Method for detection of bottom of at least one well

Abstract

To provide a method for detection of a bottom of at least one well of a multiwell plate for a pipetting device.SOLUTION: A method for detection of a bottom 118 of a well 120 comprises, using a force sensor 124 configured for measuring a resistance force depending on a force exerted on pipetting tips 116 by the bottom 118, the steps of: a) measuring the resistance force during movement of one of the pipetting tips 116 from a start position towards the bottom 118 of the well 120, and stopping the movement at a bottom position, where the bottom position is a position where a predefined resistance force is reached; and b) storing in at least one database 130 the bottom position together with a corresponding logical position of the well 120 in a multiwell plate 122.SELECTED DRAWING: Figure 1

Description

Technical Field

[0001] Technical Field The present invention relates to a method for detecting the bottom of at least one well and a pipetting device for performing the method. The present invention further relates to laboratory equipment for processing and / or analyzing a sample comprising the pipetting device. Furthermore, the present invention relates to a computer program and a computer-readable storage medium for performing the method. The method and the device can specifically be used in the field of medical or chemical laboratories, particularly in the field of automated in vitro diagnostic (IVD) sample processing. However, other application fields of the present invention are possible.

Background Art

[0002] Background Art In the field of medical or chemical laboratories, pipetting devices are often used for automated sample processing. Specifically, the pipetting device can be used to transfer a sample, specifically a sample of the human body such as blood, urine, saliva, interstitial fluid or other body fluids, a reagent or a control group, from a first container to a second container by suction and / or dispensing operations. Modern devices for processing this type of sample are almost completely automated in operation.

[0003] For the automatic operation of the pipetting device, container detection may generally be required in some cases. As examples, European Patent No. 0 223 758, Japanese Unexamined Patent Application Publication No. 01097865, European Patent No. 2 350 676, US Patent Application Publication No. 2019 / 032,4050, International Publication No. 2019 / 017,964, European Patent Application Publication No. 3 173 793, International Publication No. 2012 / 129,105, US Patent Application Publication No. 2009 / 013,0745, International Publication No. 2005 / 121,746, European Patent Application Publication No. 3 376 235, European Patent Application Publication No. 2 481 481 and European Patent Application Publication No. 3 517 974 describe pipetting devices and / or pipetting methods using automatic detection means.

[0004] Despite the advantages achieved by known methods and apparatus, several technical challenges remain. For example, automated vessel detection can be time-consuming, especially when the vessel location is used multiple times. Furthermore, in general, it may be necessary to perform numerous force-controlled movements to ensure sufficient reliability of automated vessel detection. Additionally, minimizing dead volume in the well may introduce a potential risk of pipetting tip closure at the bottom of the well.

[0005] Issues to be resolved Therefore, it is desirable to provide methods and apparatus that address the above-mentioned technical challenges at least partially. Specifically, a method, pipetting apparatus, and laboratory equipment for detecting the bottom of at least one well are proposed, enabling time-effective detection of the bottom of at least one well with high reliability and accuracy. [Overview of the Initiative]

[0006] overview This problem is addressed by a method, pipetting apparatus, and laboratory equipment for detecting the bottom of at least one well having the features of an independent claim. Advantageous embodiments that can be realized individually or in any combination are described in the dependent claims and throughout the specification.

[0007] Where used below, the terms “have,” “equip,” or “include,” or any grammatical variations thereof, are used in a non-exclusive manner. Thus, these terms may refer to both situations in which the entity described in this context has no further features beyond those introduced by these terms, and situations in which one or more additional features exist. For example, the expressions “A has B,” “A equips B,” and “A includes B” may both refer to situations in which A has no other elements besides B (i.e., A consists solely and exclusively of B), and situations in which entity A has one or more additional elements besides B, such as element C, elements C and D, and even further elements.

[0008] Furthermore, it should be noted that the terms “at least one,” “one or more,” or similar expressions indicating that a feature or element can exist one or more times are usually used only once when introducing each feature or element. In most cases below, when referring to each feature or element, the expressions “at least one” or “one or more” will not be repeated, despite the fact that each feature or element can exist one or more times.

