EP3972736A1

EP3972736A1 - Liquid screening assembly with mechanical release of very small liquid quantities

Info

Publication number: EP3972736A1
Application number: EP20727966.2A
Authority: EP
Inventors: Thomas JÄGER; Martina Cavegn; Martin Frey; Silvano DOMINIONI
Original assignee: Hamilton Storage GmbH
Current assignee: Hamilton Storage GmbH
Priority date: 2019-05-22
Filing date: 2020-05-19
Publication date: 2022-03-30
Also published as: WO2020234325A1; DE102019113679A1

Abstract

The invention relates to a liquid screening assembly (100) comprising: - a pipetting device (60) with at least one pipetting channel (58) which extends along a channel path (K) and is filled with a working fluid (71) and which has a coupling formation (70) at the free longitudinal end thereof for coupling a pipetting tip (42), - a liquid metering device (10) for ballistically dispensing a discrete metered quantity (53) of metered liquid in a metered volume range of 0.3 nl to 500 nl, and - at least one controller (156, 28, 80) for controlling the liquid screening assembly (100) and/or individual components thereof. The invention is characterized in that the the liquid screening assembly (100) has at least one transport device (130, 132, 134, 136) which is designed to move an object (112, 116, 15, 118, 126) towards the channel path (K) along a transport path (T1, T2, T3, T4) and move the object away therefrom and in that the liquid metering device (10) has: - a trigger tappet which can be moved relative to a pipetting tip receiving device (14), - a movement drive which is coupled to the trigger tappet so as to transmit a movement, and - a first and a second deformation structure, between which a pipetting tip deformation region is defined, said trigger tappet being located in the deformation region of the receiving chamber in a triggered position. (Fig. 5)

Description

Liquid screening assembly with mechanical release smallest

Amounts of liquid

description

The present invention relates to a liquid screening assembly which comprises the following components:

a pipetting device with at least one pipetting channel extending along a virtual channel path, which is at least partially filled with a working fluid different from a dosing liquid to be dosed and which has a coupling formation at its free longitudinal end for the temporary, detachable coupling of a pipette tip to it, the pipetting device having a pressure changing device has, which is designed to change the pressure of the working fluid in the pipetting channel,

a liquid dosing device for the ballistic delivery of a discrete dosing amount of dosing liquid in a dosing volume range from 0.3 nl to 500 nl from a dosing liquid supply, and

at least one control device for controlling the liquid screening assembly and / or individual components thereof.

The present invention relates to the screening of liquids, in particular liquids containing active substances, in general. Screening fluids like this is an important part of drug development. Large libraries of liquids containing active substances are tested for their potential to change or influence a biological target. For this purpose, either many chemically different liquids, preferably in the same concentration, or a single chemical liquid in different concentrations are used to examine the parametrically differing liquid test dosages with regard to their effect on the given biological target. Many of the active ingredients or chemical substances used in a screening are extremely valuable, so that, particularly in the case of screening with a high number of individual doses, it is important to be able to dose the individual doses with the lowest possible discrete dose amount possible. It should therefore be possible to dose discrete dosing quantities of less than 500 nl (nanoliters) with repeatable accuracy.

In order to prevent an active ingredient released into a target container at an earlier point in time from changing during the same screening process compared to a later released dose of the same active ingredient, for example due to oxidation or the influence of light, especially during screening with a high number of individual doses It is also important that the repeatable dispensing of discrete dosing quantities can take place as quickly as possible, so that essentially the same influencing conditions apply to all discrete dosing quantities dispensed during a screening process.

Various technologies are known in the prior art for realizing the delivery of the smallest, discrete metered quantities of liquid. WO 2005/016534 A1 discloses a "microdosing device" called liquid dosing device, according to which a liquid-filled flexible hose with a release plunger is suddenly, so very briefly, deformed and relaxed again, with an outlet opening at the end of the flexible hose Discrete dosage in the double-digit nanoliter range is thrown away by displacement of the incompressible liquid.

The longitudinal end of the flexible hose opposite the outlet opening is fluidically connected to a liquid supply, so that after a pulse-like ballistic delivery of a discrete metered amount of liquid from the liquid supply can flow into the flexible hose.

The adjustment of the dosing quantity released by a sudden deformation pulse of the release tappet is done by moving the release tappet along the flexible hose, i.e. by removing the release tappet from the outlet Opening or by approaching it, and / or by changing the stroke of the release plunger.

A pipetting device with a liquid metering device is known from WO 2006/076957 A1, which functions according to the same principle as the pipetting or microdosing device of WO 2005/016534 A1 discussed above. The flexible hose - also referred to as "elastic tube" in WO 2006/076957 A1 - is arranged as an additional component on a longitudinal dosing end of a pipette tip, which is opposite a longitudinal coupling end of the pipette tip, and includes the pipette opening of the Pipette tip. The pipetting device known from WO 2006/076957 A1 thus allegedly enables liquids to be dispensed with repetitive accuracy in discrete dosing amounts in a volume range from 0.1 nl to 100 nl using pipette tips that can be detachably coupled to the pipetting device. The known pipetting device even allows the use of conventional pipetting tips, which usually taper conically towards their pipetting opening when an adapter component is attached to their longitudinal dosing end, which has a piece of flexible hose or elastic tube on which the trigger plunger can act in a jerky or pulsed deforming manner .

The preamble of claim 1 is based on WO 2006/076957 A1.

As a liquid metering device according to the known principle of "Acoustic Droplet Ejection (ADE)" working device with the name "Echo®" from Labcyte Inc. is known, which enables a liquid drop fen by acoustic ultrasonic pulse transmission to a liquid supply from the Ballistically detaching or hurling out the liquid supply. Even with the ADE principle, discrete dosing quantities in the single-digit or two-digit nanoliter range can be dosed ballistically. However, the use of the ADE principle for dosing the smallest amounts of liquid is very expensive due to the special liquid container required for the ultrasonic coupling into the liquid. It is therefore the object of the present invention to develop the liquid screening assembly mentioned at the outset in such a way that it can reliably dose a large number of small dosing quantities in the specified dosing volume range in a very short time with as possible conventional, non-application-specific laboratory equipment.

This object is achieved according to the present invention by a liquid screening assembly of the type mentioned at the outset, which has at least one transport device which is designed to bring a laboratory object along a transport path to the channel path that is intended to be extended from the pipetting channel to the liquid metering device and to remove from this. Laboratory items required for screening can be brought closer to the pipetting channel or its channel path through the at least one transport device and removed from it again. As a result, temporal phases of movement of the pipette channel, possibly with the pipette tip coupled to it, on the one hand and of laboratory items such as pipette tips and / and pipette pit centers or / and dosing liquid containers and / and dosing liquid container carriers and / or disposal containers, on the other hand, are parallelized and movement paths are simplified which makes it possible to shorten the process duration for a screening process overall and to increase the possible throughput. The transport device is a different device than the liquid metering device, which can have moving parts. The moving parts of the liquid metering device remain permanently on the device, while the objects moved and / or movable by the transport device are only temporarily in driving engagement with the transport device.

The pipetting channel can thus be operated essentially in a stationary manner, ie the pipetting channel with its channel path does not need to be designed to be displaceable in a plane orthogonal to the course of the channel path. It may be sufficient to design the coupling of the pipetting channel, which is necessary for the detachable coupling of a pipetting is designed to be moved only in a plane containing the channel path or preferably only along the channel path. Accordingly, it may be sufficient to form the coupling formation of the pipetting device with a mobility only in a plane containing the channel path or preferably only along the channel path. As a rule, the coupling formation is movable together with the pipetting channel, for example with a pipe or cylinder that defines the pipetting channel at least in sections.

The virtual channel path is defined by the pipetting channel. In case of doubt, it is to be understood as the central axis of the area of the pipetting channel that is filled with working fluid and, if necessary, accommodates a pipetting piston. In the context of this application, the virtual channel path is intended to be a possible coordinate path, in particular the coordinate axis of the liquid screening assembly, which is always extended beyond the mere physical extent of the pipetting channel.

The object is also achieved according to the present invention in that the liquid metering device has:

a pipette tip receiving device which defines a receiving space extending along a virtual receiving axis, at least in a ready-to-dose operating position of the liquid dosing device, which is designed to receive a portion of a pipetting tip, the virtual channel path with the virtual channel path extended away from the pipetting channel towards the liquid dosing device The receiving axis is parallel or col- linear,

a release plunger which is movable relative to the pipette tip receiving device and which can be displaced between a standby position further withdrawn from the receiving space and a release position protruding further into the receiving space,

a movement-transmitting coupled with the release plunger Verlage approximately drive, which is designed to move the release plunger abruptly we at least from the standby position to the release position, and a first and a second deformation formation, wherein the first and the second deformation formation between them define an axial longitudinal region of the receiving space as a deformation region in which the first and the second deformation formation can be approached and removed from each other, wherein the release plunger is in its release position in the deformation area of the Recording room is located.

This particular configuration of the liquid metering device allows conventional pipette tips to be coupled to the coupling formation of the pipetting channel without any particular configuration for metering liquid in a metering volume range of less than 500 nl, in particular less than 100 nl, particularly preferably even less than 10 nl The first and second deformations are initially deformed in the deformation area of the receiving space, and by mechanical shock-like impulse transfer of the trigger plunger to the deformed pipette tip, more precisely to a deformed section of the pipette tip, a ballistic delivery of a discrete dosage in the dosage volume range of 0.3 nl to effect up to 500 nl.

Through the said first and second deformation formation, a preferred pipette tip, which can be part of the liquid screening assembly, but does not have to be, and which initially, i.e. in its undeformed initial state, only for conventional aspiration and dispensing in the air displacement process is designed to be deformed in a deformation section of the pipette tip into a shape suitable for a mechanical impulse transmission through the release plunger. The deformation of the pipette tip in the liquid dosing device is preferably such that the deformation section of the pipette tip created in this way absorbs an impulse transfer from the trigger plunger and transfers it to the dosing liquid supply received in the pipette tip so that it is due to the incompressibility of the dosing liquid at the pipette tip opening of the pipette ballistic detachment of a discrete amount of dosing liquid in the form of a freely falling or free-flying drop in the aforementioned dosing volume range. The momentum transmitted from the release plunger to the deformation section is Short in time compared to the duration of the deformation of the deformation section by the first and the second deformation formation. Because of the distance ballistically covered by the dispensed drop in free fall or in free flight, the present application speaks of a ballistic delivery of the discrete dose, in contrast to, for example, delivery by wetting a target surface or in a target liquid with the dosing opening immersed in the target liquid the pipette tip. Because of the triggering impulse that causes the drop to be released, the drop always travels a distance at a higher speed than is reached due to the acceleration of gravity, regardless of the direction of delivery. Since the dosing amount is preferably dispensed ballistically in the direction of the action of gravity and the distance to be covered by the dosing amount between the dosing opening and the target container is usually only a few millimeters or a few centimeters, the speed of the dosing amount is preferably larger than it at each point of the distance to be covered the place in question with the same trajectory in the free fall accelerated only by gravity.

