LIQUID TRANSFER BETWEEN ROTATING MODULES

Description

[0001] The present invention relates to devices and methods for transferring fluid between modules, while the modules each rotate around an axis of rotation such that a fluid opening of the fluid module moves along a circular path around the axis of rotation and a transfer opening of the transfer module also moves along a circular path around the axis of rotation.

[0002] Centrifugal microfluidics deals with the handling of liquids in the picoliter to milliliter range in rotating systems. These systems are typically disposable polymer cartridges used in or instead of centrifuge rotors, with the aim of automating laboratory processes. Standard laboratory procedures such as pipetting, centrifuging, mixing, or aliquoting can be implemented within a single microfluidic cartridge. For this purpose, the cartridges include channels for fluid flow and chambers for collecting liquids. Generally, such structures designed for handling fluids can be referred to as fluidic structures. Generally, such cartridges can be called fluidic modules.

[0003] New applications, such as liquid biopsies or process monitoring, may require larger sample volumes than previously possible, with the number of reagents typically scaling with the sample volume. Microfluidic platforms or cartridges can reach their throughput or capacity limits in these cases. For example, centrifugal microfluidic platforms are known that can process samples of only a few hundred microliters at most. Such microfluidic cartridges are described, for instance, by O. Strohmeier et al., Chem. Soc. Rev. 44, 6187 (2015). Furthermore, for novel applications, such as methylation pattern analysis in cell-free DNA using sequencing (cfMeDIP-seq method, see SY Shen et al., Nat. Protoc. 7, 617-636 (2012)), the number of reagents increases due to the complexity of the methods. These cannot be achieved on typical microfluidic platforms or cartridges.Furthermore, some reagents must be freshly prepared and therefore cannot be pre-filled in the microfluidic cartridge. Additionally, many of the required reagents have wetting properties, and it can happen that the liquids are distributed throughout the system by capillary action immediately after pipetting, thus causing problems in the subsequent microfluidic protocol (e.g., by clogging vents or filling transfer siphons).

[0004] Several systems are known in the art for filling centrifugal microfluidic cartridges or similar test carriers while stationary. In these systems, fluid is dispensed into a fluid port in the cartridge via a dispenser that is also stationary. The centrifugal microfluidic cartridge is then rotated to utilize the fluid in some way. For example, reference can be made to J. Steigert et al., "Direct hemoglobin measurement on a centrifugal microfluidic platform for point-of-care diagnostics," Sensors and Actuators, A: PHYSICAL 130-131, pages 228-233, 2006. A similar method is also described in US 2022 / 0008924 A1.

[0005] Furthermore, systems for filling centrifugal microfluidic cartridges while rotating the cartridge are already known in the prior art. In such systems, the dispenser is located in a fixed position. For example, M. Karle et al., "Axial Centrifugal Filtration - A Novel Approach for Rapid Bacterial Concentration from a Large Volume", Transducers and Eurosensors XXVII, The 17th International Conference on Solid-State Sensors, Actuators and Microsystems, pages 1235-1238, IEEE, Piscataway, NJ, 2013, disclose a method in which liquid is introduced into an inlet located on a center of rotation while the dispenser remains in a fixed position. A similar method is also described by AP Bouchard et al."Non-contact Addition, Metering, and Distribution of Liquids into Centrifugal Microfluidic Devices in Motion," Analytical Chemistry 82, pages 8386-8389, 2010, describes a process in which a continuous flow of liquid is introduced into a centrally located inlet opening of a rotating platform. A similar process is also described in US 2022 / 0008924 A1. S. Haeberle et al., "Centrifugal Micromixer," Chem. Eng. Technol. 28, pages 613-616, 2005, describes a process in which several annular inlet chambers are arranged on a rotating platform and filled by a quasi-continuous flow of liquid during rotation.

[0006] Devices and methods are known from US patent 7,935,522 B2 in which liquid is added via a piezoelectric dispensing device, the dispensing of liquid droplets from the device being synchronized with the rotational speed of the disk. DE 10 2016 213 000 A1 discloses a centrifugal microfluidic cartridge in which loading fluid structures with a sample can be carried out at standstill or in rotation, for example by insertion, dripping, or pipetting.

[0007] Methods and devices in which liquid or liquid drops are transferred from a dispensing unit to a receiving unit that are subject to common rotation are known, for example, from EP 3 815 788 A1, US 2003 / 0 032 071 A1, US 2014 / 0 106 395 A1, US 2015 / 0 196 907 A1, US 2019 / 0 293 598 A1 and US 2015 / 0 273 469 A1.

[0008] Furthermore, a device with coaxial modules for fluid transfer is known from US 6 742 549 B1.

[0009] In new fields of application, such as liquid biopsy, samples of 1 ml or more may be required, and it would be advantageous to be able to continuously supply samples during preparation steps or analysis.

[0010] The object underlying the present invention is to create devices and methods that make it possible to flexibly transfer even larger sample volumes and / or a larger number of reagents and / or highly wetting liquids between a fluidics module and a transfer module during sample preparation or sample analysis.

[0011] This problem is solved by a device for transferring liquid between modules rotating about an axis of rotation according to claim 1 and a method for transferring liquid between modules rotating about an axis of rotation according to claim 10. Further developments of the present invention are set out in the dependent claims.

[0012] Examples of the present invention provide a device for transferring liquid between modules rotating about an axis of rotation, which has the following features: a fluidic module having a fluid orifice oriented in a first direction and fluidically connected to fluidic structures in the fluidic module, wherein the first direction corresponds to a first axial direction with respect to the axis of rotation or has an angle of < 90° to the first axial direction; a transfer module having a transfer orifice oriented in a second direction, wherein the second direction corresponds to a second axial direction with respect to the axis of rotation that is opposite to the first axial direction or has an angle of < 90° to the second axial direction, wherein the transfer module is designed to discharge or receive fluid through the transfer orifice; a first drive designed to cause rotation of the fluidic module in order to move the fluid orifice along a circular path around the axis of rotation;a second drive designed to cause rotation of the transfer module in order to move the transfer orifice along a circular path around the axis of rotation; and a control designed to synchronize the rotation of the fluid module and the rotation of the transfer module in order to position the fluid orifice and the transfer orifice relative to each other in order to allow fluid transfer between the transfer orifice and the fluid orifice during the rotations.

