EP3793738A1

EP3793738A1 - Pipetting head, pipetting device comprising a pipetting head, and method for pipetting using a pipetting head

Info

Publication number: EP3793738A1
Application number: EP19816770.2A
Authority: EP
Inventors: Jens Wilmer; Dominik Schneider
Original assignee: Eppendorf SE
Current assignee: Eppendorf SE
Priority date: 2018-12-14
Filing date: 2019-12-12
Publication date: 2021-03-24
Also published as: EP3666379A1; CA3123348A1; US20220097038A1; CN113396017A; WO2020120683A1; JP2022514225A; AU2019398420A1

Abstract

Pipetting head having at least one pipette tip for a pipetting device, comprising: - a carrier, – at least one projection held on the carrier and on which pipette tips are to be clamped, and – two elastomer O-rings held on the projection, – wherein the two O-rings, the projection and the pipette tip are designed to securely clamp the pipette tip solely by deformation of the two O-rings on the projection, this being brought about by pressing the pipette tip onto the two O-rings.

Description

Pipetting head, pipetting device comprising a pipetting head and method for pipetting by means of a pipetting head

The invention relates to a pipetting head for receiving pipette tips, to a pipetting device comprising a pipetting head and to a method for pipetting liquids by means of a pipetting head.

Pipetting devices with a pipetting head for holding a single or for simultaneously holding a plurality of pipette tips are used in particular in medical, biological, biochemical and chemical laboratories for metering liquids.

Pipetting heads have at least one attachment that can be inserted into a push-on opening at the top of a pipette tip. Through a tip opening at the lower end of the pipette tip, liquid is absorbed into and released from the pipette tip.

After use, the pipette tip can be detached from the attachment and exchanged for a fresh pipette tip. This avoids contamination during subsequent dosing. Plastic pipette tips for single use are available at low cost.

In the embodiment as an air cushion pipetting device, at least one displacement device for air is integrated into the pipetting device and communicating via a connection hole in each approach, communicating with a pipette tip clamped thereon. An air cushion can be displaced by means of the displacement device, so that liquid is sucked into the pipette tip and ejected therefrom. The displacement device is usually a cylinder with a piston which is displaceable therein. However, displacement devices are also known with a displacement chamber and at least one deformable wall, wherein a deformation of the wall causes the displacement of the air cushion.

In the design as a direct displacement pipetting device, a small piston is arranged in the pipette tip, which piston is coupled to a piston drive of the pipetting device when the pipette tip is attached to the shoulder.

The liquid is preferably taken up in a single step or in several small steps. The liquid is dispensed in a single step when pipetting and in several small steps when dispensing.

The pipetting devices can be designed as manually or electromotively driven, manageable multi-channel pipettes, which are held in the hand by the user during pipetting (“hand pipettes”).

In the case of dosing stations (“pipetting stations”) or automatic dosing machines (“pipetting machines”), the pipetting head can be moved on a robot arm or another transfer system for moving the pipetting head above a work surface. Dosing stations or automatic dosing devices can use the pipetting head to take up fresh pipette tips from a holder, take up liquids from vessels with the pipette tips and dispense them into vessels and throw used pipette tips into a waste container. Pipetting heads can be part of laboratory machines (“workstations”), which can perform other liquid treatments in addition to dosing liquids. This includes in particular mixing, tempering and other physical treatments, chemical or biochemical conversion and the analysis of samples. The approaches for holding pipette tips are often designed as a conical, cylindrical or partly conical and partly cylindrical projection with respect to a housing or another carrier of the pipetting device. Pipette tips can be clamped onto a shoulder with a sealing seat next to a push-on opening at their upper end. For this purpose, at least one attachment is pressed into the plug-in opening of at least one pipette tip available in a holder, so that the pipette tip widens somewhat and is stuck on the attachment under pretension. The force to be applied for the clamping increases with the number of pipette tips.

To release the clamped pipette tip from the approach, the pipetting animal devices have a discharge device with a drive device and a discharge device. By actuating the drive device, the ejector is moved so that it detaches the pipette tip from the attachment. The drive device is driven either manually or by an electric motor. The ejection force for releasing pinched pipette tips from the base increases with the number of pipette tips.

High forces must be applied to clamp pipette tips onto 8, 12, 16, 24, 96 or 384 tips and to drop the pipette tips from the tips.

DE 10 2004 003 433 B4 describes a multi-channel pipette in which the force required to clamp the pipette tips on the attachments and to detach the pipette tips from the attachments is reduced in that the attachments are spring-loaded and in the axial direction by means of the ejector formed stop stand out. If the clamping force exceeds a certain value when clamping pipette tips, the tips deflect until the pipette tips are in contact with the ejector. The clamping force is hereby limited to a value

..YES limits, in which the pipette tips are held sealingly on the approaches. Accordingly, the ejection force is limited.

EP 2 735 369 A1 describes a multichannel pipette in which the ejector serves as a stop element when the pipette tips are pushed onto the tips. The ejection forces are further reduced by the fact that the launcher has a plurality of contact elements which meet the pipette tips one after the other in order to push them off the roots.

WO 01/56695 A1 describes a pipetting head with 96 channels, the approaches at the lower end having a larger cone angle than above, in order to increase the force for attaching pipette tips with a collar of greater wall thickness at the upper end and a smaller wall thickness below the collar reduce. The pipetting head comprises a stop plate for throwing off the pipette tips from the approaches. The stop plate is stepped to successively push the pipette tips away from the tips and to reduce the ejection force. Posts with pretensioning devices protrude from the stop plate. A Kol benplatte, the pistons are displaced in cylinders which are connected to the lugs, when retracting the biasing means to trigger the dropping of the pipette tips from the lugs by the stop plate. The construction with pretensioners for dropping pipette tips is agile.

WO 2005/113149 A1 and DE 20 2005 006 970 U1 describe a device for receiving and dispensing liquids with a pipetting head which has 96 approaches for pipette tips. 96 piston-cylinder units are connected to the lugs and can be operated manually using a drive mechanism. The pipetting head can be moved along a vertical guide, around pipette tips from a pipette tip holder and suck in and dispense liquid. The pipetting head can be pressed down by means of a transmission lever with increased force in order to apply the force required to hold 96 pipette tips. The lugs are passed through holes in a perforated plate which can be displaced vertically in order to strip the pipette tips from the lugs.