The liquid metering device enables, for example, the use of commercially available conventional pipette tips without specific individualization for a particular task. In contrast to WO 2006/076957 A1, it is also not necessary according to the invention to equip or qualify the conventional pipette tip for the present screening application by attaching additional components. Such a conventional pipette tip extends from its coupling longitudinal end, at which it has a coupling formation, such as a socket, for coupling to the coupling formation, such as a pin penetrated by an opening, of the pipetting channel, along a tip axis up to its metering opening. In a state coupled to the coupling formation of the pipetting channel, the tip axis and the channel path are usually collinear. Between the coupling formation and the dosing opening there is a reservoir space surrounded by the pipette tip, in which, in a state coupled to the pipetting device, dosing liquid can be taken up as a dosing liquid supply, in particular can be aspirated. Commercially available conventional pipette tips, as they can be used according to the invention for the liquid screening assembly present and / or are actually used with this, usually taper at least in sections, preferably continuously, from their coupling longitudinal end or a location closer to the coupling longitudinal end than the dosing longitudinal end along their Point axis directly up to the dosing opening. The tapered portion is in many cases conical. Such a conventional pipette tip can have conical areas with different cone angles along its axial extension in the undeformed state. Such conventional pipette tips are given before given in their still unused, undeformed initial state rotationally symmetrical with the tip axis as the rotational symmetry axis. This makes the automated coupling of the pipette tip to the coupling formation considerably easier, since the circumferential orientation of rotationally symmetrical pipette tips in the direction around the channel path is not important.

While individually designed pipette tips have to be created and used in the prior art in order to be able to dose the desired small discrete dosage amounts with repeatable accuracy, the liquid dosing device of the liquid screening assembly presented here generates the required for dosage of the desired small discrete dosage amounts on conventional pipette tips special shape at least in sections through targeted deformation by means of the first and second deformation formation. The deformed shape of the pipette tip produced in the deformation section is then used for the ballistic delivery of the metered quantity by actuating the trigger plunger. Thus, initially the specific shape of the pipette tip used in the liquid screening assembly is only important insofar as it has to be accommodated in the receiving space of the liquid metering device, so that the necessary deformation work on at least one section of the first and second deformations is then performed Pipette tip can be made. The present liquid screening assembly therefore preferably comprises at least one conventional pipette tip, preferably a plurality of conventional pipette tips configured as described above. At least one pipette tip is preferably coupled to the coupling formation of the at least one pipetting channel and thus forms an extension of the pipetting channel of the pipetting device. A plurality of pipetting tips is preferably provided as a supply in a pipetting tip carrier for coupling through the coupling configuration of the pipetting device.

The canal track can in principle have any course, but is usually a straight canal axis. The channel path, in particular as a channel axis, is to be understood as a mathematical-virtual axis that extends beyond the physical pipetting channel on both sides. Since in the present application the area that is located on the side of the coupling formation facing away from the pipetting channel - that is the side on which a coupled pipetting tip and consequently the liquid dosing device is located - is particularly important in the application Pipetting channel extended away imaginary channel path pointed out. However, this is only an indication that the virtual channel path, in particular as the channel axis, does not end at the physical limits of the pipetting channel that defines it.

The first and the second deformation formation can be implemented, for example, as tool jaws which can be approached and removed from one another and which define the receiving space between them. Depending on the respective pipette tips intended for use, one of the tool jaws or both tool jaws can be provided interchangeably on a base frame of the liquid metering device.

Since conventional pipette tips are usually made of plastic and can therefore show deformation tendencies towards their original shape after an external deforming force has ended, the liquid metering device is designed to handle the first and second deformations. to keep formation formation in a position approximated to one another, in which a pipette tip, which is at least partially deformed between them, is in a defined deformation state and is kept ge in this deformation state.

Since the use of an air displacement method enables the inclusion of a large dosing liquid supply in a pipette tip, for example a dosing liquid supply in the range of 10 to 600 ml, to name just one possible example, the pipetting device is preferably one Pipetting device operating according to the air displacement method, so that the working fluid mentioned at the beginning is preferably a gas. An inert gas, such as helium, or a quasi-inert gas, such as nitrogen, or simply and therefore preferably air can be used as the gas.

The liquid dosing device can therefore be used very well for aliquoting, since the conventional pipette tip can theoretically hold a supply of dosing liquid with at least 20 to 2-10 ⁶ times the volume of the discrete dosing amount to be dispensed in a single dosing process.

To increase the working accuracy of the liquid screening assembly and to handle dosing liquids with as little loss as possible, the pipetting device preferably has a pressure sensor which is designed and arranged to detect the pressure of the working fluid in the pipetting channel. The control device is then preferably connected to control the operation of the pressure change device in terms of signal transmission both to the pressure sensor and to the pressure change device. The control device can then advantageously be designed to control the operation of the pressure change device at least in accordance with an actual working fluid pressure detected by the pressure sensor.

The pressure changing device can comprise a pipetting plunger accommodated in the pipetting channel such that it can be displaced along the channel axis. The piston can be permanent magnetic and the rotor of a linear motor through which the piston is relocatable. Alternatively, the pressure change device can be a working fluid pressure reservoir with a switchable valve assembly through which, depending on the switching state, the pipetting channel is either fluidically separated from the ambient atmosphere and the working fluid pressure reservoir in order to keep the working fluid at a desired pressure, or from the ambient atmosphere and is fluidically connected to the working fluid pressure reservoir to increase the working fluid pressure in the pipetting channel, or is fluidly connected to the ambient atmosphere and separated from the working fluid pressure reservoir to reduce the working fluid pressure in the pipetting channel to ambient pressure.

By providing the pressure sensor, it is possible to detect the change in the actual working fluid pressure during the deformation of the pipette tip filled with dosing liquid by the first and the second deformation formation and to operate the pressure changing device in such a way that the deformation of the pipette tip is caused by the first and the second deformation does not cause any undesired discharge of dosing liquid through the dosing opening of the pipette tip.

The control device preferably regulates the pressure changing device in such a way that it changes the actual working fluid pressure in accordance with a target working fluid pressure value, in particular leads the actual working fluid pressure to a predetermined target working fluid pressure value, the target working fluid pressure value being able to vary over time, for example to compensate for temperature changes. In particular, a reliable, long and numerous aliquoting cycles, including the aliquoting operation, can be maintained, since the pipetting control device ballistically dispensed dosing liquid, which would be missing in the deformation section without further measures, from an axially between the coupling formation by a corresponding control of the pressure change device and the deformation section located dosing liquid supply can track into the deformation section. The control device of the liquid screening assembly can have a metering control device which is connected to the displacement drive in terms of signal transmission in order to control the operation of the displacement drive. By means of the dosing control device, the displacement path and / or the displacement speed and / or the displacement duration of the release plunger can be changed and adapted to the particular dosing liquid to be dosed and / or to the deformed pipette tip used.

The control device of the liquid screening assembly can have a plurality of locally distributed component control devices which are connected to one another directly or indirectly in terms of signal transmission. The control device can, however, also be a central control device by which all controllable components of the liquid screening assembly are controlled.

As a rule, when screening liquids, a plurality of different union objects is required at the same time or in a certain time sequence at predetermined locations of the liquid screening assembly, such as a target container in which the discrete dosing amount of dosing liquid is dispensed, the above-mentioned pipette tip holder for receiving new, clean pipette tips and / or a dosing liquid container or a dosing liquid container carrier in order to be able to take up dosing liquid to be dispensed in discrete dosing quantities beforehand with the at least one pipette tip. It is therefore advantageous if the liquid screening assembly comprises a plurality of transport devices, each of which is designed to bring an object, in particular another object, up to and away from the elongated channel path along a transport path.

In order to be able to ensure that each transport device can move an object assigned to it independently of another transport device, each transport device from the plurality of transport devices preferably has a transport means that can be moved along the transport path. To avoid collisions between the individual means of transport, it is advantageous if the from The means of transport of the individual transport devices are arranged in the direction of the canal path at a distance from each other and preferably without mutual penetration. "Movement space" here denotes that space which is at least temporarily occupied by the transport means when the full path of movement of a means of transport is used. Preferably, exactly one type of object is assigned to a transport means of a transport device, so that, according to a preferred development of the present invention, a transport device with its transport means always moves the same type of object with regard to the function of the object. For example, a transport device can only move pipette tip carriers, another transport device can only move dosing liquid container or dosing liquid container carrier and the like. It is therefore preferred if the term "movement space" refers to the means of transport loaded with the object assigned to it, so that the spatial separation of the movement paths of the different transport devices not only results in a collision of the means of transport, but also a collision of the means of transport assigned to it Avoid loading the object. If several different objects are assigned to a means of transport, "movement space" should refer to the means of transport which is loaded with a fictitious object, the fictitious object being formed from a summary overlay of all objects assigned to the means of transport. The movement space then comprises that space which is occupied by the loaded means of transport in addition when the means of transport, loaded with each of the different objects assigned to it, travels through its complete path of movement one after the other.

A transport device can in principle have any drive for moving the transport means, such as a spindle drive, a chain or a belt drive. Because of the advantageous, particularly space-saving arrangement and the simultaneously required high dynamic movement, at least one transport device, preferably all transport devices, comprises a linear drive for moving the means of transport. So that the means of transport are different Transport devices can reciprocally overtake, preferably each transport device with linear drive comprises its own magnet arrangement as a stator and a rotor movable along the magnet arrangement. The movable runner is connected to the respective transport means for joint movement. To increase the possible throughput, at least one transport device, preferably several transport devices, can each have at least two or more than two transport means.

For easy loading and unloading of the liquid screening assembly, it is advantageous that the transport paths of the transport devices are oriented parallel to one another, so that a spatially limited loading and unloading zone of the screening assembly can be formed in which the at least one transport device, preferably the majority from transport devices, objects can be taken over and handed over or made available for acceptance. The at least one transport device can be loaded and / or unloaded manually in the loading and unloading zone by an employee and / or automatically by a loading robot. The liquid screening assembly therefore preferably comprises at least one robot as a handling device for laboratory goods, such as one or more of the different objects mentioned above. A robot is any handling device with at least two axes of movement.

In principle, it is conceivable that the individual transport means are not only arranged along the channel path at a distance from one another, but are also arranged offset from one another orthogonally to the channel path. Due to the smaller space requirement, however, an arrangement is preferred according to which the moving spaces that can be traversed by the individual means of transport when the screening operation is intended are arranged one above the other in the direction of the canal runway, i.e. without offset of the objects transported by the different means of transport orthogonally to the canal runway .

As a result, it can be sufficient to design the pipetting device with only limited mobility of the coupling formation. So it can be enough if the coupling formation - and with it, of course, a pipette tip coupled to it - is only movable in a plane containing the channel path, the plane being oriented orthogonally to at least one transport path. This is preferably the transport path of the transport device transporting a target container as an object. This makes it possible to use the pipetting device to pipette into target containers which, in a subsequent direction orthogonally to the transport path of the assigned transport device and orthogonally to at least one channel path of the pipetting device, have a greater number of dosing quantity receptacles than the pipetting device has pipetting channels in the same following direction. In this way, it is possible, for example, to pipette into target containers whose dosing quantity receptacles have a smaller distance in the following direction than the minimum distance between two pipetting channels of the pipetting device that are immediately adjacent in the following direction.