[0009] Furthermore, where used below, the terms “preferably,” “more preferably,” “particularly,” “more especially,” “specifically,” “more specifically,” or similar terms are used in conjunction with any feature without limiting the possibility of alternatives. Thus, any features introduced by these terms are arbitrary and are not intended to restrict the scope of the claims in any way. The present invention may be implemented by using alternative features, as those skilled in the art will recognize. Similarly, any features introduced by “in embodiments of the present invention” or similar expressions are intended to be arbitrary features without limitations on alternative embodiments of the invention, without limitations on the scope of the invention, and without limitations on the possibility of combining such introduced features with other arbitrary or non-arbitrary features of the invention.

[0010] In a first embodiment, a method is proposed for detecting the bottom of at least one well of a multiwell plate for a pipetting apparatus. The pipetting apparatus comprises at least one pipetting head configured to be coupled to a plurality of pipetting tips. The method includes using at least one force sensor configured to measure a resistance force corresponding to the force exerted on the pipetting tip by the bottom.

[0011] As used herein, the term “pipetting apparatus” is a broad term and should be given its usual customary meaning to those skilled in the art, and should not be limited to any special or customized meaning. Specifically, the term may refer to an apparatus or system configured to perform at least one pipetting step, including, but not limited to, the transport and / or transfer of at least one other material, such as a liquid or dry powder. A pipetting apparatus may be configured to perform at least one pipetting step, such as aspiration and / or dispensing. A pipetting apparatus may comprise a pipetting head and at least one pipetting tip, or may be connectable to at least one pipetting tip. A pipetting apparatus is configured to perform at least one pipetting procedure on a multiwell plate. As used herein, the term “pipetting procedure” is a broad term and should be given its usual customary meaning to those skilled in the art, and should not be limited to any special or customized meaning. Specifically, the term may refer to at least one pipetting step and / or a series of pipetting steps, and / or may not be limited to any special or customized meaning.

[0012] The pipetting device can be an automatic pipetting device. Therefore, the pipetting procedure can be performed automatically, for example, without user interaction. However, the pipetting procedure may include steps that require manual action, such as loading consumables.

[0013] As used herein, the term “pipetting head” is a broad term and should be given its usual and customary meaning to those skilled in the art, and should not be limited to any special or customized meaning. Specifically, the term can refer to at least one mechanical component designed for transporting and / or transferring liquids or other materials such as dry powders. A pipetting head may comprise at least one pump and / or pumping system. For example, the pump may be a micro-annular gear pump.

[0014] As used herein, the term “pipetting tip” is a broad term and should be given its usual, customary meaning to those skilled in the art, and should not be limited to any special or customized meaning. Specifically, the term may refer to, but not limited to, a disposable pipetting tip that can be used only by a single pipetting process, and a reusable pipetting tip that can be used by two or more pipetting processes. Disposable pipetting tips are typically made of plastic and are disposed of after the pipetting process. Reusable pipetting tips can be designed as pipetting needles and are typically made of metal or any other material suitable for use with the respective liquid.

[0015] As used herein, the term “combined” is a broad term and should be given its usual customary meaning to those skilled in the art, and should not be limited to any special or customized meaning. Specifically, the term can refer, but is not limited to, a releasable bonding process of a pipetting tip to a pipetting head via a bonding unit, for example, and a permanent bonding of a pipetting tip to a bonding unit. In the latter case, the pipetting tip may be permanently bonded to the bonding unit, such as by screwing it in, except for replacement caused by damage or maintenance purposes. A pipetting head may be equipped with a disposable pipetting tip or a pipetting needle, and may be able to aspirate and dispense the sample and / or reagents necessary to perform a sample processing step. A pipetting apparatus may have one pipetting tip or needle for aspirating and / or dispensing one sample or reagent or a combination thereof. A pipetting apparatus may have multiple pipetting tips or needles for simultaneously aspirating and / or dispensing multiple samples or reagents or combinations thereof.

