CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a national stage filing based upon International PCT Application No. PCT/AT2018/060148, filed 13 Jul. 2018, which claims the benefit of priority to Austria application No. A 50593/2017, filed 14 Jul. 2017, and Austria application No. A 50595/2017, filed 14 Jul. 2017.

BACKGROUND

The invention relates to an automatic pipetting device for transferring samples and/or reagents from sample vessels and/or reagent vessels into at least one receiving vessel, for example of an analyzer for analyzing liquid samples, wherein a pipettor of the pipetting device is designed to be movable along a first direction and has at least one first pipetting needle which is designed to be movable along an arm of the pipettor along a second direction, substantially normal to the first direction, and is destined to be lowerable into the individual vessels. The invention further relates to a method for transferring liquid samples and/or reagents from sample vessels and/or reagent vessels into at least one receiving vessel of an automatic pipetting device.

Pipetting machines or pipetting devices for transferring defined quantities of liquid between different liquid vessels distributed in a grid-like manner on a surface are known from the prior art. By way of example, physical, chemical or biological liquid samples may be treated with particular reagents or dilution liquids in the context of preparing a sample for the measurement of chemico-physical parameters that is carried out in an analysis device. Said machines have one or more pipetting units with an associated pipetting needle for taking up and dispensing liquids, these being movable in one or more horizontal directions, relative to the surface on which the liquid vessels are located, and being lowerable into the liquid containers. In addition, needle washing devices are required in order to prevent liquid substance residues which adhere to the needles from being carried over into other vessels. Besides precisely metering the liquid, the construction of the pipetting machines is always aimed at achieving the greatest possible number of pipetting operations per unit of time (high throughput).

For a better understanding of the invention, a few essential technical terms used in the present application will be defined in greater detail:

Pipetting Unit:

This refers to the entire system of an automatic pipetting device for transferring liquid between different vessels, which comprises one or more movable pipettors together with all the movable and stationary components necessary for the functioning thereof, including fluidics for supply purposes (hose connections, pumps, valves, containers, etc.), sensors, controller and power supply.

Pipettor:

This describes a component of the pipetting unit which is pivotable or linearly movable horizontally in at least one direction relative to the receiving vessels (sample vessels, reagent vessels, reaction vessels or cuvettes). The pipettor includes a suspended component having at least one pipetting needle which is designed to be movable on its own or together with the pipettor and such as to be lowerable into the aforementioned vessels.

Pipetting Needle:

This refers to a cannula or hollow needle, which is attached to the pipettor, together with the associated support with connection elements for the fluidics for aspirating samples out of the sample vessels and/or for aspirating reagents out of the reagent vessels and for dispensing the aspirated liquids into the receiving vessels or cuvettes in a metered manner.

Reagent Vessel:

Vessel or container for holding reagents which are required in order to carry out the analysis.

Sample Vessel:

Vessel or container which contains, in the analyzer, the analysis sample from which multiple smaller sample quantities (aliquots) can be taken in order to analyze individual analytes or parameters. The analysis does not take place in the vessel of the analysis sample, but rather in the cuvette after the reagents have been added thereto, the cuvette in this sense serving as a reaction vessel.

EP 1 230 553 B1 (MAXMAT) discloses in this connection a chemical or biological analyzer which has a storage module for sample tubes and tubes for reagents. Also provided is an analysis module having a reaction container in the form of a microtiter plate and a sample-taking module (pipettor) which is movable on a rail and which has two pipetting needles arranged at a fixed distance from one another, which pipetting needles operate independently of one another in the z-direction in order to take samples automatically and are each equipped with a retractable aspirating pipette for transferring predetermined quantities of samples and reagents from the storage module to the analysis module. The two pipetting needles are movable only jointly in the horizontal x/y plane.

The analysis module has a heating plate for the microtiter plate, which heating plate is arranged close to the lower region of the wells of the microtiter plate in order to heat the contents of the wells by convection. The sample-taking unit further comprises a mixing device which is controlled by an electromagnet in order to bring about an alternating back-and-forth movement of the pipetting needle when the latter is in a lowered position in a well of the microtiter plate, so as to thoroughly mix the mixture consisting of samples and reagents.

In addition, EP 2 410 342 A2 (HOFFMANN-LA ROCHE) discloses a pipetting device having a pipettor with multiple flat frame elements which are arranged next to one another and which, together with the pipetting needles thereof, are jointly movable on a main frame body in a horizontal x-direction that is normal to the main frame body. The pipetting device serves to transfer samples or reagents from a first row of vessels to a second row of vessels which is offset in the x-direction. The pipetting needles are first adjusted in the y-direction to the spacing of the vessels of the first row in order to take up sample liquid or reagent liquid, and then are adapted to the spacing of the second row of vessels in order to dispense the sample liquid or reagent liquid. However, an independent movement of two pipetting needles in the x- and y-direction is not provided. Movement modules for the y-direction and the z-direction (lifting and lowering of the pipetting needles) are arranged in gaps in flat, adjacent frame elements in order to keep the spacing between the individual pipetting needles small. However, an independent movement of the pipetting needles in the y-direction is possible only to a limited extent. For example, it is not possible for the frame elements to move past one another on the transfer arm, which results in a mutual restriction of the freedom of movement of the pipetting needles in the y-direction. Such pipetting devices find a useful application particularly in connection with microtiter plates.

