310 can not leave the cavity 310. For example, a centrifugal force generated by the centrifugation of the rotor is smaller than a restoring force generated by the pressure mechanism 240. In other words, FIG. 3-A shows the possibility of using a valve 320 for closing or opening a cavity 310. The valve 320 may also be controlled by a centrifugally operated mechanism (for example, the pressure mechanism 240) by generating a lifting motion, for example, the valve 320 may be firmly locked, and a body having the cavity 310 may be controlled with respect to the Valve 320 are moved. In addition, perforated discs as a grinding valve (comparable to a spice spreader) can be used, which can be actuated by a rotational or translational movement, wherein according to some embodiments, the movement can be controlled by changing the Zentrifugationsfrequenz (or angular velocity) of the rotor.

Fig. 3-B shows a further possibility of a closure means of a cavity. The cavity shown in FIG. 3-B may, for example, be the first cavity 150a of the first body 110 according to FIGS. 1 and 2. The closure means 210a of the first cavity 150a may be formed as a membrane. The cavity 150a may be, for example, a reservoir or a supply line. In Fig. 3-B left, a restoring force generated by the pressure mechanism 240 may be greater than a centrifugal force generated by the centrifugation of the rotor, so that the closure means 210a and the membrane above the mandrel 220, for example, with a hub 260 is arranged. The mandrel 220 can be arranged, for example, on the first cavity 160a of the second body 120. In Fig. 3-B right, for example, a centrifugal force generated by the centrifugation of the rotor may be greater than a restoring force generated by the pressure mechanism 240. For example, an angular velocity of the rotor in Fig. 3-B left may be smaller than an angular velocity of the rotor in Fig. 3-B right. The cavity 150a with the closure means 210a or the membrane 210a thus descends onto the mandrel 220, or the mandrel 220 moves into the closure means 210a or the membrane 210a in order to pierce or open the membrane 210a. A liquid contained in the cavity 150a can thereby flow out of the cavity 150a, for example into a radially more remote channel opening (for example into the first cavity 160a of the second body 120 according to FIGS. 1 and 2). In other words, Fig. 3-B shows how a pressure mechanism 240 is used to pierce a membrane 210a, whereby a channel or reservoir or cavity 250a can be opened, and the liquid contained therein into radially-removed channel openings or radially removed cavity flows.

In the cavities shown in FIGS. 1 to 3 (for example the cavities 150a, 150b, 160a), various process auxiliaries may be contained. On the one hand, these process aids can be upstream liquids and solids, but on the other hand also fluidic built-in elements. Processing aids can, for. Examples include: liquid reagents (eg buffers for DNA extraction), dry reagents (eg freeze-dried polymerase, Microspheres, salts), chromatographic columns or membranes (for example for DNA extraction or for the purification of proteins), microfluidic structures, such as, for example, siphons, aliquoting structures or mixers, nozzle membranes or filters (for example so-called track etchers). Membrane), functional constructive elements for mixing, separating or defining a fluidic path (as will be described later in Fig. 4), valves (as already described in Fig. 3), magnetic particles, magnets, chemical substances which generate heat, for example, by exothermic reactions of the sample to reach a certain incubation temperature, substances which cause gas bubble formation by reaction with the sample to mix the sample under centrifugation or reducing agents and other, or swellable substances or liquids with solubility Narrowing down solutions.

FIG. 4 illustrates various possible installation elements for the cavities.

Fig. 4-a shows an example of a siphon cavity. The siphon can either be controlled by volume or by capillarity and can accordingly be used for switching liquids as a function of the rotational frequency or as a function of the fill level.

Fig. 4-b shows an example of a cavity with a cup fitting element. The cup or oscillating cup insert may be vibrated by variations in the centrifugation frequency. In the cup thereby liquids can be mixed. Furthermore, the cup installation element on the upper side has a mandrel which serves for piercing overlying reservoirs. The cup installation element shown can therefore be used, for example, in the first cavity 160a of the second body 120 of the apparatus 200 according to FIG. 2, for example in order to open the closure means 210a, 210b of the first body 110 with the piercing mandrel. Further, the cup bottom contains a predetermined breaking point, whereby at increased centrifugation frequency, the liquid can be released by breaking the predetermined breaking point in the cavity and leave the cavity through a laxative channel (or a drip nose).

Fig. 4-c shows an example of a cavity with a static mixing element. For example, a liquid in a bowl of the static mixing element may flow into the cup from an overlying cavity due to centrifugal force and be mixed through holes in the bowl of the mixing element with a liquid which has already been pre-stored in the mixing element. Fig. 4-d shows an example of a cavity with a dynamic mixing element. A perforated plate moves up and down depending on a rotational speed of a rotor of a centrifuge to thereby mix liquids located in the dynamic mixing element. A spring force of the spring can be adapted so that a centrifugal force generated by a rotation of the rotor at a first angular velocity of the rotor is smaller than the spring force, and at a second angular velocity of the rotor is greater than the spring force. The spring may for example be formed from an elastomeric material or elastic polymer material and in particular be produced by injection molding.

Figure 4-e shows an example of a cavity incorporating a silica solid phase for DNA extraction or protein purification. The cavity has in its interior a stack of a silicone ring of a silica membrane and a porous support. This layer stack is fixed on a support in the cavity. A liquid located in the cavity can, for example, depending on a centrifugation frequency of the rotor, be thrown from a first region of the cavity through the silica membrane and the porous support into a second region of the cavity.

Fig. 4-f shows an example of a cavity with a track etch membrane. This can be used, for example, to produce particles or emulsions by means of a track etch membrane. An alginate solution is divided into small droplets by the track-etch membrane pressed into a ring under the influence of the centrifuging force. The droplets can be caught by a calcium solution and gelled to solid particles. After a centrifugation process is in the cavity with a gelled alginate. Moreover, it is also possible that the cavity is followed by a body with another cavity in which the calcium solution is contained, so that the gelled alginate collects in a cavity of another body, for example so that the further body of the Device is removable. Fig. 4-g shows an example game for a cavity with a dynamic Aliquotierstruktur. In this case, the cavity can have an aliquoting structure and a second body can be connected to a body of the cavity, for example a vessel with chambers, which can be removed individually from the device. A liquid located in the cavity with the aliquoting structure distributes itself evenly to the chambers of the vessel with the chambers, for example in response to a rotation of the rotor. Fig. 4-h shows an example of a cavity with a static aliquoting structure. The catalysis with the static aliquoting structure is therefore designed as a vessel with chambers, with aliquoted liquids in the individual chambers. 4-i shows an example of a combination of a siphon and an aliquoting structure, for example a siphon can be arranged in a cavity of a radially inner body and a radially outer body can be formed as a vessel with chambers (several cavities) , A liquid located in the cavity of the radially inner body is uniformly distributed to the individual chambers of the radially outer body based on a centrifugal force generated by the rotation of the rotor.

At the beginning of a process, such as a (bio) chemical process, it may be necessary to add non-system specific materials to the process. For example, a sample such as blood can be given up. As a rule, the sample can be applied to a body (into a cavity of a body), which lies radially furthest inward during processing. For example, the sample may be introduced into the first cavity 150 a and / or into the second cavity 150 b of the first body 110 according to FIGS. 1 a, 1 b and 2. The product of the process (eg DNA extracted from blood), on the other hand, can generally be taken from the radially outermost body (or a cavity of the most outermost body). For example, the product of the process can be taken from the first cavity 160a of the second body 120 according to FIGS. 1a, 1b and 2. According to one embodiment, therefore, the body containing the product of the process can be easily removed from the container (or device 100 or 200 according to FIGS. 1a, 1b, 2) in order to gain access to the product of the process (FIG. which can also be referred to as eluate).

In some embodiments, to sample into one of the cavities of the device, at least one of the cavities of the device may be accessible from outside the device. For example, the device may have a lid which releases a cavity which is radially innermost upon rotation of the device when it is open.

According to some exemplary embodiments, a housing of a device according to an exemplary embodiment of the present invention can have at least two housing parts which can be separated from one another, such that at least one of the at least two bodies can be removed from the device when the at least two housing parts are separated. In the following, examples are to be described which, for example, allow a simple removal of product when designing a device according to an exemplary embodiment of the present invention as a centrifuge tube. For this purpose, a device or a container has an easily accessible collecting device, which may also be suitable, for example, for storing the product and which may be compatible in the format to standard reaction vessels. A collecting vessel can be attached either centrally or decentrally to the device.

5 shows various implementation variants for such collecting devices in devices according to embodiments of the present invention. In other words, Fig. 5 shows examples of advantageous, easily removable collecting devices for the product of a process (eluate) or waste liquids (so-called Waste). In this case, these collecting devices can be arranged, for example, in a device according to an exemplary embodiment of the present invention as a further body in the housing 130 of the device 100 according to FIGS. 1a, 1b. For example, the catching devices may be disposed in the housing 130 or on the housing 130 such that they are disposed radially outermost with respect to the other body of the device 100 upon rotation of the rotor. Fig. 5-a shows a part of a device according to an embodiment of the present invention with a housing 130 and a first body 110 having a first cavity 150a and a second cavity 150b. In addition, the device has a second body 120 with a first cavity 160a. Furthermore, the device has a third body 510 in the form of a decentralized eluate tube 510, which is arranged in the housing 130 such that when the second cavity 150b of the first body 110 is fluidically coupled to the first cavity 160a of the second body 120, too the tubule 510 is fluidically coupled to the first cavity 160a of the second body 120. The device is thus designed so that in the second phase, the first cavity 160a of the second body 120 is coupled both to the second cavity 150b of the first body 110 and to the eluate tube 510. In the first phase, in which the first cavity 160a of the second body 120 is fluidically coupled to the first cavity 150a of the first body 110, the first cavity 160a of the second body 120 is additionally fluidly coupled to a waste liquid container 520 of the housing 130. The first cavity 160a of the second body 120 has a sow, over which, located in the first cavity 150a and in the second cavity 150b of the first body 110, liquids are processed. The device is designed so that a liquid which is located in the first cavity 150 a of the first body 110 is processed in the first phase via the column, and a resulting waste liquid in the Ab¬ Case 520 of the housing 130 is collected. In the second phase, a liquid located in the second cavity 150b of the first body 110 can then be processed via the sows, whereby a resulting eluate is collected in the eluate tube 510. The column can therefore also be referred to as a rotating column.

Fig. 5-b shows another device according to an embodiment of the present invention. The device differs from the device shown in Fig. 5-a in that the eluate tube 510 is centrally located in the housing 130, for example so that a rotation axis 250 of the device also forms an axis of rotation of the eluate tube 510. Further, between the second body 120 and the eluent tube 510 and the waste liquid container 520 of the housing 130, the device has a fixed manifold which is adapted to direct a liquid processed through the column into the waste liquid container 520 in the first phase and into the second Into the eluate tube 510. The fixed distributor is itself arranged in the housing 130, and the second body 120 is rotatably arranged in the housing 130, as already described in FIG. 5-a.

