LU502219B1

LU502219B1 - Liquid handling device for processing liquid samples

Info

Publication number: LU502219B1
Application number: LU502219A
Authority: LU
Inventors: Da-Han Kuan; Joy Doong; Cheng-Han Tsai
Original assignee: Cytena Bioprocess Solutions Co Ltd; Cytena Gmbh
Priority date: 2022-06-03
Filing date: 2022-06-03
Publication date: 2023-12-04

Abstract

The invention relates to a liquid handling device for processing liquid sample located in at least one receptacle, wherein the liquid handling device comprises a housing with a first housing part, which delimits at least a part of a first cavity of the housing, wherein the first cavity of the housing is fluidically connectable to the receptacle and a processing unit for applying a positive or negative pressure in the first cavity. The liquid handling device is characterized in that the housing comprises a second housing part, which is connected to the first housing part and which delimits a second cavity comprising at least one storage chamber for receiving liquid, wherein the second housing part comprises an chamber opening for dispensing liquid from the storage chamber into the receptacle when a, in particular positive, pressure is applied in the storage chamber.

Description

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Liquid handling device for processing liquid samples LUS02219

The invention relates to a liquid handling device for processing liquid samples. Additionally, the invention relates to a liquid handling system comprising such a liquid handling device and the use of the liquid handling device and/or the liquid handling system in an incubator.

A cell line development process is required for most biopharmaceutical development processes. Cell line development is a method for selecting a cell line that produces protein/antibodies with high yield and optimized quality. However, the cell line development is a very complicated, labour-intensive, and costly process. Development time for most pharmaceutical products is half à year.

A core tool required in the cell line development is a bioreactor for cell incubation. Starting from incubating single cells, the scale of the cell culture is continually expanded until a high-volume production scale is reached through repeated transferring steps of selection and up-scaling.

Therefore, for different phases and different quantities of cells, bioreactors of different sizes ranging from a bioreactor at a microliter level to a large-scale bioreactor at a production level are required.

However, there is a limited ability to optimize the cell incubating environment of a smaller-sized bioreactor. An ideal bioreactor generally needs to enable cells to continually grow in suspension, dynamically monitor biosignals, and perform feedback control on dissolved oxygen content and pH value. It is difficult to achieve the foregoing functions in a microliter-level bioreactor.

A further core tool required in cell line development is a multiwell carrier that comprises a plurality of receptacles that are also known as wells. Said multiwell carrier can be arranged in the aforementioned bioreactor. Each of the wells is used to contain a liquid sample that can comprise the cell or cells.

Multiwell carriers comprising different number of wells are known (e.g. multiwell carriers having 24, 38, 96 or more wells). Additionally, liquid handling devices are known that are attached to the multiwell carrier in order to process liquid sample in order to improve scaling of cell culture.

As mentioned before among others the oxygen content and pH value are monitored. If during the cell incubation it is recognized that the oxygen content and/or pH value has an undesirable value, the incubation process is stopped and liquid is added manually to the liquid sample in order achieve the desired oxygen content and/or pH value. However, manually adding liquid into the receptacle is time 1

03.06.2022 006A0003LU consuming. Additionally, said process requires removing the receptacle containing the liquid from the LUS02219 bioreactor which can be disadvantageous for the cell incubation.

The object of the invention is to provide a liquid handling device by means of which it is possible to adjust a physical or chemical property of the liquid sample without removing the receptacle comprising the liquid sample from a bioreactor.

The object is solved by a liquid handling device for processing liquid sample located in at least one receptacle, wherein the liquid handling device comprises a housing with a first housing part, which delimits at least a part of a first cavity of the housing, wherein the first cavity of the housing is fluidically connectable to the receptacle and a processing unit for applying a positive or negative pressure in the first cavity, characterized in that the housing comprises a second housing part, which is connected to the first housing part and which delimits a second cavity comprising at least one storage chamber for receiving liquid, wherein the second housing part comprises an chamber opening for dispensing liquid from the storage chamber into the receptacle when a, in particular positive, pressure is applied in the storage chamber.

The invention has the advantage that the liquid handling device comprises a second cavity with at least one storage chamber that can hold liquid which could be added to the liquid sample during incubation. Thus, it is possible to automatically adjust the physical or chemical property of the liquid sample arranged in the receptacle. That means, it is hot necessary to manually adjust the physical or chemical property and/or to remove the liquid handling device and the receptacle from e.g. a bioreactor. Thus, the cell incubation is not disturbed by adjusting the physical or chemical properties of the liquid sample arranged in the receptacle. A further advantage of the invention is that a liquid handling device is provided by means of which the liquid sample arranged in the receptacle can be processed and in addition by means of which the liquid sample property can be adjusted.

The liquid sample depends on the usage field of the liquid handling device. If the liquid handling device is used in a bioreactor, the liquid sample comprises a biological particle. The biological particles may be microorganisms such as bacteria, archaean, yeast, fungi, and viruses or cells, DNA, RNA, or proteins.

The liquid sample may comprise a single or multiple of the aforementioned biological particles. The liquid sample can contain a liquid and at least one biological particle. The liquid can promote the 2

03.06.2022 006A0003LU growth or the function of the biological particles arranged in the liquid. If the liquid handling device is LUS02219 used in a chemical reactor, the liquid sample can comprise one or more chemical reagents.

By adding the liquid into the liquid sample, the physical and/or chemical property of the liquid sample can be changed. The physical and/or chemical property can be the pH value of the liquid sample. The liquid can differ from the liquid located in the receptacle. In said case the liquid can be a media with pH buffer or a sugar solution.

The storage chamber and/or the second housing part delimiting the storage chamber are capable of holding and releasing a liquid onto a target plate or carrier comprising a receptacle only when a defined pressure, in particular a positive pressure pulse, is applied to the storage chamber. In particular, pressure is applied on the liquid arranged in the storage chamber. When there is no pressure applied on the storage chamber, no liquid is released since capillary forces keep the liquid in the storage chamber. That means, no liquid is released due to the atmosphere pressure acting on the liquid.

The positive or negative pressure is defined with regards to the atmospheric pressure. Thus, a positive pressure is a pressure that is higher than the atmospheric pressure and the negative pressure is a pressure that is lower than the atmospheric pressure.

The chamber opening of the second housing part, can have a diameter between 0.2 mm (millimeter) to 2 mm. The dispensed liquid can be a liquid droplet or a liquid jet. The receptacle can have a volume between 2 microliters to 17 milliliters.