DE 20 2008 013 533 U1 describes a pipetting device with a base plate and an elastic sealing plate that covers this on the outside on the outside, a plurality of pipetting channels arranged in a predetermined grid being passed through the base plate and the sealing plate. A magazine equipped in the same grid with pipette tips, each of which has a collar, is connected to the base plate in a lying manner in a magazine holder indirectly via the collars and the sealing plate. The magazine holder is formed by a magazine frame which can be raised and lowered by a drive motor via an eccentric gear in order to bring the pipette tips into a sealing position on the sealing plate or to detach them from the sealing plate.

Automatic pipetting machines, in which pipette tips are received in a magazine in a magazine holder and pressed onto a sealing plate, are manufactured by Apricot Designs, Inc., Covina, CA, USA, under the product names "i-Pipette" and "i-Pipette Pro" marketed.

The disadvantage is that these pipetting machines can only work together with special pipette tips in a special magazine. A further disadvantage is that the magazine holder is loaded by hand. EP 0 337 726 A2 describes a device for simultaneously receiving several pipette tips by means of parallel approaches in a straight row, each of which has an elastomeric O-ring in an annular groove with an adjustable groove width. The extent of the O-rings in the circumferential direction can be changed by adjusting the groove widths in order to tightly clamp the pipette tips tightly on the attachments and to detach the pipette tips from the attachments. To adjust the groove widths, the grooves are each limited by a threaded sleeve screwed onto the neck, which is rotatable on the neck by means of a coupled gear mechanism. Each threaded sleeve is firmly connected to a gear. The gears mesh with a single rack, which is driven by a rotatable hand grip. In an alternative embodiment, each individual threaded sleeve is individually driven by an electric motor and the electric motors are connected to a common voltage supply for synchronous operation. The drive for clamping the pipette tips on the approaches is structurally complex.

DE 199 17 375 C2 describes a pipetting unit with a pipette tip and an attachment, which has a pipetting tube with a coupling sleeve at the lower end, an O-ring made of elastically deformable material and pushed onto the pipetting tube, and a sleeve pushed onto the pipetting tube. The sleeve serves to axially pinch the O-ring, so that it deforms radially and engages in a sealing manner in an annular groove on the inner circumference of the pipette tip. The O-ring can be relieved to release the pipette tip. To hold the pipette tip on the attachment in a predetermined position, the attachment and the pipette tip have cooperating axial positioning means. The fact that the O-ring engages in an annular groove in the pipette tip prestresses the axial positioning means which are in contact with one another. To eject the pipette tip, a movable ejector is provided, which is designed as an ejector tube surrounding the sleeve

... p is. The ejector can be operated hydraulically or by an electric motor or by means of a pretensioning spring which is tensioned when the pipette tip is placed on the pipetting unit. The actuating means for clamping and releasing the pipette tip at the base are complex and take up a lot of space. The attachment of the pipette tips in the defined coupling position can easily be prevented by manufacturing tolerances or inaccurate positioning of the pipette tip on the attachment. The annular groove and the axial positioning means restrict the use of different pipette tips.

WO 2018/002254 A1 and DE 10 2016 111 912 A1 describe a dosing head for a dosing device with a carrier, on which a number of parallel approaches for receiving pipette tips are arranged side by side. Each approach has a tube with a at the lower end from the outer periphery outwardly projecting, at least partially circumferential Stützvor jump, at least one sleeve which surrounds the tube and is axially displaceable on the tube, and at least one elastomeric O-ring on the tube encloses and is arranged next to the lower end of the sleeve. Above the sleeves there is a pressure plate with a plurality of first holes through which the tubes extend, the pressure plate along the tubes between a release position at a first distance from the support projections and a clamping position at a second distance below the first distance is displaceable from the support projections, the pressure plate in the clamping position presses against the upper edge of the adjacent sleeves of all the lugs, that the sleeves are pressed with the lower ends onto the adjacent O-rings and the O-rings are expanded in order to be pushed onto the lugs Clamp pipette tips. A first displacement device is connected to the pressure plate and is designed to shift the pressure plate between the release position and the clamping position. Simultaneous clamping and loosening of a large number of pipette tips is made possible by evenly pressing the pressure plate against all sleeves and by evenly releasing all sleeves. The transmission of force from the first adjustment device via the pressure plate to the sleeves favors a relatively simple, compact and lightweight construction. Clamping by widening the O-rings favors the use of pipette tips with different shapes and dimensions.

DE 10 2006 036 764 writes a pipetting system with a pipetting device with at least one push-on shaft, which has a detent bead encircling the outer circumference and underneath it two circumferential annular grooves which are spaced apart from one another and each accommodate a sealing ring. The pipetting system comprises a pipette tip which can be clamped onto the latching bead with a latching groove and has a sealing area beneath it, against which the sealing rings bear in a sealing manner. Due to the latching, a defined fit of the pipette tip on the plug-on shaft is achieved and the sealing rings seal the pipette tip against the plug-on shaft. Relatively high attachment forces are required to lock the locking bead and locking groove.

Proceeding from this, the object of the invention is to provide a pipetting head with at least one attachment and at least one pipette tip for securely picking up and releasing the pipette tip on the attachment with reduced effort and reduced construction effort.

The object is achieved by a pipetting head with at least one pipette tip with the features of claim 1. Advantageous embodiments of the invention are specified in the subclaims. The pipetting head according to the invention with at least one pipette tip for a pipetting device comprises:

A carrier,

• at least one approach held on the carrier for clamping pipette tips and

Two elastomer O-rings held on the base,

• The two O-rings, the shoulder and the pipette tip are designed to clamp the pipette tip on the shoulder solely by deforming the two O-rings by pressing the pipette tip onto the two O-rings.