Fig. 5-c shows another device according to an embodiment of the present invention. The device differs from the device shown in Fig. 5-b in that the eluate tube 510 has a screw thread, for example with a screw cap (eg, Saarstedt screw cap tube, 2 mm).

Fig. 5-d shows another device according to an embodiment of the present invention. The device differs from the device in FIG. 5-a in that the decentralized eluate tube 510 has an integrated lid. The lid can be designed, for example, such that when the eluate tube 510 is withdrawn from the housing 130, the lid of the eluate tube 510 automatically closes. Fig. 5-e shows another device according to an embodiment of the present invention. The device shown in Figs. 5-e differs from the device shown in Figs. 5-d in that the decentralized eluate tube 510 with lid is placed obliquely in the housing 130. According to a further embodiment, an eluate tube 510 (also referred to as a reaction vessel) may also have a screw cap instead of a lid.

Fig. 5-f shows another device according to an embodiment of the present invention. The device shown in FIGS. 5-f differs from those in FIGS. a to Fig. 5-e devices in that the eluate is collected in another body 510 (for example, in addition to the first body 110 and the second body 120) and in that the further body 510 is disposed on the housing 130 and is deductible from this. The further body 510 can therefore also be referred to as a removable catching turret, which is part of the housing 130. The removable collecting turret may be fastened to the housing 130, for example via a screwed connection, or clamped to the housing 130.

Fig. 5-g shows a further device according to an embodiment of the present invention. The device shown in FIGS. 5-g differs from the devices shown in FIGS. 5-a to 5-f in that the eluate tube 510 is injection-molded onto the housing 130 and separated from the housing 130 via a predetermined breaking point can be. The eluate tube may possibly be threaded. The eluate is therefore collected in the cast eluate tube with a predetermined breaking point.

If, in addition to the sample in the adjacent cavity, waste liquids are still to be collected, some of which are still wetting, for example, capillary reflux can be prevented by introducing a suction sponge into the cavities.

FIG. 6 shows an apparatus 600 according to an embodiment of the present invention. The device 600 differs from the device 100 shown in FIGS. 1 a and 1 b in that it has a third body 510 within the housing 130. The third body 510 is arranged in the housing 130 in the stacking direction in such a way that, when the device 600 rotates about the rotational axis 140 of the centrifuge, a distance l _{3 of} the third body 510 to the axis of rotation 140 is greater than the distance l ₂ of the second body 120 to the axis of rotation 140 of the centrifuge. As in the case of the device 100, the distance 1 _{2 of} the second body 120 to the rotational axis 140 of the centrifuge is greater than the distance Ii of the first body 110 to the rotational axis 140 of the centrifuge. In other words, the third body 510 is disposed radially outermost radially upon rotation of the apparatus 600 about the axis of rotation 140 of the centrifuge, and the first body 110 is disposed radially innermost, while the second body 120 is disposed between the first bodies 110 and the third body 510 is arranged. Furthermore, the first body 110 has a plurality of cavities R1-Rn, where n is an index to a number of the cavities of the first body 110 and n can be any integer number. The cavities R1-Rn can also be referred to as reagent pre-storage chambers. The first body 110 can therefore be used for reagent pre-storage and, in addition, a sample (as in For example, blood) in one of the reagent storage chambers Rl-Rn be abandoned. For example, all of the reagents needed to perform a specific (bio) chemical process can be pre-stored in the reagent storage chambers R1-Rn. For example, reagents such as a lyase, a proteinase, and other reagents required for DNA extraction may be pre-stored for DNA extraction.

Further, the second body 120 has any plurality of cavities Kl-Km, where m is an index for a number of the cavities of the second body 120, and where m can take any integer value. The cavities K1-Km can also be referred to as processing cavities K1-Km. In particular, a processing of the reagents upstream of the reagent storage chambers R 1 -Rn can take place in these processing cavities K 1 -Km. In other words, the second body 120 may include processing cavities K1 -Km for processing (such as mixing, lysing, sedimentation, binding, or else elution).

According to further embodiments, the second body 120 may comprise separation devices F, which are arranged, for example, radially behind the processing cavities Kl-Km in the second body 120.

The third body 510 has a plurality of cavities Al-Ak, where k is an index for a number of cavities Al-Ak of the third body 510, and where k can take any integer value. The cavities Al-Ak can also be referred to as analysis chambers Al-Ak. The analysis chambers Al-Ak can serve to capture the fluids processed in the second body 120. The liquids collected in the analysis chambers Al-Ak can be used for analysis or further processing. In other words, the third body 510 with its analysis chambers Al-Ak can serve for interception, read-out and possibly for further processing. The third body 510 may be removable from the housing 130, for example.

According to some embodiments of the present invention, the housing 130, which is adapted to be inserted in a holder of a rotor of a centrifuge, may be formed as a casing having the dimensions of a standard cavity of a laboratory centrifuge. According to some embodiments, the bodies 110, 120, 510 may be cylindrical bodies with an axis of rotation 250 of the body running in the stacking direction of the bodies. In the exemplary embodiment shown in FIG. 6, a fluidic coupling of the various cavities of the three bodies 110, 120, 510 can take place by rotating the second body 120 about the rotation axis 250 of the bodies. For example, by rotating the second body 120, any fluidic path from the reagent storage chambers Rl-Rn via the processing cavities Kl-Km (and via the separation device F if the second body 120 has) to the analysis chambers Al-Ak realizable. According to further exemplary embodiments, it may also be possible for the first body 110 and / or the third body 510 to be rotated or rotated about the rotation axis 250 of the body. According to some embodiments, the second body 120 may be configured to translate, for example, around a hub 260. The translation of the second body 120 may be due to an interaction of the centrifugal force generated by the rotation of the rotor about the axis of rotation 140 of the centrifuge with a counterforce, such as spring force, magnetic force, or weight force. The rotation of the second body 120 about the axis of rotation 250 of the body can thereby based on the translation of the second body 120 with a suitable mechanism (such as a ball-writing mechanism, as for example still explained by Fig. 9 or a ratchet mechanism, as still with reference of Fig. 12). The translation of the second body 120, for example along the axis of rotation 250 about a stroke 260, may also be used to open, for example, reagent pre-storage chamber closure means R1-Rn. For this purpose, the second body 120 can, for example, have one or more mandrels which, upon displacement of the second body 120 in the direction of the first body 110, can open closure means, which can be for example a membrane, of the reagent pre-storage chambers R1-Rn. According to some embodiments, a number of reagent pre-storage chambers Rl-Rn, a number of processing cavities Kl-Kn, a number of the separation device F, and a number of analysis chambers Al-Ak may vary in different devices according to embodiments of the present invention, for example, one device to a particular one to adapt (bio) chemical process. For example, a different number of reagent storage chambers R1-Rn may be needed for DNA extraction than for a synthesis of radiopharmaceuticals. According to some further exemplary embodiments, a number of the bodies may also vary in different devices according to exemplary embodiments of the present invention, for example adapted to a specific (bio) chemical process. In particular, with a suitable mechanism, bodies located inside a housing 130 in the device can rotate relative to one another based on a rotation of a rotor of a centrifuge.

7 shows a sectional view of a device 700 for insertion into a rotor of a centrifuge according to an exemplary embodiment of the present invention. The device 700 differs from the device 100 shown in FIGS. 1 a and 1 b in that it has a third body 510 in the stacking direction, which, as in the device 600 according to FIG. 6, rotates around the device 700 Rotation axis 140 of the centrifuge is arranged radially outermost with respect to the other two bodies 110, 120 of the device 700. The third body 510 has a first cavity 720a and a second cavity 720b. The first cavity 720a of the third body 510 may be, for example, an eluate collection vessel or an eluate chamber, and the second cavity 720b of the third body 510 may be, for example, a so-called waste tank or a waste chamber. Furthermore, the second body 120 has in its cavity 160a a mixing device 730 which is designed to mix at least two fluids located in the cavity 160a in response to a rotation of the rotor. The mixing device 730 will be described in detail in Fig. 8c. Furthermore, the first body 110 has eight cavities, for example as reagent storage chambers.

Furthermore, the housing 130 has two housing parts 132, 134 which can be separated from one another, so that when these two housing parts 132, 134 are separated, at least one of the bodies of the device 700 (for example the third body 510) can be removed from the device 700. According to further embodiments, the housing 130 may also include a plurality of housing parts 132, 134. The individual housing parts 132, 134 may, for example, be inserted into one another via springs and grooves or may also be screwed together via screw connections. A first housing part 132 of the two housing parts 132, 134 of the housing 130 may also be referred to as a first sleeve 132, and a second housing part 134 of the two housing parts of the housing 130 may also be referred to as a second sleeve 134. As shown in FIG. 7, in order to close the housing 130, the second sleeve 134 is attached to the first sleeve 132. Each of the three bodies can also be called a revolver. Thus, the first body 110 may be referred to as a first turret 110, the second body 120 as a second turret 120, and the third body 510 as a third turret 510.

The first turret 110 has, as already described above, a reagent storage.

The second turret 120 has the mixing device 730 as already described above. The third turret 510 has, as already described above, an eluate chamber 720a and a waste chamber 720b.

Furthermore, the device 700 has a spring 710 for the lateral movement of the three revolvers 110, 120, 510. The spring 710 serves to generate a restoring force which acts in opposition to a centrifugal force generated by the rotation of the rotor to allow a shifting operation (for example, a rotation of the second revolver 120 relative to the other two revolvers). The spring 710 may, for example, be comparable to a return spring for a ballpoint pen, a rotation of the second revolver 120 with respect to the other two turrets 110 and 510 may be based on a ball-type recorder mechanism which will be explained with reference to FIG. 9.

The device 700 shown in Fig. 7 with three turrets 110, 120, 510 can be used for example for the purpose of DNA extraction. As previously described, a ballpoint pen mechanism may translate the centrifugation protocol into a stepwise rotation of the second turret 120 relative to the first turret 110 and the third turret 510.

The spring 710 below the third turret 510 regulates the distance to the casing or to the housing 130, which has (or consists of) the two housing parts 132, 134. By the interaction of the spring 710 with the centrifugal force, the three turrets 110, 120, 510 are moved. Thereby, the ballpoint pen mechanism of the device 700 is driven, and the second turret 120 is rotated with respect to the other two turrets 110, 510. The spring 710 may be formed as a compression spring or tension spring. Furthermore, according to further embodiments, the spring 710 may also be formed as another return means, which generates a restoring force on at least one body of the device 700. In particular, as restoring means, for example elastomers (rubber band), Metal springs, thermoplastics or thermosets are used. According to further exemplary embodiments, the return means can be manufactured as part of a body (for example, as part of the third body 510). Such manufacturing methods are known from the packaging industry and z. B. used in the manufacture of disgusting tablets of tablets by injection molding. In this way, both the number of parts of embodiments of the present invention can be reduced, and the assembly can be simplified.