[0016] A pipetting apparatus can be an element of at least one laboratory apparatus for processing samples. The term “laboratory apparatus” as used herein is a broad term and should be given its usual customary meaning to those skilled in the art, and not limited to any special or customized meaning. Specifically, the term can refer to any apparatus configured to perform processing steps for a sample or sample container. For example, the laboratory apparatus may be a clinical diagnostic analyzer. A pipetting apparatus may be located in a laboratory pipetting station. The laboratory apparatus may comprise multiple pipetting stations.

[0017] Laboratory equipment can consist of one or more pre-analytical instruments, analytical instruments, or post-analytical instruments. Pre-analytical instruments can typically be used for the preliminary processing of samples or sample containers. Analytical instruments can, for example, be designed to use a sample or a portion of a sample and reagents to generate a measurable signal, which can then be used to determine whether an analyte is present and, if necessary, at what concentration. Post-analytical instruments can typically be used for post-processing of samples, such as sample storage. Laboratory equipment may include a pipetting device for pipetting samples, a sorting device for sorting samples or sample containers, a cap removal device for removing caps or closures from sample containers, a cap attachment device for attaching caps or closures to sample containers, an aliquoting device for aliquoting samples, a centrifuge for centrifuging samples, an analytical device for analyzing samples, a heating device for heating samples, a cooling device for cooling samples, a mixing device for mixing samples, a separation device for isolating analytes from samples, a storage device for preserving samples, a storage device for storing samples, a sample container type determination device for determining the type of sample container, and a sample quality determination device for determining sample quality.

[0018] As used herein, the term “sample” is a broad term and should be given its usual customary meaning to those skilled in the art, and should not be limited to any special or customized meaning. Specifically, the term may refer to any substance suspected to contain the analyte of interest, but not limited to these. Samples may originate from any biological source, such as physiological fluids including blood, saliva, eyepiece solution, cerebrospinal fluid, sweat, urine, milk, ascites, mucus, synovial fluid, peritoneal fluid, amniotic fluid, tissue, cells, etc. Samples may be pretreated before use, such as by preparing plasma from blood, diluting or dissolving viscous fluids; methods of treatment may include filtration, distillation, concentration, inactivation of interfering components, and addition of reagents. Samples may be used as is obtained from the source or directly after pretreatment to modify the characteristics of the sample, for example, after being diluted with another solution or mixed with reagents, or after being used to perform one or more diagnostic assays, such as clinical chemistry assays, immunoassays, coagulation assays, nucleic acid tests, etc. Therefore, as used herein, the term “sample” refers not only to the original sample but also to a sample that has already been processed, such as being dispensed by pipetting, diluted, mixed with reagents, concentrated, purified, or amplified. As used herein, the term “analyte” may refer to the compound or composition being detected or measured.

[0019] As used herein, the term “process a sample” is a broad term and should be given its usual customary meaning to those skilled in the art, and should not be limited to any special or customized meaning. Specifically, the term can refer to any processing of a sample, but is not limited to any specific processing. For example, processing may include one or more of the following: transferring a sample, aliquoting, isolating, purifying, incubating, reacting, or combining a reagent with a sample. As used herein, the term “reagent” is a broad term and should be given its usual customary meaning to those skilled in the art, and should not be limited to any special or customized meaning. Specifically, the term can refer to any composition necessary for processing a sample, but is not limited to any specific specific processing. A reagent may be any liquid, e.g., a solvent or chemical solution, that needs to be mixed in sequence with a sample and / or other reagents, for example, to induce a reaction or to enable detection. A reagent may be, for example, a diluent containing water, an organic solvent, a cleaning agent, or a buffer. A reagent may also be a dry reagent adapted to be soluble by, for example, a sample, another reagent, or a diluent. In a more precise sense, a reagent can be a liquid solution containing, typically a compound or drug, a reactant that can bind to or chemically convert one or more analytes present in a sample. Examples of reactants include enzymes, enzyme substrates, conjugated dyes, protein-binding molecules, nucleic acid-binding molecules, antibodies, chelating agents, promoters, inhibitors, epitopes, and antigens.