Finally, U.S. Pat. No. 5,897,837 A (TOA MEDICAL) describes an automatic pipetting device or a pipetting machine for pretreating samples for an immunoassay analyzer. As shown inFIG.1of the present application, the pipetting machine10has a first pipettor20which is movable horizontally in the x- and y-direction and which is equipped with two pipetting needles11and12, it being possible for said pipetting needles to be lowered or lifted in the vertical direction independently of one another. In this case, one of the two needles11may be assigned to reagents, while the other needle12is assigned to samples which are arranged in different sections14to19of a table plane23. In addition, a second pipettor21is also present, which is movable in the x-y direction and has a lowerable pipetting needle13.

The first, horizontally movable pipettor20carries a needle washing unit22, which can move back and forth horizontally between the vertical lowering paths of the two pipetting needles11,12. In each case, alternately one of the two needles can be being cleaned, while the other needle is carrying out a pipetting process. The two pipetting needles11,12of the first pipettor20can only be moved jointly in the x- or y-direction.

This has the disadvantage that the weights of the robotics components of the pipettor20cannot be distributed across the two horizontal movement axes x and y, so that the weight of the second pipetting unit must always also be accelerated in order to move to positions in the y direction. Likewise, the weight of the needle washing unit22together with the needle washing vessel must also always be accelerated in both horizontal directions. Furthermore, due to the joint horizontal movement, it is not possible for example to use both needles11,12simultaneously for pipetting at different vessel rows which are not adjacent in the x-direction.

WO 2011/119441 A1 (BIONEX SOLUTIONS) discloses a transfer and testing device for materials, which is equipped with independently movable carrier devices and receiving devices. The carrier devices, which are movable in the X- and Z-direction and which have hollow needles, are arranged in a manner suspended on the underside of a stationary beam construction, which is supported at both ends of the device. The receiving devices are arranged such as to be movable in the Y-direction and rotatable in the X/Y plane and are equipped for example with microplates, into the wells of which sample materials can be transferred. Due to the combined translational and rotational movement of the carrier devices and receiving devices, the movement distances can be minimized.

The object of the invention is to considerably shorten the average duration of pipetting processes in a pipetting machine or a pipetting device, and thus to achieve the greatest possible throughput, particularly in the case of pipetting tasks in which the type and quantity of dispensed reagents and samples constantly changes between individual pipetting operations.

SUMMARY OF THE INVENTION

This object is achieved according to the invention in that the arm of the movable pipettor has at least one second pipetting needle which, regardless of the current position of the first pipetting needle, is movable independently past the first pipetting needle and is lowerable into the individual vessels.

The movement distance available to each pipetting needle on the arm of the pipettor can thus be used in its entirety, regardless of the position of the respective other pipettor.

The method according to the invention for transferring liquid samples and/or reagents from sample vessels and/or reagent vessels into at least one receiving vessel of an automatic pipetting device, using a pipettor which is movable horizontally along a first direction, is characterized by the following steps:moving a first pipetting needle of the pipettor along a horizontal second direction, substantially normal to the first direction, in order to transfer a predetermined quantity of a liquid sample or reagent from a sample vessel or reagent vessel into the receiving vessel;lowering the first pipetting needle into the sample vessel or reagent vessel;taking up a predetermined quantity of sample liquid or reagent liquid and moving the first pipetting needle to the position of the receiving vessel;dispensing the predetermined quantity of sample liquid or reagent liquid into the receiving vessel; andmoving a second pipetting needle of the same pipettor in the second direction, regardless of the current position of the first pipetting needle, in order to simultaneously carry out additional pipetting tasks.

An increase in throughput is thus achieved as a result of the fact that the two pipetting needles can move past one another unhindered, wherein the first pipetting needle can pipette samples for example, while the second pipetting needle can pipette reagents at the same time as and independently of the first pipetting needle, or also a second type of sample or reagent can be pipetted. In addition, a sample can be split between the two pipetting needles and then can be pipetted simultaneously into two different, non-adjacent vessels which are freely selectable in the y-direction.

One embodiment variant of the invention provides that the pipettor of the pipetting device has different pipetting needles, wherein the pipetting needles each have hollow needles or cannulas which differ in the type of materials used, the internal volumes and/or the geometry of the hollow needles or cannulas.