Then, however, if the arrangement of a plurality of pipetting channels of the pipetting device in number and division in the following direction corresponds to the number and division of the dosing receptacles of a target container or can be brought into agreement, it may be sufficient that the coupling formation of the pipetting animal device only longitudinally the canal track can be moved and has no degree of freedom of movement orthogonal to the canal track. Then a drive in only one spatial direction is sufficient for moving the pipette tip, namely along the channel path. This can also be a linear drive. The construction of the pipetting device can thus be considerably simplified. In addition, movements of the pipette tip on the one hand and of mobile objects of the liquid screening module on the other hand, such as pipette tip carriers, dosing liquid containers, dosing liquid container carriers, target containers and disposal containers, can be parallelized over time, which increases the throughput of dosing processes per unit of time of the liquid -Screening assembly increased further. The liquid screening assembly can have at least one of the above-mentioned objects: pipetting tip holder, dosing liquid container, dosing liquid container carrier, target container and disposal container. A titer plate that has proven itself for screening processes is preferably provided as the target container, which is also referred to in the relevant specialist field as a "microtiter plate" or as an "assay-ready plate". For example, a standardized embodiment of a microtiter plate (MTP) is an MTP with 8 x 12 = 96 dosage volume receptacles, which are arranged in a uniform orthogonal grid spacing of 9 mm. This means that the division, that is to say the distance between two directly adjacent dosing quantity receptacles, is always 9 mm in every possible subsequent direction of the grid. According to the current state of the art, immediately adjacent pipette tips of a pipetting device can be brought closer to a distance of 9 mm, so that a pipetting device with 8 or 12 parallel pipetting channels can dose in parallel into a 96-MTP line by line or column, depending on the orientation of the 96-MTP can, without having to perform a movement in the subsequent direction of the dosing quantity receptacles, into which the dosing is currently carried out in rows or columns. A pipetting device is sufficient here, the coupling formation of which can only be moved along the direction of the virtual channel path.

When using another standardized MTP with 16 x 24 = 384 dosing volume receptacles in a uniform orthogonal grid graduation of 4.5 mm, the grid graduation is smaller than the minimum distance between adjacent pipetting channels that can currently be produced on many pipetting devices. In this case, mobility of the coupling formation is also necessary in the following direction of the dosing quantity receptacles following one another in the 384 MTP, into which dosing is to be carried out simultaneously from the plurality of pipetting channels. In an MTP, a dose receiving vessel is usually referred to as a "well".

The subsequent direction is preferably either the row or the column direction of metered-dose receptacles arranged in an orthogonal row-column grid spacing. The target container with a plurality of metered quantity receptacles arranged one after the other in a sequence direction is preferably arranged in the transport device transporting it in such a way that the sequential direction is parallel to a row direction along which a plurality of pipetting channels of a pipetting device with parallel pipetting channels is arranged.

Since the liquid dosing device must always be spatially present where the pipette tip coupled to the pipetting channel is located during the dispensing of the discrete dosing quantities, the liquid dosing device can be stationary, i.e. relative to, if the coupling formation of the pipetting channel is only movable along the channel path be arranged immobile Lich a frame of the screening assembly. In addition, in order to provide short movement paths while at the same time minimizing or completely avoiding the risk of collision, at least the pipette tip receiving device of the liquid metering device is arranged between two movement spaces, which are provided by two transport means that are spaced apart in the direction along the channel path when screening is intended Operation are passable. Preferably, the receiving axis of the liquid metering device does not change its location relative to the frame of the liquid screening assembly during the intended screening operation.

The liquid metering device can be arranged to be movable in the following direction so that it can follow the at least one pipetting channel if necessary. In the event that the pipetting device has a plurality of pipetting channels arranged one behind the other in the row direction, which are movable in the row direction, the liquid metering device is also arranged movable in the row direction. To avoid alignment of the at least one pipetting channel relative to the liquid metering device after each movement in the subsequent or row direction, the liquid metering device can advantageously be movable in the subsequent or row direction together with the at least one pipetting channel or with its coupling formation. The liquid metering device can be physically connected to one another by a physical connecting device for joint movement in the sequence or row direction. In order to be able to keep the dosing liquid containers loaded into the liquid screening module and to be processed closed as long as possible and thus to prevent the atmosphere from influencing the dosing liquids contained in the dosing liquid container for as long as possible, it is advantageous if the liquid screening module has a Has container opening device, which is designed to open at least one dosing liquid container. Advantageously, the container opening device can be arranged along at least one transport path at a distance from the channel path, so that one or more dosing fluid containers are opened by the container opening device at a location remote from the channel path and from there in the open state of the channel path for removal of dosing liquid can be fed into one or more pipetting tips.

The container opening device is preferably also designed to close at least one dosing liquid container in order to be able to reseal unused dosing liquid and to be able to store it for a later screening process. The container opening device can be approached and removed from a transport device. The container opening device is preferably stationary relative to the frame of the liquid screening assembly, so that no movement drive - with the exception of the opening drive - is to be provided for the container opening device. A transport device can transport a dosing liquid container and / or a dosing liquid container carrier between the container opening device and the pipetting device or the channel path as required.

To avoid cross-contamination, pipette tips are preferably disposable pipette tips, which are disposed of after a single use. In the present case, disposal after a single use is generally also indicated because of the deformation of the pipette tip by the first and second deformation formation, since this deformation usually always has a non-negligible plastic deformation component. For the most hygienic disposal of used pipette tips, the liquid screening assembly can have a disposal have generation device, which is formed for receiving used pipette tip. The disposal device can comprise a disposal container arranged immovably in extension of the channel path and relative to the channel path, into which the pipetting device discards used pipette tips. The disposal container is also preferably movable by a transport device between a disposal position in which the pipetting device can drop a used pipette tip into it and the above-mentioned loading and unloading zone in order to empty the disposal container as little as possible disruptive to the further operation of the screening assembly To facilitate operating personnel. The disposal position is preferably a position in which the Ent supply container is set by the channel path of the at least one pipetting channel.

The at least one transport device is preferably movable only in one spatial direction along its transport path. It is particularly preferable for a plurality of existing transport devices to be movable in only one spatial direction along their transport path.

In a further development of the invention, as already explained above, it can be provided that a transport device is designed as a dosing container transport device for transporting at least one dosing liquid container and / or that one transport device is designed as a pipetting tip transport device for transporting at least one unused pipetting tip and / or that a transport device is designed as a target container transport device for transporting at least one target container receiving the discrete dosage amount. Additionally or alternatively, a disposal device transport device designed to transport the above-mentioned disposal device can be provided.

Preferably, several, preferably all of the above-mentioned objects to be transported have a uniform design of a take-away engagement area with which the respective object can be transported in take-away intervention with the transport means of a transport device can be brought. Then preferably identical means of transport or even identical transport devices can be used on the liquid screening assembly. The driving engagement area is preferably a foot area of the respective object with which it can be placed on a means of transport.

To achieve the highest possible throughput of discrete dosing quantities per unit of time, the following arrangement of transport devices with a particularly low movement requirement has proven itself: the liquid screening assembly has the dosing container transport device, the pipette tip transport device and the target container transport device, wherein in a Be Zugsstatus in which the coupling formation along the at least one channel path is maximally withdrawn from the target container transport device, the dosing container transport device of the said transport devices is located closest to the coupling formation along the coupling path and the target container transport device from the coupling formation longitudinally is furthest away from the coupling railway. Then, if the Entsorgungsvor direction transport device is provided, this is in the reference state preferably even further away from the coupling formation along the coupling path.

In the reference state, the liquid metering device is preferably closer to the coupling formation than the means of transport of the target container transport device.

For the reliable and repeatable deformation of an initially un deformed conventional pipette tip, the liquid metering device of the liquid screening assembly can be developed in such a way that the first and second deformation formation can be moved relative to one another between a further apart loading position in which the pipette tip receptacle Device for receiving a pipette tip in the pipette tip receiving device and / or for removing the pipette tip from the pipette tip Receiving device is configured, and a more closely approximated De deformation position in which a portion of a pipette tip received in the receiving space located in the deformation region is deformed by the first and the second deformation formation, the control device being designed to only displace the release plunger from the standby position to drive into the release position when the first and second Verformungsfor mation are in the deformation position.

As already mentioned above, the pipette tip extends between its coupling longitudinal end and its dosing longitudinal end along a virtual tip axis. In a state of the pipette tip received in the receiving space, the pipette tip projects over the deformation area axially with respect to the tip axis, preferably on both sides. This means that, along the tip axis, the deformation section of the pipette tip, which is actually deformed by the first and the second deformation, is preferably joined by pipette tip sections that are undeformed on both sides. In particular, both the dosing longitudinal end of the pipette tip facing the dosing opening and the coupling longitudinal end of the pipette tip having the coupling formation remain undeformed. In this way, the shapes of the metering opening and the coupling formation can be retained to ensure their functionality. The undeformed pipette tip sections are preferably at least partially, preferably completely rotationally symmetrical with the tip axis as the rotational symmetry axis.

The pressure wave induced by the release plunger in the dispensing liquid of the deformed pipette tip spreads from the point of impact of the release plunger to the deformation section of the pipette tip arranged in the deformation area of the receiving space on all sides. Along the propagation path, the pressure wave is dampened by internal friction in the dosing liquid. In order to be able to effect a ballistic delivery of the desired dosage in the nanoliter range with the release tappet as reliably and reproducibly as possible, it is advantageous if the deformation area is located closer to the dosing longitudinal end than to the coupling longitudinal end. Then the pressure wave reaches the meniscus of the dosing liquid closer to the dosing opening as little damped as possible. The deformation area is preferably located completely in the half of the axial extension area of the pipette tip starting from the dosing longitudinal end.

In its received state in the receiving space, the first and the second deformation formation being in the deformation position, the pipette tip has the deformation section located in the deformation area of the receiving space with two inner wall surface sections opposite one another across a gap inside the pipette tip. The gap produced by the deformation formations on the pipette tip has a gap width of at least 20 μm, preferably of at least 50 μm and particularly preferably of at least 70 μm, in the direction orthogonal to the tip axis. Likewise, the gap width is not greater than 900 μm, preferably not greater than 500 μm and particularly preferably not greater than 200 μm. In tests, a gap width of 100 μm has proven to be particularly advantageous. Such a gap in the above dimensional limits forms the necessary narrow dosing liquid area described above for almost all dosing liquids, in which pressure waves can be induced by mechanical pulse transmission by means of the release plunger, which lead to the ballistic detachment of the desired small dosing amount at the dosing longitudinal end.

Although the specific shape of the gap and the inner wall surfaces of the pipette tip forming it can in principle be chosen arbitrarily within the dimensions mentioned above, the inner wall surfaces lying opposite one another along the gap width are preferably even or flat in order to achieve dosing results with high accuracy and repeatability, especially when aliquoting / and parallel to each other.

For safe transmission of the mechanical impulse from the release plunger to the deformation section and from there to the dosing liquid in the pipette tip, the release plunger preferably contacts the Verformungsab section of the pipette tip in the release position. The release plunger can already remove the deformation section Contact before reaching the release position, so that the release plunger is deformed briefly from the contacting of the deformation section until the release position is reached. This release deformation, which extends over a significantly shorter period of time than the deformation of the deformation section merely preparatory to the dosing, occurs for a short time in addition to the last-mentioned preparatory deformation, for example for a period of no more than 50 or 90 or 150 milliseconds, added.

The release deformation is preferably an exclusively elastic deformation. The deformation preparatory to the dosage has a plastic deformation component because of its higher degree of deformation compared to the release deformation and the longer deformation duration.

As already described above, the liquid metering device is preferably designed to deform a portion of a pipette tip received in the receiving space in the deformation area over a deformation period, the deformation period compared to the displacement period that the displacement movement of the release plunger from the standby position to the release position lasts, is long.

The deformation section of the pipette tip, which is preferably located between the dosing opening and the coupling formation, has, after deformation by the deformation formations, two opposing inner wall surface sections across a gap in the interior of the pipetting tip, the gap in a first, larger extension direction orthogonal to the tip axis parallel to the opposing inner wall surface sections at least five times, preferably at least ten times, particularly preferably at least 50 times as large a clear width as in a second, smaller extension direction orthogonal to both the tip axis and the first extension direction.