[0013] Examples of the present invention provide a method for transferring liquid between modules rotating about an axis of rotation, comprising the following features: Causing a rotation of a fluidic module having a fluid opening oriented in a first direction and fluidically connected to fluidic structures in the fluidic module to move the fluid opening along a circular path around the axis of rotation, wherein the first direction corresponds to a first axial direction with respect to the axis of rotation or has an angle < 90° to the first axial direction;Causing a rotation of a transfer module having a transfer port oriented in a second axial direction with respect to the axis of rotation opposite to the first axial direction, wherein the second direction corresponds to a second axial direction with respect to the axis of rotation opposite to the first axial direction or has an angle of less than 90° to the second axial direction, wherein the transfer module is configured to discharge or receive fluid through the transfer port in order to move the transfer port along a circular path around the axis of rotation; synchronizing the rotation of the fluid module and the rotation of the transfer module to position the fluid port and the transfer port relative to each other; and causing a fluid transfer between the transfer port and the fluid port during the rotations of the fluid module and the transfer module.

[0014] According to the invention, the fluid module is driven by a first drive and the transfer module is driven by a second drive. The first drive and the second drive are independently controllable. To enable fluid transfer during the rotations of the fluid module and the transfer module caused by the drives, the rotations are synchronized by the control system so that the fluid port and the transfer port are positioned relative to each other, i.e., aligned, to allow fluid transfer between them during rotation. This makes it possible to flexibly effect fluid transfer between the fluid module and the transfer module while both modules are rotating, so that fluid can be transferred in preparation for, during, or after an analysis, while the modules are rotating, i.e., without having to stop them.

[0015] In some examples, fluid can be discharged or received through the transfer port during the rotation of the fluid module and the transfer module. The transfer module can be designed to continuously eject fluid from the transfer port as a jet or discontinuously as drops. The fluid port and the transfer port are aligned relative to each other due to synchronization, allowing the fluid to flow from the transfer port to the fluid port. In some examples, the fluid port and the transfer port can be positioned azimuthally (isoradially) relative to each other with respect to the axis of rotation, i.e., offset, to compensate for any misalignment of the trajectory along the free path between the transfer port and the fluid port.In some examples, the circular path along which the fluid opening moves and the circular path along which the transfer opening moves can have the same radius. In other embodiments, the circular path along which the transfer opening moves can have a slightly smaller radius than the circular path along which the fluid opening moves, in order to compensate for centrifugal deflection of the fluid on the free path between the transfer opening and the fluid opening. Examples of the invention can thus be designed to achieve a reliable transfer of fluids between the transfer opening and the fluid opening.

[0016] In some examples, the transfer module can include an electronic pipette with a pipette tip, wherein the transfer opening is formed at the pipette tip. Examples of the invention can thus be designed to withdraw liquid from the fluidic module while the fluidic module is rotating. For this purpose, some examples can provide a maneuvering device designed to move the pipette tip and / or the fluidic module in the first or second direction, for example, in the axial direction with respect to the axis of rotation, during the synchronous rotation of the fluidic module and the transfer module, in order to immerse the pipette tip in the fluid opening. Thus, liquid can be withdrawn from the fluid opening by means of the pipette tip during the rotations.

[0017] In some examples, the fluidic module can have multiple fluid ports, and the rotation of the fluidic module and the rotation of the transfer module can be synchronized to successively position each of the multiple fluid ports and the transfer port relative to each other, thus enabling fluid transfer between the transfer port and the corresponding fluid port. In other examples, the transfer module can have multiple transfer ports, and the rotation of the fluidic module and the rotation of the transfer module can be synchronized to position the multiple transfer ports and multiple fluid ports relative to each other, thus enabling fluid transfer between the transfer ports and the fluid ports. This allows fluid transfer to occur between multiple fluid ports and the transfer port.In some examples, the radial position of the transfer opening is adjustable to achieve a radial alignment of the transfer opening with the fluid opening, or to successively align the transfer opening with each of several fluid openings arranged at different radial positions.

[0018] In exemplary embodiments, the first drive is a centrifuge rotor or a rotary motor. In examples, the second drive comprises a rotary motor, a multi-axis robot arm, or a linear axis system. Examples of the invention thus enable a combination of robotics for dispensing liquid during an analysis or sample preparation step and a centrifugal microfluidic cartridge on which a process chain is carried out, allowing for the processing of larger sample volumes. Examples of the invention are therefore directed toward a combination of robotics and microfluidic platforms that advantageously and flexibly enables the automation of laboratory processes associated with biological process chains.

[0019] In some examples, the controller is designed to control the first or second drive to cause the fluidic module to rotate at a frequency equal to the transfer module, or to cause the transfer module to rotate at a frequency equal to the fluidic module. The controller may be designed to detect an angular misalignment between the fluid orifice and the transfer orifice and to control the rotation of the fluidic module and / or the transfer module to bring the angular misalignment within a tolerance range. In other examples, the controller may be designed to detect the angular misalignment based on a difference between the actual position of the fluid orifice (or the transfer orifice) and a target position when the transfer orifice (or the fluid orifice) is at a specific position along the respective circular path.Thus, examples of the invention make it possible to synchronize the rotations of the fluid module and the transfer module in a simple way.

[0020] In the examples, the first direction in which the transfer port is oriented is the first axial direction with respect to the axis of rotation, and the second direction in which the fluid port is oriented is the second axial direction opposite to the first axial direction with respect to the axis of rotation. The examples also show that the transfer port(s) and / or the fluid port(s) can be oriented in a direction that has an angle of less than 90°, less than 60°, less than 45°, or less than 30° with respect to the axis of rotation. Brief description of the drawings

[0021] Exemplary embodiments of the invention are explained in more detail below with reference to the accompanying drawings. These show: Fig. 1 a schematic representation of a device for transferring liquid according to an example of the present invention; Fig. 2 a schematic representation of an example of a device for transferring liquid according to the present invention; Fig. 3 a flowchart of an example of a method according to the present invention; Fig. 4 a schematic representation of an example of a second drive comprising a robot arm operating according to the so-called SCARA principle; Fig. 5 a schematic representation of an example of a second drive comprising a linear axis system; Fig. 6 a schematic representation of a second drive comprising a combination of a linear axis system and a rotation system; Fig. 7 a flowchart of an example of a method according to the present invention; Fig. 8 a flowchart of an example of a method for synchronizing the rotations; and Fig.9a schematic representation of an angular offset and a rotor frequency diagram to illustrate the synchronization of . Fig. 8 . Detailed description

[0022] Examples of the present disclosure are described in detail below, using the accompanying drawings. It should be noted that identical elements or elements with the same functionality are designated with the same or similar reference numerals, and repeated descriptions of elements with the same or similar reference numerals are typically omitted. Descriptions of elements with the same or similar reference numerals may be interchangeable. Many details are described below to provide a more thorough explanation of examples of the disclosure. However, it is obvious to those skilled in the art that other examples can be implemented without these specific details.Features of the different described examples can be combined with each other, unless features of a corresponding combination are mutually exclusive or such a combination is expressly excluded.