The receptacle can be part of the carrier. The carrier can have one or more receptacles. Carriers that have more than one receptacle are also indicated as multiwell plate. In particular, carriers are known to have 6, 12, 24, 48, 96, 384, 1536 and 3456 receptacles. The receptacles are arranged in a matrix structure on a carrier element. The receptacle and the carrier element can be made as one component. “Fluidically connectable” means that the first cavity is configured such that a fluid can flow from the receptacle to the processing unit or vice versa. Thus, due to the fluid connection a pressure applied 3

03.06.2022 006A0003LU by the processing unit applies also on the receptacle, in particular on the liquid sample arranged in LUS02219 the receptacle.

Processing of liquid sample can comprise the supply of fluid into the receptacle. For example, the liquid arranged in the storage chamber can be added into the receptacle and/or positive or negative gas pressure can be applied in the first cavity and thus the receptacle. Additionally or alternatively, processing of liquid sample can comprise mixing of the liquid sample in the receptacle and/or moving of the liquid sample and/or agitation of biological particles in the liquid sample. Moving of the liquid sample can be performed in order to apply shear stress to e.g. cells by means of the moved liquid.

Mixing of the liquid sample is understood as a process in which the components of the liquid sample, in particular the biological particles, are moved relative to each other in such a way that a new arrangement pattern is created.

According to an embodiment the first housing part can comprise at least one extension tube for extending into the receptacle. In particular, the extension tube extends into the receptacle when the liquid handling device is arranged on or attached to the receptacle. The extension tube can extend into the receptacle such that a centre axis of the extension tube is coaxial and/or parallel to a central axis of the receptacle.

The extension tube can delimit, in particular surround, a cavity part of the first cavity. Thus, by applying a negative pressure in the first cavity, at least a part of the liquid sample arranged in the receptacle can be sucked into the extension tube, i.e. into the cavity part of the first cavity surrounded by the extension tube. Alternatively, by applying a positive pressure in the first cavity, the liquid sample arranged in the extension tube can be dispensed from the cavity part of the first cavity that is surrounded by the extension tube. The extension tube surrounds the cavity part of the first cavity in a tangential direction with respect to the length axis of the extension tube and/or with respect to the central axis of the receptacle.

The first housing part can have a contact portion that comes into contact with a receptacle wall when the liquid handling device, in particular the housing, is arranged on the receptacle or attached to the receptacle. Such a liquid handling device is compact resulting in a compact liquid handling system when the liquid handling device is attached to or arranged on the receptacle. 4

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The second housing part can delimit a part of the first cavity. Thus, the second housing part can delimit at least a part of the second cavity and a part of the first cavity resulting in a compact liquid handling device. The first housing part and the second housing part are firmly connected to each other. A “firm connection” means that the two components are connected such that they do not move relative to each other, wherein the connection can be releasable. Thus, the first housing part and the second housing part cannot move relative to each other. In particular, the first housing part and the second housing part can be integrally connected to each other. In said case the first housing part and the second housing part are formed as one component and cannot be separated from each other without destroying at least one of said housing parts.

A portion of the second housing part can extend into the extension tube. That means, the portion of the second housing part that delimits the storage chamber can extend into the part of the first cavity that is surrounded by the extension tube. This leads to a compact structure of the liquid handling device. The portion of the second housing part can be arranged such that a central axis of the portion of the second housing part is coaxial to the length axis of the extension tube. The chamber opening of the second housing part can be arranged in a cavity part of the first cavity delimited, in particular, surrounded, by the extension tube. Alternatively, the chamber opening can be arranged in a first cavity part which is not surrounded by the extension tube. The chamber opening can be arranged such that a plane exists that extends parallel to a centre axis of the extension tube and comprises a part of the chamber opening. Thus, it is secured that the liquid is dispensed from the portion of the second housing part into the cavity part of the first cavity that is surrounded by the extension tube.

As the extension tube extends into a receptacle, it is secured that the liquid is dispensed into the receptacle.

The portion of the second housing part that delimits the storage chamber can have a tapered portion.

The chamber opening can be arranged at the tip of the tapered portion. The provision of the tapered portion has the advantage that a condensed liquid of the liquid sample arranged in the receptacle collects at the tip end and drips from the tip end back into the receptacle due to gravity. A tapered tip end has the advantage that the volume and/or mass of the condensed liquid is reached faster than for example in a rectangular shape end so that the condensed liquid falls back sooner into the receptacle than in an embodiment in which the second housing part has a rectangular shape. 5

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Alternatively, the portion of the second housing part can have a cylindrical or rectangular portion LUS02219 wherein the chamber opening is arranged in a bottom of the cylindrical portion or the rectangular portion.

A gap, in particular in radial direction with respect to the length axis of the extension tube, can exist between the portion of the second housing part and the extension tube. In particular, an outer contour of the portion of the second housing part can be smaller than an inner contour of the extension tube. The gap is part of the first cavity. Due to the provision of the gap, the fluid connection between the processing unit and the receptacle is hot disconnected by the storage chamber extending into the extension tube.

According to an embodiment the second housing part can delimit several storage chambers. In particular, the second housing part can comprise several portions that delimit a storage chamber, respectively. The portions can be connected to each other and/or arranged at a distance to each other.

As described above the first housing part and the second housing part can be formed as one component so that the user of the liquid handling device does not have to assemble the liquid handling device. Liquid can be filed into some or all of the said storage chambers.

The housing, in particular the second cavity, is configured such that the storage chambers can be fluidically connected to each other. The second cavity can comprise a connection chamber which fluidically connects the storage chambers. The connection chamber can be configured such that pressure applied in the connection chamber is applied to the storage chambers.

The first housing part can comprise several extension tubes. The number of extension tubes can correspond to the number of storage chambers. In said case the storage chamber can be arranged such that it is coaxial to the length axis of the length axis of the extension tube. Alternatively, the number of extension tubes can be less than the number of storage chambers. In said case several storage chambers can extend into the extension tubes. This has the advantage that different liquids can be added into the same receptacle. Alternatively, the number of extension tubes can be greater than the number of storage chambers. The portion of the second housing part can extend into the extension tube such that the central axis of the portion of the second housing part is parallel or coaxial to the length axis of the extension tube. 6

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The number of extension tubes can correspond to the number of receptacles of the carrier.

Additionally, the extension tubes can be arranged in the same manner as the receptacles on the carrier. This ensures that the liquid handling device can be easily connected to the receptacle.

All extension tubes of the liquid handling device can be designed in the same way. Alternatively, the extension tubes can have a different diameter and/or shape. All extension tubes can be firmly fixed to the remaining part of the first housing part. That means, the extension tube and the remaining part of the first housing part cannot move relative to each other. In particular, the extension tube can be integrated with the first housing part.