In order for the gap formed in the deformation section of the pipette tip to generate a pressure wave induced by the release plunger up to the ballistic delivery of a dose In the nanoliter range at the dosing liquid meniscus closer to the dosing opening, it is advantageous if the dimension of the gap along the tip axis is at least 0.5 times its maximum clear width along the first direction of extent.

Since, for the reasons mentioned above, a ballistic delivery caused by a mechanical impulse only works particularly well if a pipette tip received in the receiving space is deformed by the deformations in the deformation area to form a narrow liquid space mentioned above, so when the first and the second deformation are in their one of the approximated deformation position, the control device is preferably designed to only drive the release plunger to shift from the standby position to the release position when the first and the second deformation formation are in the deformation position.

Since the liquid metering device discussed here is also capable of aliquoting operation, in which the release plunger is shifted abruptly in the deformation area into the release position several times in succession, the deformation duration defined by the arrangement of the first and the second deformation formation in the deformation position lasts for at least several seconds , while the relocation of the release plunger from the ready position to the release position takes less than 1 second, preferably less than 0.25 seconds and particularly preferably less than 0.05 seconds. Preferably, therefore, the duration of the preparatory deformation of the pipette tip is at least three times, particularly preferably at least thirty times, as long as the duration of the displacement of the release plunger from the standby position to the release position.

The release plunger is preferably not only shifted from the standby position to the release position, but also immediately shifted from the release position back to the standby position so that the release plunger does not remain in the release position, but the release position is merely a reverse dead center of the release displacement of the release plunger is. The control device and / or the However, the bearing drive can also be designed to hold the release tappet in the release position for a predetermined or a predetermined period of time before it begins to be returned to the standby position.

In principle, the release tappet can be provided separately from the first and second deformation formation, which in particular facilitates the design of the release tappet with low mass and, as a result, its acceleration to high displacement speeds in a short time. Since the release plunger is intended to act in a force-transmitting manner in the deformation area of the receiving space defined by the first and second deformation formation, it is preferred, however, if the release plunger is at least part of the first deformation formation, since this is already located on the deformation area. Preferably, the release tappet for reducing the number of components required to form the liquid metering device is the first deformation. Thus, the release plunger can initially contribute to the deformation of the pipette tip received in the receiving space and then, when the first and the second deformation formation are in the deformation position, be abruptly displaced into the release position relative to the second deformation formation. The position of the trigger plunger that it assumes in the deformation position relative to the second deformation formation is then preferably the standby position.

In principle, the release plunger can be moved in a first deformation movement to deform a pipette tip received in the receiving space, so that the pipette tip is deformed into its ready position by moving the release plunger from an initial position retracted further from the receiving space. After reaching the ready position, the release tappet can then be shifted abruptly into the release position for ballistic delivery of a metered quantity. Preferably, however, the trigger tappet can only be displaced between the standby position and the trigger position.

In order to be able to pick up a pipette tip as safely as possible and with a clear orientation in the receiving space, it can be provided that the second deformation Information formation, which preferably lies opposite the release plunger in a direction orthogonal to the receiving axis, comprises a wall section delimiting the receiving space. An outside wall section of a pipette tip can then apply to this wall section, for example to fit snugly when the first and second deformations are moved relative to one another from the loading position to the deformation position.

For the most secure and unambiguous fixing of a pipette tip in the receiving space of the pipette tip receiving device, the pipette tip receiving device can have a first device part closer to the release plunger and a second device part further away from the release plunger. In addition to the trigger plunger, the first or also the second device part can cause a deformation of a pipette tip received in the receiving space, for example in order to locally increase a flow resistance of the pipette tip along the tip axis. For this purpose, the first and / or the second device part can have a constriction section at an axial distance from the trigger plunger relative to the receiving axis, in which the receiving space has a smaller cross-sectional area, at least in the deformation position, than axially directly on both sides of the constriction section. The above-mentioned first deformation formation can thus include both the release tappet and the, preferably first, device part with the constriction section.

To provide kinematics that can be easily implemented and maintained, the first device part can be arranged in a stationary manner relative to a base frame of the liquid metering device, that is to say fixed in a base frame. When the base frame is stationary with respect to the frame of the liquid screening device, the first device part is also stationary with respect to the frame of the liquid screening device.

To move the first and second device formation relative to one another between the loading position and the deformation position, it is advantageously sufficient if the second device part can be removed from the first device part fixed to the base frame and can be brought closer to it. The release tappet is in its ready Shaft position immobile relative to the base frame. The deformation movement is then only carried out by the second device part and the release displacement is only carried out by the release plunger.

A spatially compact pipette tip receiving device with as little installation space as possible can be obtained in that the first device part is penetrated or can be penetrated by the release plunger. The second deformation formation can advantageously be formed on the second device part.

The first device part can form a first of the above-mentioned tool jaws together with the release plunger held in the standby position. The second device part can bake a second of the above-mentioned tools.

In principle, the two deformation formations can be manually moved between their loading position and their deformation position, the liquid metering device preferably having a guide formation which guides the two device formations relative to one another for their movement between loading position and deformation position.

To increase its productivity, the liquid metering device can have a movement drive which drives the two deformation formations relative to one another to move them in at least one direction between the loading position and the deformation position, preferably in both directions. As described above, the second deformation formation alone is preferably coupled to the movement drive. Then, when the pipette tip receiving device has the second device part described above, the liquid metering device preferably has a motion drive coupled to the second device part, by means of which the second device part between an opening position further away from the first device part and an opening position on the first Device part is more closely approximated closed position movable. Then, when the second device part has the second deformation formation, there are preferably the first and the second deformation formation when the second device part is in the open position, relative to one another in the loading position, and when the second device part is in the closed position, in the deformation position.

In order to prevent the motion drive from having to be energized or generally supplied with energy for the entire duration of the deformation of a pipette tip in the deformation area of the receiving space, provision can be made for the second device part to be pretensioned in one of its positions. The second device part is preferably pretensioned into the closed position, so that a pretensioning device providing the pretensioning, for example a mechanical and / and pneumatic and / or hydraulic spring arrangement, also supplies the deformation force by which a pipette tip accommodated in the receiving space is deformed in sections. Then the movement drive only needs to be supplied with energy for a short time in order to move the second device part into the open position or the first and second deformations relative to one another into the loading position.

Likewise, the release tappet can be preloaded into one of its positions by a preloading device, for example again by a mechanical and / and pneumatic and / or hydraulic spring arrangement. The release plunger is preferably preloaded into the standby position, so that it only needs to be shifted abruptly against the preload force of the preload device into the release position by the displacement drive and is immediately shifted back into the standby position after reaching the release position by switching off the displacement drive . In this way, a particularly short displacement period and, in particular, a particularly short dwell time of the release plunger in the release position can be achieved.

For the most precise possible pulse transfer from the release plunger to a deformation section of a pipette tip received in the receiving space, the release position of the release plunger can be defined by a mechanical stop. In front- Preferably, the stop for adapting the liquid metering device to different metering liquids and / or to different metering quantities is adjustable along the displacement path of the release plunger. The displacement path of the release tappet can thus also be changed.

A particularly effective pulse transfer from the release plunger to the deformation section of a pipette tip can be achieved if a displacement path along which the release plunger can be displaced between its standby position and its release position, with the virtual receiving axis, forms an angle in the range of 70 ° to 1 10 ° includes. The included angle is preferably a right angle so that the release plunger can strike the deformation section of a pipette tip as orthogonally as possible to the tip axis which is at least parallel or even collinear to the receiving axis.

For the most effective possible use of an available deformation force to deform a pipette tip received in the receiving space, according to a preferred development of the present invention, a movement path, along which the first and second device parts can approach one another, closes an angle in the range of 70 ° to with the virtual receiving axis 1 10 ° a. In turn, the angle is preferably a right angle for the advantageous avoidance of deformation components acting along the receiving or tip axis.

Consequently, the displacement path and the movement path are at least partially, preferably completely, in two mutually parallel planes or in a common plane. An advantageously slim liquid metering device with a slim operating space in which its movable components move can be obtained when the displacement path and the movement path are parallel to one another.

As already mentioned above, in order to increase the possible throughput of discrete dosing quantities per unit of time, the pipetting device can surround a plurality of parallel pipetting channels, each extending along a virtual channel path. grasp, which are each at least partially filled with a working fluid different from a dosing liquid to be dosed and which each have a coupling formation for the temporary, releasable coupling of a pipette tip to it at their free longitudinal end. The pipetting channels are preferably arranged one after the other in the above-mentioned row direction.

The liquid metering device is then preferably designed to deform a plurality of pipette tips simultaneously as described above in preparation for a ballistic delivery of a discrete metered quantity. In order to be able to parallelize the ballistic dispensing itself, the liquid dosing device preferably has a plurality of release plungers which are movable relative to the pipette tip receiving device and which can be displaced between the standby position, which is further withdrawn from the receiving space and the release position protruding further into the receiving space.

The pipetting channels are preferably designed identically. If the pipetting channels each have a piston in the pipetting channel driven by a linear motor, the pistons of the individual pipetting channels can be displaced independently of one another in the pipetting animal channel along the channel path.

When a plurality of pipetting channels is provided, it is advantageous if a plurality of pipette tips can be formed simultaneously by a first and a second deformation formation. For this purpose, the liquid metering device can have a deformation tool with a first tool jaw arrangement and a second tool jaw arrangement, the first and the second tool jaw arrangement being able to approach one another for deforming a plurality of pipette tips arranged between them, each tool jaw arrangement

has or is a collective tool jaw, which for the deforming interaction with a plurality of pipette tips is only designed to be movable or immovable relative to the plurality of pipette tips, or and

has a single tool jaw, which is formed independently of further individual tool jaws or collective tool jaws of the same tool jaw assembly relative to the other tool jaw assembly be movable for deforming interaction with exactly one pipette tip.

The single tool jaw can be formed like a tool jaw described above. The collective tool jaw can in principle also be designed according to the above description of a tool jaw, with the proviso that it has a piece of jaw component for the common, simultaneous deformation of several pipette tips. This can be a one-piece first or second device part which is simultaneously effective for a plurality of pipette tips, as described above. The one-piece first device part can be penetrated by a plurality of release tappets which can be displaced relative to the first device part.

For this purpose, a tool jaw arrangement composed of a first and second tool jaw arrangement can be a tool jaw arrangement positioned with respect to a stationary frame of the liquid screening assembly. The respective other tool jaw arrangement can then be movable relative to the most positioned tool jaw arrangement, the most positioned tool jaw arrangement being a collective tool jaw and the movable tool jaw arrangement having or being a collective tool jaw and / or having one or more individual tool jaws.

The use of individual tool jaws in a tool jaw arrangement enables the formation of differently deformed deformation sections on the respective pipette tips and thus the simultaneous use of different pipette tips and / and the simultaneous dosing of different dosing fluids on the plurality of pipetting channels. The greatest possible freedom of design The screening operation exists when the movable tool jaw arrangement has only single tool jaws.

What has been said above about the tool jaw arrangements applies mutatis mutandis to the component of the liquid metering device which transmits mechanical impulses, that is to say to the plurality of release tappets. It can consequently be provided here that the liquid metering device

has a collective triggering tappet arrangement which comprises a plurality of triggering tappets which can only be displaced jointly into the triggering position for triggering a respective dosing amount at each pipette tip from a plurality of pipette tips,

or and

comprises at least one single trigger plunger, which can be displaced into the trigger position for triggering a metered quantity on exactly one pipette tip from the plurality of pipette tips independently of the other trigger tappets from the plurality of trigger tappets.