8a shows on the left the first housing part 132 of the housing 130 in a side view and a sectional view along a section axis A-A. Furthermore, Fig. 8a right shows the second housing part 134 of the housing 130 in a side view and a sectional view along a section axis A-A. The second housing part 134 forms a lower end of the device 700, d. H. During a rotation of the device 700, the second housing part 134 is arranged radially outermost, and in particular radially further outward than the first housing part 132. The first housing part 132 has a cylindrical shape and a circular cross-section. On a base side 804 of the first housing part 132, the first housing part 132 has two opposing hooks 810. The two opposed hooks 810 are configured to be received in two opposing hook receivers 812 of the second housing 134. The two hooks 810 project beyond the base side 804 of the first housing part 132.

In other embodiments, the housing portion 132 may include a viewing window 814 (eg, on a transparent plastic material) that, in combination with, for example, a display on the second body 120 forms a phase indication to a phase in which the device 700 is at the time of tapping to display.

According to further exemplary embodiments, the first housing part 132 can have on an inner side a plurality of guide grooves 816 which extend in a direction at least in a partial area of the inner area of the first housing part 132 in a direction orthogonal to a cover side 802 of the first housing part 132. The guide grooves 816 may each have beveled ends at an end facing the base side 804. The inner region of the first housing part 132 can be accessible, for example, from the base side 804 of the first housing part 132, for example in order to insert the three revolvers 110, 120, 510 into the first housing part 132. Furthermore, the first housing part 132 can be open or closed on its cover side 802 and, for example, can have a cover on the cover side 802. The second housing part 134 has on a cover side 806 the same circular cross-section as the first housing part 132 on its base side 804. The Hakenaufhahmen 812, adapted to the hook 810 of the first housing part 132, rearwardly offset relative to the top side 806 of the second housing part 134 on the second housing part 134 arranged net. The circular cross-section of the second housing part 134 may taper in a region in which the hook receivers 812 no longer extend to a base side 808 of the second housing part 134, ie the housing part 134 may be truncated cone-shaped at an end opposite the cover side 806. Within the frusto-conical end, the housing part 134 may have a receptacle 818 for the spring 710. An inner region of the second housing part 134 may be accessible from the cover side 806 of the second housing part 134, for example to receive the third body 510, or to remove it from the housing 130.

A length from the cover side 802 to the base side 804 of the first housing part 132 may be greater than a length from the cover side 806 to the base side 808 of the second housing part 134.

The housing 130 and thus the two housing parts 132, 134 may correspond in their external dimensions of a standard laboratory centrifuge cavity, for example, with a volume of 500ml, 250ml, 50ml, 18ml-12ml, 15ml, 2ml, 1.5ml, or 0.5ml.

FIG. 8b shows schematic representations of the first body 110 of the device 700 according to FIG. 7. FIG. 8b-a shows the first body 110 and the first revolver 110 in a side view. As already mentioned above, the first body 110 is a cylindrical body 110 with a cover side 820 and an opposite base side 822. The first body 110 has a plurality of guide springs 824 on its outside. The number of guide springs 824 may, for example, be adapted to the number of guide grooves 816 of the first housing part 132 (ie of the housing 130). The guide springs 824 of the first body 110 are designed to engage with the guide grooves 816 of the housing part 132. The guide springs 824 may be formed (in conjunction with the guide grooves 816 of the first housing part 132) to prevent rotation of the first body 110 with respect to the other bodies 120, 510 (for example, in a transition from a first phase to a second phase). The guide springs 824 of the first body 110 may be chamfered on the cover side 820 facing ends, for example, to allow easier insertion of the first body 110 in the housing 130 (ie in the second housing part 134). Due to the tapered ends of the guide springs 824, a wedging of the guide springs 824 with the Guide grooves 816 of the first housing 132, when inserting the first body 110, excluded (or at least almost excluded).

According to further embodiments, the first body 110 may have at its base side 822 a plurality of tread teeth 826, which are arranged circumferentially around the first body 110. For example, a number of the profile teeth 826 may be adapted to a number of the process steps to be performed in the device. Thus, a number of the teeth may vary in different devices which are suitable for different (bio) chemical processes. Similarly, the number of guide springs 824 and the guide grooves 816 may vary. In the exemplary embodiment shown in FIGS. 8 a and 8 b, the first housing part 132 has eight guide grooves 816. In addition, the first body 110 has eight guide springs 824 and eight profile teeth 826. The profile teeth 826 may be formed, for example, to allow a guide of the second body 120 and the second turret 120. In other words, FIG. 8b-a shows in a side view of the first turret 110 structures for the ballpoint pen mechanism with grooves between guide springs 824 for guiding in the column (in the first housing part 132) and recesses (profiled teeth 826) for guiding the second revolver 120th

FIG. 8b-b shows a plan view of the first turret 110 with a multiplicity of cavities for the preliminary reagent storage. In the specific exemplary embodiment shown here, the first turret 110 has eight cavities. In the eight cavities, for example, eight different reagents can be pre-stored for processing.

8b-c shows a bottom view of the first turret 110 with tracks of three spikes, which are arranged, for example, on the second revolver 120 for opening closure means of the cavities of the first turret 110. Each of the three mandrels pierces the chambers (the cavities) with the upstream reagents. In Fig. 8b-c are the respective tracks that tread the individual mandrels in the rotation of the second body 120 with respect to the first body 110, are shown. A path of a first mandrel 828a is shown with a dotted arrow. A path of a second mandrel 828b is shown with a dashed arrow and a path of a third mandrel 828c is shown with a solid arrow. The individual numbers in the respective cavities, both in FIGS. 8b-b and in FIGS. 8b-c, indicate in which phase, ie also in which order, the individual cavities or their closure means are pierced by one of the mandrels. For example, a first cavity 150a of the The first body 110 is pierced by the first mandrel 828a in a first phase. A liquid or a process agent located in the first cavity 150a of the first body 110 can then flow into a cavity of the second body 120. In a second phase, in which the second body 120 is rotated by one step with respect to the first body 110 (compared to the first phase), a second cavity 10 b of the first body 110 is pierced by the first mandrel 828 a, so that an in The second cavity 150 b of the first body 110 can flow liquid into a cavity of the second body 120 (for example, in the same cavity in which even the liquid from the first cavity 150 a of the first body 110 has flowed). In a third phase, a third cavity 150c is pierced by the first mandrel 828a, so that a liquid located in the third cavity 150c can flow into a cavity of the second body 120. The first mandrel 828a may in this case be connected to a cavity of the second body 120, so that liquids of cavities which have been pierced by the first mandrel 828a all flow into one and the same cavity within the second body 120. In a fourth phase, a seventh cavity 150 g of the first body 110 is pierced by the second mandrel 828 b, so that a liquid located in the seventh cavity 150 g flows into a cavity of the second body 120. In a fifth phase, an eighth cavity 150h of the first body 110 is pierced by the second mandrel 828b such that a liquid located in the eighth cavity 828a enters a cavity of the second body 120 (e.g., the same cavity into which the liquid from the seventh cavity has flowed 150g) flows. In this case, the second mandrel 828b may be configured analogously to the first mandrel 828a such that liquids from cavities pierced by the second mandrel 828b flow into a common cavity in the second body 120 or at least via a common fluid path in the second body 120 run. In a sixth phase, a fourth cavity 150d is pierced by the third mandrel 828c so that a liquid located in the fourth cavity 150d flows into a cavity of the second body 120. In a fifth cavity 150e and a sixth cavity 150f, further reagents may be upstream, or no reagents may be upstream.

In order to prevent a mandrel from piercing a cavity before the liquid from the respective cavity is required, the mandrels can be arranged offset on the second body 120, and the closure means of the respective cavities only at certain locations, which are shown in FIGS. 8b-b and 8b-c are hatched, pierced by the thorns. Furthermore, it is also possible for the individual mandrels 828a, 828b, 828c to be extended out of the second body 120 in a phase in which they are needed, and moved into the body 120 in another phase. This can be initiated, for example, via the centrifugation protocol. Fig. 8c shows the second body 120 (the second turret 120) from different views. Fig. 8c-a shows the second body 120 in a side view. Fig. 8c-b shows the second body in a sectional view taken along a section axis AA. Fig. 8c-c shows the second body 120 in an isometric view. Fig. 8c-d shows the second body 120 in a plan view. 8c-e shows the second body 120 in a further sectional view along a section axis BB. The second body 120 is a cylindrical body having a top side 830 and a base side 832 opposite thereto. The second body 120 has on its cover side 830, which may also be referred to as a cover, the three pins 828a, 828b, 828c. The three mandrels have a different distance from a rotation axis 250 of the body 120. The first mandrel 828a is farthest from the axis of rotation 250, and the third mandrel 828c is least distant from the axis of rotation. The second body 120 further includes a plurality of guide springs 834 disposed on an outer side of the second body 120. In the embodiment shown in FIG. 8 c, the second body 120 has four guide springs 834. The guide springs 834 project beyond the top side 830 of the second body 120 and each have bevelled ends in an end region in which they project beyond the top side 830. The guide springs are configured to interengage with the tread teeth 826 of the first body 110 and the guide grooves 816 of the housing 130 upon transition from one phase of the device 700 to a next phase (eg, from the first phase to the second phase) , A number of the guide springs 834 may depend on the number of process steps to be performed for a process for which the device 700 is provided. Further, the second body 120 may include a mixing device 730 configured to mix at least two different fluids or liquids within the first cavity 160 a of the second body 120. The cavity 160a of the second body 120 can therefore also be referred to below as the mixing chamber 160a. The mixing device 730 has a first mixing spring 836 for mixing within the mixing chamber 160a. Furthermore, the mixing device 730 has a separation device 840 or hole well 840 locked in the mixing chamber 160a to the first body 120 with (through) openings 845 (or holes 845). The well 840 may also be referred to as a perforated plate 840. The openings 845 of the hole trough 840 are arranged on the hole trough 840 such that when the device 700 is received in a rotor, a centrifuge, and with a rotation of the rotor, the openings 845 are arranged radially outermost with respect to the hole trough 840. The well 840 may be open to the top 830 of the second body 120 such that liquid from a cavity of the first body 110 into the cavity 160a of the second body 120, and thus into the hole trough 840 can flow. Furthermore, the mixing device 730 has a mixing trough 835 or a mixing trough 835 in the mixing chamber 160a. The mixing trough 835 is movably supported relative to the hole trough 840 within the mixing chamber 160a. The mixing trough 835 is arranged so that during a rotation of the device 700, the mixing trough 835 is arranged radially further outside than the hole trough 840. A liquid which may be in the well 840 may flow from the well 840 into the mixing well 835 through the openings 845 due to the centrifugal force created by the rotation. The hole trough 840 and the mixing trough 835 are designed in such a way that, when the mixing trough 835 moves, the hole trough 840 can be moved into the mixing trough 835. The mixing trough 835 therefore has a larger cross-section than the hole trough 840 to accommodate the hole trough 840 as the mixing trough 835 moves. The mixing trough 835 has an elevation 846 for receiving the first mixing spring 836. Furthermore, the hole trough 840 has an elevation 848, which is adapted to the elevation 846 of the mixing trough 835, so that the hole trough 840 can be received by the mixing trough 835 when the mixing trough 835 moves toward the perforated plate 840. In this case, the first mixing spring 836 is arranged between the mixing trough 835 and the second body 120 in order to exert a restoring force acting on the mixing trough 835 in the opposite direction to the centrifugal force.