Pipette tips are elongated tubes which have a tip opening at their lower end and a sealing seat at their upper end next to a push-on opening, with which they can be clamped onto the attachment. The inside diameter and outside diameter of the pipette tips generally increases from the tip opening to the plug-on opening. If a pipette tip is picked up on a neck of a pipetting head that has no O-ring, only one O-ring or a locking bead and two O-rings, high absorption forces arise (push-on forces, clamping forces) because the pipette tip, which is made of polypropylene, polyethylene or another hard elastic plastic, comes into direct contact with the attachment when pushed onto the attachment and deforms in the process. Characterized in that in the pipetting head according to the invention, the two O-rings, the neck and the pipette tip are designed such that a pipette tip can be clamped onto the neck solely by deformation of the two O-rings caused by pressing the pipette tip onto the two O-rings , direct contact of the pipette tip with the approach by which the pipette tip is expanded is avoided. Either the pipette tip points no direct contact with the attachment or is only in contact with the attachment without a force that deforms the pipette tip acting between the attachment and the pipette tip. As a result, when the pipette tips are picked up by the pipetting head, only the two O-rings are deformed. The pipette tip is not clamped directly on the attachment by widening, but by means of the two O-rings which are held on the attachment and bear against the pipette tip under prestress due to their deformation. Since the O-rings are made of an elastomer, they can be deformed more easily than the pipette tip. This reduces the absorption force required to hold the pipette tips. By reducing the clamping forces on a hand-held pipette, the load on the user during manual pipetting can be reduced. In the case of a pipetting station, an automatic pipetting machine or a laboratory machine, this reduces the requirements for the transmission system, in particular for its strength and the performance of the drives.

In addition, the two O-rings ensure that the pipette tips are precisely aligned with the attachment. This is advantageous for the insertion of pipette tips into the openings of vessels without colliding with the vessels. In this way, in particular a tilting of the pipette tip can be avoided if it contacts the wall of the vessel with the lower end during hand pipetting. This is recommended by the pipette manufacturers so that the liquid flows out of the tip opening under uniform conditions.

Another advantage of the two O-rings on each attachment is that all tips can be pushed onto the attachment in such a way that they can subsequently be pushed up further on the attachment and later pushed up into a position for pipetting. Alternatively, all tips can be up to

... / ll ejector or stop on the base so that the clamped pipette tips are always at the same height.

According to one embodiment of the invention, the inner diameter of the sealing seat of the pipette tip at the point that contacts an O-ring is smaller than the outer diameter of the respective O-ring, so that it is deformed when pushed on and the pipette tip clamps on the shoulder. According to a further embodiment, the inner dimensions of a sealing seat of the pipette tip are dimensioned such that the sealing seat has no direct contact with the attachment or is in contact with the attachment without the attachment exerting a deforming force on the pipette tip when the pipette tip is deformed by deformation of the two O-rings are clamped on the neck. A preferred embodiment combines the features of the two aforementioned embodiments, which relate to the inside diameter and the inside dimensions of the sealing seat. According to a preferred embodiment, this combination replaces the feature group in the last outline point of claim 1.

According to a further embodiment, the sealing seat has a circular cylindrical shape or a conical shape that widens towards the plug opening. According to a further embodiment, the inner diameter of the sealing seat is larger or the same size as the outer diameter which the attachment has in the same cross-sectional plane as the sealing seat when the pipette tip is clamped on the attachment by deformation of the two O-rings.

According to a preferred embodiment, the pipette tips can be tightly clamped onto the attachment, so that the pipetting head can be used to absorb and dispense liquid by means of at least one clamped-on pipette tip. The pipetting head has at least one for this Displacement device, which is connected via at least one line to a connection hole at the end of the neck in order to displace an air cushion and to take up liquid through the tip opening into a clamped pipette tip and to dispense it from the latter. Due to the radial deformability of the two O-rings, it is possible to hold pipette tips with different dimensions on the same attachment and to pipette with the different sized pipette tips. As a result, the effort for performing various pipetting tasks can be reduced. For example, the O-rings and the attachment can be designed such that pipette tips with a nominal volume of 10 pl and 50 mΐ or with a nominal volume of 300 mΐ and 1,000 mΐ can be clamped on the same attachment. Commercial pipette tips from different manufacturers can be used for this, since these have matching dimensions in the sealing area.

If the dimensions of the different pipette tips differ more, the pipetting head can, if necessary, be used to transfer pipette tips of different sizes, e.g. from one pipette tip holder to another pipette tip holder, since the pipette tips are not tightly clamped on the tips, but so firmly on the tips Approaches sit that they are transferable by means of the pipetting head. This can be used in particular for the automatic transfer of pipette tips in a laboratory machine. For example, the O-rings and the attachment can be designed so that commercially available pipette tips with a nominal volume of 10, 50, 300 and 1,000 mΐ can be picked up and transferred using the same attachment. The invention includes pipetting heads that can be used for the transfer of pipette tips, but not for the absorption and dispensing of liquids. Such a pipetting head for transferring pipette tips can without Displacement device are formed and is also referred to below as a transfer head.

According to a further embodiment, the O-rings are made from a soft elastomer. According to a further embodiment, the O-rings are made of rubber, silicone rubber, fluororubber (FEPM - for example Viton® from DuPont Performance Elastomers), hydrogenated nitrile rubber (HNBR), ethylene-propylene-diene rubber (EPDM) or a thermoplastic Made of elastomer. O-rings made of a soft elastomer (silicone rubber) are marketed in particular by C. Otto Gerckens GmbH & Co. KG Dichtung stechnik, Pinneberg, Germany under the name VMQ.

According to a further embodiment, the attachment has devices for the axial securing of position, which are designed to support each of the two O-rings in a certain upper and in a certain lower position and to allow deformation of the two O-rings in the radial direction. As a result, the two O-rings can be held on the shoulder in defined positions or areas. These can be matched to the pipette tips that are to be held on the attachment.

According to a further embodiment, the devices for securing the axial position are annular grooves. Each ring groove can partially accommodate at least one O-ring, the O-ring being guided on the base of the ring groove on the shoulder and prevented by the two flanks of the ring groove from being displaced upwards and downwards. The ring grooves can be dimensioned such that each O-ring is held in the respective ring groove with a precise fit, or with an axial play or in a slightly compressed manner in the axial direction. It is also possible to keep both O-rings in the same ring groove. Here both O-rings are supported in

...HA same annular groove from each other and the upper O-ring is supported on the upper flank and the lower O-ring on the lower flank of the annular groove.

According to another embodiment, the devices for the axial securing of position are formed by one or more projections which are arranged on both sides of at least one O-ring on the circumference of the extension. A displacement in the axial direction is prevented or limited by the at least one projection on both sides of at least one O-ring.

According to a preferred embodiment, each approach has only two O-rings. According to another embodiment, each approach has more than two O-rings. For each O-ring there can be a separate ring groove or other devices for axial securing of the position or several O-rings can be arranged together in the same ring groove or held on the shoulder by the same devices for axial securing of the position.