All storage chambers of the liquid handling device can be designed in the same way. Alternatively, the storage chambers can have a different cross section and/or shape and/or volumes for receiving the liquid. All portions of the second housing part that are delimiting a storage chamber, respectively, can be firmly fixed to the remaining part of the second housing part. That means, the portions of the second housing part and the remaining part of the second housing part cannot move relative to each other.

According to an embodiment the first cavity can be configured such that the pressure applied in the first cavity is applied to the cavity parts of the first cavity delimited, in particular surrounded, by an extension tube, respectively. Thus, it is possible to process the liquid samples located in different receptacles at the same time. Thereto, the positive or negative pressure provided by the processing unit is applied to the liquid samples located in the different receptacles.

The liquid handling device can be arranged on the receptacle and/or attached to the receptacle. This means, the receptacle is not part of the liquid handling device. The extension tube of the liquid handling device protrudes into the receptacle when the liquid handling device is attached to and/or arranged on the receptacle. For attaching the liquid handling device to the receptacle, the liquid handling device can be moved in a direction that is parallel to the length axis of the extension tube.

The liquid handling device can be configured such that a pressure applied in the first cavity differs from a pressure applied in the second cavity. The pressure applied in the first cavity can differ from 7

03.06.2022 006A0003LU the pressure applied in the second cavity in the absolute value. A further difference can be that only LUS02219 positive pressure is applied to the second cavity for the purpose of dispensing liquid from the storage chamber whereas either positive or negative pressure may be applied to the first cavity in order to process the liquid sample arranged in the receptacle.

For applying pressure, in particular the positive or negative pressure, in the first cavity the liquid handling device can comprise the processing unit. The processing unit can be a pressure application device, in particular a pump, for providing positive or negative pressure. The housing can comprise a first fluid connection part that is fluidically connected to the first cavity. Additionally, the first fluid connection part can be connected or is connected to the processing unit of the liquid handling device.

The processing unit supplies gas, in particular air, into the first cavity in order to increase the pressure in the first cavity or removes gas, in particular air, from the first cavity in order to decrease the pressure in the first cavity.

According to an embodiment the liquid handling device can comprise a valve. The valve can be configured to be in a close position when pressure is applied in the second cavity. In that case the pressure can be released by means of dispensing the liquid from the storage chamber. The valve can also be configured to be in an open position after a liquid is dispensed from the storage chamber. In that case the positive pressure applied by the processing unit in the second cavity is released. Thus, unwanted liquid dispensing is prevented in an easy manner. The valve can be connected to the housing, in particular the second housing part, and/or is arranged in the housing, in particular the second housing part.

The liquid handling device can comprise a pressure application device for applying pressure, in particular a positive pressure, in the second cavity for dispensing liquid from the storage chamber. As discussed below, there exist several possibilities as to how the pressure can be applied on the liquid arranged in the at least one storage chamber. The pressure application device can be arranged separately from the processing unit. The pressure application device supplies gas, in particular air, into the second cavity in order to increase the pressure in the second cavity or removes gas, in particular air, from the second cavity in order to decrease pressure in the second cavity. 8

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The liquid handling device, in particular, the housing can comprise a second fluid connection part. The LUS02219 second fluid connection part can be fluidically connected to the second cavity. In addition, the second fluid connection part can be fluidically connected or is connected to the pressure application device of the liquid handling device. In said case the pressure application device can be a pump for applying pressure, in particular positive pressure. The first fluid connection part and the second fluid connection part can extend from the same housing side.

The housing, in particular the second housing part, can have at least one inlet opening for inserting liquid into the storage chamber. The number of inlet openings can correspond to the number of storage chambers. Thus, it is possible to fill the storage chamber from which liquid shall be dispensed into the receptacle. The liquid handling device can comprise a closing element for closing the inlet opening. Thus, it is ensured that an applied pressure is not released through the inlet opening. As the dispensed liquid volume depends on the pressure applied in the second cavity, an accurate dispensing volume can be achieved by ensuring that there is no pressure loss in the second cavity.

According to an embodiment the pressure application device can comprise a membrane that delimits and/or closes the second cavity. As discussed below the membrane is used to apply pressure in the storage chamber. Additionally, the membrane has a housing function as it delimits the second cavity and thus enables to apply a pressure in the second cavity.

A membrane can be a component which extension in two space directions is, in particular much larger, than its extension in a third space direction. The membrane can comprise at least one inlet opening for inserting liquid into the storage chamber. In particular, the membrane can comprise several inlet openings wherein the inlet openings are assigned to at least one storage chamber. Thus, it is easy to fill a predetermined storage chamber via the inlet opening.

Additionally or alternatively the membrane can have a bending stiffness that is lower than the bending stiffness of the housing, in particular the second housing part. By providing such a membrane it is possible to apply a pressure in the storage chamber. For applying pressure in the storage chamber a forceis applied on the membrane to bend the membrane. Due to the membrane bending pressure is applied on the liquid arranged in the storage chamber resulting in liquid dispensing from the storage chamber. 9

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The membrane can be configured to delimit the second cavity such that the storage chambers are not fluidically connected to each other. Thereto, the membrane can be, in particular directly, arranged on the second housing part. In particular, the membrane can be arranged on a remaining portion of the second housing part that connects the portions of the second housing part that delimit the storage chambers. The membrane can be firmly connected to the remaining second housing part. That means, said connection part of the membrane cannot move relative to the second housing part. In said case the cavity does not have a connection chamber to fluidically connect the storage chambers.

Liquid dispensing from different storage chambers can be achieved by bending a portion of the membrane that is assigned to the respective storage chamber. Said assigned membrane portion can be arranged above the storage chamber. Thus, a liquid handling device is provided in which liquid can be dispensed from a storage chamber without affecting other storage chambers. Each of the storage chambers can be delimited by the membrane and the portion of the second housing part.

For applying a force on the membrane, the pressure application device can comprise an actuating element. The actuating element is used to actuate the membrane, i.e. to apply a force on the membrane in order to apply a pressure in the storage chamber. In particular, the actuating element is arranged such that it can actuate the membrane such that a pressure is applied to the liquid located inthe storage chamber resulting in liquid dispensing from said storage chamber.

The actuating element can be arranged such that it covers the inlet opening when the actuating element actuates the membrane. Thus, the actuating element prevents the applied pressure from releasing via the inlet opening.