Further, the mixing well 835 may include a hole 841 (or a plurality of holes 841) with a closure means such as a lid sheet 847. The hole 841 of the mixing trough 835 is arranged on the mixing trough 835 such that upon rotation of the rotor, the hole 841 is arranged radially outermost with respect to the mixing trough 835. A mandrel 833 may be disposed on the second body 120. The dome 833 may be disposed on the second body 120 so as to pierce the lid sheet 847 of the hole 841 in response to a given angular velocity of the rotor. Mandrel 833, in conjunction with hole 841 and cover sheet 847, thus forms a valve of mixing tub 835 and also mixing chamber 160a of second body 120. Mixing device 730 may further include a second mixing spring 837 within mixing chamber 160a. The second mixing spring 837, like the first mixing spring 836, may be disposed between the mixing trough 835 and the second body 120, wherein a spring constant of the second mixing spring 837 may be greater than a spring constant of the first mixing spring 836. That is, a restoring force generated by the first mixing spring 836 is less than a restoring force generated by the second mixing spring 837.

Furthermore, the second body 120 may have a drip-hare 843 on its base 832. Depending on the rotational frequency or angular velocity of a rotor of a centrifuge, the first mixing spring 836 moves the mixing trough 835 up and down within the cavity 160a (the mixing chamber 160a), whereby a liquid in the mixing chamber 160a is in communication with another in the mixing chamber 160a Liquid is mixed. In other words, the mixing trough 835 is moved by the changing centrifugal force with a change in the angular velocity of the rotor and the opposite of the centrifugal force restoring force of the first mixing spring 836. Thus, the mixing tub 835 is moved radially outward by the centrifugal force to a point, and the first mixing spring 836 counteracts this movement. Due to the changing rotational frequency of the centrifuge, the mixing trough 835 moves back and forth. A liquid present in the mixing trough 835 is transported through the openings 845 of the hole trough 840 with each movement of the mixing trough 835. This results in mixing with a suitable design of the hole trough 840 and the openings 845. In other words, the liquid flows through the openings 845 of the hole trough 840 with a variable spring length, whereby a mixing process takes place. This mixture is realized by the interaction of centrifugal force and restoring force (generated by the first mixing spring 836). The change in the rotational frequency of the centrifuge (or in the angular velocity of the rotor of the centrifuge) moves the mixing trough (or mixing bowl) 835 from a radially further inward to a radially outward location, and vice versa. The liquid present in the mixing bowl 835 is guided through the openings 845 of the hole trough 840, which results in thorough mixing. The second mixing spring 837 is used to switch the valve (formed from the hole 841, the cover sheet 847 and the mandrel 833). As already mentioned, the second mixing spring 837 has a higher spring constant than the first mixing spring 836, thereby only at relatively high rotational frequencies of the centrifuge, the second mixing spring 837 compressed and the mandrel 833 opens the cover sheet 847 of the hole 841. One for the compression of the second Blade spring 837 required angular velocity of the rotor of the centrifuge can, in particular, be greater than an angular velocity of the rotor required for a compression of the first mixing spring 836. Further, a spring constant of the first mixing spring 836 may be greater than a spring constant of the spring 710 which serves to rotate the second body 120 with respect to the other two bodies 110, 510 of the device 700.

After the opening of the cover sheet 847 with the mandrel 833, the liquid in the mixing trough 835 can move the second turret 120 over a column 838 (for example over leaving a silica column 838) in the mixing chamber 160a through the drip nose 843 and flowing, for example, into the waste collection bin (into the waste chamber) 720b or into the eluate collection bin (into the eluate chamber) 720a of the third body 510. The mandrels 828a, 828b, 828c may have on the top side 830 of the second body 120 fluid guides, for example in the form of funnels and subsequent channels, or in the form of bevels so as to provide different paths for fluids whose cavities they pierce within the mixing chamber 160a , enable. For example, fluids released by the first mandrel 828a may be directed into the well 840 with a first fluid guide 829a formed as a bevel. Fluids released from the second mandrel 828b may, for example, be formed with a second fluid guide 829b forming a funnel with a channel passing the hole trough 840 and the mixing trough 835, onto the pillar 838, or into an area the mixing chamber 160a, outside the mixing trough 835, are passed. For example, the region may be fluidly connected to the column 838 so that the fluid flows from the region to the column 838. Fluids released from the third mandrel 828c may, for example, be passed directly over the column 838 with a third fluid guide 829c, which is also formed as a funnel with a channel passing the hole trough 840 and the mixing trough 835 , The channel of the third fluid guide 829c may have a smaller cross section than the channel of the second fluid guide 829b, for example, such that a fluid flows through the third fluid guide 829c slower than through the second fluid guide 829b.

Further, the mixing chamber 160a may be frusto-conical in a region below the mixing trough 835 (radially further outward than the mixing trough 835), for example, around a funnel toward the drip nose 843 for the fluids in the mixing chamber 160a.

According to further embodiments, the valve in the mixing chamber 160a may also be formed as a predetermined breaking point or a siphon, for example to mix together several liquids or reagents from the first body 110 within the mixing chamber 160a, and in a predetermined process step this valve or the To open the predetermined breaking point or the siphon, so that the mixed reagents can leave the mixing chamber 160a (for example via the drip nose 843). As previously described, the mixing chamber 160a may have a (chromatographic) column 838 at an exit (at the drip nose 843) facing the base 832, such as required for DNA extraction to form reagents. A mixed liquid can, as described above, be passed through the column 838 via a valve or via a predetermined breaking point or via a siphon. As described above, the mixing chamber 160a may include a foil 847 or a membrane 847 which may be pierced by a mandrel 833 located in the second body 120 in response to a given angular velocity of the rotor.

According to further exemplary embodiments, the mixing trough 835 may be locked in the second body 120 or mounted on the second mixing spring 837. In this case, the hole trough 840, based on the variable angular velocity of the rotor, within the mixing trough 835 move up and down. For example, the first mixing spring 836 may be arranged between the mixing trough 835 and the hole trough 840.

According to further embodiments, the second body 120 may have a plurality of cavities and thus also a plurality of mixing chambers, for example with separate mixing devices.

According to further exemplary embodiments, the second body 120 may have on its outer side a scale display 842 which, for example in conjunction with the viewing window 814 of the first housing part 132, may form a phase display of the device 700. For example, the scale display 842 may simply consist of letters and / or numbers indicating a phase of the device 700.

Fig. 8d shows the third body 510 (the third turret 510) in two different views. Fig. 8d-a shows the third body 510 in a side view and Fig. 8d-b shows the third body 510 in an isometric view. The third body 510 is a cylindrical body with a cover side 850 and a base side 852 lying opposite thereto. The third body 510 has, as already described with reference to FIG. 7, a waste chamber 720b and an eluate chamber 720a for collecting the eluate, such as the concentrated DNA on. Furthermore, the third body 510 has guide springs 854 on its outer side, for example to prevent a rotation of the third body 510 during a transition from one phase to a next phase of the device 700. According to further embodiments, the third body 510 may be configured to be removable from the housing 130, for example to perform further processing of the liquid collected in the eluate chamber 720a. According to further embodiments, the third body 510 may also have any desired plurality of cavities.

The third turret 510 may also be referred to as a waste tapping refuse catcher and eluate.

According to further embodiments, the device 700 may also include any plurality of bodies, wherein each of the bodies may have any number of cavities, for example, depending on a processing for which the apparatus is suitable.

The principle of the ballpoint pen mechanism will now be explained with reference to FIG. 9, as used by the device according to FIG. 7. Reference numerals used in the drawings are merely illustrative of what parts of the pen principle correspond to what parts of the device 700.

The printing mechanism used in the device 700 according to FIG. 7 is based on a principle which is also used in the ballpoint pen. The pressure mechanism of a ballpoint pen ensures that the writing lead either disappears into the handle tube or protrudes from the case, ready for writing. The different positions of the mine are realized by toothed elements, wherein elements also rotate relative to each other when operating the printing mechanism. This twist is also used in promotional pens used to display a changed text every time you print. Such a pressure mechanism in the ballpoint pen comprises the following four elements, a stator which is formed in the device 700 by the housing 130 and the guide grooves 816, a piston which in the device 700 through the first body 110 with its guide springs 824 and formed on the profile teeth 826, a rotor formed in the apparatus 700 by the second body 120 and its guide springs 834, and a spring formed in the apparatus 700 by the spring 710.

Fig. 9 left shows schematically the interaction of the four elements in a ballpoint pen. The stator (sleeve) is shown in this illustration, similar to an exploded drawing above and normally surrounds the piston (pressure sleeve) and the rotor (Advancing sleeve). The stator with an inserted profile (guide grooves 816) ensures that the piston (first body 110) can only move upwards or downwards. The rotor (second body 120), however, can both move vertically and rotate about the axis of rotation (eg, the axis of rotation 250).

Stator (housing 130) and piston (first body 110) together provide for the rotation of the rotor (second body 120) upon release of the manual pressure force (in the device 700 upon release of the centrifugal force). First, the required horizontal force component is created between the piston (first body 110) and the rotor (second body 120), shortly thereafter between the rotor (second body 120) and the stator (housing 130). For ballpoint pens, the rotor can engage in vertically different positions via grooves of different lengths in the stator.

In the case of ballpoint pens, therefore, a change from manual pressure force and a restoring force made by a spring leads to a stepwise rotation of the rotor.

Fig. 9 right shows the profile of the printing mechanism, which is required for the rotation. Since the spring constantly pushes up, creates a horizontal force share at the oblique ends, which are attached to the elements. This is used for the twisting. Due to the rotation, the states Mine extended and Mine retracted can be defined. In other words, sloping profiles create a horizontal force component and cause the rotor to twist.

Such a ballpoint pen mechanism is also shown in DE20000422U1.

Fig. 10 shows an angular velocity over time chart. Ω stands for an angular velocity of a rotor of a centrifuge, in which a device according to an embodiment of the present invention (for example, the device 700) is introduced. At various times, the rotor of the centrifuge has different angular velocities. On a curve 1010 of the diagram, different angular velocity-time combinations are marked with the symbols l la-l lf, which means that an angular velocity-time combination I Ia corresponds to FIG. I Ia, an angular velocity-time combination I Ib with the The curve 1010 thus shows by way of example a schematic rotational frequency course during a working step of the device 700.