According to a further embodiment, the devices for the axial securing of position are formed in one piece with the attachment. According to another embodiment, the devices for axially securing the position are sleeves and / or rings which are pushed onto the neck and receive the O-rings between them, which are guided on the inside of the neck. The sleeves and / or rings are either fixed on the neck or loosely guided on the neck and prevented from being stripped from the neck by additional means for securing the position axially. These can be formed, for example, at the top by the carrier and at the bottom by a securing ring which is held in an additional annular groove on the circumference of the attachment. According to a further embodiment, the two O-rings are arranged on the shoulder at a distance from one another. This is particularly advantageous for the precise alignment of the pipette tips on the approach. This also enables a particularly gentle increase in the clamping forces when clamping a pipette tip.

According to a further embodiment, the approach has at least one conical section. This is advantageous for clamping pipette tips onto the attachment with a gradual increase in the clamping forces.

According to a further embodiment, the extension has at least one cylindrical section. The guidance and sealing of a pipette tip at the base can be improved by the cylindrical section.

According to a further embodiment, the projection has an upper cylindrical section at the top, a lower cylindrical section at the bottom, a conical section tapering from top to bottom between them, and between the upper cylindrical section and the conical section, upper devices for securing the axial position and between the conical section and the lower cylindrical section lower devices for axial position securing. In this way, it can be achieved that the clamping forces gradually increase when the pipette tip is clamped onto the attachment and the pipette tip is well guided and aligned on the attachment.

According to a further embodiment, the upper O-ring has a larger inner diameter and / or a cross section with a larger diameter than the lower O-ring. This is advantageous for a gradual increase in the push-on forces when a pipette tip is clamped onto the attachment. According to a further embodiment, the diameter of the cross section of the upper O-ring is larger than the depth of the upper ring groove and / or the width of the upper ring groove is equal to or larger than the diameter of the cross section of the upper O-ring and / or the diameter of the Cross section of the lower O-ring is greater than the height of the lower ring groove and / or the width of the lower ring groove is equal to or greater than the diameter of the cross section of the lower O-ring. The depth of the respective annular groove ensures that the respective O-ring can be deformed in the radial direction by clamping a pipette tip onto the shoulder and / or the length of the respective annular groove results in a long deformation s away with low clamping forces.

According to a further embodiment, the pipetting head has approaches which are arranged next to one another in parallel in one or more rows. As a result, the pipetting head can be used for the simultaneous clamping of a large number of pipette tips, for which it is particularly well suited due to the low clamping forces.

According to a further embodiment, the approaches are firmly connected to the carrier. The clamping forces can be kept low by the two O-rings, so that it is in particular not necessary to support the attachments via springs on the carrier. According to another embodiment of the pipetting head according to the invention, the lugs are supported on the carrier via springs in order to thereby additionally limit the attachment forces.

According to a further embodiment, the carrier is a housing or part of a housing or a chassis or part of a chassis of the pipetting head. For example, the carrier is a lower housing wall of the housing or a lower part of a chassis of the pipetting head. The approach can be held in particular by screwing in a lower housing wall or in a lower part of a chassis. If the extension is held in a lower part of a chassis, the housing in a lower housing wall can have a through hole for each extension or the lower housing wall can be missing.

Furthermore, the invention relates to a pipetting device or a transfer device comprising a pipetting head according to one of claims 1 to 11 or one of the above embodiments. The pipetting device or transfer device can in particular be designed as a manually or electromotively driven, manageable pipetting device or transfer device with one or more channels, which can be held in the hand by the user when pipetting or transferring pipette tips (hand pipette).

Furthermore, the invention relates to a pipetting station or an automatic pipetting device or an automatic laboratory device comprising a pipetting device and / or a transfer device according to claim 12. The pipetting station or the automatic pipetting device or the automatic laboratory device can be used for the (automatic) pipetting or transfer of pipettes. The laboratory machine can be used for automatic pipetting, for transferring pipette tips and also for other treatments of liquids, for example for tempering, mixing, carrying out chemical or biochemical reactions and other physical, chemical or biochemical treatments.

In a pipetting station, a pipetting machine or a laboratory machine, the pipetting head can be designed such that it can be attached to and detached from the pipetting station, the pipetting machine or the laboratory machine by means of a quick-change device in order to attach another one Attach pipetting head (e.g. for other pipette tip sizes), a gripper tool for transporting laboratory items (labware) or another tool. This type of design is also referred to as a pipetting tool.

Furthermore, the invention relates to the use of a pipetting head according to one of claims 1 to 11, a pipetting device according to claim 12 or a pipetting station or an automatic pipetting device or an automatic laboratory device according to claim 13, in which

A pipette tip is clamped onto each attachment of the pipetting head,

The pipetting head is displaced until each clamped pipette tip has with its lower end contact with a vessel which is provided on a work surface,

The pipetting head is displaced until the lower end of each clamped pipette tip is at a certain distance from a bottom of the vessel, and

• Liquid from the container is taken up in each clamped pipette tip.

For a variety of applications, it is desirable to take the liquid in a pipette tip in close proximity to the bottom of a vessel. These applications include, for example, efficient washing steps and the optimal recovery of liquids below phase limits. There are a number of tolerances in a pipetting station, an automatic pipetting machine or in a laboratory machine, which influence the final positioning of the tip opening in the vertical direction. In particular when using multi-channel pipetting heads, in particular in the version with a quick-change device (multi-channel pipetting tools), the exact positioning of the individual pipette tips is not possible. The use of a pipetting head with two O-rings per approach makes it possible to allow unknown tolerance chains due to slight differences in the fit of the pipette tips with the same dosing quality. For this purpose, the pipette tips are first picked up by means of a pipetting head with only one or more channels, until pipette tips are clamped onto all the approaches. Here, the pipette tips are not pushed completely onto the attachments, ie not up to an ejector or a stop, so that they can be pushed even further up onto the attachments. The pipetting head is then moved and the lower ends of all clamped pipette tips are placed on the vessel from which liquid is to be removed or released into the liquid. Known and unknown tolerances are compensated for by placing the lower ends of the pipette tips on the tubes. Here, the pipette tips can be pushed a little further up onto the attachments, to a different extent, depending on whether they touch the vessels with their lower ends sooner or later. Then all clamped pipette tips are immersed in a vessel until they are a short distance from the bottom of the vessel. This creates a small gap for the absorption of liquids between the tip opening and the bottom of the vessel. The process can be carried out fully automatically, so that there is no additional effort for the user. The process can take place during a program run of a laboratory machine. The seat of the clamped pipette tips can be adapted to the individual receptacles (cavities) of the single or multiple receptacles used or other consumables (disposables).