For certain pipetting tasks, in which two different types of pipetting needles must be used, it may be advantageous that two different pipetting needles are used on one and the same pipettor. By way of example, one of the pipetting needles attached to the pipettor may have a particularly small internal volume of the hollow needle in the μl range in order to increase the precision, while the second hollow needle has a correspondingly larger internal volume in order to dispense larger volumes. In another embodiment according to the invention, one of the hollow needles may be made at least in part of a different material (for example of a corrosion-resistant alloy, plastic or steer, or may for example be coated with hydrophobic or hydrophilic substances on the inner and/or outer side of the hollow needle in order to control the wetting. The needles may also differ by other modifications which do not necessarily concern only the surfaces that come into contact with media, such as for example conductive needle components, sensors, heating devices or cooling devices, which are part of the hollow needle or are in contact with the hollow needle. However, the second needle may also differ in terms of its geometry; for example, it may have a different tip angle in order to facilitate the detachment of droplets, or it may have a different length, or a different diameter, in order to better adapt the needle to the pipetting tasks in question.

Thus, by using different pipetting needles which are independently movable in the y-direction on one and the same pipettor, a wide variety of pipetting tasks can be made possible without requiring an additional pipettor or a needle exchange station. Furthermore, contrary to when a second pipettor is used, a collision of two pipetting needles during operation is not possible, thereby simplifying the movement paths and making it easier to control the pipetting device.

Regardless of the type of pipetting task, a further increase in throughput is achieved when the pipettor of the pipetting device has at least one needle washing unit for the first and the second pipetting needles, which needle washing unit is movable with the pipettor. By way of example, a pipetting process can be carried out with one pipetting needle, while at the same time the second pipetting needle is being cleaned. The configuration of the pipettor is characterized in that the y-movement of the respective pipetting needle is possible without also moving the weight of the needle washing unit carried on the pipettor, as a result of which the two pipetting needles can be accelerated and slowed much faster in the y-direction.

It is particularly advantageous to carry a separate needle washing unit for each of the two pipetting needles.

According to another preferred embodiment of the pipettor, the first and the second pipetting needle are designed to be movable substantially parallel to one another at least in sub-regions of the arm of the pipettor. This configuration has the advantage of higher precision when stopping at a stop point (for example a liquid vessel) located in the horizontal, since the guide rails for the pipetting needles, which are attached to the side surface of the pipettor arm that is formed for example of sheet-metal or metal profiles, can be better aligned and supported. In addition, the guide rails act like strut elements and, by increasing the stiffness of the pipettor arm, have an advantageous effect on the ability of the pipettor to accelerate in the x-direction.

In one preferred embodiment variant of the invention, the two independently movable pipetting needles are arranged on opposite longitudinal sides or side faces of the arm of the pipettor. This embodiment enables an unhindered movement of the pipetting needles along the entire length of the arm and of the working area. In addition, the stiffness of the arm is increased, as a result of which the latter can be made thinner and lighter.

Further advantages of attaching the two pipetting needles to the sides are that the automatic pipetting device can be made more compact and the width thereof does not exceed the total length of the horizontal arm. In addition, the energy chains necessary for supplying power to the pipetting needles can be guided along the top side of the arm without any problem, wherein there is also more space available for the hose lines of the fluidics, particularly if the latter can form movement loops in the upward direction without hindrance during a lifting movement of the pipetting needles.

According to one embodiment variant of the invention, on at least one side of the arm of the pipettor, two jointly movable pipetting needles are connected via a lifting mechanism such that the two pipetting needles can be moved in opposite directions or in an antiparallel manner in the z-direction.

It is also advantageous if the horizontal arm of the pipettor is attached to a vertical tower which is movably attached to a rail extending in the x-direction. As a result, the rail extending in the x-direction can be attached, for example, to the transversely extending supports of a working area of the pipetting device, as a result of which, compared to a known suspended portal, the tolerances of the suspended pipettor can be kept small. In addition, by virtue of this configuration, short hose lines and power supply lines to the pipettor moving in the x-direction are possible, which has an advantageous effect on the pipetting accuracy and also on the total weight of the pipettor that has to be moved.

According to another advantageous embodiment of the pipetting device, the pipettor with its vertical tower and the horizontal arm has a substantially L-shaped basic structure, as a result of which on the one hand the working area is not interrupted by the width of the rail of the pipettor extending in the x-direction, and on the other hand some of the movement distances in the y-direction are considerably shortened.

The ability of the pipettor to accelerate in the x-direction can be considerably increased by another embodiment variant if the pipettor has with its vertical tower and the horizontal arm has a substantially T-shaped basic structure. This adds a further plane of symmetry to the basic structure of the pipettor, and makes it possible to further increase the stiffness of the pipettor. With a further reduced material thickness, the tower and the arm of the pipettor can have a reduced weight, and the pipettor can thus be better accelerated and slowed.