FIGS. 1 a - 1 f show a partial area of a device according to an embodiment of the present invention (for example, the device 700) according to FIG. 7. The partial area shows the toothing of the first body 110 with the second body 120.

FIG. 11a shows the device in the starting position; an angular velocity of the rotor is minimal in the starting position with regard to the rotational frequency profile. The first body 110 (the revolver 110) touches with its guide springs 824 the upper stop of the guide, so the upper stop of the guide grooves 816 of the housing 130. The second body 120 touches with its guide springs 834, the tread teeth 826 of the first body 110, and can due to the guide grooves 816 of the housing 130 do not approach closer to the body 110.

FIG. 11b shows the partial region when the angular velocity is increased compared to FIG. 11a. Due to the increase in frequency, the revolvers (the two bodies 110, 120) travel downwards (radially outward). The second turret 120 is prevented from rotating by the guide of the sleeve, that is, by the guide grooves 816 of the housing 130.

In Fig. 11c, the rotational frequency is further increased, the second turret 120 travels beyond the guide of the sleeve (beyond the guide grooves 816 of the housing 130) and rotates due to a between the tread teeth 826 of the first body 110 and the guide springs 834 of second body 120 resulting horizontal force to the left. At this time, the first turret 110 and the second turret 120 converge toward each other, and a spike of the lid (the top 830 of the second turret 120) pierces the lid film (a cavity closure means) from the first turret 110. The guide springs 834 of the second body 120 are A fluid located in a cavity pierced by a spike of the second body 120 may now flow from that cavity into a cavity of the second body 120.

FIG. 1 d shows the partial area after a further increase in the rotational frequency, the two revolvers 110, 120 are completely deflected. The spring 710, which generates a restoring force to the centrifugal force is maximally compressed at the maximum deflection of the turrets 110, 120, since the centrifugal force generated by the rotation of the rotor is greater than the restoring force generated by the spring 710. Fig. 1 le shows the sub-area at a throttled rotational frequency compared to Fig. 11c. The spring force (the restoring force) of the spring 710 presses the two revolvers 110, 120 back up. The second turret 120 moves along the oblique guide of sleeve 1 (or along boundaries of the guide grooves 816 of the first housing part 132 of FIG Housing 130) further to the left. The first turret 110 and the second turret 120 move apart and the mandrel of the second turret 120 is released.

Fig. L lf shows the portions after further throttling the rotational frequency. The system is in home position and is turned one-eighth turn to the left from the position in FIG. 11a. A guide spring 834a, which in FIG. 11a was engaged with a guide groove 816a of the housing 130 and a first profile tooth 826a of the first body, is shown in FIG. 11f with a second guide groove 816b of the housing adjacent to the first guide groove 816a 130 and a second, adjacent to the first profiled tooth 826a, profile tooth 826b of the first body 110 is engaged.

FIG. 12 shows by way of example how a ratchet mechanism can be used as a printing mechanism for a device according to an exemplary embodiment of the present invention in order to be automated, that is, H. Depending on a Zentrifugationsprotokoll different cavities of radially arranged bodies to couple together.

Fig. 12-A shows a return element 1210, which runs in a conveyor rail 1212. The return member 1210 may be formed, for example, as a spring having a pin 1219 at one end with a mass. The restoring element is designed so that it causes an opposing the centrifugal force acting restoring force. A direction of the arrow 1218 indicates the direction in which the restoring force acts and a length of the arrow indicates an amount of the restoring force generated by the restoring element 1210. A direction of the arrow 1217 indicates a direction of the centrifugal force generated by the rotation of the rotor. A length of the arrow 1217 indicates a magnitude of the centrifugal force generated by the rotation of the rotor. In Fig. 12-A can be clearly seen that the centrifugal force is smaller than the restoring force. A rotational direction of the rotor of the centrifuge is represented by an arrow 1214. Thus, Fig. 12-A shows a low angular velocity condition, the elastic return member 1210 is contracted and pulls a pin located at the end with the mass toward the center (to the axis of rotation 140 of the rotor). A body of a device according to an exemplary embodiment of the present invention, for example the first body 110 of the device 100, which is connected to the restoring element 1210, can thereby be rotated one half step further. Fig. 12-B shows a state at an increased angular velocity, by increasing the angular velocity, the mass deflects the pin 1219 running in the radial guide rail 1212 to the outside. As a result, the body which is connected to the restoring element 1210 (that is to say, for example, the first body 110) is moved to another half position. step rotates. In Fig. 12-B, the centrifugal force generated by the rotation of the rotor is larger than the restoring force generated by the return member 1210.

Fig. 12-C shows a portion of a device 1200 for insertion into a rotor of a centrifuge according to one embodiment of the present invention. The device 1200 comprises two stacked, separable bodies 1220, 1230. Furthermore, the device 1200 has a housing 130, which is designed to be inserted in a holder of the rotor of the centrifuge. The two bodies 1220, 1230 are arranged in the housing 130 in a stacking direction so that, when the apparatus 1200 is properly received in the rotor of the centrifuge and when the rotor rotates, a distance of one of the two bodies 1220, 1230 from an axis of rotation 140 of the rotor Rotor is smaller than a distance of another of the two bodies 1220, 1230 to the rotational axis of the rotor 140. In the concrete embodiment shown in FIG. 12, a distance of a first body 1220 to the rotation axis 140 is less than a distance of a second body 1230 to the axis of rotation 140 of the rotor. In other words, the second body 1230 is disposed in the housing 130 radially outward of the first body 1220. The first body 1220 has a cavity 1222a. The second body 1230 has a plurality of cavities 1232. The two bodies 1220, 1230 are movably disposed in the housing 130 to fluidly couple the cavity 1222a of the first body 1220 to a first cavity 1232a of the cavities 1232 of the second body 1230 in response to rotation of the rotor in a first phase In a second phase, the cavity 1222a of the first body 1220 fluidly couples to a second cavity 1232b of the second body 1230. The radial guide rail 1212 can be designed so that it is adapted to the number of cavities 1232 of the second body 1230. Furthermore, the radial guide rail 1212 may be configured such that at a high angular velocity of the rotor, for example when the centrifugal force is greater than the restoring force, the cavity 1222a of the first body 1220 is coupled to a cavity of the cavities 1232 of the second body 1230, respectively. FIG. 12-C thus illustrates how a ratchet mechanism may be used to sequentially interconnect a channel exit or cavity 1222a of a first body 1220 with various channel entrances or cavities 1232 of a second body 1230. In this case, a liquid flow 1240 can be conducted from the cavity 1222a into, in each case, one of the cavities 1232a-1232n of the second body 1230 in phases of high angular velocity of the rotor (thus also in phases of high centrifugal force). A conveying direction, that is to say a direction of rotation of the rotor of the centrifuge, can be opposite to a direction of rotation of the first body 1220 relative to the second body 1230. Although in the embodiment shown in FIG. 12, the first body 1220 twists with respect to the second body 1230, in other embodiments, the second body 1230 may also rotate with respect to the first body 1220.

As described with reference to FIGS. 11 and 12, in order to achieve displacement of the bodies relative to one another in embodiments of the present invention, an actuation mechanism may be used, which may be characterized in that the variable centrifugal force interacts with one independent of the centrifugation Restoring force (eg spring force, magnetic force, gravity) is, whereby a change in the centrifugation frequency causes the movement of an actuator. Depending on the design of the mechanism, this can be a linear, rotational movement or guided along specific paths. Various mechanisms have been shown (ballpoint pen mechanism, ratchet mechanism), which performs such a function. When the centrifugation frequency is increased, the movement of the actuator can go in one direction, and if the centrifugation frequency is lowered, the movement of the actuator can go in the other direction. According to one embodiment, the movement of the actuator can drive a ratchet mechanism as shown in FIG. 12, whereby also a feed in only one direction can be achieved. The feed can be linear or rotary. According to further exemplary embodiments, the feed movement can also be coupled with a lifting movement with an additional directional component. This lifting movement can be performed, for example bistable. In summary, these components can form a printing mechanism, such as that used in ballpoint pens. However, in contrast to the pen, the printing mechanism is operated by the changing centrifugal force. Through each centrifugation step, the mechanism can be moved one step further, whereby a stepwise mutual displacement of the body takes place. In this way, different channel outputs can be brought into contact with different channel inputs (or different cavities) sequentially. The use of a pressure mechanism, as in the pen principle, as shown in Fig. 11, may imply a lifting movement that can be used to change the distance of the bodies from each other or to other components. If necessary, the lifting movement can be bistable or obtained by using a curved path a special course. According to some exemplary embodiments, the lifting movement can be used (as shown in FIGS. 1 la-1 lf) to puncture the lid (or the closure means) of a cavity with a mandrel for a defined process step. In this way, a valve can be realized which can be used to control the process. As already described above, an actuation mechanism is based on the one hand on the centrifugal force, which is generated by a rotation of the rotor, and on the other hand on a restoring force. The restoring force can, as already mentioned above, be caused by a spring, a magnetic field or the gravitational field. In preferred embodiments, a return means for generating the restoring force may be formed as a spring.

The actuation mechanism described in FIGS. 11 and 12, which serves for the rotation and / or for the generation of the stroke, can either be an integral part of the devices according to embodiments of the present invention. Furthermore, the actuation mechanism can also be brought into contact with the device as an external reusable mechanism before use.

If the mechanism is an integral part of the device, it can either be attached to each individual unit that is to be rotated or alternatively only to a single unit. The movement can be transmitted in the latter case to other units by means of a shaft.

In the execution as external reusable mechanics, the mechanism may be mounted externally, for. B. are placed on the centrifuge tube. The rotational and / or lifting movements generated in the mechanism can be transmitted to the devices to be moved with a shaft or with plungers.

Devices according to embodiments of the present invention may in particular be designed as disposable articles, for example with already upstream reagents, which are disposed of after carrying out a process for which they are suitable and after removal of the eluate.

FIG. 13 shows a flow chart of a method 1300 for fluidically coupling cavities according to an embodiment of the present invention. The method 1300 includes a first step 1310 of rotating a rotor of a centrifuge at a first speed. In a holder of the rotor, a housing is used, in which at least two stacked bodies are arranged in a stacking direction. The at least two stacked bodies are arranged in the stacking direction such that when the rotor is rotated, a distance of one of the at least two bodies from its axis of rotation of the rotor is less than a distance of another of the at least two bodies from the axis of rotation of the rotor. A first of the at least two bodies has at least a first and a second cavity and a second of the at least At least two bodies have at least one first cavity. The at least two bodies are movably disposed within the housing to fluidly couple the first cavity of the first body with the first cavity of the second body in response to rotation of the rotor in a first phase and the second cavity of the first in a second phase To couple body with the first cavity of the second body fluidly. The first speed is selected so that the first cavity of the first body is fluidically coupled to the first cavity of the second body. Thus, in the first phase, a liquid or fluid located in the first cavity of the first body may flow into the first cavity of the second body if the first body is located radially further inward than the second body or if so the first body is located radially further outward than the second body, a liquid or fluid located in the first cavity of the second body may flow into the first cavity of the first body.