According to one embodiment, the pipetting head is shifted until all clamped pipette tips with the lower ends simultaneously come into contact with the Have bottom of a vessel and then the pipetting head is moved until the lower ends of all pipette tips are a certain distance from the bottom of the vessel. As a result, a particularly small gap can be achieved between the lower ends of the pipette tips clamped in each case and the bottom of the vessels. According to another embodiment, the pipetting head is moved until the lower ends of all clamped pipette tips are in contact with a part of the surface of the vessel other than the bottom. In this way, at least an exact alignment of the pipette tips to the vessels is achieved, only tolerances between the position of the contacted surface and the bottom of the vessel not being compensated for.

According to a further embodiment, the pipetting head is a multi-channel pipetting head and the vessel is a multiple vessel, in particular a micro test plate (micro titer plate). The invention is particularly suitable for the simultaneous compensation of a large number of tolerances between clamped pipette tips and a micro test plate. Here, each pipette tip is first brought into contact with a surface of the multiple vessel or with the bottom of a well (well) or other cavity of the multiple vessel and then at a short distance from the bottom of the cavity.

If it is not possible to move the pipetting head so that each clamped pipette tip has its lower end in contact with a vessel that is provided on a work surface, for example because the vessel is filled with a liquid that is not in contact with the pipette tip the pipetting head can also be used in such a way that all pipette tips are pushed up to an ejector or stop on the shoulder, so that all clamped pipette tips have the same height. This reduces the errors due to tolerances, although not in the same extent as when moving the pipetting head so that the clamped pipette tips are in contact with the vessel at their lower end.

Furthermore, the object is achieved by a pipetting head according to number 1 below or one of its embodiments according to numbers 2 to 15 below.

1. A pipetting head for a pipetting device comprising: a carrier, at least one shoulder held on the carrier for clamping pipette tips and two O-rings held on the shoulder from an elastomer, the two O-rings and the shoulder being formed, a pipette tip alone by clamping the two O-rings on the shoulder.

2. Pipetting head according to number 1, in which the O-rings are made of a soft rubber, silicone or thermoplastic elastomer.

3. Pipetting head according to number 1 or 2, in which the approach has devices for axial position securing, which are designed to support each of the two O-rings in a certain upper and in a certain lower position and a deformation of the two O-rings in the radial direction Allow direction. Pipetting head according to number 3, in which the devices for securing the position in the axial direction on the circumference of the attachment are circumferential ring grooves which partially accommodate at least one O-ring or one or more projections on the circumference of the attachment which accommodate at least one O-ring between them. Pipetting head according to one of the numbers 1-4, in which the attachment has at least one conical section and / or in which the attachment has at least one cylindrical section. Pipetting head according to numbers 4 and 5, in which the approach has an upper cylindrical section at the top, a lower cylindrical section at the bottom, a conical section tapering from top to bottom between them, and upper devices for securing the position in between and between the upper cylindrical section and the conical section the conical section and the lower cylindrical section has lower devices for axially securing the position. Pipetting head according to one of the numbers 1-6, in which the upper O-ring has a larger inner diameter and / or a cross-section with a larger diameter than the lower O-ring. Pipetting head according to one of the numbers 1-7, in which the diameter of the cross section of the upper O-ring is larger than the depth of the upper ring groove and / or the width of the upper ring groove is equal to or larger than the diameter of the cross section of the upper O-ring and / or the diameter of the cross section of the lower O-ring is larger than the height of the lower ring groove and / or the width of the lower ring groove is equal to or larger than the diameter of the cross section of the lower O-ring. Pipetting head according to one of the numbers 1-8, which has approaches arranged in parallel next to one another in one or more rows. Pipetting head according to one of the numbers 1-9, in which the approaches are firmly connected to the carrier. Pipetting device or transfer device comprising a pipetting head according to one of the numbers 1-10. Pipetting station or automatic pipetting device or laboratory machine comprising a pipetting device and / or a transfer device according to number 11.Use of a pipetting head according to one of the numbers 1-10, a pipetting device or transfer device according to number 11 or a pipetting station, an automatic pipetting device or a laboratory machine according to number 12, in which a pipette tip is clamped onto each attachment of the pipetting head, the pipette head is displaced until each clamped pipette tip has its lower end in contact with a vessel provided on a work surface, the pipetting head is displaced until the lower end of each clamped pipette tip a certain distance (x) from a bottom of the vessel and

Liquid from the vessel is taken up in each clamped pipette tip.

...HA 14.Use according to section 13, in which the pipetting head is moved until all clamped pipette tips with the lower ends are simultaneously in contact with the bottom of the vessel and then the pipetting head is moved until the lower ends of all pipette tips are a certain distance from the bottom of the vessel exhibit.

15. Use according to paragraph 13 or 14, in which the pipetting head is a multi-channel pipetting head and the vessel is a microtiter plate.

The invention is described below with reference to the accompanying drawings of

Embodiments explained in more detail. The drawings show:

Fig. 1 shows a pipetting head with clamped pipette tips in the

Front view;

2 shows the same pipetting head without pipette tips in the rear view; Fig. 3 the same pipetting head with clamped pipette tips in one

Vertical section;

Fig. 4 shows an approach of the same pipetting head with a clamped

Pipette tip in an enlarged vertical section;

Fig. 5 on insertion forces depending on the path of the pipetting head

Clamping on a conventional and on a pipetting head according to the invention in a diagram;

Fig. 6 tolerance chains and sums in a dosing system in a roughly schematic view;

Fig. 7 approaches of a multi-channel pipetting head with recorded

Pipette tips above the bottom of a microtiter plate in a roughly schematic view; Fig. 8 shows the pipetting tool by placing it on the bottom area of the

Microtiter plate individually set pipette tips in a rough schematic view;

Fig. 9 the pipetting tool with individually adjusted pipette tips withdrawn to a small distance from the bottom area of the microtiter plate in a roughly schematic view.

In this application, the information “above” and “below”, “horizontally” and “vertically” relates to an alignment of the pipetting head with the lugs in the vertical direction, the lugs being arranged below and the remaining parts of the pipetting head above.