According to an embodiment the liquid handling device, in particular the housing, can comprise a lid element. The lid element can be firmly connected with the second housing element. That means, the lid element can be connected to the second housing part so that the lid element and the second housing part cannot move relative to each other. Additionally, the lid element can be connected to the second housing part in a releasable manner. 10

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The liquid handling device can comprise at least one valve device, which is movable in the second LUS02219 cavity. The valve device can, in particular merely, move in a linear direction. Additionally, the valve device can be configured such that in an open position, pressure can be applied on the liquid in the storage chamber for liquid dispensing and/or in that in a closed position the valve device prevents a pressure from being applied on the liquid in the storage chamber. Thus, the valve position is able to control the pressure applied in the storage chamber from which the liquid shall be dispensed.

Independent on the position of the valve device, a part of the valve device can protrude into the storage chamber.

The valve device can be in contact with the second housing part when the valve device is arranged in the closed position. In particular, the valve device is arranged on the second housing part. The valve device is not in contact with the second housing part when it is arranged in the open position. That means, in the open position the valve device does not disconnect the fluid connection between parts of the second cavity and the second fluid connection part and/or the pressure application device.

Alternatively, the valve device can function as a pressure application device. In that embodiment pressure is applied on the liquid arranged in the storage chamber when the valve device is rapidly moved from the open position to the closed position.

The valve device can be connected to a holding membrane of the liquid handling device. The holding membrane can be arranged in a cavity between the lid element and the second housing part. In an embodiment in which the liquid handling device comprises several valve devices, the valve devices can be connected to the holding membrane of the liquid handling device. The holding membrane can have a bending stiffness that is lower than the bending stiffness of the lid element. Thus, with its flexibility, the holding membrane ensures that the valve device can move between the open and closed position and additionally supports the valve device or valve devices. The valve device can comprise an inlet opening for inserting liquid into the storage chamber. As each valve device can be assigned to a receptacle, it is possible to easily fill the storage chamber assigned to the valve device.

For controlling the position of the valve device, the liquid handling device can comprise an actuating device. The valve device can comprise a magnet which enables a releasable connection with the actuating device. This enables the valve device to transfer to its open or closed position as explained below in more detail. 11

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The valve device can act as pressure application device and thus can be used for liquid dispensing from the storage chamber. A pressure is applied on the liquid in the storage chamber for liquid dispensing when the valve device is moved from the open position to the closed position. Additionally or alternatively no pressure is applied on the liquid in the storage chamber for liquid dispensing when the valve device is arranged in the open position.

The actuating device can be arranged on the liquid handling device and/or attached to the liquid handling device. Additionally, the actuating device can be configured to control the position of the valve device or the valve devices. In particular, the actuating device can control the position of a valve device independent of the position of other valve devices. Thereto, the actuating device can have one or more actuating units each of which is assigned to a valve device. The actuating unit can be moved linearly towards the valve device or away from the valve device. Additionally, the actuating unit can comprise a magnet. Thus, when the actuating unit is moved to a position that is close to the valve device, the valve device can move from its closed position to the open position due to magnetic force.

When the actuating unit is moved away from the valve device, the valve device can fall towards the closed position due to gravity. Alternatively, the actuating device and the valve device can be connected to each other. In said case the valve device follows the movement direction of the actuating device. Thus, the valve device can be moved in an open or closed position by following the movement of the actuating unit due to the connection between the valve device and the actuating unit.

According to an embodiment the liquid handling device can comprise a control unit which controls the processing unit and/or the pressure application device. Additionally or alternatively, the control unit can control the valve and/or the actuating device. The control unit is an electric or electronic unit.

The control unit can comprise one or more processors for processing data. Alternatively, the control unit can be a processor for processing data. In particular, the control unit can comprise a printed circuit board.

The control unit can control the processing unit such that a positive pressure and a negative pressure is alternately applied in the first cavity. This can be performed multiple times in order to mix the liquid sample arranged in the receptacle. Additionally or alternatively, the control unit can apply a positive 12

03.06.2022 006A0003LU pressure or a hegative pressure in the first cavity. Thus, the liquid sample level in the extension tube LUS02219 can be controlled.

The control unit can control the pressure application device such that liquid is dispensed from the storage chamber into the receptacle in order to alter the liquid sample in the receptacle. Alternatively, the control unit can control the pressure application device such that the liquid is arranged outside the chamber opening of the storage chamber but does not fall into the receptacle. Specifically, the liquid is in contact with a surface of the second housing part that faces towards the receptacle. In that case, the control unit can control the processing unit such that a negative pressure is applied in the first cavity so that the liquid sample level in the extension tube increases. In particular, the processing unit can be controlled such that the liquid level increases so much that the liquid sample in the extension tube comes into contact with the liquid that adheres to the surface of the second housing part and outside of the chamber opening of the second housing part.

According to an aspect of the invention a liquid handling system is provided. The liquid handling system comprises an inventive liquid handling device and at least one receptacle. In the liquid handling system the liquid handling device is attached to the receptacle and/or arranged on the receptacle.

Of particular advantage is the use of a liquid handling device according to the invention or a liquid handling system according to the invention in reactor for liquid samples. The reactor can be a bioreactor or a chemical reactor. À bioreactor is a device used to create controlled conditions for various development and growth processes. Thus, temperature and/or humidity in a bioreactor chamber in which the liquid handling system can be arranged can be controlled for the incubation.

Inthe figures, the subject-matter of the invention is schematically shown, wherein identical or similarly acting elements are usually provided with the same reference signs. Therein shows:

Fig. 1 a liquid handling system with a liquid handling device according to a first embodiment,

Fig.2Ato 2D different steps of liquid processing with the liquid handling device according to the first embodiment, 13

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Fig. 3 a liquid handling system with a liquid handling device according to a second LUS02219 embodiment,

Fig. 4Ato 4D different steps of liquid processing with the liquid handling device according to the second embodiment,

Fig. 5A a liquid handling system with a liquid handling device according to a third embodiment, wherein every actuating unit is connected to a valve device, respectively,

Fig. 5B a liquid handling system with the liquid handling device according to the third embodiment, wherein one actuating unit is not connected to a valve device,

Fig. 6Ato6D different steps of liquid processing with the liquid handling device according to the third embodiment,

Fig. 7 a liquid handling system with a liquid handling device according to a fourth embodiment,

Fig. 8Ato 8D different steps of a liquid processing with the liquid handling device according to the fourth embodiment,

Fig. 9 a liquid handling system with a liquid handling device according to a fifth embodiment,

Fig. 10 a liquid handling system including a liquid handling device comprising an actuating device and

Fig. 11 a liquid handling system as shown in fig. 10 wherein an actuating unit of the actuating device is shown.

A liquid handling system 29 shown in fig. 1 comprises a liquid handling device 1 for processing a liquid sample 2 device according to a firstembodiment and a carrier 30 having two receptacles 3. The carrier can have more than two receptacles 3. A liquid sample 2 is arranged in each of the receptacles 3.