A collective trigger tappet arrangement can have all the trigger tappets of the liquid metering device or only a part thereof. Another part of the release tappet can be formed by individual release tappets.

In turn, the use of individual trigger plungers enables the transmission of different mechanical impulses to the respective deformation sections of several pipette tips in one and the same dosing process in which the several pipette tips are involved. Because of the greater freedom in designing the screening operation, all trigger tappets are preferably single trigger tappets. Since the individual release plungers are preferably arranged on the base frame or on a component that is stationary relative to the base frame for displacement between the standby position and the release position, the individual release plungers are preferably arranged to penetrate a collective tool jaw, the collective tool jaw being one of the number of individual Release plungers corresponding number of individual tool jaws movable opposite. In order to further increase the throughput of discrete dosage quantities dosed per unit of time, a plurality of liquid screening assemblies, as described above and developed further, can be combined to form a liquid dosing station.

In accordance with the above description, the present invention also relates to a method for screening liquids, comprising the following method steps:

Taking up liquid as dosing liquid in a pipette tip by changing the pressure of a working fluid in a pipetting channel of a pipetting device facing the pipette tip and thereby forming a dosing liquid supply in the pipette tip,

after aspirating liquid: deforming a section of the pipetting tip,

After deforming the section of the pipette tip: exerting an impact-like trigger pulse on the deformed section of the pipette tip and thereby triggering a ballistic delivery of a discrete dosing amount of dosing liquid in a dosing volume range from 0.3 nl to 500 nl from the dosing liquid supply in the pipetting tip.

The above-described liquid screening assembly is preferably designed to carry out this screening method.

In order to avoid undesirable gas bubbles in the pipetting tip that falsify the dispensing result during the ballistic delivery of discrete dosing quantities, a section of the pipetting tip is preferably deformed during the step of deforming a section of the pipetting tip which contains at least part of the dispensing liquid supply before and after the deformation step . The deformation section of the pipette tip is preferably completely and exclusively filled with dosing liquid immediately after the deformation step. To achieve a high throughput of the liquid screening assembly, the method can comprise at least one of the following further steps:

Transport of a dosing liquid container to a container opening device by a first transport device in a first movement space,

Removal of the dosing liquid container from the container opening device,

A pipette tip is transported in an aligned arrangement with the pipetting channel of the pipetting device by a second transport device in a second movement space,

A dosing liquid container is transported in an aligned arrangement with the pipetting channel of the pipetting device through the first transport device in the first movement space,

Removal of the dosing liquid container from the aligned arrangement with the pipetting channel,

A third transport device in a third movement space transports a target container that holds the discrete dosage amount in an aligned arrangement with the pipetting channel of the pipetting device,

Removal of the target container from the aligned arrangement with the pipet animal channel,

A fourth transport device in a fourth movement space and removal of the disposal container from the aligned arrangement with the pipetting channel) transport a used laboratory goods receiving Entsorgungsbehäl age in alignment with the pipetting channel of the pipetting device).

The used laboratory ware is primarily used pipette tips. However, other items can also constitute used laboratory ware, such as vessels and cleaning components.

For the first, second, third and fourth movement space, what has already been explained above for the device applies accordingly. The areas of movement run preferentially parallel to one another and along the direction of the channel path at a distance from one another, particularly preferably without an offset orthogonal to the channel path direction.

The present invention will be described in more detail below with reference to the accompanying drawings. It shows:

1 shows a side view of an embodiment of a liquid dosing device with a pipetting tip used in a liquid screening assembly according to the invention, a first and a second device part of the liquid dosing device being shown separated from a main body of the device in an exploded view and the pipetting tip connected to a pipetting channel of a pipetting device the liquid screening assembly according to the invention is coupled,

FIG. 2 shows a perspective illustration of the liquid metering device from FIG.

1 without pipetting device,

Fig. 3 shows the liquid metering device in the view of Fig. 1, with the first and the second device formation in the deformation position, as in turn without a pipetting device,

4 shows the first and second device parts used in FIGS. 1 to 3 in a perspective view of their surfaces facing each other during operation,

Fig. 5 is a rough schematic representation of an embodiment according to the invention form of a liquid screening assembly of the present application and

6 is a perspective view of a more detailed illustration of a liquid screening station according to the invention, comprising two liquid screening assemblies of the present application. First, an embodiment of a liquid screening assembly 100 according to the invention will be generally described in connection with FIGS. 5 and 6. FIG. 5 shows only a rough schematic representation of a liquid screening assembly 100 according to the invention. A coordinate tripod in FIGS. 5 and 6 indicates the respective position and orientation of a Cartesian coordinate system of the axes of movement x, y and z of the components of the liquid screening assembly 100 of Figures 5 and 6.

The liquid screening assembly 100 comprises a frame 110 which forms a fixed reference system of the liquid screening assembly 100.

The liquid screening assembly 100 comprises a pipetting device 60 with a straight pipetting channel 58 which defines a channel path K, which is a straight channel axis K here. The pipetting channel 58 has a coupling formation 70 to which a pipette tip 42 with its coupling formation 56 is coupled in a fluid-tight manner. The pipette tip 42 extends along a tip axis S from its coupling longitudinal end with the coupling formation 56 to its dosing longitudinal end with the dosing opening 50. The channel path K or channel axis K and the tip axis S are in the one shown in Figure 5 to the coupling formation 70 and thus the state of the pipette tip 42 coupled to the pipetting channel 58 is collinear.

The pipetting device 60 or the pipetting channel 58 can be moved in the z-axis direction. The pipetting channel 58 and with it the coupling formation 56 which is fixed relative to the pipetting channel 58 can also be moved in the y-axis direction. In the example shown, the z-axis direction is parallel to the channel axis K.

Under the pipetting device 60 there is a liquid metering device 10, either positioned relative to the frame 110 or, if the pipetting channel 58 can be moved in the y-axis direction, also movable in the y-axis direction, which will be described further below in connection with FIGS to 4 will be explained in more detail. The liquid dosing device 10 is used to deform the originally conventional pipette tip 42 in sections and to keep it deformed in order to transfer a very small, discrete dosing amount 51 of dosing liquid 53 through the dosing opening 50 by transmitting a very short mechanical impulse to the deformation section of the pipette tip 42 (see also Fig Fig. 3) in the order of 0.3 nl to 500 nl ballistically.

The dosing liquid is dispensed into a target container 112 designed as a microtiter plate with a plurality of dosing quantity receptacles 114.

A disposal container 1 16 is located along the channel axis K under the target container 112. In this, used pipette tips 42 can be discarded from the pipette channel 58 after use. The direction of the action of gravity runs in FIGS. 5 and 6 parallel to the channel axis K and opposite to the z-axis direction.

The liquid screening assembly 100 further includes a pipette tip carrier 118 in which new, unused and previously deformed pipette tips 42 are provided for reception by the coupling formation 70 of the pipette channel 58.

The liquid screening assembly 100 comprises a container opening device 120 which can either only be moved parallel to the z-axis direction or both parallel to the z-axis direction and also parallel to the y-axis direction. In the scrap example shown, the container opening device 120 comprises a screwing tool 122 which can be rotated in opposite directions about a screw axis C running parallel to the z-axis direction, with which screw caps 124 can be unscrewed and screwed on again from dosing liquid containers 128 provided in a dosing liquid container carrier 126 . The loading container opening device 120 thus serves both to open dosing liquid keitsbehältern 128 and the closing of the same. The screw axis C is parallel to the channel axis K.

The liquid screening assembly 100 further comprises a first transport device 130, a second transport device 132, a third transport device 134 and a fourth transport device 136. The transport devices 130, 132, 134 and 136 have a first transport means 138, a second transport means 140, and a third Transport means 142 and a fourth transport means 144. The first to fourth transport means 138 to 144, which are each assigned to the transport device 130 to 136 with the same ordinal number, are all movable both longitudinally to one another and parallel to the x-axis direction, virtual straight-line transport paths T1, T2, T3 and T4. They are preferably only movable parallel to the x-axis direction. For example, the first to fourth transport means 138 to 144 can each be designed as linearly guided carriages, in particular tray carriages. Preferably, each of the first to fourth transport means 138 to 144 can be driven linearly by a motor for movement along its assigned transport belt T1 to T4.

The same laboratory objects 42, 112, 116, 118, 126 and 128 are preferably always assigned the same transport devices 130 to 136. In screening mode, this means that the first transport device 130 preferably only transports the dosing liquid container carrier 126 with or without the dosing liquid container 128 received therein. A dosing liquid container carrier 126 can be transported through the first transport device 130 or the first transport means 138 belonging to the first transport device 130 the container opening device 120 such that the at least one screw axis C of the container opening direction 120 is collinear with a screw axis F of at least one screw closure 124 or is sufficiently collinear for a tool engagement with the screw tool 122. For the sake of clarity, not all of the screw connection axes F of the individual screw connections 124 are shown in FIG. 5 and FIG. By moving in the z-axis direction, the container opening device 120 can be moved out of the movement space 146 of the first transport device 130 in order to avoid an undesired collision with the first transport means 138 loaded with a dosing liquid container carrier 126. The movement space 146 is the sum of all those places in the space that are completely loaded with a fully loaded dosing liquid container carrier 126 first transport means 138 during a process of the first transport means 138 between tween the end positions of the first transport device 130 along the transport path T1 be taken.

After positioning the dosing liquid container carrier 126 with at least one dosing liquid container 128 in such a way that the screw axis C of at least one screwing tool 122 and the screwing axis F of at least one screw cap 124 are oriented sufficiently collinearly, the container opening device 120 is lowered so that the screwing tool 122 engages the tool to bring with the screw cap 124 and to unscrew or open the relevant dosing liquid container 128 with the screwing tool 122.

At the same time as this, the second transport device, which exclusively transports pipetting tip carriers 1 18, can have been brought closer to the channel axis K in such a way that the tip axis S of a pipette tip 42 that has not yet been used in the pipetting tip carrier 1 18 is collinear or for establishing a coupling engagement with the coupling formation 70 is sufficiently collinear with the channel axis K.

To avoid a collision with the fully loaded second transport means 140, the coupling formation 70 is moved out of the movement space 148 of the second transport device 132 or the second transport means 140 along the z-axis direction during the transport of a new pipette tip 42 under the coupling formation 70. The movement space 148 of the second trans port device 132 is the sum of all those locations in the space which are of the second fully loaded with a fully equipped pipette tip carrier 118 Transport means 140 during a process of the second transport means 140 between tween the end positions of the second transport device 132 along the second transport path T2.

The third transport device 134 only transports target containers 1 12. Again, in parallel to the two movements described, the target container 1 12 can be moved along the conveyor belt T3 of the third transport device 134 in such a way that a next-to-receive dosing quantity receptacle 1 14 with the channel axis K is aligned so that the virtual channel axis K, which is imagined to be extended beyond the coupling formation 70, intersects the dosing quantity receptacle 114.

Since the coupling formation 70 is already withdrawn along the z-axis direction from the movement space 148 of the second transport device 132 in the case of a temporally parallel execution, the coupling formation 70 and thus the pipetting channel 58 is even more withdrawn from the movement space 150 of the third transport device 134. A collision between the pipetting channel 58 and / and the coupling formation 70 on the one hand and the third transport means 142 loaded with the target container 112 is therefore impossible.