[0023] Examples of the present invention relate to devices and methods for the temporally and spatially defined supply of liquids to a rotating microfluidic module. For this purpose, a transfer module, for example, a liquid dispensing system such as an electronic pipette or a dispenser (e.g., a piezoelectric pump, syringe pump, pneumatic pump, or peristaltic pump), or its outlet (e.g., a nozzle or a tube end), is set in rotation to transfer liquid to a second rotating fluidic system. The dispensing takes place with synchronization of the rotational movement of both systems, both with respect to rotational frequency and with respect to the radial and isoradial position of the dispensing point and the receiving point of the liquid.The delivery point can be the transfer port, for example in a pipette tip, and the intake point the fluid port, for example an inlet to a microfluidic module. The aim is the temporally and spatially defined provision of liquids, for example washing buffers, which are required for carrying out processes, such as the purification of a biological sample. In this way, processes with large volumes of both sample and reagents can be implemented with a small footprint. In contrast to previous methods, which either fill the fluidic module while it is stationary, resulting in disruptive capillary forces, or use triggered droplet dispensing and thus a low flow rate, the invention allows larger quantities of liquid to be transferred into or out of the fluidic module more reliably and quickly.A further advantage lies in the programmable volume of liquid dispensed. Besides a very wide range of volumes from the microliter to the milliliter range, the volume can be determined and dispensed depending on the ongoing process, for example, by optically measuring the concentration of a mixture obtained by adding liquid to the fluid module. Examples of the invention thus provide the possibility of online process control. In some examples, the method can also be used in reverse to extract liquids from the rotating fluid module, for example, a finished product obtained through a process chain. In summary, examples of the invention provide a novel operation for dispensing liquids from fluid modules at any time and at any location, in the form of inlet chambers at different positions on the fluid module, with any desired volume of liquid.to supply or remove several different liquids.

[0024] Examples of the invention thus make it possible to overcome disadvantages encountered in known methods. For instance, according to the invention, it is not necessary to perform the transfer of media into or out of the fluidic module while it is stationary, so that disruptive capillary forces play a lesser or no role. Examples of the invention do not require functionalization of the fluidic module surfaces, such as hydrophobization. Examples of the invention do not require the insertion of large containers, which are ultimately limited in volume, such as tube bags or so-called stick packs. Examples of the invention enable high volume flows during the transfer of liquids into the fluidic module, which is not possible with known methods, such as the discrete dispensing of drops using trigger signals.Examples of the invention enable electronic programming and thus online process control, for example, also with adjustments to the transfer volumes. In contrast to known methods, examples of the invention are also suitable for extracting liquid products from the fluidic module under rotation.

[0025] Before examples of the present invention are explained in more detail, definitions of some terms used herein will be given.

[0026] In this context, a rotating module is understood to be a module that performs a circular motion in a defined plane and around a defined center of rotation. For example, such rotation can be achieved using a robot arm, an axis system, or a rotary motor.

[0027] In this context, a transfer module is defined as a device for the precise and time-controlled dispensing or intake of liquids or other substances and mixtures. Examples of devices for the precise and time-controlled dispensing of liquids include dispensers, pumps, and pipettes, which may, for example, be attached to a gripper. The transfer module can be a rotating module or it can be attached to a rotating module and thus follow its circular motion. The transfer module transfers liquid, samples, and / or reagents into the fluidic module and, if applicable, products from the fluidic module. In some examples, the transfer module may be positioned above the fluidic module and thus be referred to as the upper rotating module.

[0028] In this context, a fluidic module is understood to be a device for carrying out fluidic and / or biochemical processes under rotation. Besides the fluid orifice, the fluidic module may contain other fluidic structures, such as channels and chambers. The fluidic module may include microstructures and / or macroscopic structures. For example, the fluidic module may be designed as a centrifugal microfluidic chip. In other examples, the fluidic module may have macroscopic structures, such as a microtiter plate or microreaction vessels. In addition to the fluid orifice, the fluidic module may also have a fluid chamber and, in a simple case, may be designed as a microreaction vessel. The fluidic module may be a rotating module or may be connected to a rotating module and thus follow its circular motion.In some examples, the fluidics module can be located below the transfer module and thus be referred to as the lower rotating module.

[0029] In this context, a control system is understood to be a method that synchronizes the two rotating modules based on real-time measurement data. The transfer module can be controlled in relation to the movement of the fluidic module, or vice versa, or both can be controlled simultaneously. Another function of the control system can be to activate the transfer module as soon as the synchronization of the rotational movements is within a predefined tolerance range.

[0030] In this context, a sample is defined as a liquid or liquid mixture that can be fully or partially analyzed within the fluidic module or prepared within it for subsequent analysis, such as DNA extraction. Examples of such samples include blood samples, water samples, process samples, liquefied skin samples, liquefied insect samples, etc. In this context, reagents are defined as all substances and mixtures, particularly liquids, required for the analysis or preparation of the sample within the fluidic module, such as wash buffers, acids, diluents, nanoparticles, and the like. In this context, a product is defined as a result or intermediate result of a process in the rotating fluidic module, such as purified DNA.

[0031] Fig. 1Figure 1 schematically shows an example of a device for transferring fluid between modules rotating about an axis of rotation. The device includes a fluid module 10 in the form of a rotating body, also referred to herein as the rotor. In other examples, the fluid module may be embedded within a rotating body. The fluid module 10 has a fluid opening 12 oriented in a first axial direction with respect to an axis of rotation R. The fluid opening 12 is fluidically connected to fluidic structures within the fluid module 10, for example, one or more fluid chambers and / or fluid channels (not shown). In the example shown, the first axial direction with respect to the axis of rotation R is upwards. The device includes a transfer module 14, which has a transfer opening 16, formed, for example, at a lower end of the transfer module 14.In some examples, the transfer module 14 can be formed by an electronic pipette, with the transfer orifice 16 being formed by an opening at the pipette tip. The transfer orifice is oriented in a second axial direction with respect to the axis of rotation R, downwards in the example shown. Thus, the fluid orifice and the transfer orifice face each other.