[0020] As used herein, the term “multiwell plate” is a broad term and should be given its usual customary meaning to those skilled in the art, and should not be limited to any special or customized meaning. Specifically, the term can refer to any plate-like device configured to permanently or temporarily store small amounts of fluid, but not limited to these. In this regard, small amounts should be understood as amounts of fluid in the range of nl to ml, such as 10 nl to 100 ml, preferably 0.1 μl to 10 ml, and more preferably 0.1 μl to 5 ml. Essentially, the design of a multiwell plate can depend on the respective application of the laboratory equipment. A multiwell plate may be designed as a device for storing a single fluid sample or multiple fluid samples. Similarly, the geometric shape of each storage area of ​​a multiwell plate can depend on the respective application of the multiwell plate. The storage area may be designed as a well, channel, depression, recess, etc. For example, a multiwell plate may contain multiple wells. As used herein, the term “multiwell plate” can refer to a plate having multiple “wells” used as small test tubes. Such a multiwell plate is also known as a microtiter plate. Microplates have become a standard tool in analytical research and clinical diagnostic laboratories. A very common use is in enzyme-linked immunosorbent assays (ELISA), which are the basis of modern medical diagnostic tests in humans and animals. Multiwell plates typically have 6, 24, 96, 384, or 1536 sample wells arranged in a 2:3 rectangular matrix. Some microplates are even manufactured with 3456 or 9600 wells, and "array tape" products have been developed that provide continuous strips of embossed microplates on flexible plastic tape. Each well in a microplate typically holds tens of picoliters to several milliliters of liquid. They can also be used to store dry powders or as racks to support glass tube inserts. Wells can be either round or square.For compound storage applications, square wells with tightly fitting silicone caps are preferred. Microplates can be stored for long periods at low temperatures, heated to increase the rate of solvent evaporation from their wells, and even heat-sealed with foil or transparent film. Microplates with a layer of filter material have also been developed, and today there are microplates for almost every application in life science research, including filtration, separation, optical detection, storage, reaction mixing, cell culture, and detection of antimicrobial activity. For example, a multiwell plate may be a processing plate. A processing plate may be configured to undergo at least one sample processing step. Sample processing may include one or more steps such as sample-specific steps, aliquoting, heating, cooling, magnetic separation, mixing, washing, elution, dilution, chemical reaction, sample dissolution, nucleic acid capture, nucleic acid release, and nucleic acid extraction. For example, a multiwell plate may be an AD plate. An AD plate may be configured to undergo at least one preparation for subsequent analysis. After preparation, an AD plate may contain a sample that has been last processed and purified with at least one reagent.

[0021] The wells of a multiwell plate may include at least one receptacle designed to contain contents housed in a receptacle. The wells extend downward from the surface of the multiwell plate. The wells may have an elongated shape. The wells may have a cylindrical shape, such as a tube. However, embodiments of wells having shapes deviating from cylindrical shapes may be possible. The wells include a bottom. As used herein, the term “bottom” is a broad term and should be given its usual customary meaning to those skilled in the art, and should not be limited to any special or customized meaning. Specifically, the term may refer to the closure of a receptacle, but is not limited to this. The bottom can generally have any shape, such as a circular bottom, e.g., a U-bottom; a conical bottom, e.g., a V-bottom; a flat bottom; or a flat bottom with a curved edge. Other shapes may also be possible.

[0022] The wells of a multiwell plate can form an array or matrix having rows and columns. The array or matrix may be a rectangle having m rows and n columns, where m and n are independently positive integers. Entries in the array or matrix are referred to herein as logical positions. Wells may be located at logical positions within the multiwell plate.