Furthermore, the method 1300 includes a step 1310 of varying the speed of the rotor of the centrifuge so that the second cavity of the first body is fluidically coupled to the first cavity of the second body. If the first body is located radially further inward than the second body, a liquid located in the second cavity of the first body may flow into the first cavity of the second body and, for example, mix with a liquid therein. If the first body is arranged radially further outward than the second body, then a liquid located in the first cavity of the second body can flow into the second cavity of the first body and, for example, mix there with an already upstream liquid. For example, the method 1300 may be used to mix different liquids or reagents that are upstream of a device according to an embodiment of the present invention, for example, to perform a (bio) chemical process, such as DNA extraction. According to further embodiments, in order to mix a plurality of different liquids with each other, or to couple several different cavities fluidly with one another, the step 1320 of changing the speed of the rotor can be performed as often as desired, for example, depending on the required process steps. The device 700 according to FIG. 7 with three revolvers on the application example of a DNA extraction on the basis of the method 1300 according to FIG. 13 will be described below with reference to FIGS. 14, 15 a, 15 b. The device 700 and other devices are According to embodiments of the present invention are also suitable for the automation of other (bio-) chemical processes.

14 shows a diagram between time and angular velocity of a rotor of a centrifuge in a method for fluidically coupling a plurality of cavities according to an exemplary embodiment of the present invention. Ω stands for the angular velocity of the rotor of the centrifuge. The times marked with black dots in the numbering 1-6 indicate times at which the device 700 moves from one phase to a next phase. A hatched box indicates when an opening of the mixing chamber 160a of the second revolver 120 occurs.

FIGS. 15a and 15b show states of the individual revolvers 110, 120, 510 relative to each other as they occur when carrying out the method 1300 using the time-angular-velocity diagram according to FIG. 14. FIGS. 15 a, 15 b thus show a process graphic of a process sequence in the device 700 using the example of DNA extraction. The current liquid flow is indicated by an arrow. The revolvers are shown unrolled. In the first turret 110 are located in the cavities all vorzulagernden reagents. In the second revolver 120 is the mixing chamber 160a and a predetermined breaking point 1510, for example as described in FIG. 4-b. The third revolver 510 is a catch tray for the waste liquid (waste) in the waste container (in the waste chamber) 720b and the eluate in the eluate collection container (in the eluate chamber) 720a.

In the container (device 700) shown in Fig. 15a, the first turret 110 is preceded by the binding buffer (B), the lysis buffer (L), the two wash buffers (W1, W2) and the elution buffer (E). In the second turret 120, a chromatographic column 838 and a mixing device 730 (not shown in FIG. 15a) are integrated.

Before the DNA extraction can be started, the following manual steps have to be carried out. A sample is pipetted into a chamber (cavity (P)) of the first turret 110, for which purpose its lid is pierced. The sample rehydrates the lyophilized upstream proteinase. Thereafter, the centrifuge tube (the device 700) is transferred to the centrifuge, the lid of the centrifuge is closed, and a stored program or a manually entered program with frequency profiles is started.

The following steps are performed automatically by the centrifuge without the need for a user to intervene in the process. In a first step of the method (eg, step 1310 of method 1300), the centrifuge accelerates the rotor to a predetermined angular velocity G - The integrated spring 710 is compressed by the turrets 110, 120, 510 and the turrets 110, 120, 510 move radially outward. From a further angular speed ω 1 _ί α, the second turret 120 leaves the guide of the sleeve 130 (the guide grooves 816 of the housing 830) and can rotate along its axis of rotation 250. This is due to the guide structure in the first turret 110 (due to the tread teeth 826 of the first turret 110) and the distance between the first turret 110 and the second turret 120 is reduced and one of the mandrels (in the particular embodiment, the first mandrel 828a) pierces one Upper cavity (L) of the first turret 110, in which the lysis buffer is located on. The lysis buffer flows into the second revolver 120. After a predetermined time, the rotor is braked in the centrifuge. As soon as the angular velocity (Okrito) is exceeded, the spring 710 presses the revolvers 110, 120, 510 radially inwards, on the oblique profiles which are attached to the second revolver 120 and the sleeve 130 (ie to the guide grooves 834 of the second revolver 120 and the boundaries of the guide grooves 816 of the housing 130), a force component is created which further rotates the second turret 120 relative to the remaining components A twist of the first body 110 is due to the engagement of the guide springs 824 of the first body 110 with the guide grooves 816 of the housing 130. A rotation of the third body 510 is prevented due to the outer webs 854 of the third body 510. In other words, in the first step, a lower lid or means of a cavity (L) is pierced by the first turret 110 and the lysis buffer thrown into the mixing chamber 160a of the second turret 120.

In a further step (2nd in Fig. 15a), for example, the step 1320 of the method 1300, the cavity of the sample is pierced with the first mandrel 828a, the sample also passes into the mixing chamber 160a of the second turret 120. Lysis buffer and sample collect in the mixing chamber 160a, in which also sedimentation cavities can be attached. By changing the angular velocity of the centrifuge, a mixing action is produced in the second turret (in the mixing chamber 160a). The sample and lysis mix in the cavity 160a (or mixing chamber 160a) in the second turret 120. Bacteria and other solids of greater density than the liquid mixture can be sedimented off. In other words, the sample is thrown into the mixing chamber 160a and mixed, thereby cells are lysed and, if appropriate, subsequently insoluble cell constituents are sedimented. In a further step (3 in FIG. 15 a), after a certain mixing time, a cavity (B) of the binding buffer is pierced by the second mandrel 828 b and reaches the mixing chamber 160 a. It is mixed again. In a further step (3b in Fig. 15b), a valve in the mixing chamber 160a is switched. The mixture is conveyed by the centrifugal force via the column 838 into the waste chamber (waste collection bin) 720b of the third turret 510. By way of example, four different possibilities of valve switching will be mentioned below. A first possibility is the capillary filling of a siphon when the centrifuge's rotational frequency is slowed down below a critical value C0k _r it3a. A second possibility is an overflow siphon, which is switched by a further lancing step in which an additional binding buffer is fed into the system. A third possibility is that another mandrel, for example in the second turret 120, pierces into a designated location in the mixing chamber 160a. A fourth possibility, which is shown in FIGS. 15a, 15b, is that a predetermined breaking point 1510 shifts to over a critical rotational frequency C0k _r it3b during acceleration. The result is the same in all four ways, the DNA binds to the chromatographic column 838 and thus the DNA from the sample is bound to the chromatographic column 838. In other words, in the concrete embodiment shown in FIGS. 15a, 15b increases the centrifugation frequency. The mixture of sample, lysis buffer and binding buffer is passed over the DNA binding (chromatographic) column 838. The passing liquid is collected in the waste chamber 720b of the third turret 510.

In a fourth and a fifth step (4th-5th in Fig. 15b) avitations (Wl, W2) are pierced by washing buffer. The wash buffers pass through the column 838 into the waste chamber 720b of the third turret 510. The second turret 120 (the mixing chamber 160a of the second turret 120) is washed. Depending on the quality of the washing, of the starting substances, only the DNA of the sample in the second turret 120 is bound to the column 838. The cavities (W1, W2) of the washing buffers in the concrete embodiment shown here are from the second mandrel 828b of the second turret 120 ripped up. In other words, the two wash buffers are successively passed over the column 838. The wash buffers are collected in the waste chamber (in the waste bin) of the third turret 510. In the last centrifugation step (FIGS. 15b-6.), Elution buffer (E) is centrifuged down through column 838. The column 838 of the second revolver 120 is located above the eluate chamber 720a of the third revolver 510. The elution buffer (E) dissolves the bound DNA and the eluate is in a cavity (in the eluate chamber 720a) in the third revolver 510 collected. In the specific embodiment shown here, a cavity (E) of the elution buffer is pierced over the third mandrel 828c. According to some embodiments, the elution buffer may be routed within the mixing chamber 160a of the second body 120 via a dedicated fluid conduit 1520 (eg, the third fluid conduit 829c of FIG. 8c). This fluid guide 1520 may be used, for example, to influence a flow rate of the elution buffer.

The concentrated DNA in the elution buffer is now in the eluate chamber 720a. All other substances are in the waste chamber 720b. The rotor of the centrifuge stops and the started program is finished.

The centrifuge tube (device 700) can now be removed from the rotor of the centrifuge, and the concentrated DNA removed from the centrifuge tube (device 700), for example by removing the third turret 510, and provided for further processing.

According to further exemplary embodiments, the revolvers 110, 120, 510 shown in FIGS. 15a and 15b can also be microtiter plates 110, 120, 510 with cavities which are displaced in translation relative to one another based on the angular velocity of the rotor.

The method shown here in connection with the device 700 offers the advantage, in particular in comparison to manual methods, that the individual steps for mixing the sample with the various different reagents need not be carried out manually, but automated within the centrifuge, depending on the centrifugation protocol , be performed. In a manual procedure, the centrifuge would have to be stopped after each of the individual steps indicated, and then to add the necessary reagents for the step, such as binding buffer, wash buffer or eluate to the sample. Especially in large numbers, the method shown here has an immense time advantage and thus cost advantage over manual methods. Furthermore, for the method shown here, a standard centrifuge (for example, a pivoting or fixed angle centrifuge) can be used, which is available as standard in laboratories. Special devices, as shown in the prior art, are not required for the method shown here in connection with the devices shown here.

According to some embodiments, an apparatus according to an embodiment of the present invention may also be formed in a microtiter plate format be, for example, to carry out an immunoassay. An implementation of an immunoassay on stacked bodies or microtiter plates can take place, for example, by virtue of the fact that the bodies stacked one on the other move by means of a ballpoint pen mechanism in two directions in the laboratory centrifuge, so that one channel outlet can address a plurality of channel entrances.

For example, a sandwich immunoassay protocol may be implemented in a device according to one embodiment of the present invention. The immunoassay protocol may include the following steps. A first step is to give up the sample on the microtiter plate. In the following, three to five washing steps can be carried out and then a second antibody (detection antibody) can be added. After another three to five washes, a substrate can be added. In a final step, detection (for example, by a technique known to those skilled in the art such as chemiluminescence, fluorescence, staining reaction, GMR, gold particles, etc.) may be performed, for example, in an external microtiter plate reader.

For the detection of various parameters simultaneously, the column 838 may be formed as shown in FIG. FIG. 16 therefore shows a column 838 for the detection of different parameters simultaneously. In column 838, different capture antibodies (Akl-Ab4) are vertically immobilized in substrates. A sample can therefore be tested for multiple antigens simultaneously (using the detector).