[0032] The device comprises a first drive 20 designed to effect a rotary motion, or rotation, of the fluid module 10 about the axis of rotation R, in order to move the fluid opening 12 along a circular path 22 around the axis of rotation R. In some examples, the first drive 20 may be a centrifuge or a rotary motor, such as a stepper motor or a servo motor. The first drive 20 may be designed to effect a precise and time-controlled execution of the circular motion of the fluid opening 12 in a defined plane perpendicular to the axis of rotation R and around a defined center of rotation, the axis of rotation R. In some examples, the first drive may be attached to a linear axis. Thus, the first drive may serve as a maneuvering device by which the fluid opening is moved along the axis of rotation R in the direction of the transfer opening.Thus, the electronic pipette can transfer liquid between the fluid opening and the transfer opening in the direction from the fluid opening to the transfer opening.

[0033] The device has a second drive 24 designed to cause a rotational movement of the transfer module 14 about the axis of rotation R, in order to move the transfer opening 16 along a circular path 26 about the axis of rotation R. The circular path 26 can have the same radius as the circular path 22. In some examples, the radius of the circular path 26 can be slightly smaller than the radius of the circular path 22 to compensate for centrifugal deflection of the fluid on the free path between the transfer opening 16 and the fluid opening 12. In some examples, the second drive 24 can be a rotary motor to whose rotor the transfer module 14 is attached to cause its rotation. In other examples, the transfer module 14 can be attached to the first drive via a support element.The first drive is designed to execute a precise and time-controlled circular motion in a defined plane perpendicular to the axis of rotation R and around a defined center of rotation, the axis of rotation R. In examples, the second drive could be a rotary motor, a robot arm, or an axis system.

[0034] The device includes a control unit 30 designed to synchronize the rotation of the fluid module 10 and the rotation of the transfer module 14 in order to position the fluid port 12 and the transfer port 16 relative to each other, thus enabling fluid transfer between the transfer port 16 and the fluid port 12 during rotation. As is obvious to those skilled in the art, the control unit may, for example, comprise one or more appropriately programmed computing units, one or more microprocessors, and / or one or more user-specific integrated circuits. In some examples, the control unit may be distributed, with parts of the control unit being formed by a computer and other parts of the control unit by microprocessors assigned to the respective drives.The controller 30 can be configured to automatically or upon manual input by a user execute the procedures described herein and to control the drives accordingly. For this purpose, the controller 30 is communicatively connected to the drives 20 and 24, as shown by the dashed lines 32 in the figure. Fig. 1 shown.

[0035] Examples of the device are designed to perform a process such as that described, for example, in Fig. 3as shown, to be carried out. At 40, a rotation of the fluidic module 10 is effected to move the fluid orifice 12 along the circular path 22. At 42, a rotation of the transfer module 14 is effected to move the transfer orifice along the circular path 26. The rotations of the fluidic module and the transfer module are synchronized, 44, to position the fluid orifice and the transfer orifice relative to each other. Once synchronization is achieved, a fluid transfer between the fluid orifice and the transfer orifice is effected, step 46 in Fig. 3 .

[0036] In some examples, the first drive 20 is started, causing the fluidic module 10 to perform a circular motion. The second drive is then started, causing the transfer module 14 to perform a second circular motion. Using the controller 30, a control process is then carried out to synchronize the two circular motions, ensuring that the transfer opening of the transfer module and the fluidic module's opening maintain a defined distance from each other in all spatial directions within a specified tolerance range. Once this synchronization is achieved, substances or mixtures are transferred from the transfer module 14 to the fluidic module 10, or vice versa. After the transfer is complete, the circular motion of the transfer module can, for example, be stopped.At a later time, the circular motion of the transfer module can be restarted in order to effect the transfer of further substances or mixtures of substances after further synchronization.

[0037] It goes without saying that real-time measurement data required for control is provided or acquired. For this purpose, appropriate sensors can be provided to detect the positions, absolute or relative to each other, of the fluid opening and the transfer opening. For example, rotary angle sensors can be provided to detect the respective angular position of the openings. Furthermore, sensors can be provided to detect a radial position of the transfer opening and / or a radial position of the fluid opening relative to the axis of rotation R. The real-time measurement data thus acquired can be made available to the controller 30 via communication links 32 in order to synchronize the rotations based on this data.

[0038] In examples of the present invention, the second drive can have a robot arm with multiple axes, at the end of which an electronic pipette is located. Fig. 2Figure 1 schematically shows an example where the second drive 24 has a robot arm with several arm sections 50a and 50b, wherein arm section 50a is rotatable about an axis A1 and arm section 50b about an axis A2 relative to arm section 50a. By appropriately controlling the rotations of the arm sections about their respective axes, a rotation of the transfer module 14, which is attached to the end of arm section 50b spaced from axis A2, can be effected, so that the transfer opening 16 moves along the circular path 26.

[0039] In some examples, the second drive can have a robotic upper arm with multiple joints and axes, at the end of which the transfer module, for example in the form of an electronic pipette, is located. Alternatively, the robotic arm of the second drive can be a multi-axis robotic arm, for example, five axes of a so-called five-axis robotic arm. With such a multi-axis robotic arm, a synchronized circular motion can be generated by superimposing several joint movements.