[0023] As used herein, the term “bottom detection” is a broad term and should be given its usual customary meaning to those skilled in the art, and should not be limited to any special or customized meaning. Specifically, the term can refer to determining the depth of a well, but is not limited to this. Bottom detection may include determining the position of the bottom in the coordinate system of a pipetting apparatus and / or relative to the surface of a multiwell plate. The pipetting apparatus may include a three-dimensional Cartesian coordinate system including a first direction (also indicated as x-), a y direction (also indicated as y-), and a third direction (also indicated as z-), aligned perpendicular to each other, where the first and second directions (x, y) span a plane and the third direction (z) is aligned perpendicular to the plane. The first and second directions (x, y) may span a horizontal plane and the third direction (z) may be aligned perpendicularly (down direction). The horizontal plane may be the plane of the surface of the multiwell plate. Bottom detection may include determining the z-coordinate of the bottom and / or its relative distance to the surface of the multiwell plate along the z-direction.

[0024] As used herein, the term "force sensor" is a broad term and should be given its ordinary and customary meaning to those skilled in the art and should not be limited to a special or customized meaning. Specifically, without limitation, this term can refer to a sensor configured to convert a load into an electrical output signal also called a sensor signal. The sensor signal may be a raw sensor signal or a pre-processed sensor signal. The force sensor may include a load cell configured to generate a sensor signal proportional to the resistance force exerted on the pipetting tip. For example, the load cell may be a strain gauge beam arrangement. The force sensor may be disposed within the pipetting head.

[0025] The method steps may be executed in a given order or in a different order. Further, one or more additional method steps not enumerated may exist. Further, one, multiple, or even all of the method steps can be repeatedly executed.

[0026] The method is as follows: a) Measuring the resistance force while one of the pipetting tips moves downstream from the starting position towards the bottom of the well and stopping the movement at the bottom position, where the bottom position is the position where a pre-defined resistance force is reached, measuring the resistance force and stopping the movement at the bottom position; b) Storing the bottom position in at least one database together with the corresponding logical position of the well within the multi-well plate; and including.

[0027] As used herein, the term "starting position" is a broad term and should be given its ordinary and customary meaning to those skilled in the art and should not be limited to a special or customized meaning. Specifically, without limitation, this term can refer to the initial position of a pipetting tip before performing a pipetting procedure, for example, the z coordinate. As used herein, the term "downstream" is a broad term and should be given its ordinary and customary meaning to those skilled in the art and should not be limited to a special or customized meaning. Specifically, without limitation, this term can refer to a direction along the z-axis, for example, the falling direction.

[0028] The predefined resistance force at which the movement of the pipetting tip stops can be in the range of 10 to 120 N, specifically in the range of 10 to 96 N, and more specifically 20 N.

[0029] The movement of the pipetting tip may be controlled by at least one control unit. The term “control unit” as used herein is a broad term and should be given its usual and customary meaning to those skilled in the art, and not limited to any special or customized meaning. Specifically, the term can refer to any device or system configured to perform a specified operation, preferably by using at least one data processing device, more preferably by using at least one processor and / or at least one application-specific integrated circuit. Thus, as an example, at least one control unit may comprise at least one data processing device storing software code containing several computer commands. The control unit may provide one or more hardware elements for performing one or more of the specified operations, and / or provide one or more processors with software to be executed for performing one or more of the specified operations. The control unit may comprise one or more computers, one or more application-specific integrated circuits (ASICs), digital signal processors (DSPs), or one or more programmable devices such as field-programmable gate arrays (FPGAs). However, additionally or alternatively, the control unit may also be fully or partially embodied in hardware.

[0030] As used herein, the terms “processor” or “processing device” are broad terms and should be given their usual and customary meanings to those skilled in the art, and should not be limited to any special or customized meanings. Specifically, the term can refer to any logic circuit and / or generally any device configured to perform basic operations of a computer or system, but not limited to these. In particular, a processor can be configured to process basic instructions that drive a computer or system. For example, a processor can include at least one arithmetic logic unit (ALU), at least one floating-point unit (FPU), such as a numerical coprocessor or numeric coprocessor, a number of registers, specifically registers configured to supply operands to the ALU and store the results of calculations, and memory such as L1 and L2 cache memories. In particular, a processor can be a multi-core processor. Specifically, a processor can be or include a central processing unit (CPU). Additionally or alternatively, a processor can be or include a microprocessor, and therefore specifically, the elements of a processor can be contained in a single integrated circuit (IC) chip. Additionally or alternatively, the processor may comprise or comprise one or more chips, such as one or more application-specific integrated circuits (ASICs) and / or one or more field-programmable gate arrays (FPGAs) and / or one or more tensor processing units (TPUs) and / or dedicated machine learning optimization chips. Specifically, the processor may be configured to perform one or more evaluation operations, for example, by software programming.