In the description of various embodiments, the same reference numerals are used for components with identical designations.

1 and 2, the pipetting head 1 has a housing 2, which is formed from a front and a rear housing shell 3, 4, which are assembled in a vertical plane.

From the underside of the pipetting head 1 there are eight parallel lugs 5 (pins) for clamping pipette tips 6 vertically downwards (FIGS. 3 and 4).

A strip-shaped carrier plate 7 is arranged on the top of the housing 2. A mounting pin 8 projects upward from the carrier plate 7.

According to FIG. 3, eight parallel piston-cylinder units 9 are arranged in a row next to one another in the pipetting head 1. Each piston-cylinder unit 9 has a cylinder 10 in which a piston 11 is slidably arranged. Each cylinder 10 has an external thread 12 with which it is screwed into a corresponding internal thread 13 in a through hole 14 in a horizontal lower housing wall 15. The screwing in of the cylinders 10 into the lower housing wall 15 is limited by shoulders 16 on the outer circumference of the cylinders 10, with which they rest on the upper side of the lower housing wall 15.

The lower part of the cylinders 10 projects outwards from the underside of the lower housing wall 15 and forms the lugs 5 there. Housing 2 is thus a carrier for the lugs 5.

According to FIG. 4, each extension 5 has an upper cylindrical section 17 at the top, a lower cylindrical section 18 at the bottom and, in between, a conical section 19 which tapers from top to bottom. On each lug 5 are between the upper cylindrical section 17 and the conical section 19 upper devices for axial position securing 20 in the form of an upper annular groove 21 and between the conical section 19 and the lower cylindrical section 18 lower devices for axial position securing 22 in the form of a lower Ring groove 23 available.

An O-ring 24, 25 made of an elastomer, preferably made of a soft elastomer, in particular made of a soft silicone rubber, is inserted into each annular groove 21, 23. Each O-ring 24, 25 is guided at the bottom of the annular groove 21, 23 and has a cross section with a diameter which is greater than the depth of the annular groove 21, 23 and which is smaller than the width of the annular groove 21, 23 in which he is arranged.

... 121 The interior 26 of each cylinder 10, into which the piston 11 dips from above, extends down to a connecting hole 27 in the lower end face of the extension 5.

At the top of each cylinder 10 there is a bushing 28, through which a piston 11 is sealingly inserted into the cylinder 10.

Each piston 11 is designed as a cylindrical rod which is inserted at the top into a central bore 29 of a cylindrical piston head 30 and fastened therein (e.g. glued or pressed in). Each piston head 30 has a circumferential annular ring groove 31 on the outer circumference.

A strip-shaped piston plate 33 parallel to this is arranged below a horizontal upper housing wall 32. The piston plate 33 has eight downwardly open channels 34, which are aligned parallel to one another. Each channel is delimited by two strip-shaped channel walls 35 and by two channel shoulders 36 protruding inwards from the lower ends of the channel walls. The channel walls 35 on the two outer edges of the piston plate 33 each delimit an adjacent channel 34 on only one side. The remaining channel walls 35 each delimit two adjacent channels 34 on one side. Between the channel shoulders 36, each channel has a slot opening 37 on the underside of the piston plate 33.

At the edges of the piston plate 33, which are aligned parallel to the front and rear of the housing 2, the channels 34 have end openings 38. The piston heads 30 are inserted into the channels 34 with upper sections through the end openings 38, so that the channel shoulders 36 form-fit the Engage piston head ring grooves 31. As a result, the pistons 11 can be moved together in the cylinders by vertically displacing the piston plate 33.

An axially displaceable threaded nut 39 is arranged centrally in the fastening pin 8, the lower end of which is firmly connected to the piston plate 33 in order to displace the piston plate 33 in the axial direction of the cylinder 10.

The fastening pin 8 has a cylindrical upper pin section 40 at the top. The upper pin section 40 carries on the outer circumference two connecting elements 41 which are offset by 180 ° to one another and radially outwardly projecting, in each case partially circumferential, with which a bayonet connection can be formed. The connecting elements 41 have a slight thread pitch on the underside for bracing with a matching connecting element in a pin receptacle of a bayonet connection.

Adjacent to the upper pin section 40, the fastening section 8 has a cylindrical central pin section 42 with a larger outer diameter than the upper pin section 40.

Underneath, the fastening pin 8 has a lower pin section 43 that widens conically downward. The lower pin section 43 is firmly connected at its base to the carrier plate 7.

A central bore 44 extends in the longitudinal direction of the fastening pin 8. This has two diametrically opposed longitudinal grooves 45. In the central bore 44, the sleeve-shaped threaded nut 39 is inserted, which is guided with two radially projecting wings 46 at its upper end in the longitudinal grooves 45.

Furthermore, a spindle 47 is screwed into the threaded nut 39. This has a protruding bearing pin 49 above its thread 48, on which it is mounted in a ball bearing 50. The ball bearing 50 is held in a bearing bush 51 of a bearing bracket 52 which has two tabs which protrude diametrically from the sides and which rest on the upper edge of the upper pin section 40 and are fixed there by means of screws.

On the part of the bearing pin 49 which projects beyond the ball bearing 50, a driver 54 is fixed in a rotationally fixed manner by means of a radial threaded pin 53 and has a radially and axially extending slot 55 on its upper end face for inserting a pawl-shaped drive element.

The spindle 47 is supported on the lower end face of the ball bearing 50. The driver 54 is supported on the upper end face of the ball bearing 50. As a result, the spindle 47 is not axially displaceably held in the fastening pin 8.

In a wing 46 of the threaded nut 39, a cylindrical pin 56 is fixed, which, parallel to the central axis of the threaded nut 39, is guided through a groove of the bearing bracket 52 and protrudes from the fastening pin 8 at the top.

By turning the driver 54, the spindle 47, which is held axially in the fastening pin 8, moves the threaded nut 39, which is non-rotatably guided in the fastening pin 8, in the axial direction. As a result, the piston plate 33 is displaced and the pistons 11 are displaced in the cylinders 10. By turning the Driver 54 in different directions, the pistons 11 are displaceable in different directions in the cylinders 10. By scanning the position of the cylinder pin 56, it is possible to determine the respective position of the pistons 11 in the cylinders 10.

The fastening pin 8 and the drive integrated therein with a threaded nut 39 and spindle 47 correspond to the embodiments of FIGS. 1 to 4 and 6 according to EP 1 407 861 B1. In this regard, reference is made to EP 1 407 861 B1, the content of which is hereby is included in this application.