[0040] In some examples, the second drive can include a SCARA-type robot arm. An example of such a robot arm 50 is shown in Fig. 4The robot arm has a base 52, a shoulder joint 54, an inner connecting part 56, and an outer connecting part 58. The inner connecting part 56 and the outer connecting part 58 are connected via an elbow joint 60. A rotatable quill 62 is arranged at the end of the outer connecting part 58 spaced apart from the elbow joint 60. One end of the inner connecting part 56 is rotatable relative to the base 52 via the shoulder joint 54, see J1 in Fig. 4 The outer connecting part 58 is rotatable relative to the inner connecting part 56 via the elbow joint 60, J2 in Fig. 4 The quill 62 is rotatable about a pivot axis, J4 in Fig. 4 , and axially movable relative to the axis of rotation, J3 in Fig. 4By appropriately controlling the robot arm 50, for example via wired connections 64, using the controller 30, the movement of the transfer module 14 can be regulated to synchronize the movement of the transfer opening along the circular path with the movement of the fluid opening along the circular path. In a robot arm based on the SCARA principle, a synchronized circular motion can thus be generated by superimposing several joint movements, in which Fig. 4 The example shown is achieved through a superimposed movement J1, J2 of joints 54 and 60. The in Fig. 4 The SCARA-type robot arm shown can, for example, be called the robot arm 50 in Fig. 2 can be used. By appropriately controlling the joints of the robot arm, a radial position of the transfer module relative to the axis of rotation around which the transfer module rotates can also be set.

[0041] In some examples, the transfer module, in the form of an electronic pipette, can be attached to the robot arm, for instance, the quill 62. The robot arm can be controlled to move the pipette tip axially with respect to the axis of rotation. Thus, the robot arm can serve as a maneuvering device, allowing the pipette opening to be immersed in a fluid port of a rotor and in a fluid chamber adjacent to the fluid port. The electronic pipette can then transfer fluid between the fluid port and the transfer port.

[0042] In some examples, a linear axis system can be used to effect the rotation of the transfer module. An example of such a linear axis system is shown in Fig. 5The linear axis system is shown purely schematically. It has support rods 70 that allow movement of a crossbar 72 in one direction along a first linear axis x. The crossbar 72 enables movement of an end effector 74 in the direction of a second linear axis y. Thus, by moving the crossbar 72 in the x direction and the end effector 74 in the y direction, a circular motion of the end effector 74 can be achieved. The transfer module 14 can be attached to the end effector 74, so that, by appropriate control, the transfer opening of the transfer module can be moved along the circular path. Therefore, in this linear axis system, the synchronized rotary motion can be achieved by superimposing a sine and cosine function in the motion sequence of two orthogonally arranged linear axes (x, y) to generate a resulting circular motion.

[0043] In some examples, the transfer module, in the form of an electronic pipette, can be attached to the end effector 74. The end effector allows movement of the transfer module along a third linear axis z. Thus, the end effector can be controlled to move the pipette tip axially with respect to the axis of rotation. The end effector can therefore serve as a maneuvering device, allowing the pipette opening to be immersed in a fluid port of a rotor and in a fluid chamber adjacent to the fluid port. The electronic pipette can then transfer fluid between the fluid port and the transfer port in the direction from the fluid port to the transfer port.

[0044] In alternative examples, the second drive can have a rotary motor, for example a stepper motor or a servo motor, to whose rotor the transfer module is attached. In other examples, a rotary motor can also be attached to the end effector of a respective drive, for example the far end of arm section 50b in Fig. 2 , of the outer connecting part 58 in Fig. 4 or the end effector 74 in Fig. 5 .

[0045] It goes without saying that any automation system suitable for effecting a corresponding movement of the transfer module can be used, which in turn causes the transfer opening to rotate along the circular path around the axis of rotation. For example, shows Fig. 6The diagram schematically represents an automation system consisting of a combination of a linear axis system and a rotary system. A rotary system 80 is attached to the end effector 74 of a linear axis system, which can cause rotation of the transfer module 14, as indicated by arrow 82. Fig. 6 This is indicated. In this example as well, the end effector enables movement of the transfer module along the third linear axis z.

[0046] As can be seen from the description above, examples of the invention include a maneuvering device by which the transfer module and / or the fluidic module can be moved in one direction (first / second direction) to move the transfer module and the fluidic module towards and away from each other, thereby decreasing and increasing the distance between the fluid port(s) and the transfer port(s). Such movement can be advantageous to enable the aspiration of liquids from the fluidic module, for example a tube, or the dispensing of liquids with a small distance between the transfer module and the fluidic module. In examples, the transfer module can be designed to effect a corresponding movement of the transfer port, as may be the case with electronic pipettes that have an integrated "z-axis".

[0047] In some examples, the transfer module may include an electronic pipette designed to aspirate and / or dispense liquid through a pipette opening. Generally, an electronic pipette in this context refers to a system that can be filled or emptied by an electronic signal, unlike conventional pipettes which require manual operation. Such an electronic pipette is mounted at the end of the second drive (the upper rotating system) and connected to the controller, either wired via a signal line or wirelessly. The electronic pipette can thus be actuated by the controller. The electronic pipette may also include an integrated linear axis, which, in addition to or instead of one of the methods described above, moves the pipette tip axially with respect to the axis of rotation.In alternative embodiments, the transfer module may include an electronic dispenser or a pump, or the outlet of a pump in the form of a tube, from which liquid ejection can be effected, for example, by means of a piezoelectric actuator or electromagnetically. It goes without saying that the transfer module may include any system capable of automatically ejecting or receiving liquid through a transfer opening, for example, by means of electronic control using the control described herein.

[0048] Referring to the Figure 7 and 8An example of a method for synchronizing the rotations of the fluidic module and the transfer module will now be described. It is assumed that the fluidic module forms a rotor with the first drive, and that the second drive comprises a robot arm to which the transfer module is attached. It goes without saying that a corresponding method can also be implemented with all other fluidic modules, transfer modules, first drives, and second drives described herein.

[0049] The procedure begins at S1. At S2, the rotor position is calibrated. For example, a microcontroller on the rotor might be configured to display an angular position of zero when the rotor is in the zero position. At S3, a target position for the fluid orifice is defined to facilitate fluid transfer. This includes setting a target angular position of the rotor and, typically, a radius relative to the axis of rotation. For instance, a radius might be set at S3 if the rotor has multiple fluid orifices at different radial positions. If the axial position of the fluid orifice is adjustable, e.g.,By moving the rotor in the axial direction, setting the target position can also include setting an axial position of the fluid orifice, with the procedure then involving adjusting the axial position of the fluid orifice to the target position. Furthermore, fluid to be transferred can be drawn into the transfer module, which may be an electronic pipette, if the electronic pipette has not been pre-filled. The zero-point calibration in step S2 can be performed once at the beginning of the procedure, while step S3 is typically performed with each fluid transfer.