It is also true for the movement space 150 that this is defined by the sum of all those locations in the space which the third transport means 142 loaded with a target container 112 during a movement of the third transport means 142 between the end positions of the third transport device 134 along the third Transport track T3 are taken.

Merely for the sake of completeness it should be noted that the fourth transport device 136 only transports the disposal container 116. The fourth transport means 144 moves in a state loaded with a disposal container 116 during a movement between the end positions of the fourth transport device 136 along the fourth transport path T4 in the movement space 152. The first to fourth transport means 138 to 144 can be loaded and unloaded in a loading and unloading zone 154, which can be located in a spatial region of the liquid screening assembly 100 that is close to the first to fourth transport devices 130 to 136. In this loading and unloading zone 154, which is easily accessible for an employee and / or for a handling robot (not shown), objects can be removed from the respective first to fourth transport means 138 to 144 and the first to fourth transport means 138 can to 144 are loaded with other objects.

After aligning a new pipette tip 42 with the pipetting channel 58 and its coupling formation 70, the coupling formation 70 can be lowered counter to the z-axis direction to the new pipetting tip 42 and thus the new pipetting tip 42 is coupled to the coupling formation 70 in a fluid-tight manner.

After this coupling process, the pipette tip 42 coupled to the coupling formation 70 can be moved out of the movement space 146 of the first transport device 130 in the z-axis direction, so that the dosing liquid container 128, which is opened in the meantime by the container opening direction 120, is thus longitudinally moved by the first transport device 130 the first conveyor belt T1 are brought into alignment with the channel axis K so that, by lowering the coupled pipette tip 42, its dosing opening 50 can be immersed in the opened dosing liquid container 128 and in the dosing liquid contained therein. After this immersion, dosing liquid can be removed from the dosing liquid container 128 by aspiration from the pipette tip 42.

In the meantime, the second transport means 140 with the pipette tip support 118 can be removed from the channel axis K along the second transport path T2 along the second transport path T2, for example in the direction of the loading and unloading zone 154, parallel to the process of withdrawing dosing liquid by aspiration. After removing the first transport means 138 with the dosing liquid container carrier 126 from the channel axis K, for example back to the container opening device 120, in order to close the opened dosing liquid container (s) 128 again, the pipetting tip 42, which is now filled with dosing liquid, can together with the pipetting channel 58 are lowered into the liquid metering device 10 counter to the z-axis direction into the position shown in FIG.

As will be described in detail below, the liquid metering device 10 can dispense very small, discrete metered amounts with repeat accuracy ballistically from the metering opening 50 of the then deformed pipette tip 42.

Aliquots are preferred in the screening operation. Flierzu is after ballistic dispensing of a discrete dose in a dosed quantity receiving vessel 1 14 provided in alignment in the channel axis K of the target container 1 12 by the third transport device 134 by a vessel division along the third transport track T3, so that a new dose receiving vessel 114, into which has not yet been dosed, is arranged under the dosing opening 50. In this new dosing amount receptacle 114, a discrete dosing amount is then ballistically dispensed by the liquid dosing device 10.

After the dosing tasks to be performed on the target container 112 have been completed, the target container 112 is brought into the loading and unloading zone 154 and removed from the third transport means 142 for further processing.

If another dosing liquid is to be dispensed into a subsequent target container 1 12, those dosing liquid containers 128 from which the current dosing liquid has been taken are reopened in the manner described above through the container opening direction 120 and then aligned with the channel axis K of the pipetting device 60 so that the residual liquid remaining in the then deformed, coupled pipetting tip 42 can be dispensed into the opened dosing liquid container 128. After the emptied, used and deformed pipette tip 42 has been dropped into the disposal container 116, a new screening process can begin in which a dosing liquid container 128 is opened with the dosing liquid then to be dosed and a new, unused pipette tip 42 is picked up by the pipetting channel 58 on the coupling formation 70 etc.

A controller 156 controls the operation of the liquid screening assembly 100.

FIG. 6 shows a less highly abstracted embodiment of two liquid screening assemblies 100 from FIG. 5, which are combined to form a liquid screening station 160. For the sake of clarity, some components of the liquid screening station 160 and its liquid screening assemblies 100 are not shown in FIG. For example, although the fourth transport device 136 with disposal container 116 shown in FIG. 5 is present at the liquid screening station 160, it is not shown. Each pipetting device 60 of the two liquid screening assemblies 100 in FIG. 6 comprises exactly 12 pipetting channels 58, which are arranged in succession with channel axes K parallel to one another and parallel to the y-axis direction. The y-axis direction is therefore the row direction in the sense of the introduction to the description. The channel axes K of the pipetting channels 58 of each pipetting device 60 thus lie for each pipetting device 60 in a plane which is orthogonal to the x-axis direction. Of the 12 pipetting channels 58 of each pipetting device 60, only 10 pipetting channels 58 are shown.

The target container 1 12 is consequently a 384 microtiter plate with 16 by 24 dosage quantity receptacles 114 arranged in an orthogonal grid. The target container 1 12 is accommodated in the transport means 142 of the third transport device 134 in such a way that 24 dosage quantity receptacles 114 in y-axis direction and that 16 lines each with 24 dosing-quantity receptacles 1 14 follow one another in the x-axis direction. The y-axis direction is therefore a consequence direction in the sense of the introduction to the description. Since the 12 pipetting channels 58 of each pipetting device 60, the pipetting devices 60 cannot be brought closer than 9 mm to one another along the y-axis direction due to the design and furthermore the grid division of the dosing quantity receptacles 1 14 of the target container 1 12 in both x and in y-axis direction is 4.5 mm, the pipetting channels 58 of each pipetting device 60 of the liquid screening station can be displaced at least together in the y-axis direction. Thus, in a first dosing substep, dosing into every second dosing quantity receptacle 1 14 of a 24 column, after which the 12 pipetting channels 58 with a pitch of 9 mm in the row direction by 4.5 mm in the following direction identical to the row direction are moved, whereupon in a second metering part step is metered into the remaining 12 metered quantity receptacles 114.

The dosing liquid container carrier 126 has dosing liquid containers 128 following one another in the y-axis direction 12, so that all pipetting channels 58 of a pipetting device 60 can receive dosing liquid at the same time.

Although both liquid screening modules 100 of the liquid screening station 160 have a first to fourth transport device 130 to 136, the two liquid screening modules 100 share the first to fourth transport devices 130 to 136, so that each transport device 130 to 136 in FIG 6, two liquid screening assemblies 100 are assigned. On the transport devices 130 to 136, each liquid screening assembly 100 is assigned a transport means 138 to 144, of which, for the sake of clarity, only the transport means 138 is shown twice, of which only once in the loaded state (left transport means 138 in FIG. 6). The two liquid screening assemblies 100 of the station 160 also share a common frame 110.

Each transport means 138 to 144 has a linearly guided transport slide 162 to 166 (the transport slide of the fourth transport device 136, not shown in FIG. 6, is also not shown). The transport carriages 162 to 166 shown in Figure 6 are on linear guides 168 to 172, which are preferably sliding Nen guides are guided for movement along the x-axis direction. Each Schlit th 162 to 166 and the carriage (not shown) of the fourth Transportvorrich device 136 are runners of an electromagnetic linear drive, the stator of which is mounted on the carrier of the linear guides 168 to 172. Preferably, the stator comprises a sequence of alternately polarized permanent magnets arranged in the x-axis direction and comprise the transport carriages 162 to 166 in their function as runners of a linear motor, so that several transport carriages on one and the same transport device 130 to 136 are independent of one another in the x-axis direction can be moved. The linear guides 168 to 172 are not shown continuously in FIG. 6 in the x-axis direction. However, they run continuously from one longitudinal end in the x-axis direction to the opposite longitudinal end of the liquid screening station 160.

Since the transport means 138 to 144 of a liquid screening assembly 100 cannot overtake one another in the example shown, a loading and unloading zone 154 is set up at each longitudinal end of the liquid screening station 160 in the x-axis direction. At each longitudinal end of the liquid screening station 160 there is therefore a flandling robot 176 for the automated loading and unloading of the transport means 138 to 144 of the first to fourth transport device 130 to 136. The flandling robots 176 can also be controlled by the control device 156.

Since the liquid dosing devices 10 for the dosing of very small discrete dosing amounts 53 into the dosing amount receptacles 114 of the target container 112 must be able to follow the pipetting channels 58 of a pipetting device 60 and their pipetting tips 42 coupled to them in the y-axis direction, each liquid dosing device 10 is shown in FIG 6 can be displaced in the y-axis direction by a displacement device 174. The liquid metering devices 10 in FIG. 6 can only be displaced in the y-axis direction, the coupling formation in 70 of the pipetting channels 58 of a pipetting device 60 can only be moved in a plane spanned by the y- and z-axis directions in FIG. All of the multiple components in FIG. 6 are preferably constructed identically, such as the two container opening devices 120, the pipetting devices 60 and their pipetting channels 58, multiple means of transport (see transport means 138), etc.

With reference to FIGS. 1 to 3, the liquid dosing device 10 will be described below in terms of its mode of operation and in its cooperation with the pipetting device 60. The liquid metering device 10 comprises a housing 12 that is generally stationary during operation, for example with respect to the frame 110 of the liquid screening assemblies 100 or the liquid screening station 160, on which a pipette tip receiving device 14 is provided. The housing 12 of the liquid metering device 10 forms a base frame of the same as mentioned in the introduction to the description.

In the embodiment shown, the pipette tip receiving device 14 comprises a first device part 16, which is generally fixed to the housing or base frame, and a second device part 18 that is movable relative to this.

The movement of the second device part 18 is guided by guide means, for example two parallel guide rods 20 and 22, which enforce the first device part 16 Vorrich. The second device part 18 is along a movement path B parallel to the plane of the drawing in FIG. 1 between an open position further away from the first device part 16 (see, for example, FIGS. 1 and 2) and a closed position which is closer to the first device part 16 (see FIG 3) movable.

As a movement drive 24 of the second device part 18 at least from the opening position to the closed position, the liquid metering device 20 has two manually operable screws 24a and 24b. With the screws 24a and 24b, the second device part 18 can be brought closer to the first device part 16 up to the closed position with a defined force. In the opposite direction of rotation, at least one mobility of the second device part 18 along the movement production path B in the direction of the first device part 16 away. A movement of the second device part 18 from the closed to the open position can thus be carried out by an operator by means of a manual operating attack on the second device part 18.

However, it is readily apparent to those skilled in the art that, instead of the screws 24a and 24b of the movement drive 24, which are only shown as examples, the movement drive 24 can have an actuating actuator which can be coupled to the second device part 18 along the movement path B for joint movement. For example, the movement drive 24 can be a pneumatically or hydraulically actuated movement drive, the piston rod or piston rods of which can be coupled to the second device part 18 for joint movement. Alternatively, the movement drive 24 can be an electromotive movement drive, for example a spindle drive, in order to take up the functional principle of the screws 24a and 24b shown as an example. For this purpose, a threaded rod of the spindle drive can be in screw engagement with an internal thread of an opening passing through the second device part 18 parallel to the movement path B, so that the second device part 18 acts as a nut which, when the at least one threaded rod rotates along the thread's longitudinal axis, corresponds to the speed and the pitch of the thread used on the threaded rod along the path B is moved.

Deviating from the kinematics described above, in addition to the second device part 18, the first device part 16 can also be driven by a movement drive to move along the movement path B, but this would only increase the number of movement drives to be provided without the associated benefit increasing significantly.