The liquid handling device 1 is attached to a carrier 30. In particular, the liquid handling device 1 is arranged on the carrier 30 and is supported by the carrier 30 on a connection portion of the liquid handling device 1 that is not shown in the figures. 30 The liquid handling device 1 comprises a housing 4 with a first housing part 5 and a second housing part 8. The first housing part 5 delimits at least a part of a first cavity 6 of the housing 4 wherein the first cavity 6 of the housing 4 is fluidically connected to the receptacle 2 and a processing unit 7 for 14

03.06.2022 006A0003LU applying a positive or negative pressure in the first cavity 6. The processing unit 7 can be a pump. The LUS02219 pressure that is applied by the processing unit 7 applies on both receptacles 3.

The second housing part 8 delimits at least a part of a second cavity 9 and is connected to the first housing part 5. In particular, the first housing part 5 and the second housing part 8 are integrally connected to each other. The second housing part 8 delimits a storage chamber 10 for receiving liquid 11.

The first housing part 5 comprises several extension tubes 13. All extension tubes 13 are designed identically so that in the following only one extension tube 13 is discussed. The extension tube 13 extends into the receptacle 3 and delimits a cavity part of the first cavity 6. In particular, the extension tube surrounds the cavity part in a tangential direction with respect to a centre axis M of the receptacle 3 and/or the extension tube 13. The extension tube 13 comprises an outlet opening so that liquid sample 2 can be sucked into the extension tube 13 or dispensed from the extension tube 13 into the receptacle 3.

The second housing part 8 has portions delimiting two storage chambers 10. The storage chambers 10 are fluidically connected to each other by means of connection chamber 31 of the second cavity 9.

Each of the storage chambers 10 is assigned to a receptacle 3. Additionally, each of the portions of the second housing part 8 delimiting the storage chamber 10 comprises an chamber opening 12 for dispensing liquid 11 from the storage chamber 10 into the receptacle 2 when a, in particular positive, pressure is applied in the second cavity 9. The dispensed liquid falls into the receptacle 3 that is assigned to the respective storage chamber 10.

All portions of the second housing part 8 for delimiting a storage chamber 10 are designed identically so that in the following only one portion of the second housing part 8 is discussed. The second housing part 8 has tapered portion wherein the chamber opening 12 is arranged at the tip of the tapered portion. A portion of the second housing part 8 protrudes into the extension tube 13. In particular, this portion of the second housing part is arranged in the part of the first cavity 6 that is delimited, in particular surrounded, by the extension tube 13. Said portion of the second housing part extends into the extension tube 13 such that the chamber opening 12 of the second housing part 8 is arranged in the part of the first cavity 6 that is delimited by the extension tube 13. 15

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The storage chamber 10 is arranged coaxial to the extension tube 13. As in the embodiment shown in fig. 1 the extension tube 13 and the receptacle 3 are arranged coaxial to each other.

The second housing part 8 comprises several inlet openings 20 for inserting liquid into the second cavity 9. The inlet openings 20 are assigned to one storage chamber 10. Thus, liquid 11 can be inserted into the assigned storage chamber 10 via the inlet opening 20. The inlet openings 20 are covered by a cover element 21. The cover element 21 is arranged on the second housing part 8 comprising the inlet openings 20. Thus, it is ensured that pressure applied in the second cavity 9 is not released via the inlet openings 20.

Housing 4 comprises a first fluid connection part 15 and a second fluid connection part 18. Both fluid connection parts extend from the same housing side. The processing unit 7 is connected to the first fluid connection part 15. The first fluid connection part 15 fluidically connects the processing unit 7 with the first cavity 6 and thus with the receptacle 3. A pressure application device 17 is connected to the second fluid connection part 18. The second fluid connection part 18 fluidically connects the pressure application device 17 with the second cavity 9. The pressure application device 17 can be a pump. In the embodiment shown in fig. 1 the pressure application device 17 applies a positive pressure in the second cavity 9 as it is indicated by the arrow. This positive pressure results in liquid dispensing from all storage chambers 10 into the respective receptacles 3.

The liquid handling device 1 comprises a valve 16. Depending on the position of the valve 16, the valve 16 fluidically connects the second cavity 9 with the surrounding or fluidically disconnects the second cavity 9 from the surrounding. The valve 16 is arranged in a closed position in fig. 1 in which second cavity 9 is fluidically disconnected from the surrounding. In said valve position the pressure applied in the second cavity 9 is released by liquid dispensing and not via the valve 16 to the surrounding. In an open valve position, it is not possible to increase the pressure inside the second cavity 9 so that no liquid is dispensed when the valve 16 is in an open position.

The liquid handling device 1 comprises a control unit 28. The control unit 28 controls the position of the valve 16. Additionally, the control unit 28 controls the processing unit 7 and the pressure 16

03.06.2022 006A0003LU application device 17. The control unit 28 is electrically connected to the aforementioned components LUS02219 as indicated by the dotted lines in fig. 1.

Fig. 2A to 2D shows different liquid processing steps of with the liquid handling device 1 according to the first embodiment. The same liquid processing can be performed with the liquid handling device 1 according to the first embodiment shown in fig. 1. Fig. 2A shows a state in which the pressure application device 17 (not shown) does not apply a pressure on the second cavity 9 and in which the valve 16 is opened. This means, the pressure in the second cavity 9 corresponds to the atmospheric pressure.

Fig. 2B shows a state in which the control unit 28 (not shown) acts on the valve 16 to move to the closed position. Additionally, the control unit 28 acts on the pressure application device 17 (not shown) so that a positive pressure is applied in the second cavity 9 as it is indicated by the arrow. The positive pressure exerts a force on liquid 11 that is greater than the capillary force such that liquid leaves through the chamber opening 12. However, the force acting on liquid 11 is not sufficiently high for the drop of liquid 11 to drip into the receptacle 3, instead the liquid 12 adheres on the surface of the portion of the second housing part 8 that faces the receptacle 3.

Fig. 2C shows the next step of the process, in which the control unit 28 (not shown) acts on the processing unit 7 such that a negative pressure is applied in the first cavity 6. As a result, the level of the liquid sample arranged within the extension tube 13 rises in comparison to the state shown in fig. 2B. The value of the negative pressure is chosen such that the liquid sample level rises to the level of the liquid that is arranged outside the chamber opening 12. As is shown in fig. 2C the liquid sample level rises in all extension tubes 13 and is the same in all extension tubes 13.