[0050] In step S4, the robot arm, which represents the second drive, is rotated at a specific rotational frequency. This frequency can be, for example, in a range of 3–10 Hz. Since the actual rotational frequency can deviate from the specified frequency, step S5 measures the actual rotational frequency of the robot arm, and step S6 determines whether the measured rotational frequency is stable. If the rotational frequency is not stable, steps S5 and S6 are repeated until it is. If step S6 confirms that the rotational frequency is stable, step S7 synchronizes the rotor's rotation with the robot arm's rotation. The rotor may already be rotating (e.g., at a higher rotational frequency from a previous process step) or may be set in motion for the first time (e.g.,(during the execution of the first process step of an application protocol). In step S8, it is checked whether the synchronization was successful. If it is determined that the synchronization was unsuccessful, steps S7 and S8 are repeated. If step S8 determines that the synchronization was successful, indicating that the transfer port and the fluid port are correctly aligned, the procedure jumps to step S9, where fluid is transferred between the transfer port and the fluid port. The procedure then ends at step S10.

[0051] Referring to the Fig. 8 and 9 An example will now be described of how synchronization can take place in steps S7 and S8. The procedure begins after step S6 in Fig. 7 , where it was determined that the rotation frequency of the robot arm is stable, S20 in Fig. 8At S22, this stable rotation frequency of the robot arm is measured.

[0052] At S24, the rotor's rotation frequency is set to match the robot arm's rotation frequency. At S26, it is determined whether a robot arm trigger has been detected. A robot arm trigger is activated when a physical feature of the robot arm is at a specific angular position, thus indicating a predetermined angular position of the robot arm's end effector on its circular path. For example, a robot arm trigger might be activated once per 360° rotation of the end effector. The activation of the robot arm trigger is used as periodic position feedback to determine whether the end effector has reached a predetermined, known position.

[0053] When step S26 detects that the robot arm trigger has been activated, the rotor angle position at that moment is set as the instantaneous rotor angle position. In other words, the instantaneous rotor angle position is measured at the moment the robot arm trigger is activated. Subsequently, in step S28, a difference between the target angle position and the instantaneous rotor angle position is determined. At step S30, it is checked whether the magnitude of the calculated difference is within a predetermined tolerance range. If the magnitude of the calculated difference is within the tolerance range, the synchronization was successful and ends at step S32. The procedure then jumps to step S9. Fig. 7If the calculated difference at S30 is not within the tolerance range, correction parameters are determined. These parameters are used to control the first drive, i.e., the rotor, in order to synchronize the rotor's rotation with the robot arm's rotation. For this purpose, a correction frequency and correction time can be calculated at S34 using linear interpolation. At S36, the correction parameters are applied to the rotor's rotation to reduce or, ideally, compensate for the angular difference calculated at S30. The process then returns to step S26, after which steps S26 to S30 are repeated until step S30 determines that the calculated difference is within the predetermined tolerance range. If this is the case, the synchronization was successful, and the process proceeds to step S9. Fig. 7The predetermined tolerance range is set such that, if the angular difference is within it, fluid transfer between the transfer port and the fluid port is possible during the rotations of the transfer module and the fluid module.

[0054] The control of the rotor's rotation to synchronize it with the rotation of the robot arm is described with reference to Fig. 9 explained again. Fig. 9Figure 1 schematically shows a rotor 10 with a fluid opening 12 to which fluid transfer is to take place. At the time of the robot arm trigger, which is schematically shown at 102, the fluid opening 12 is located at position P1. The target angle position, at which the fluid opening 12 should be located at the time of the robot arm trigger 102, is at P2. Thus, there is an angular offset Φ between the actually measured angle and the target angle. This angular offset is brought into the predetermined tolerance range by the described synchronization. For this purpose, as shown in Fig. 9As shown, the rotor frequency is first increased from the robot arm rotation frequency frobotarm to an increased rotation frequency frobotarm + corrFreq for an acceleration time tacc, held at this increased frequency for a holding time thold, and then reduced to the robot arm rotation frequency frobotarm for a deceleration time tdecel. This causes a relative rotation between the robot arm and the rotor, which compensates for the offset angle Φ between the transfer port, which rotates with the robot arm, and the fluid port, which rotates with the rotor, so that they are aligned to allow fluid transfer between them.

[0055] Although in the described example the rotation of the fluidic module is controlled to synchronize with the rotation of the transfer module, in other embodiments the rotation of the transfer module can be synchronized with the rotation of the fluidic module. In some examples, the rotations can also be synchronized by applying correction parameters to both rotations to compensate for any detected offset angles between them.

[0056] In these examples, a control system is implemented to synchronize the rotations of the transfer module and the fluid module based on real-time data representing the respective angular positions of the transfer and fluid openings. Corresponding signals can be transmitted between the respective sensors and components that comprise the control system using any suitable communication protocol. For example, a trigger signal can be transmitted from the second drive to the control system once per revolution of the second drive, and a motion stop signal can be transmitted from the control system to the second drive, for example, when a fluid transfer has been completed. A position signal representing the angular position of the first drive (rotor) can be transmitted from the first drive to the control system.The controller can transmit appropriate signals to the first and second drives, based on sensor signals, to adjust their rotational frequency and synchronize them. Any suitable communication protocols and interfaces, such as UART (Universal Asynchronous Receiver / Transmitter), TCP / IP (Transmission Control Protocol / Internet Protocol), CAN (Controller Area Network), and / or MODBUS, can be used for this communication.

[0057] Using examples from the present invention, substances or mixtures of substances in the form of liquids can thus be introduced and / or removed from any desired location within a fluidic module with minimal or no loss and with precision. A method in which a fluidic module and a transfer module are each set in rotation using separate drives, with the rotations being synchronized, was previously unknown. Instead, it was customary to either stop the rotation of the fluidic module or to introduce the substances or mixtures before the first rotational step began. In particular, it was not apparent that it was possible to achieve highly precise and stable synchronization of the two circular movements over an extended transfer period.It was further surprisingly discovered that when using an electronic pipette, the liquid-filled pipette tip does not empty uncontrollably, for example prematurely, under the centrifugal forces, but only after achieving stable synchronization in response to an electronic actuation signal. Thus, according to examples of the invention, it is possible to effect the liquid transfer precisely after achieving stable synchronization by electronically actuating the pipette, in order to achieve controlled emptying of the pipette into the fluid opening of the fluidic module and thus into the fluidic structures of the fluidic module.