A laboratory machine is provided with a complementary pin receptacle of a bayonet connection, which can be connected to the fastening pin. The complementary connection steeply of the laboratory machine corresponds to the tool holder according to FIGS. 7 to 10 of EP 1 407 861 B1. In this regard reference is made to EP 1 407 861 B1, the content of which is hereby incorporated into this application.

A stripper plate 57 is arranged below the lower housing wall 15 and has further through holes 58 through which the pins 5 project downwards. The stripping plate 57 is connected on one long side to a linkage 59 which is guided upwards in a bulge 60 of the rear housing shell 4, which has an opening at the top through which the linkage 59 protrudes from the housing 2. A driver 61 projects laterally from the upper end of the linkage 59. By means of a spring device, not shown, the linkage 59 is pressed up in the idle state until the stripping plate 57 abuts the underside of the lower housing wall 15. The laboratory automat has a drive with a drive element with which the driver 61 can be pressed down, whereby the stripping plate 57 is taken down to strip pipette tips 6 from the approaches 5.

3 and 4, pipette tips 6 are clamped onto the attachments 5. The pipette tips 6 are tubes with a tip opening 62 at the lower end 63 and a push-on opening 64 at the upper end 65. The inner diameter and the outer diameter of the pipette tip 6 generally increase from the tip opening 62 to the push-on opening 64. In the example, the pipette tips 6 have a plurality of conical regions 64, 65, 66 and a cylindrical extension 67 in the vicinity of the upper end 65. In the region of the cylindrical extension 67 and in the region below, the pipette tip has a sealing seat 68 on the inside.

3 and 4, the lugs 5 of the pipetting head 1 are inserted into the pipette tips 6 through the plug-on openings 64. The O-rings 24, 25 are arranged at the level of the sealing seat 68. As a result, the O-rings 24, 25 are compressed somewhat in the radial direction, so that the pipette tips 6 clamp on the shoulders 5 and are sealed off from the shoulders 5. Since the O-rings 24, 25 consist of soft elastic material and the pipette tips 6 are otherwise not in contact with the projections 5, the attachment forces for attaching the pipette tips 6 to the projections 5 are relatively small.

5 shows the measured attachment forces when attaching pipette tips as a function of the path of the pipetting head for an inventive pipetting head 1 with eight channels and two O-rings 24, 25 on each attachment 5 and a conventional pipetting head with eight channels without O-rings 24 , 25 shown side by side on the approaches. According to the three curves on the left in the diagram, the attachment forces increase when using a conventional pipetting head strong until they are sufficiently firm and sealing on the roots. This is the case with an attachment force of 120 Newtons and a displacement of the pipetting head of 2.2 mm. According to the curves on the right in the diagram, an adequately firm and sealing connection is established even with attachment forces of approx. 30 Newton and a displacement of the pipetting head of 2 mm. Here, only the O-rings 24, 25 are elastically deformed. Above this value, the push-on forces rise steeply, since this also requires a deformation of the pipette tips 6.

The reduced plug-on forces also reduce the forces for throwing off the pipette tips 6 from the projections 5.

The use according to the invention is explained below with reference to FIGS. 6 to 9. 6, an automatic laboratory machine 70 has a large number of tolerances which influence the positioning of the tip opening 64 of pipette tips 6 in the vertical direction. These tolerances include the tolerances of the positioning of a multi-axis transmitter 71 (robot arm or other transmission system). In addition, there are the tolerances of the fixation of a pipetting head 1 (pipetting tool) in the tool holder 72 held on the multi-axis transmitter 71. Furthermore, manufacturing tolerances of the pipetting head 1 must be taken into account. In addition, the approaches 5 for receiving the pipette tips 6 and the pipette tips 6 themselves have tolerances. Microtiter plates 73 and adapters 74 for positioning the microtiter plates 73 on a work surface 75 (deck) of the laboratory automat 70 have further tolerances. Finally, the work surface 75 itself also has tolerances. In particular when using multi-channel pipetting heads 1, the exact positioning of the individual pipette tips 6 is not possible, since the same height must be used for all pipette tips 6.

For many target applications, such as next-generation sequencing (NGS), this leads to quality losses due to reduced efficiency of the washing steps and / or reduced yields of sample material. In the worst case, contamination is carried over, e.g. if a sample is to be aspirated under another phase (e.g. oil-covered samples) and parts of the overlay are carried over.

The reduction in tolerance ranges leads to lower process reliability and thus to an increased risk of sample loss. In addition, it only partially solves the problem, since certain tolerance ranges are not to be undercut. Often the immediate need for a very precise adjustment of the device increases in order to minimize individual tolerances.

"Surface teaching" addresses certain tolerances on the system (e.g. positioning offset and tool tolerance), but is very labor intensive for the user and requires a lot of effort. Furthermore, a large number of tolerances are not covered by surface teaching (e.g. well (well) geometry, microtiter plate seat on adapter, pipette tip geometry, pipette tip seat, tool holder etc.), as this does not take place during the dosing process, but in advance of the application.

The use of two O-rings 24, 25 on each approach 5 enables unknown tolerance chains due to slight differences in the fit of the To allow pipette tips with constant dosing quality. The process consists of three steps:

7, several pipette tips 6 are received on a single or multi-channel pipetting head 1. After the pipette tips 6 have been picked up on the attachments 5 of the pipetting head 1, all pipette tips 6 are at a comparable height and can be pushed onto the attachments 5 with a small amount of force.

The pipette tips 6 are pressed onto the respective attachments 5 to different degrees by a dedicated movement in the vertical direction below the soil tolerance range of a surface (e.g. the bottom of a microtiter plate 73). With the same alignment of the approaches 5 in the vertical direction, the individual pipette tips 6 have individual heights after this step, which heights have been determined by the unknown base geometry and the tolerance chains. This is shown in Figure 8.

Then a small movement of the pipetting head 1 upwards creates a gap x between the lower ends 63 of the pipette tips 6 and the surface of the vessel (e.g. microtiter plate 73). This gap x is required for aspiration of liquid into the pipette tips 6 in order to avoid the pipette tips 6 from blocking. Due to the individual positioning of the pipette tips 6, the lower ends of all pipette tips 6 have the same distance from the surface of the vessel according to this method. This is shown in FIG. 9.