Afterwards, as shown in fig. 2D, the control unit 28 (not shown) acts on the processing unit 7 such that a positive pressure is applied in the first cavity 6. This pushes some of the liquid sample arranged in the extension tube 13 out of the extension tube 13.

Fig. 3 shows a liquid handling system 29 with a liquid handling device 1 according to a second embodiment. This liquid handling device 1 differs from the liquid handling devices discussed above in that the liquid handling device 1 comprises a membrane 22 that together with the second housing 17

03.06.2022 006A0003LU part 8 delimits and/or closes the second cavity 9. The membrane 22 is arranged on the second housing LUS02219 part 8. In particular, the membrane 22 is attached to the second housing part 8. The membrane 22 comprises a bending stiffness that is lower than the bending stiffness of the second housing part 8.

Additionally, the membrane 22 comprises inlet openings 20. The inlet openings 20 are assigned to a storage chamber 10, respectively, and used to fill liquid into the storage chamber 10.

In this embodiment the membrane 22 and actuating elements 23 are part of the pressure application device 17. For applying a pressure in the second cavity 9, the actuating element 23 presses against the membrane 22 resulting in membrane bending. This compression applies pressure on the liquid located in the storage chamber 10, resulting in liquid dispensing. The positions of the actuating elements 23 are controlled by the control unit 28 shown in fig. 1.

The number of actuating elements 23 corresponds to the number of receptacles 3. Each actuating elements 22 is assigned to a receptacle 3. For dispensing liquid from a receptacle 3, the actuating element 22, which is assigned to the receptacle 3, presses against the membrane 22. The actuating element 23 is arranged such that the actuating element 23 covers the inlet opening 20 when the actuating element 23 is in contact with the membrane 22.

A further difference of the embodiment shown in fig. 3 from the other liquid handling devices is that the membrane 22 separates the storage chambers 10 from each other and/or the second cavity 9 does not have a connection chamber 31 for fluidically connecting the storage chambers 10 to each other. This means that the control unit 28 can control whether a liquid shall be dispensed or not for each storage chamber 10.

Fig. 4A to 4D shows different liquid processing steps with the liquid handling device according to the second embodiment. This process is similar to the process described in fig. 2A to 2D so the following discussion focuses on their differences. Arrows are used to indicate whether a positive (see fig. 4A, 4D) or negative (see fig. 4C) pressure is applied in the first cavity 6.

As seen from fig. 4B, the actuating element is moved towards the membrane 22 in order to apply a force on the membrane 22. The membrane 22 bends and applies pressure on the liquid 11 via the compression of air so that liquid 11 leaves the chamber opening 12 of the storage chamber 10. As 18

03.06.2022 006A0003LU the two storage chambers 10 are not fluidically connected to each other, no liquid leaves the LUS02219 chamber opening 12 of the storage chamber for which the actuating element 23 is not actuated.

Fig. 5A shows a liquid handling system 29 with a liquid handling device 1 according to a third embodiment. The liquid handling device 1 comprises a lid element 24. The lid element 24 is releasably connected to the second housing part 8. Both components are firmly connected to each other so that they cannot move relative to each other.

Additionally, the liquid handling device 1 comprises valve devices 25 wherein the valve devices 25 are assigned to a storage chamber 10, respectively. In the embodiment shown in fig. 5A one valve device 25 is arranged in the open position and the other valve device 25 is arranged in the closed position.

In the open position of the valve device 25, the pressure application device 17 (not shown) can exert pressure on the liquid 11 so that the liquid is dispensed. In the closed position of the valve device 25, the pressure application device 17 cannot exert pressure on the liquid 11 that is arranged in the storage chamber 10 assigned to the valve device 25 in the closed position. The valve device 25 is in contact with the second housing part 8 when the valve device is arranged in the closed position. In the open position, the valve device 25 is not in contact with the second housing part 8.

Both valve devices 25 are identically designed so that only one is described below more in detail. The valve device 25 comprises a magnet 32. The magnet 32 is arranged at the end of the valve device 25 that is arranged distant to the storage chamber 10. The valve device 25 is connected to a holding membrane 26. In particular, the valve device 25 is connected to the holding membrane 26 at the end which is distant to the storage chamber 10. Additionally, the valve device 25 is arranged coaxial to the storage chamber 10. The holding membrane 26 is arranged in a cavity of the lid element 24. The valve device 25 comprises an inlet opening 20 through which liquid can be inserted into the storage chamber 10.

Fig 5A also shows parts of actuating units 33 of an actuating device 27 (not shown). Each actuating unit 33 is assigned to a valve device 25. The actuating unit 33 can move linearly in the vertical direction and with its movement control the position of the valve device 25. The actuating unit 33 is arranged outside the housing 4 and/or the lid element 24. The actuation unit 33 comprises a further magnet 34 19

03.06.2022 006A0003LU so that the actuating unit 33 and the corresponding valve device 25 can be magnetically connected. LUS02219

The actuating unit 33 and the valve device 25 are arranged opposite to each other with respect to the holding membrane 26. Every actuating unit 33 is connected to a respective valve device 25.

Fig. 5B shows a liquid handling system with a liquid handling device 1 according to the third embodiment in which one actuating unit 33 is not connected to a valve device 25. As the actuating unit 33 is not connected to the valve device 25, the valve device 25 falls due to gravity into the closed position. As is evident from fig. 5B the actuating unit 33 is retracted so that it is not in contact with the holding membrane 26.

Fig. 6A to 6D shows different liquid processing steps with the liquid handling device according to the third embodiment. This process is similar to the processes discussed above so the following discussion explains their differences. As evident from fig. 6A, the actuating unit 33 moves according to the direction D shown in the figure. This movement shifts the valve device 25 assigned to this actuating unit 33 to the closed position. During said movement of the valve device 25, the valve 16 is arranged in the open position.

In the next step shown in fig. 6B, the valve 16 is closed and the processing unit 7 applies a positive pressure in the second cavity 9. As the other valve device 25 is arranged in the open position, liquid is pushed outside the chamber opening 12 of the second housing part 8. This happens for the storage chamber 10 that is assigned to the valve device 25 arranged in the open position. However, no liquid is dispensed from the storage chamber 10 that is assigned to the valve device 25 that is arranged in the closed position. The subsequent steps illustrated in fig. 6C and 6D correspond to the steps discussed above for fig. 2C and 2D. In particular, negative pressure is applied in the first cavity 6 resulting in a liquid level increase in the extension tube 13.

Fig. 7 shows a liquid handling system with a liquid handling device 1 according to a fourth embodiment.