Alternatively, the second device part 18 could be fixed to the housing or base frame and only the first device part 16 could be displaceable along the movement path B by a movement drive. The further functions and effects of the first and second Vorrich device parts 16 and 18 will be discussed in more detail below in connection with FIG. First, however, the functionality of the liquid metering device 10 will be explained further.

In a coupled to the pipetting channel 58 pipette tip 42, more precisely in its reservoir space 62, a supply 55 of dosing liquid 51 is taken up by aspiration.

The liquid metering device 10 has a release tappet 26 which can be displaced along a displacement path V between a standby position further retracted into the housing 12 and a release position pushed further out of the housing 12. The displacement path V and the movement path B are preferably collinear or at least parallel.

The flow of the trigger plunger 26 between its two mentioned operating positions is considerably smaller than the relative movement path of the first device part 16 and the second device part 18 along the path B between their operating positions: open position and closed position. While the relative movement path of the first and second device parts 16 and 18 is at least in the single-digit millimeter range, the stroke of the release plunger 26 between its mentioned operating positions: standby position and release position, usually less than 50 miti, preferably less than 40 miti , particularly preferably less than 36 gm. The information about the stroke of the trigger plunger and the relative movement of the first and second Vorrich device parts 16 and 18 apply not only to the exemplary embodiment of the present invention shown in FIGS. 1 to 3 but more generally for the liquid metering device of the present invention. The stroke of the trigger plunger is preferably always smaller, about at least a factor of 5 smaller than the movement path of the device parts 16 and 18 between their operating positions. To control the movement of the release plunger 26, the liquid metering device 10 has a sub-control device 28 shown in dashed lines in the housing 12 only in FIGS. 1 and 3 for the sake of clarity. The sub-control device 28 is in signal transmission connection with a displacement drive 30 in the exemplary form of a piezo actuator through the line 32. The sub-controller 28 is in signal transmission communication with the controller 156. The controller 156 may be a master controller, while the sub-controller 28 is a slave controller.

Energy, in the example shown electrical energy through the connection socket 34a, and data, in the example shown through the connection socket 34b in the form of an RJ45 socket, can be transmitted into the interior of the housing 12 through connection sockets 34a and 34b. The energy can be supplied as drive energy by the sub-control device 28 via the line 32 to the piezo actuator of the displacement drive 30. Thus, by energizing the displacement drive 30, the release plunger 26 can be displaced from the housing 12 into the release position against the prestressing preload of a spring 36 (see FIG. 3) which restores it. When the power supply to the piezo actuator of the Verla gerungsantriebs 30 is interrupted, the release plunger 26 is immediately displaced by means of the preload by the coil spring 36 in the more retracted into the housing 12 Be ready position.

The housing 12 can be spatially aligned with respect to a frame and / or with respect to the pipetting device 60 shown in FIG. 1 via positioning pins 36a and 36b.

Instead of a piezo actuator, the displacement drive 30 can comprise an electromagnet which, when energized or not energized, generates or does not generate a magnetic field that displaces the release plunger 26. In the case of an electromagnetic displacement force, the release tappet 26 may comprise a permanent magnet or a soft magnetic armature, which is driven by the electromagnetic displacement drive depending on its current supply stood generated magnetic field along the displacement path V together with the release plunger 26 carrying it is displaceable.

In the exemplary embodiment shown, the release tappet 26 protrudes into a recess 38 passing through the first device part 16 and penetrates this recess both in its standby position and in its release position.

For a better understanding of the functioning of the liquid metering device 10, the device parts shown in FIG. 4: first device part 16 and second device part 18 are explained in more detail:

The mutually facing surfaces 16a and 18a of the two device parts 16 and 18 have a contour such that when the two device parts 16 and 18 are in their approximated closed position along the movement path B, between the two device parts 16 and 18, a receiving space 40 is defined, in which at least an axial section of a pipette tip 42 can be received. The receiving space 40 extends along a virtual receiving axis A, which coincides with a virtual tip axis S of a pipetting tip 42 received in the receiving space 40. The Vorrich device parts 16 and 18 are in their closed position.

The first device part 16 forms a first tool jaw arrangement 17, the second device part a second tool jaw arrangement 19. In the example shown in FIGS. 1 to 4, the tool jaw arrangements 17 and 19 have only single tool jaws. One or both of the tool jaw arrangements 17 and 19 can, however, also have collective tool jaws in that they are longer than shown orthogonally to the virtual receiving axis A and the formations 38 and 48a explained below along the extension direction, that is the y-axis direction in the present case, at the distance of the Pipettierkanaltei development of a pipetting device 60 are formed repeatedly. The trigger plunger 26, the first device part 16 through which it passes, and the second device part 18 have deformation formations which define a deformation area 44 on the pipetting tip receiving device 14, in which a conventional pipette tip 42 received in the receiving space 40 is mechanically deformed in sections, when the first and second parts 16 and 18 are respectively in the closed position.

Said deformation formations include a first deformation formation 46 located closer to the housing 12 and a second, second deformation formation 48 realized on the second device part 18.

The first deformation formation 46 comprises the end face 46a of the release plunger 26 pointing towards the second device part 18 (see FIG. 1) and comprises a constriction section 46b provided along the receiving axis A at a distance from the penetration opening 38 on the first device part 16.

The second deformation formation 48 comprises an essentially flat surface 48a on the second device part 18 that is orthogonal to the movement path B, as well as a step section 48b, with which a clear width between the facing surfaces 16a and 18a of the device parts 16 and 18 in the deformation area 44 gradually tapers becomes. The step region 48b can alternatively also be formed entirely or partially by an inclined surface.

Since the deformation formation 46 is formed on the release plunger 26 and on the first device part 16, since the deformation 48 is formed on the second device part 18 and since finally the release plunger 26 remains in its ready position at least until the first and the second device part 16 or before 18 are in their closed position, the deformation formations 46 and 48 are then in a deformation position in which a deformation section 64 of a pipette tip 42 received in the receiving space 40 is deformed when the first and second device parts 16 and 18 are in the Are in the closed position and the release tappet 26 is in the ready position is located. Furthermore, the deformation formations 46 and 48 are then in a loading position that facilitates receiving or removing a pipette tip 42 from the pipette tip receiving device 14 when the first and second device parts 16 and 18 are in the open position. Because the stroke of the release plunger 26 is considerably smaller in terms of amount compared to the device parts 16 and 18, the position of the release plunger 26 is not important. This will, however, be in the ready position, since the sub-control device 28 is designed to only move the release tappet 26 into the release position when the device parts 16 and 18 are in the closed position.

In its release position, the release plunger 26 protrudes more strongly into the receiving space 40, in particular in its deformation region 44, than in its standby position.

In operation, the end face 46a of the release plunger 26 and the surface 48a of the second device part 18 lie opposite one another and define an essentially flat gap with, in the example shown, a constant gap size to be measured along the movement path B over the entire end face 46a of the release plunger 26 defined cleavage area. In fact, the end face 46a of the release tappet 26 and / or the face 48a of the second deformation formation 48 can have a contour that deviates from a planar shape. Manufacturing technology is simpler, however, to share the creation of flat surfaces on said construction.

The constriction section 46b is intended to cause a constriction of a pipette tip 42 received in the receiving space 40 on the side of the penetration opening 38 that is further away from a metering opening 50 of the pipetting tip 42. This constriction is intended to reduce the clear width inside the pipette tip 42 and thereby increase the flow resistance of dosing liquid in the pipette tip 42 starting from the deformation area 44 in the direction away from the dosing opening 50. This is to ensure that when the release The plunger 26 mechanically exerts a short mechanical impulse with a duration in the two-digit or low three-digit millisecond range on a deformed section of the pipette tip 42 in the deformation area 44 of the pipette tip receiving device 14, a pressure wave induced in the dosing liquid of the pipette tip 42 to throw off a Dosing drop leads through the dosing opening 50 and not to a movement of the liquid away from the dosing opening 50 towards increasing cross-sections of the pipette tip 42 which tapers conically towards the dosing opening 50.

With the liquid dosing device 10, conventional pipette tips 42 that are not customized for a specific task can advantageously be used for dosing dosing liquid 51 in dosing quantities 53 in the nanoliter range, although the conventional pipette tips 42 in the undeformed initial state only for dosing dosing liquids 51 in the so-called "air -Displacement "- methods are formed, wherein in the said dosing method precisely no dosing amounts in the nanoliter range can be dosed.

The liquid metering device 10 is excellently suited for aliquoting in that, for example, the displacement drive 30 is operated in a pulsating manner by the sub-control device 28.

The pipette tip 42, which extends along the virtual tip axis S, which is supposed to penetrate it centrally, has a reservoir space 62 between the coupling longitudinal end 54 and the metering longitudinal end 52, in which a metering liquid supply 55 can be received, for example by aspiration through the metering opening 50.

The aforementioned constriction section 46b in the first device part 16 forms in the closed position of the device parts 16 and 18 a constriction in the reservoir space 62 on the protruding from the gap in the direction of the coupling longitudinal end 54 from the gap formed between the release plunger 26 and the surface 48a Pipette tip 42. Then, when the pipette tip 42 is received in the receiving space 40 and the device parts 16 and 18 are in the closed position, the deformation area 44 of the pipette tip receiving device 14 and the trigger plunger 26 are formed as a deformation section 64 on the pipette tip 42.

The pipette tip 42 is preferably designed to be rotationally symmetrical with respect to its tip axis S as a rotational symmetry axis in the undeformed state.

For the metering of metering liquid quantities in the nanoliter range, the liquid metering device 10 is supported by the pipetting device 60 shown as an example and roughly schematically in FIG. 1. In addition, the pipetting device 60 with its pipetting channel 58 can be coupled to the coupling formation 56 of the pipetting tip 42 via a coupling formation 70, which is only indicated in FIG. In the pipetting channel 58 there is gas as working fluid 71, the pressure of which can be detected by a pressure sensor 72.

The pressure of the working fluid 71 in the pipetting channel 58 can be changed in a manner known per se by a pressure changing device 74 which, for example, can comprise a pipetting piston 76 accommodated in the pipetting channel 58 such that it can be displaced along a channel axis K.

The pressure changing device 74 can have an adjustment drive 78 beyond the pipetting piston 76, by means of which the pipetting piston 76 can be adjusted along the channel path K in the pipetting channel 58 and consequently the pressure of the working fluid 71 in the pipetting channel 58 can be changed. A pipetting control device 80, which is connected in terms of signal transmission to both the pressure sensor 72 and the adjustment drive 78 of the pipetting piston 76, can adjust the adjustment of the pipetting piston 76 as a function of an actual working fluid pressure measured by the pressure sensor 72 and, if necessary, also as a function of a Effect storage device of the pipetting control device 80 stored setpoint working fluid pressure by appropriate control of the adjustment drive 78. The pipetting control device 80 can be connected in terms of signal transmission to the sub-control device 28 of the liquid metering device 10. In the example shown, it is connected in terms of signal transmission to the control device 156 of the liquid screening station 160, which can also serve as the master control device for the pipetting control device 80, for which the pipetting control device 80 can be a further slave control device.

Each liquid screening assembly 100 of the liquid screening station 160 can have its own assembly control device. Preferably, a common control device 156 controls all liquid screening assemblies 100 of the liquid screening station 160.