[0058] In examples of the invention, the fluid module can have several corresponding fluid openings and / or the transfer module can have several corresponding transfer openings. Thus, examples allow different liquids to be transferred simultaneously or at different times and locations between the transfer module and the fluid module, or vice versa. For example, the transfer module could have a number of dispenser heads, e.g., five integrated dispenser heads, and be rotated to transfer five different liquids into the fluid openings of the fluid module at different times / locations.

[0059] Examples of the invention provide devices and methods in which a liquid dispensing system is set in rotation to transport liquids into or from a second rotating fluidic system. The liquid dispensing can be continuous as a jet or discontinuous as drops, depending on the actuation of the transfer module. In some examples, the offset of the trajectory on the free path between the dispensing system (transfer module) and the fluidic system (fluidic module) can be compensated. In some examples, a robot arm based on the SCARA principle can be used to rotate the dispensing system. In others, a circular motion generated by the superposition of two computer-controlled linear axes can be used to rotate the dispensing system. In still others, a module with an integrated rotary motor can be used to rotate the dispensing system.In some examples, a fluid delivery system can be used to supply multiple rotating fluidic systems, for instance, by having a fluidic module with several fluidic collection chambers, each with its own fluid orifice. In such systems, the second drive can be designed to position the transfer orifice relative to each of the fluid orifices and hold it in place during rotation, thus enabling fluid transfer between the respective fluid orifice and the transfer orifice. Furthermore, in such examples, the second drive can be designed to change or adjust the radial position of the transfer orifice with respect to the axis of rotation.

[0060] Examples of the invention can be applied in a variety of fields. Examples can be used in the automation of extraction protocols to isolate analytes, e.g., DNA, from biological samples, e.g., blood plasma. Examples can be used in the automation of sample preparation protocols to prepare for analyses, e.g., next-generation sequencing, for example, DNA library preparation protocols. Examples can be used in the automation of cell culture protocols to add and / or remove media at defined intervals or as needed, thus creating controlled conditions (online process control).

[0061] Examples of the invention offer numerous advantages over conventional methods. For instance, the transfer of media into a fluidic module is enabled under rotation, thus maintaining centrifugal forces within the fluidic module. This prevents, for example, capillary wetting of channels or resuspension of previously sedimented substances or analytes. Examples of the invention allow for the transfer of complexity from the consumable, the fluidic module, to the device, resulting in long-term cost savings. For example, functionalizations within the fluidic module or the use of tubular bags can be avoided. The inventive method eliminates the need for pre-storage in the consumable, freeing up surface area on the fluidic module that can be used for longer or more complex applications.It can be used in more complex process chains or for the parallel processing of multiple samples in a single fluidics module. Examples allow the introduction of very large liquid volumes in the range of several milliliters, which is not possible with conventional pre-storage techniques. Examples also allow the introduction of very small liquid volumes in the range of a few microliters, which is not possible with conventional pre-storage techniques. This is particularly advantageous in applications where expensive reagents are used. Examples enable electronic programming of the supply of substances and mixtures, thus allowing for active process control (online process control).Electronically controlled substance delivery, as implemented in examples of the invention, enables high process robustness, since manufacturing-related uncertainties caused by sealing seams of tubular bags, wax valves, and the like can be avoided. Furthermore, examples of the invention allow not only the dispensing of liquids from the transfer module into the fluidic module, but also the removal of products from the fluidic module under rotation, which in turn prevents, for example, capillary wetting of channels or resuspension of previously sedimented substances or analytes.

[0062] Although features of the invention have been described in each case with reference to device features or process features, it is obvious to those skilled in the art that corresponding features can also be part of a process or a device. Thus, the device can be configured to carry out corresponding process steps, and the respective functionality of the device can represent corresponding process steps.

[0063] In the preceding detailed description, various features were sometimes grouped together in examples to streamline the disclosure. This type of disclosure is not intended to imply that the claimed examples have more features than are expressly stated in each claim. Rather, as the following claims reflect, the subject matter may consist of fewer than all the features of a single disclosed example. Consequently, the following claims are hereby incorporated into the detailed description, with each claim potentially representing a separate example.While each claim can stand as its own separate example, it should be noted that, although dependent claims refer back to a specific combination with one or more other claims, other examples also include a combination of dependent claims with the subject matter of any other dependent claim, or a combination of any feature with other dependent or independent claims. Such combinations are included unless it is stated that a specific combination is not intended. Furthermore, it is intended that a combination of features of a claim with any other independent claim is also included, even if that claim is not directly dependent on the independent claim.

[0064] The examples described above are merely illustrative of the principles of this disclosure. It is understood that the modifications and variations of the requirements and details described are obvious to those skilled in the art. Therefore, it is intended that the invention is limited only by the appended claims and not by the specific details set forth for the purpose of explaining the examples.

Claims

1. An apparatus for transferring liquid between modules (10, 14) rotating around a rotation axis (R), comprising: a fluidic module (10) comprising a fluid opening (12) oriented in a first direction and fluidically connected to fluidic structures in the fluidic module (10), wherein the first direction corresponds to a first axial direction with respect to the rotation axis (R) or comprises an angle of < 90° to the first axial direction; a transfer module (14) comprising a transfer opening (16) oriented in a second direction, wherein the second direction corresponds to a second axial direction with respect to the rotation axis (R) that is opposite to the first axial direction or comprises an angle of < 90° to the second axial direction, wherein the transfer module (14) is configured to dispense or receive liquid through the transfer opening (16); a first drive (20) configured to effect a rotation of the fluidic module (10) to move the fluid opening (12) along a circular path around the rotation axis (R); a second drive (24) configured to effect a rotation of the transfer module (14) to move the transfer opening (16) along a circular path around the rotation axis (R); and a controller (30) configured to synchronize the rotation of the fluidic module (10) and the rotation of the transfer module (14) to position the fluid opening (12) and the transfer opening (16) relative to each other to allow liquid transfer between the transfer opening (16) and the fluid opening (12) during the rotations.

2. The apparatus according to claim 1, wherein the controller (30) is configured to control the transfer module (14) to dispense or receive liquid through the transfer opening (16), while the rotation of the fluidic module (10) and the rotation of the transfer module (14) are synchronized.

3. The apparatus according to claim 1 or 2, wherein the transfer module (14) is configured to eject liquid in the first direction from the transfer opening (16) continuously as a jet or discontinuously as drops.