Furthermore, a device according to an embodiment of the present invention can be applied to the synthesis of radioactive compounds. In (K.Hamacher, HH Coenen, G. Stöcklin; "Efficient Stereospecific Synthesis of No-Carrier-Added 2- [18F] Fluoro-2-Deoxy-D-Glucose Using Aminopolyether Supported Nucleophilic Substitution," Journal of Nuclear Medicine; Production of radioisotopes outside the device can be carried out by means of a positron emitter by bombarding a so-called target (target) as gas or liquid in a cyclotron as solid phase reactions) may be the following.

A first step could be a phase transfer to transfer radioisotopes (eg 18F) from the target liquid (eg H2180) to an organic solvent. Subsequently, a radiolabelling of the starting material can take place. Thereafter, a deprotection of the labeled starting material and finally a purification. Embodiments of the present invention thus relate to apparatus and methods for automated handling of liquids using a standard laboratory centrifuge. Among others, chemical or (biochemical preparative or analytical processes.

Exemplary embodiments of the present invention are based on the idea of the automation of individual process steps of the simplified handling of process liquids and the development of cost-effective and very compact systems, which are related to the development of lab-on-a-chip systems.

Embodiments of the present invention may be used as needed for processing various volumes of liquid.

Lab-on-a-chip systems described in the prior art often have the disadvantage that automatable processes can only comprise a few steps with these systems and the sensitivity of these methods is limited. Up to now, Lab-on-a-Chip systems consisting of a solid support and a standard laboratory device, for example a laboratory centrifuge, which is used to actuate the solid support were not known. Such standard laboratory equipment (laboratory centrifuges) belong to the basic equipment of almost all laboratories. If a lab-on-a-chip cartridge could be processed with the aid of such a standard laboratory device, the user would not have to acquire any special instruments to automate processes with the aid of the cartridge. The market entry barrier for the use of such a cartridge would consequently be lower than for the application of an ordinary Lab-on-a-Chip system or a pipetting robot. Embodiments of the present invention solve this problem by enabling automated processing of liquids with the aid of a standard laboratory centrifuge.

In many (bio) chemical processes (synthesis, analysis and purification), the centrifugation principle of centrifugation used in embodiments of the present invention is an essential part of the processing anyway. The centrifugal force is used either for the transport of liquids from a process step located radially further inward to a process step located radially further outward, or used for the purpose of substance separation by density differences. Embodiments of the present invention therefore require no (or only insignificantly increased) additional effort in the implementation of (bio) chemical processes.

Exemplary embodiments are described in particular with respect to specially developed centrifuge systems, as described, for example, in US Pat. Nos. 5,044,047 and 5,087,369. significantly cheaper and easier to use. None of the cited documents merely describes an insert which is integrated into a standard centrifuge in order to carry out a desired process, such as DNA extraction, fully automatically.

According to some embodiments, in order to achieve a displacement of the bodies of the device, an actuation mechanism is used which is characterized in that the variable centrifugal force interacts with a restoring force independent of the centrifugation (eg spring force, magnetic force, gravity) a change in the centrifugation frequency causes the movement of an actuator. Depending on the design of the mechanism, this can be a linear, rotational movement or guided along specific paths. Various mechanisms have been mentioned (ratchet mechanism, ballpoint pen mechanism), which perform such a function. When the centrifugation frequency is increased, the movement of the actuator can go in one direction, and the frequency can be reduced in the other direction. According to some embodiments, the movement of the actuator can drive a ratchet mechanism, whereby a feed in only one direction can be achieved. The feed can be linear or rotary. According to some exemplary embodiments, however, the feed movement can also be coupled with a lifting movement with an additional directional component. This lifting movement can, as shown in the ballpoint pen mechanism, be made bistable.

According to some embodiments, the configuration of the body may depend in part on the chosen configuration of the container (the device). In the case of a rotary embodiment of the device, bodies which are designed as cylindrical revolvers can be inserted into the centrifuge tube (into the device). A revolver can have a base body, an axis of rotation and concentrically arranged channels (cavities). The channels can be provided on one or two sides with a valve or cover (or a closure means) and form a cavity in this way.

In the case of the translational embodiment of devices according to embodiments of the present invention, the bodies may be designed as microtiter plates, ie plates with a field of channels and, as in the rotary embodiment, may be closed with valves or lids to form cavities in this way. As described above, in all variants, the cavities can be equipped with process agents or contain microfluidically functional internals or structures (which has been shown in FIG. 4). According to some embodiments of the present invention, on the one hand the centrifugal force and on the other hand a restoring force can be used to operate the actuation mechanism. The restoring force can be caused by a spring, a magnetic field, or the gravitational field as mentioned above. A spring, for example, as a component of a body, as it can be easily manufactured in an injection molding process is particularly easy to implement.

According to further embodiments, a process control may be required in the context of quality management. This process control can be carried out, for example, by means of a mechanical counter or other counting systems in the form of a phase display integrated in devices according to embodiments of the present invention or coupled to the device. By means of such a counter, it is possible to check whether the number of rotations of the stacked units required for successful processing has taken place. A simple counter can be made by attaching marks and a scale to mutually displacing components of the device. As an alternative to numbers, labels can also be attached that identify the current process step. In FIG. 8c, this can be recognized by means of the letters 842 arranged on the outside of the second body 120.

Possible production methods of devices according to embodiments of the present invention are known to the person skilled in the art. For mass production of the device may be a preferred method of injection molding, for a prototyping (prototype design) may be preferable to turning, milling and stereolithography.

According to some embodiments of the present invention, a device may be partially or completely formed from a plastic material. In particular, exemplary embodiments of the present invention can be manufactured as disposable articles.

The cavities in the units (bodies) of the devices can be partially closed, for example, for the pre-storage of liquids with a lid (closure means). Again, different methods are available. For example, closure means can be provided by an adhesive bond or by gluing a self-adhesive film by means of solvent bonding, as well as thermal bonding. Preferably, the use of capping films with good barrier properties that can be easily opened by a mandrel and have for example a plastic-coated aluminum mim ^'umfolie. An advantage of embodiments of the present invention is thus the automation of (bio) chemical processes in a laboratory centrifuge, which is part of the basic equipment of most laboratories worldwide. There is no additional, expensive laboratory equipment necessary to automate processes using the device according to the invention. This facilitates market entry and market penetration for embodiments of the present invention.

Another significant advantage of embodiments of the present invention lies in the variety of applications. It is possible to automate (bio) chemical processes of various kinds. Furthermore, the risk of contamination during the process is greatly reduced as it is a closed system.

Another advantage is that no specialist personnel are required to carry out the process.

In addition, the production costs for embodiments of the present invention are not significantly higher (or only insignificantly higher) than for disposable items that may be required for manual or automatic processing of (bio) chemical processes. This has the advantage that laboratory automation by exemplary embodiments of the present invention is superior even with small sample numbers of a manual ProzessdurcMührung and even with large numbers of samples is no more expensive than an automated solution, for example based on pipetting robots or special centrifuges. A variety of laboratory protocols known to those skilled in the art may be implemented in embodiments of the present invention. Thus, for example, DNA extraction, immunoassay, nucleic acid analysis (possibly with recombinase polymerase amplification (RPA)), protein purification, HPLC / purification, laboratory protocols, food monitoring or even the synthesis of radioactive compounds (radiopharmaceuticals) for nuclear medicine can be implemented.

In the following, several properties of some embodiments of the present invention will be summarized again. According to some embodiments, the sequential fluidic contacting of the cavities contained in the bodies of the device can take place by moving the bodies against one another in a tangential direction, without having to remove the device from the centrifuge. In a first centrifugation step can thereby a substance is conveyed from a first radially inner source channel of a first body into a further radially outer target channel of a second body. After a relative displacement of the two bodies, in a second centrifugation step a substance can be conveyed from the second radially further inward located source channel of the first body into the same radially further outward target channel. By carrying out further centrifugation steps, a sequence of process steps can be realized in this way, in which various substances or process aids involved in a process can be brought into contact with each other sequentially. According to embodiments of the present invention, the mutual displacement of the bodies may be initiated by the centrifugation protocol, and the energy required for displacement may be obtained from the centrifugation energy. A time and / or extent of the shift can be determined by a time-varying centrifugation frequency. The mutual displacement of the body can be carried out linearly or rotationally. The mutual displacement of the bodies can be brought about in particular by an actuation mechanism which causes a change in position of the two bodies relative to one another by an interaction of the variable centrifugal force with a restoring force independent of the centrifugation (eg spring force, magnetic force, gravitational force). A change in the centrifugation frequency can cause the movement of an actuator, the movement depending on the design of the mechanism linear, rotational or along a predetermined path. When the centrifugation frequency is increased, the actuator can, for example, move in one direction and, when the centrifugation frequency is lowered, the actuator can move in the other direction. For this purpose, the actuation mechanism can be used, for example, to drive a ratchet mechanism which permits a feed movement of the actuator in only one direction, wherein this feed movement can likewise run linearly, rotationally or along a specific path.

According to some embodiments, the advancing movement of the actuator can also be coupled with an additional movement in another direction, for example a lifting movement. This lifting movement can be performed in particular bistable, whereby a movement can be achieved, as found in the printing mechanism of a ballpoint pen application. This pressure mechanism can thus be operated by a changing centrifugal force, whereby at each step the mechanism can be moved one step further, whereby a stepwise mutual displacement of adjacent bodies can be achieved. This makes it possible to bring sequentially different channel outputs with different channel inputs (or different cavities) in contact. At the same time, according to some embodiments the use of the pressure mechanism allows to carry out an on-demand bistable lifting movement which results in changing the distance of the bodies from each other. In particular, the change in the distance can be used to puncture the lid (the closure means) of a cavity with a mandrel at a defined time or process step. In this way, a valve can be realized which can be used to control the process to be automated.

According to some embodiments, as described above, the cavities of the individual bodies can have lids which can be opened automatically during the centrifugation protocol. The opening can be done by a mandrel or by, for example, centrifugal pressure. The liquid or solid substances contained in the cavities can then be transported by means of the centrifugal force from a cavity located radially further inward into a cavity located radially further outward. According to some embodiments, the stacked bodies may be separable from each other.

According to further embodiments, the return means is configured such that a first amount of force acting in a direction opposite to the restoring force based on a centrifugal force, at a first angular velocity in the first phase, is greater than an amount of the restoring force, and so that a second Amount of the force acting in the opposite direction to the restoring force, at a second angular velocity at a transition from the first to the second phase, is less than the amount of the restoring force. The force based on the centrifugal force may be generated by deflection of the centrifugal force, for example by means of mechanics, hydraulics, pneumatics or the like, and may act in a direction other than the centrifugal force.