The difference from the liquid handling device 1 shown in fig. SA is that the liquid handling device 1 in fig. 7 does not comprise a second fluid connection part. In this embodiment, the valve device 25 also acts as a pressure application device. That means, the pressure is applied on the liquid 11 by rapidly moving the valve device 25 from an open position to the closed position. As is evident from the arrow 20

03.06.2022 006A0003LU direction, the actuating unit 33 applies a force on the valve device 25 resulting in the valve device 25 LUS02219 moving into the close position.

Fig. 8A to 8D shows different liquid processing steps with the liquid handling device according to the fourth embodiment. This process is similar to the process discussed for fig. 6A to 6D. The difference is the speed at which the valve device 25 moves from the open position to the closed position. In the third embodiment the speed of the valve device 25 is higher than the speed of the valve device 25 shown in fig. 6A to 6D. This leads to a pressure being applied to the liquid arranged in the storage chamber assigned to said valve device 25.

Fig. 8C corresponds to the step explained in fig. 2C. Fig. 8D shows a state in which positive pressure is applied in the first cavity 6 to lower the liquid level arranged in the extension tube 13. Additionally, the actuating unit 33 is moved in a direction opposite to the movement direction shown in fig. 8B. This leads to the valve device 25 moving into the open position.

Fig. 9 shows a liquid handling system 29 with a liquid handling device 1 according to a fifth embodiment. This embodiment differs from the embodiment shown in fig. 5 in that an upper portion of the second housing part 8 can be removed from the remaining part of the second housing part 8.

This permits direct pipetting of liquids into the storage chambers 10. A seal 35 is arranged between the upper portion of the second housing part 8 and the remaining second housing part 8. The seal 35 is around the perimeter of the second housing part 8. The upper portion of the second housing part 8 is fastened to the remaining second housing part 8 by non-shown parts.

Fig. 10 shows a liquid handling system 29 with a stacked configuration. The liquid handling system 29 comprises a liquid handling device 1 and an actuating device 27. The liquid handling device 1 is arranged on the carrier 30 comprising the receptacles 3. The actuating device 27 is arranged on the liquid handling device 1.

Fig. 11 shows a liquid handling system as shown in fig. 10 wherein the majority of the parts of the actuating device 27 and a part of the lid element 24 of the liquid handling device 1 are removed. In particular, one actuating unit 33 is shown in fig. 11. As mentioned before each valve device 25 is assigned to an actuating unit 33. The actuating device 27 comprises devices (not shown) by means of 21

03.06.2022 006A0003LU which the position of each actuating unit 33 can be controlled.

The control unit 28 controls the LUS02219 actuating device 27 in order to control the position of the actuating unit 33 and, thus, the position of the valve device 25.

22

03.06.2022 006A0003LU

Reference Signs LUS02219 1 liquid handling device 2 liquid sample 3 receptacle 4 housing 5 first housing part 6 first cavity 7 processing unit 8 second housing part 9 second cavity 10 storage chamber 11 liquid 12 chamber opening 13 extension tube 14 gap 15 first fluid connection part 16 valve 17 pressure application device 18 second fluid connection part 20 inlet opening 21 closing element 22 membrane 23 actuating element 24 lid element 25 valve device 26 holding membrane 27 actuating device 28 control unit 29 liquid handling system 30 carrier 31 connection chamber 32 magnet 33 actuating unit 34 further magnet 35 seal

D movement direction of an actuating unit

M the centre axis of extension tube 23

Claims

03.06.2022 006A0003LU Patent claims LUS02219

1. Liquid handling device (1) for processing liquid sample (2) located in at least one receptacle (3), wherein the liquid handling device (1) comprises a housing (4) with a first housing part (5), which delimits at least a part of a first cavity (6) of the housing (4), wherein the first cavity (6) of the housing (4) is fluidically connectable to the receptacle (3) and a processing unit (7) for applying a positive or negative pressure in the first cavity (6), characterized in that the housing (4) comprises a second housing part (8), which is connected to the first housing part (5) and which delimits a second cavity (9) comprising at least one storage chamber (10) for receiving liquid (11), wherein the second housing part (8) comprises an chamber opening (12) for dispensing liquid (11) from the storage chamber (10) into the receptacle (2) when a, in particular positive, pressure is applied in the storage chamber (10).

2. Liquid handling device (1) according to claim 1, characterized in that a. the first housing part (5) comprises at least one extension tube (13) for extending into the receptacle (3) and/or in that b. the first housing part (5) comprises at least one extension tube (13), which delimits, in particular surrounds, a part of the first cavity (6).

3. Liquid handling device (1) according to claim 1 or 2, characterized in that the second housing part (8) delimits a part of the first cavity (6).

4. Liquid handling device (1) according to at least one of the claims 1 to 3, characterized in that a. the first housing part (5) and the second housing part (8) are integrally connected to each other and/or in that b. the first housing part (5) and the second housing part (8) are firmly connected to each other.

5. Liquid handling device (1) according to at least one of the claims 2 to 4, characterized in that a. a portion of the second housing part (8) extends into the extension tube (13) and/or in that b. the chamber opening (12) of the second housing part (8) is arranged in a part of the cavity (6) delimited, in particular surrounded, by the extension tube (13) and/or in that 24

03.06.2022 006A0003LU

C. the chamber opening (12) is arranged such that a plane exists that extends parallel to LUS02219 a centre axis (M) of the extension tube (13) and comprises a part of the chamber opening (12). € Liquid handling device (1) according to at least one of the claims 2 to 5, characterized in that a. a gap (14) exists between a portion of the second housing part (8) extending into the extension tube (13) and the extension tube (13) and/or in that b. an outer contour of a portion of the second housing part (8) is smaller than an inner contour of the extension tube (13).

7. Liquid handling device(1) according to at least one of the claims 1 to 6, characterized in that a. the second housing part (8) delimits several storage chambers (10) and/or in that b. the second housing part (8) comprises several portions that are connected to each other and/or are arranged at a distance to each other, wherein each portion of the second housing part (8) delimits a storage chamber (10) for receiving liquid.

8. Liquid handling device(1) according to claim 7, characterized in that a. the storage chambers (10) are fluidically connected to each other within the housing (4) and/or in that b. the second cavity (9) comprises a connection chamber (31) which fluidically connects the storage chambers (10) to each other so that a pressure applied in the connection chamber (31) is applied to the storage chambers (10).

9. Liquid handling device(1) according to at least one of the claims 2 to 8, characterized in that a. the first housing part (5) comprises several extension tubes (13) and/or in that b. the first housing part (5) comprises several extension tubes (13), wherein the number of extension tubes (13) corresponds to the number of storage chambers (10) or is less than the number of storage chambers (10) or is greater than the number of storage chambers (10). 25

03.06.2022 006A0003LU

10. Liquid handling device (1) according to claim 9, characterized in that the first cavity (6) is LUS02219 configured such that the same pressure is applied in the cavity parts delimited, in particular surrounded, by an extension tube (13), respectively.