Claims

Expectations

1. Liquid screening assembly (100), which comprises the following components:

a pipetting device (60) with at least one pipetting channel (58) extending along a virtual channel path (K) which is at least partially filled with a working fluid (71) different from a dosing liquid (51) and which is at its free longitudinal end a coupling formation (70) for the temporary, detachable coupling of a pipette tip (42) thereon, the pipetting device (60) having a pressure changing device (74) which is designed to control the pressure of the working fluid (71) in the pipetting channel (58 ) to change,

a liquid dosing device (10) for the ballistic delivery of a discrete dosing amount (53) of dosing liquid in a dosing volume from 0.3 nl to 500 nl from a dosing liquid supply (55), and

at least one control device (156, 28, 80) for controlling the liquid screening assembly (100) and / or individual components thereof,

characterized in that the liquid screening assembly (100) has at least one transport device (130, 132, 134, 136) which is designed to carry an object (1 12, 1) along a transport path (T1, T2, T3, T4) 16, 1 18, 126) to approach and remove from the pipetting channel (58) away to the liquid metering device (10), the imaginary channel path (K), and by virtue of the fact that the liquid metering device (10) has:

a pipette tip receiving device (14) which, at least in an operational position of the liquid metering device (10) ready for dosing, defines a receiving space (40) which extends along a virtual receiving axis (A) and is designed to receive a section of a pipette tip (42), wherein the away from the pipetting channel (58) towards the liquid metering device (10), the imaginary channel path (K) with the virtual receiving axis (A) is parallel or collinear, a release plunger (26) which is movable relative to the pipette tip receiving device (14) and which can be displaced between a further out of the receiving space (40) ) retracted standby position and a release position protruding further into the receiving space (40), a displacement drive (30) which is coupled to the release plunger (26) in a motion-transmitting manner and which is designed to push the release plunger (26) at least from the standby position into the release position relocate, and

a first (46) and a second deformation formation (48), the first (46) and the second deformation formation (48) defining between them an axial longitudinal region of the receiving space (40) as a deformation region (44) in which the first (46) and the second deformation formation (48) can be approached and removed from one another, the release plunger (26) being in its release position in the deformation area (44) of the receiving space (40).

2. liquid screening assembly (100) according to claim 1,

characterized in that the pipetting device (60) has a pressure sensor (72) which is designed and arranged to detect the pressure of the working fluid (71) in the pipetting channel (58), the control device (156, 28, 80) for control of the operation of the pressure change device (74) is connected in terms of signal transmission to both the pressure sensor (72) and the pressure change device (74), and wherein the control device (156, 28, 80) is designed to control the operation of the pressure change device (74) at least according to an actual working fluid pressure detected by the pressure sensor (72).

3. liquid screening assembly (100) according to claim 1 or 2,

characterized in that the liquid screening assembly (100) comprises a plurality of transport devices (130, 132, 134, 136) of each of which is designed to approach an object (1 12, 116, 1 18, 126) along a transport path (T1, T2, T3, T4) to and remove it from the imaginary elongated channel path (K).

4. liquid screening assembly (100) according to claim 3,

characterized in that each transport device (130, 132, 134, 136) from the plurality of transport devices (130, 132, 134, 136) has at least one transport means (138, 140) movable along the transport path (T1, T2, T3, T4) , 142, 144), with the movement spaces (146, 148, 150, 152) that can be driven through by the transport means (138, 140, 142, 144) of the individual transport devices (130, 132, 134, 136) during normal screening operation. in the direction along the channel runway (K) with stand from each other are arranged.

5. liquid screening assembly (100) according to claim 3 or 4,

characterized in that the transport tracks (T1, T2, T3, T4) of the transport devices (130, 132, 134, 136) are oriented parallel to one another and / and that the individual transport means (138, 140, 142, 144) when used as intended Screening operation traversable movement spaces (146, 148, 150, 152) in the direction along the channel path (K) are arranged one above the other.

6. liquid screening assembly (100) according to any one of claims 4 or 5, characterized in that at least the pipette tip receiving device (14) of the liquid metering device (10) between two movement spaces (140, 142) is arranged, which of two Transport means (140, 142) arranged at a distance from one another can be driven through in the direction of the channel runway (K) when the screening operation is intended.

7. liquid screening assembly (100) according to one of the preceding claims, characterized in that the coupling formation (70) of the pipetting device (60) can only be displaced along the channel path (K) or only in a plane orthogonal to a transport path (T1, T2, T3, T4).

8. liquid screening assembly (100) according to one of the preceding claims,

characterized in that the liquid screening assembly (100) has a container opening device (120) which is arranged along at least one transport path (T1, T2, T3, T4) at a distance from the channel path (K) and which is designed for this purpose to open at least one dosing liquid container (128).

9. liquid screening assembly (100) according to one of the preceding claims,

characterized in that the liquid screening assembly (100) has a disposal device (1 16) which is designed to receive used pipette tip (42).

10. liquid screening assembly (100) according to one of the preceding claims,

characterized in that a transport device (130) is designed as a dosing container transport device (130) for transporting at least one dosing liquid container (128) and / or the one transport device (132) as a pipette tip transport device (132) for transporting at least one unused pipette tip (42) and / or that a transport device (134) is designed as a target container transport device (134) for transporting at least one target container (1 12) receiving the discrete dosing quantity (53).

1 1. liquid screening assembly (100) according to claim 10, including claim 3, characterized in that the liquid screening assembly (100) has the dosing container transport device (130), the pipette tip transport device (132) and the target container transport device (134), wherein in a reference state in which the coupling formation (70) along the channel path (K) is maximally withdrawn from the target container transport device (134), of the mentioned transport devices (103, 132, 134) the dosing container transport device (130) of the coupling formation (70) along the coupling path (K) closest is located and the target container transport device (134) from the coupling formation (70) along the coupling path (K) is located furthest away.

12. Liquid screening assembly (100) according to one of the preceding claims,

characterized in that the first (46) and the second deformation formation (48) can be moved relative to one another between a loading position further away from one another, in which the pipette tip receiving device (14) for receiving a pipette tip (42) in the pipette tips - Receiving device (14) and / or for removing the pipette tip (42) from the pipette tip receiving device (14) is configured, and a deformation position more closely approximated to one another, in which a section located in the deformation area (44) is in the receiving space (40 ) recorded pipette tip (42) is deformed by the first (46) and the second deformation formation (48), wherein the control device (156, 28) is designed to only move the release plunger (26) from the standby position in to drive the release position when the first (46) and the second deformation formation (48) are in the deformation position.

13. Liquid screening assembly (100) according to one of the preceding claims,

characterized in that the liquid metering device (10) is designed to accommodate a receiving space (40) in the deformation area (44) to deform taken portion of a pipette tip (42) over a deformation period, the deformation period compared to the Verla gerungsurance that takes the displacement movement of the release plunger (26) from the standby position to the release position, is long.

14. Liquid screening assembly (100) according to one of the preceding claims,

characterized in that the pipetting device (60) comprises a plurality of parallel pipetting channels (58), each extending along a virtual channel path (K), which are each at least partially filled with a working fluid (71) different from a dosing liquid to be dosed and which each have a coupling formation (70) at their free longitudinal end for the temporary, releasable coupling of a pipette tip (42) to it, the liquid metering device (10) being designed to deform a plurality of pipette tips (42) simultaneously, the liquid metering device (10 ) has a plurality of release plungers (26) which are movable relative to the pipette tip receiving device (14) and which can be displaced between the standby position further withdrawn from the receiving space (40) and the release position protruding further into the receiving space (40).

15. The liquid screening assembly (100) of claim 14,

characterized in that the liquid metering device (10) has a deformation tool with a first tool jaw arrangement (17) and a second tool jaw arrangement (19), the first and the second tool jaw arrangement (17, 19) for deforming a plurality of pipette tips arranged between them ( 42) are approachable, each tool jaw arrangement (17, 19)

has or is a collective tool jaw which is designed to deform the interaction with a plurality of pipette tips only uniformly movable or immovable relative to the plurality of pipette tips, or and

has an individual tool jaw (16, 18) which, independently of further individual tool jaws or collective tool jaws of the same tool jaw arrangement (17, 19), is movable relative to the other tool jaw arrangement (17, 19) for the deforming interaction with exactly one pipette tip ( 42) is formed.

16. The liquid screening assembly (100) of claim 15,

characterized in that a tool jaw arrangement (17) made up of first and second tool jaw arrangements (17, 19) is a tool jaw arrangement (17) tested in relation to a stationary frame (1 10) of the liquid screening assembly (100) and the other tool jaw arrangement (19) ) is movable relative to the most positioned tool jaw arrangement (17), wherein the most positioned tool jaw arrangement (17) is a collective tool jaw and the movable tool jaw arrangement (19) has or is a collective tool jaw and / or one or more individual Has tool jaws (18).

17. Liquid screening assembly (100) according to one of claims 14 to 16, characterized in that the liquid metering device (10)

has a collective triggering tappet arrangement which comprises a plurality of triggering tappets (26) which can only be displaced jointly into the triggering position for triggering a respective dosing quantity (53) on each pipetting tip (41) from a plurality of pipetting tips (42),

or and

comprises at least one single trigger plunger (26), which is used to trigger a dosing quantity (53) on exactly one pipette tip (42) from the plurality of pipette tips (42) independently of the other trigger plungers (26) from the plurality of trigger plungers (26) can be moved into the release position.

18. Liquid metering station (10) comprising a plurality of liquid screening assemblies (100) according to one of the preceding claims.

19. A method of screening liquid, comprising the following procedural steps:

Taking up liquid as dosing liquid in a pipette tip (42) by changing the pressure of a working fluid (71) in a pipetting channel (58) of a pipetting device (60) having the pipetting tip (42) and thereby forming a dosing liquid supply (55) in the pipetting tip (42),

after aspirating liquid: deforming a section (64) of the pipette tip (42),

After the deformation of the section (64) of the pipette tip (42): From exerting an impact-like trigger pulse on the deformed section of the pipette tip (42) and thereby triggering a ballistic delivery of a discrete dosing amount (53) of dosing liquid (51) in a dosing volume range of 0 , 3 nl to 500 nl from the dosing liquid supply (55) in the pipette tip (42).

20. The method according to claim 19,

characterized in that during the step of deforming a section (64) of the pipette tip (42) a section (64) of the pipette tip (42) is deformed which contains at least part of the dosing liquid supply (55) before and after the deformation step.

21. The method according to claim 19 or 20,

characterized in that it comprises at least one of the following further steps:

A dosing liquid container (128) is conveyed to a container opening device (120) by a first transport device (130) in a first movement space (146), Removal of the dosing liquid container (128) from the container opening device (120),

A pipette tip (42) is transported in an aligned arrangement with the pipetting channel (58) of the pipetting device (60) by a second transport device (132) in a second movement space (148),

A dosing liquid container (128) is transported in an aligned arrangement with the pipetting channel (58) of the pipetting device (60) by the first transport device (130) in the first movement space (146), the dosing liquid container (128) is transported away from the aligned arrangement with the pipetting channel ( 58),

A third transport device (132) in a third movement space (150) transports a target container (1 12) receiving the discrete dosage (53) in an aligned arrangement with the pipetting channel (58) of the pipetting device (60),

- Removal of the target container (1 12) from the aligned arrangement with the pipetting channel (58),

A fourth transport device (136) in a fourth movement space (152) and transport of a used laboratory goods receiving disposal container (1 16) in an aligned arrangement with the pipetting channel (158) of the pipetting device (60)

Removal of the disposal container (1 16) from the aligned Anord voltage with the pipetting channel (58).