According to further embodiments, the return means may be configured such that a first amount of a component of the centrifugal force acting in the opposite direction to the restoring force, at a first angular velocity in the first phase, is greater than an amount of the restoring force, and thus a second amount the component of the centrifugal force acting in the opposite direction to the restoring force, at a second angular velocity at a transition from the first to the second phase, is smaller than the amount of the restoring force, so that at least during the transition from the first phase to the second phase one of the at least two bodies moves within the housing.

Claims

claims

An apparatus for insertion into a rotor of a centrifuge, comprising: at least two bodies (110, 120, 510, 1220, 1230) stacked one above the other; and a housing (130, 132, 134) which is adapted to be inserted into a holder of the rotor of the centrifuge; wherein the at least two bodies (110, 120, 510; 1220, 1230) are arranged in the housing (130, 132, 135) in a stacking direction so that when the device (100, 200, 700, 1200) is received in the intended manner the rotor of the centrifuge, and with a rotation of the rotor, a distance () of a body (110, 1220) of the at least two bodies (110, 120) to an axis of rotation (140) of the rotor is less than a distance (1 ₂ ) another body (120, 1230) of the at least two bodies (110, 120) to the axis of rotation (140) of the rotor; wherein a first body (110; 1230) of the at least two bodies (110, 120) has at least a first cavity (150a; 1232a) and a second cavity (150b; 1232b); wherein a second body (120; 1220) of the at least two bodies (110, 120) has at least one first cavity (160a; 1222a) cavity; wherein the at least two bodies (110, 120; 1220, 1230) in the housing (130, 132, 134) are movably arranged to, in response to rotation of the rotor, in a first phase, the first cavity (150a, 1223a). the first body (110; 1230) to fluidically couple with the first cavity (160; 1222a) of the second body (120; 1220) and, in a second phase, the second cavity (150b; 1232b) of the first body (110; 1230) ) to fluidly couple with the first cavity (160a; 1222a) of the second body (120; 1220); a return means (710, 1210); wherein the return means exerts a restoring force on at least one of the at least two bodies (110, 120, 510; 1220, 1230) in order, depending on an angle speed of the rotor to hold the at least two bodies (110, 120, 510, 1220, 1230) in a given position with respect to the housing (130, 132, 134); and wherein the return means (710, 1210) is arranged such that a first amount of a centrifugally force-based force acting in an opposite direction to the restoring force at a first angular velocity in the first phase is greater than an amount of the restoring force, and so that a second amount of the force acting in the opposite direction to the restoring force, at a second angular velocity at a transition from the first to the second phase, smaller than the amount of the restoring force, so that in the transition from the first phase in the second phase of at least one of the at least two bodies (110, 120, 510, 1220, 1230) within the housing (130, 132, 134) moves.

The device of claim 1, further configured such that upon a transition from the first phase to the second phase, a position of the at least two bodies changes with respect to each other such that a position of the first body (110; 1230) relative to the second body ( 120; 1220) in the first phase is different from a position of the first body (110; 1230) with respect to the second body (120; 1220) in the second phase, and wherein the device is further configured such that the transition from the first Phase in the second phase in response to a change in an angular velocity of the rotor with respect to an angular velocity of the rotor in the first phase takes place.

Device according to one of claims 1 or 2, which is further formed so that a transition from the first phase to the second phase takes place without a change in the direction of rotation of the rotor of the centrifuge.

The apparatus of claim 1, further configured such that an amount of a first angular velocity of the rotor in the first phase and an amount of a second angular velocity of the rotor in the second phase are higher than an amount of a third angular velocity at a Transition from the first phase to the second phase.

Device according to one of Claims 1 to 4, in which at least one of the cavities (150a, 150b) of the first body (110) has a closure means (210a, 210b) on a side facing the first cavity (160a) of the second body (120) ) on- wherein the device (100, 200, 700, 1200) is further configured to move the closure means (210a, 210b) in a phase in which the cavity (150a, 150b) of the first body (110) exposing the closure means (210) 210a, 210b) is fluidically coupled to the first cavity (160a) of the second body (120).

The device according to claim 5, wherein the closure means (210a, 210b) is a membrane, and wherein the second body (120) has at least one mandrel (828a, 828b, 828c) on a side facing the first body (110) , which is designed to puncture the membrane.

Apparatus according to claim 5, wherein the closure means (210a, 210b) is a pressure-sensitive membrane, the pressure-sensitive membrane being adapted to receive, in response to pressure generated by a given angular velocity of the rotor of the centrifuge, one of the sealing means Rupture the cavity (150a, 150b).

8. Device according to one of claims 1 to 7, wherein the at least two bodies (110, 120) are formed as microtiter plates, wherein the device is further formed so that in a transition from the first phase to the second phase, the at least two bodies (110, 120) to each other.

9. Device according to one of claims 1 to 7, wherein the at least two bodies (110, 120) are cylindrical bodies (110, 120, 510), each having a cover side and a base side opposite in the stacking direction; wherein a base side (822) of the first body (110) is disposed opposite to a top side (830) of the second body (120); wherein the first cavity (150a) of the first body (110) and the second cavity (150b) of the first body (110) abut the base (822) of the first body (110); wherein the first cavity (160a) of the second body (120) abuts the top side (830) of the second body (120); and wherein the device is further configured such that, in a transition from the first phase to the second phase, the second body (120) with respect to the first Body (110) about a stacking axis of rotation (250) of the at least two bodies (110, 120) rotated.

Apparatus according to claim 9, wherein the housing (130, 132, 134) has on an inner side a plurality of guide grooves (816, 816a, 816b) extending in an axial direction along the axis of rotation (250) of the bodies (110, 120 , 510) extend at least in a region of the housing (130, 132), and in which the first body (110) has on an outer side a plurality of guide springs (824) which are designed to engage with the plurality of guide grooves (816, 816a, 816b) of the housing (130, 132) for rotation of the first body (110) about the rotation axis (250) of the bodies (110, 120, 510) during the transition from the first phase to the second phase. to prevent.

The device according to claim 10, further comprising the first body (110) on the Base (822) has a plurality of tread teeth (826, 826a, 826b) circumferentially disposed around the first body (110), and further wherein the second body (120) has on an outer side a plurality of guide springs (834, 834a ) having; wherein the plurality of guide springs (834, 834a) of the second body (120) project beyond the top surface (830) of the second body (120), and each have tapered ends in an end portion in which they project beyond the top surface (830); wherein the plurality of guide springs (834, 834a) of the second body (120) are configured to alternate with the plurality of tread teeth (826, 826a, 826b) of the first body (110) in the transition from the first phase to the second phase. and the plurality of guide grooves (816, 816a, 816b) of the housing (130, 132) engage; wherein a first guide spring (834a) of the plurality of guide springs (834, 834a) of the second body (120) in the first phase comprises a first tooth (826a) of the plurality of tread teeth (826, 826a, 826b) of the first body (826a). 110) is engaged; and wherein the first guide spring (834a) of the plurality of guide springs (834, 834a) of the second body (120) in the second phase with a second, adjacent to the first tooth profile (826a), tooth profile (826b) of the plurality of tread teeth (826, 826a, 826b) of the first body (110) is engaged.

The apparatus of any of claims 1 to 9, further comprising a ratchet mechanism (1210, 1222, 1212) configured to position the first body (1230) relative to the second body (1220) in response to rotation of the rotor of the centrifuge ) to change.

13. Device according to one of claims 1-12, wherein the return means (710, 1210) comprises a spring made of a plastic material.

14. Device according to one of claims 1 to 13, wherein a distance of the at least two bodies (110, 120, 510) to each other in a transition from the first phase to the second phase is greater than a distance of the at least two bodies (110 , 120, 510) to each other in the first phase and in the second phase.

15. The apparatus of claim 1, further comprising a third stacked body having a first cavity and a second cavity, the apparatus being configured to engage in a phase to fluidically couple the first cavity (720b) of the third body (510) with the first cavity (160a) of the second body (120), and in a further phase, the second cavity (720a) of the third body (510) to fluidically couple to the first cavity (160a) of the second body (120).

16. An apparatus according to any of claims 1 to 15, wherein the first body (110) further comprises a third cavity (150c), the apparatus (700) being further configured to, in response to a rotation of the rotor, in a third phase, fluidly coupling the third cavity (150c) of the first body (110) with the first cavity (160a) of the second body (120).

17. Device according to one of claims 1 to 16, wherein the second body (120) within its first cavity (160a) comprises a mixing device (730); wherein the mixing device (730) has a mixing trough (835) and a separation device (840) with at least one passage opening (845); and wherein, responsive to rotation of the rotor, a distance between at least one wall portion of the mixing trough (835) and the separation device (840) is variable so that a liquid in the mixing trough (835) passes through at least one passage opening (845) of the separation device (840) is pressed through.

Device according to one of claims 1 to 17, wherein the housing (130, 132, 134) at least two separate housing parts (132, 134), so that in a separation of the at least two housing parts (132, 134) at least one of at least two bodies (110, 120, 510) can be removed from the device (700).

The apparatus of any one of claims 1 to 18, further comprising a phase display (814, 842) readable from outside the device, wherein the phase display (814, 842) is adapted to indicate in what phase the device (700) is at a time of the Abiesens is located.

Device according to one of claims 1 to 19, wherein at least one of the cavities (150a, 150b, 160a, 1222, 1232) of the device is accessible from outside the device.

Device according to one of claims 1 to 20, wherein the device comprises plastic material.

Centrifuge with a device according to one of claims 1 to 21. A method for fluidically coupling cavities with:

Rotating (1310) a rotor of a centrifuge at a first speed; wherein in a holder of the rotor, a housing is used, in which at least two stacked bodies are arranged in a stacking direction so that upon rotation of the rotor, a distance of one of the at least two bodies to an axis of rotation of the rotor is less than a distance of a another of the at least two bodies to the axis of rotation of the rotor; wherein a first of the at least two bodies has at least a first and a second cavity; wherein a second of the at least two bodies has at least a first cavity; wherein the at least two bodies in the housing are movably arranged to fluidly couple the first cavity of the first body with the first cavity of the second body in response to rotation of the rotor in a first phase, and in a second phase the second cavity of first fluidically coupling the first body with the first cavity of the second body; and wherein the first velocity is selected such that the first cavity of the first body is fluidically coupled to the first cavity of the second body; the housing further comprising return means; wherein the return means applies a restoring force to at least one of the at least two bodies to maintain the at least two bodies in a given position with respect to the housing, depending on an angular velocity of the rotor; and wherein the return means is arranged such that a first amount of a centrifugally force-based force acting in the opposite direction to the restoring force, at a first angular velocity in the first phase, is greater than an amount of the restoring force, and thus a second amount the force acting in the opposite direction to the restoring force, at a second angular velocity at a transition from the first to the second phase, is less than the amount of the restoring force, so that at least one of the transition from the first phase to the second phase at least two bodies moved within the housing; and

Changing (1320) the speed of the rotor of the centrifuge so that the second cavity of the first body is fluidically coupled to the first cavity of the second body.

A process for the preparation of a labeled starting material using a process according to claim 23.