The advantage of this method is that all (known and unknown) tolerances are completely compensated for in each metering step. Furthermore, this process takes place automatically, since it is carried out by the laboratory automat 70 without additional effort can be executed for the user. The method is carried out during a run of the laboratory automat 70 with the individual combinations of pipette tips 6 and the corresponding individual cavities single or multiple vessels (eg microtiter plates 73).

Reference symbol list

Pipetting head

Housing (carrier)

, 4 housing shell

Neck

Pipette tip

Mounting plate (carrier plate)

Mounting pin

Piston-cylinder unit

0 cylinder

1 piston

2 external threads

3 internal threads

4 through hole

5 housing wall

6 paragraph

7 upper cylindrical section

8 lower cylindrical section

9 conical section

0 upper devices for axial position securing 1 upper ring groove

2 lower devices for axial position securing 3 lower ring groove

4, 25 O-rings

6 interior

7 connection sloch Liner

drilling

cylindrical piston head

Piston head ring groove

Housing wall

Piston plate

channels

Canal wall

Canal shoulder

Slot opening

Forehead opening

Threaded nut on the upper pin section

Connection element middle pin section lower pin section

drilling

Longitudinal groove

wing

spindle

thread

Bearing journal

ball-bearing

Bearing bush

Bearing bracket

Grub screw

Carrier

slot Dowel pin

Scraper plate

Through hole

Linkage

bulge

Carrier

Tip opening

lower end

Push-on opening

top end

, 65, 66 conical areas

cylindrical extension

Sealing seat

Laboratory machine

Multi-axis transformer (robot arm)

Tool holder

Microtiter plate

adapter

Work surface

Claims

Expectations

A pipetting head with at least one pipette tip for a pipetting device comprising: a carrier (2), at least one attachment (5) held on the support (2) for clamping pipette tips (6) and two O-rings held on the attachment (5) (24, 25) made of an elastomer, the two O-rings (24, 25), the shoulder (5) and the pipette tip (6) being formed, the pipette tip (6) solely by pressing on the pipette tip (6) on the two O-rings (24, 25) caused deformation of the two O-rings (24, 25) on the shoulder (5).

2. Pipetting head with at least one pipette tip according to claim 1, wherein the inner diameter of the sealing seat (68) of the pipette tip (6) at the point that contacts an O-ring (24, 25) is smaller than the outer diameter of the respective O-ring (24, 25) and / or in which the internal dimensions of a sealing seat (68) of the pipette tip (6) are dimensioned such that the sealing seat (68) has no direct contact with the attachment (5) or on the attachment (5) rests without the attachment (5) exerting a force deforming the pipette tip (6) when the pipette tip (6) is clamped onto the attachment (5) by deformation of the two O-rings (24, 25).

... 12

3. pipetting head with at least one pipette tip according to claim 1 or 2, wherein the O-rings (24, 25) are made of a soft rubber, silicone or thermoplastic elastomer.

4. Pipetting head with at least one pipette tip according to one of claims 1 to 3, in which the projection (5) has devices for axial position securing (20, 22) which are designed to each of the two O-rings (24, 25) in one support certain upper and in a certain lower position and allow deformation of the two O-rings (24, 25) in the radial direction.

5. pipetting head with at least one pipette tip according to claim 4, wherein the devices for the axial position securing (20, 22) on the periphery of the approach are circumferential annular grooves (21, 23) which partially accommodate at least one O-ring (24, 25), or are one or more projections on the circumference of the approach, which receive at least one O-ring (24, 25) between them.

6. Pipetting head with at least one pipette tip according to one of claims 1-5, in which the extension (5) has at least one conical section (19) and / or in which the extension (5) has at least one cylindrical section (17, 18) .

7. Pipetting head with at least one pipette tip according to claim 5 and 6, in which the extension (5) has an upper cylindrical section (17) at the top, a lower cylindrical section (18) below, and a conical section (19 ) and between the upper cylindrical section (17) and the conical section (19) upper devices for axially securing the position (20) and between the conical ../3 Section (19) and the lower cylindrical section (18) has lower devices for axially securing the position (22).

8. pipetting head with at least one pipette tip according to one of claims 1-7, wherein the upper O-rings (24) has a larger inner diameter and / or a cross section with a larger diameter than the lower O-ring (25).

9. pipetting head with at least one pipette tip according to one of claims 1-5, wherein the diameter of the cross section of an upper O-ring (24) is greater than the depth of the upper annular groove (21) and / or the width of the upper annular groove (21 ) is equal to or larger than the diameter of the cross section of the upper O-ring (24) and / or the diameter of the cross section of a lower O-ring (25) is greater than the height of the lower ring groove (23) and / or at which the Width of the lower annular groove (23) is equal to or greater than the diameter of the cross section of the lower O-ring (25).

10. pipetting head with at least one pipette tip according to one of claims 1-9, which has in one or more rows parallel to each other approaches (5).

11. Pipetting head with at least one pipette tip according to one of claims 1-10, in which the lugs (5) are firmly connected to the carrier (2).

12. Pipetting device or transfer device comprising a pipetting head (1) with at least one pipette tip according to one of claims 1-11.

13. pipetting station or automatic pipetting device or laboratory automatic device (70) comprising a pipetting device and / or a transfer device according to claim 12.

..YES

14. Use of a pipetting head (1) with at least one pipette tip (6) according to one of claims 1-11, a pipetting device or transfer device according to claim 12 or a pipetting station, an automatic pipetting device or an automatic laboratory device (70) according to claim 13, in which

a pipette tip (6) is clamped onto each attachment (5) of the pipetting head (1), the pipetting head (1) is displaced until each clamped pipette tip (6) has contact with a vessel (73) with its lower end (63), which is provided on a work surface (75), the pipetting head (1) is displaced until the lower end (63) of each clamped pipette tip (6) is at a certain distance (x) from a bottom of the vessel (73) and

Liquid from the vessel (73) is taken up in each clamped pipette tip (6).

15. Use according to claim 14, in which the pipetting head (1) is displaced until all clamped pipette tips (6) have the lower ends (63) at the same time in contact with the bottom of the vessel (73) and then the pipetting head (1) is displaced until the lower ends (63) of all pipette tips (6) are at a certain distance from the bottom of the vessel (73).

16. Use according to claim 14 or 15, wherein the pipetting head (1) is a multi-channel pipetting head and the vessel is a microtiter plate (73).