11. Liquid handling device (1) according to at least one of the claims 1 to 10, characterized in that the liquid handling device (1) is arrangeable on and/or attachable to the receptacle (3).

12. Liquid handling device (1) according to at least one of the claims 1 to 11, characterized in that the liquid handling device (1) is configured such that a pressure applied in the first cavity (6) differs from a pressure applied in the second cavity (9).

13. Liquid handling device (1) according to at least one of the claims 1 to 12, characterized in that the liquid handling device (1) comprises the processing unit (7) which applies pressure in the first cavity (6).

14. Liquid handling device(1) according to at least one of the claims 1 to 13, characterized in that the housing (4) comprises a first fluid connection part (15) that a. is fluidically connected to the first cavity (6) and/or in that b. is fluidically connectable or connected to the processing unit (7) of the liquid handling device (1).

15. Liquid handling device (1) according to at least one of the claims 1 to 14, characterized in that the liquid handling device (1) comprises a valve (16) which a. is configured to be in a close position when pressure is applied in the second cavity (9) and/or which b. is configured to be in an open position after liquid (11) is dispensed from the storage chamber (10) and/or which

C. is connected to the housing (4) and/or is arranged in the housing (4).

16. Liquid handling device (1) according to at least one of the claims 1 to 15, characterized in that 26

03.06.2022 006A0003LU a. the liquid handling device (1) comprises a pressure application device (17) for applying LUS02219 pressure in the storage chamber (10) for dispensing liquid (11) from the storage chamber (10) or in that b. the liquid handling device(1) comprises a pressure application device (17) for applying pressure in the storage chamber (10) for dispensing liquid (11) from the storage chamber (10), wherein the pressure application device (17) is arranged separately from the processing unit (7).

17. Liquid handling device (1) according to at least one of the claims 1 to 16, characterized in that the housing (4) comprises a second fluid connection part (18) that a. is fluidically connected to the second cavity (9), in particular to the storage chamber (10), and/or in that b. is fluidically connectable or connected to a pressure application device (17) of the liquid handling device (1).

18. Liquid handling device (1) according to at least one of the claims 1 to 17, characterized in that the housing, in particular the second housing part (8), has at least one inlet opening (20) for inserting liquid (11) into the storage chamber (10).

19. Liquid handling device (1) according to claim 18, characterized in that the liquid handling device (1) comprises a closing element (21) for closing the inlet opening (20).

20. Liquid handling device (1) according to at least one of the claims 1 to 19, characterized in that the pressure application device (17) comprises a membrane (22) that delimits and/or closes the second cavity (9), in particular the storage chamber (10).

21. Liquid handling device (1) according to claim 20, characterized in that a. the membrane (22) comprises at least one inlet opening (20) for inserting liquid (11) into the storage chamber (10) and/or in that b. the membrane (22) has a bending stiffness that is lower than the bending stiffness of the housing (4), in particular the second housing part (8), and/or in that 27

03.06.2022 006A0003LU

C. the membrane (22) is configured to fluidically disconnect the storage chambers from LUS02219 one another (10).

22. Liquid handling device (1) according to claim 20 or 21, characterized in that a. the pressure application device (17) comprises an actuating element (23) for actuating the membrane (22) or in that b. the pressure application device (17) comprises an actuating element (23) for actuating the membrane (22) such that a pressure is applied to the liquid (11) located in the storage chamber (10).

23. Liquid handling device (1) according to at least one of the claims 1 to 22, characterized in that the housing (4) comprises a lid element (24) for closing the at least one storage chamber (10) and/or for delimiting and/or closing the second cavity (9).

24. Liquid handling device (1) according to at least one of the claims 1 to 23, characterized in that the liquid handling device (1), in particular the pressure application device (17), comprises at least one valve device (25) which is movable in the second cavity (9).

25. Liquid handling device (1) according to claim 24, characterized in that a. the valve device (25) is configured such that in an open position of the valve device (25) a pressure is applicable on the liquid (11) in the storage chamber (10) for liquid dispensing and/or in that b. the valve device (25) is configured such thatin a closed position of the valve device (25) the valve device (25) prevents a pressure apply on the liquid (11) in the storage chamber (10).

26. Liquid handling device (1) according to claim 24, characterized in that the liquid handling device (1) is configured such that a. a pressure is applied on the liquid (11) in the storage chamber (10) for liquid dispensing by moving the valve device (25) from the open position to the closed position and/or in that 28

03.06.2022 006A0003LU b. no pressure is applicable on the liquid (11) in the storage chamber (10) for liquid LUS02219 dispensing when the valve device (25) is arranged in the open position.

27. Liquid handling device (1) according to at least one of the claims 24 to 26, characterized in that a. the valve device (25) is connected to a holding membrane (26) of the liquid handling device (1) and/or in that b. the liquid handling device (1) comprises several valve devices (25) wherein the valve devices (25) are connected to a holding membrane (26) of the liquid handling device (1) and/or in that

C. the valve device (25) comprises an inlet opening (20) for inserting liquid (11) into the storage chamber (10).

28. Liquid handling device (1) according to at least one of the claims 24 to 27, characterized in that the liquid handling device (1) comprises an actuating device (27) for moving the valve device (25).

29. Liquid handling device (1) according to at least one of the claims 1 to 28, characterized in that the liquid handling device (1) comprises a control unit (28) which controls the processing unit (1) and/or the pressure application device (17).

30. Liquid handling device (1) according to claim 29, characterized in that the control unit (28) controls the processing unit (7) such that a. a positive pressure and a negative pressure are alternately applied in the first cavity (6) or in that b. a positive pressure or a negative pressure is applied in the first cavity (6).

31. Liquid handling device (1) according to claim 29 or 30, characterized in that the control unit (28) controls the pressure application device (17) such that a. liquid (11) is dispensed from the storage chamber (10) or in that b. liquid (11) is arranged outside the chamber opening (12) of the storage chamber (10) but does not fall into the receptacle (2). 29

03.06.2022 006A0003LU

32. Liquid handling system (29) comprising a liquid handling device (1) according to any of the LUS02219 claims 1 to 31 and at least one receptacle (3) wherein the liquid handling device (1) is attached to the receptacle (3) and/or arranged on the receptacle (3). 33 Use of a liquid handling device (1) according to any of the claims according 1 to 31 or a liquid handling system (29) according to claim 32 in a reactor for liquid samples, in particular a bioreactor or a chemical reactor.