4. The apparatus according to claim 3, wherein, during the synchronous rotation, the fluid opening (12) and transfer opening (16) are positioned relative to each other in azimuthal direction with respect to the rotation axis (R) to compensate an offset of the trajectory on the free path between the transfer opening (16) and the fluid opening (12), and / or wherein, during the synchronous rotation, the fluid opening (12) and transfer opening (16) are positioned relative to each other in radial direction with respect to the rotation axis (R) to compensate for centrifugal deflection of the liquid on the free path between the transfer opening (16) and the fluid opening (12).

5. The apparatus according to claim 1 or 2, wherein the transfer module (14) comprises an electronic pipet with a pipet tip, wherein the transfer opening (16) is formed at the pipet tip, wherein the apparatus optionally comprises manoeuvring means configured to move, during the synchronous rotation, the pipet tip in the first direction and / or the fluidic module (10) in the second direction to dip the pipet tip into the fluid opening (12).

6. The apparatus according to any one of claims 1 to 5, wherein the fluidic module (10) comprises several fluid openings (12) oriented in the first direction with respect to the rotation axis (R), wherein the controller (30) is configured to synchronize the rotation of the fluidic module (10) and the rotation of the transfer module (14) to position one of the several fluidic openings (12) and the transfer opening (16) relative to each other to successively allow liquid transfer between the transfer opening (16) and the several fluid openings (12) and / or wherein the transfer module (14) comprises several transfer openings (16), wherein the controller (30) is configured to synchronize the rotation of the fluidic module (10) and the rotation of the transfer module (14) to position the several transfer openings (16) and several fluid openings (12) relative to each other to allow liquid transfer between the transfer openings (16) and several fluid openings (12) of the fluidic module (10).

7. The apparatus according to any one of claims 1 to 6, wherein the radial position of the transfer opening (16) can be adjusted, and / or wherein the second drive (24) comprises a rotating motor, a robot arm having several axis or a linear axis system.

8. The apparatus according to any one of claims 1 to 7, wherein the controller (30) is configured to control the first or second drive (20, 24) to effect a rotation of one of the fluidic module (10) and the transfer module (14) at a rotation frequency that corresponds to the rotation frequency of the other one of the fluidic module (10) and the transfer module (14).

9. The apparatus according to claim 8, wherein the controller (30) is configured to detect an angular offset between the fluid opening (12) and the transfer opening (16) and to control the rotation of the fluidic module (10) and / or the transfer module (14) to bring the angular offset into a tolerance range, and wherein the controller (30) is optionally configured to detect the angular offset at a time when one of the fluid opening (12) and the transfer opening (16) is located at a specific position along the respective circular path, based on a difference between an actual position of the other one of the fluid opening (12) and the transfer opening (16) and a target position.

10. A method for transferring liquid between modules (10, 14) rotating around a rotation axis (R), comprising: effecting (40) a rotation of a fluidic module (10) comprising a fluid opening (12) oriented in a first direction and fluidically connected to fluidic structures in the fluidic module (10) to move the fluid opening (12) along a circular path around the rotation axis (R), wherein the first direction corresponds to a first axial direction with respect to the rotation axis (R) or comprises an angle of < 90° to the first axial direction; effecting (42) a rotation of a transfer module (14) comprising a transfer opening (16) oriented in a second direction, wherein the second direction corresponds to a second axial direction with respect to the rotation axis (R) that is opposite to the first axial direction or comprises an angle of < 90° to the second axial direction, wherein the transfer module (14) is configured to dispense or receive liquid through the transfer opening (16), to move the transfer opening (16) along a circular path around the rotation axis (R); synchronizing (44) the rotation of the fluidic module (10) and the rotation of the transfer module (14) to position the fluid opening (12) and the transfer opening (16) relative to each other; and effecting (46) a liquid transfer between the transfer opening (16) and the fluid opening (12) during the rotations of the fluidic modules (10) and the transfer modules (14).

11. The method according to claim 10, wherein, during the synchronous rotation of the fluidic module (10) and the transfer module (14), the fluid opening (12) and the transfer opening (16) are positioned relative to each other in azimuthal direction with respect to the rotation axis (R) to compensate an offset of the trajectory on the free path between transfer opening (16) and fluid opening (12), and / or the fluid opening (12) and the transfer opening (16) are positioned relative to each other in radial direction with respect to the rotation axis (R) to compensate a centrifugal deflection of the liquid on the free path between transfer opening (16) and fluid opening (12).

12. The method according to claim 10 or 11, wherein the transfer module (14) comprises an electronic pipet with a pipet tip, wherein the transfer opening (16) is formed at the pipet tip and wherein the method comprises moving the pipet tip in the first direction and / or the fluidic module (10) in the second direction during the synchronous rotation to dip the pipet tip into the fluid opening (12).

13. The method according to any one of claims 10 to 12, further comprising adjusting a radial position of the transfer openings (16) to successively effect liquid transfer between the transfer opening (16) and several fluid openings (12) formed in the fluidic module (10) while the rotations of the fluidic module (10) and the transfer module (14) are synchronized with each other.

14. The method according to any one of claims 10 to 13, wherein the rotations of the fluidic module (10) and the rotation of the transfer module (14) are synchronized such that one of several fluid openings (12) of the fluidic module (10) and the transfer opening (16) or one of several transfer openings (16) of the transfer module (14) are positioned relative to each other and liquid transfer between the transfer opening (16) or the transfer openings (16) and several fluid openings (12) is effected successively or simultaneously.

15. The method according to any of claims 11 to 14, wherein synchronizing the rotations comprises: rotating the fluidic module (10) and rotating the transfer module (14) at the same rotation frequency; detecting an angular offset between the fluid opening (12) and the transfer opening (16); and controlling the rotation of the fluidic module (10) and / or the transfer module (14) to bring the angular offset into a tolerance range, and wherein detecting the angular offset optionally comprises: detecting that one of the fluid opening (12) and the transfer opening (16) is located at a specific angular position along the respective circular path; detecting the angular position of the other one of the fluid opening (12) and the transfer opening (16) when the one of the fluid opening (12) and the transfer opening (16) is located at the predetermined angular position; determining the angular offset based on a difference between the detected angular position of the other one of the fluid opening (12) and the transfer opening (16) and a target position.