[0031] The bottom position, along with the corresponding logical position of the wells in the multiwell plate, is stored in at least one database. This allows for mapping the bottom position to the logical position of the multiwell plate. The term “database” as used herein is a broad term and should be given its usual customary meaning to those skilled in the art, and should not be limited to any special or customized meaning. Specifically, the term can refer to an organized collection of data that is stored and accessed electronically from a computer or computer system, but not limited to these. A database may comprise a data storage device, or may be provided by a data storage device. A database may comprise at least one database management system comprising software running on a computer or computer system, the software enabling interaction with one or more of a user, an application, or the database itself, for example, to capture and analyze the data contained in the database. The database management system may further include equipment for managing the database. Thus, a database containing data may consist of a database system that, in addition to the data, includes one or more associated applications.

[0032] The method may be performed automatically. The term “automatically” as used herein is a broad term and should be given its usual and customary meaning to those skilled in the art, and should not be limited to any special or customized meaning. Specifically, the term can refer to a process performed entirely by at least one computer and / or computer network and / or machine, without any manual action and / or user interaction. The method may be computer-implemented. However, the method may include manual actions such as loading consumables. A control unit may be configured to perform the method according to the present invention, such as steps a) and b).

[0033] This method can be performed during aspiration and / or suction, and during dispensing, particularly during mixing and / or dispensing. Aspiration may include drawing up the contents of a well. Dispensing may include delivering the contents of a well. The term "dispensing" may refer to "direct dispensing." The term "suction and dispensing" may refer to suction and dispensing dispensing, for example, an intermediate transport mechanism for dispensing. Suction and dispensing may include, for example, drawing liquid from a container and then releasing the liquid onto a well. Suction and dispensing may be performed specifically for the purpose of mixing samples, reagents, etc.

[0034] For example, this method can be performed during aspiration and / or sipping, and during dispensing. This method may include, after step a), moving the pipetting tip upward until the resistance force decreases to a predetermined residual force, and moving the pipetting tip upward by a predetermined distance to its final position for aspiration and / or sipping and dispensing. The pipetting tip may come into contact with the bottom of the well and the resistance force may begin to increase. The pipetting tip and / or well may then bend until the predetermined resistance force is reached. The pipetting tip can then be moved upward until the resistance force decreases to a predetermined residual force. The pipetting tip and / or well may not be bent until the predetermined residual force is reached. The predetermined residual force may be in the range of 1 to 20 N, specifically in the range of 4 to 10 N. The predetermined distance may be an offset. The detected bottom may be stored for future use. The final position can be reached within an accuracy of ±0.25 mm. The proposed method can handle hardware and consumable intolerances that can be >1 mm. The proposed method may be advantageous when the residual volume in the well must be minimized, for example, less than 7 μl. The proposed method can also ensure that the pipetting tip does not come into contact with the bottom and that the tip remains fully open for liquid handling.

[0035] For example, this method may be performed during dispensing. A force sensor may be used to detect the bottom of the well. In the first step, the pipetting tip can be moved downward toward the bottom of the well. Upon contact with the bottom, the resistance force begins to increase. The movement is stopped when a predetermined resistance force is reached. This is the final position for dispensing. The detected bottom may be memorized for future use. The proposed method can accommodate hardware and consumable intolerances that may be >1 mm. The proposed method can ensure that the pipetting tip is in contact with the bottom for liquid handling. It is important to have an airtight connection to prevent bubbles from leaking during liquid handling.

[0036] This method may include considering, specifically reusing, a stored bottom position for at least one subsequent pipetting procedure, such as one or more subsequent aspiration, dispensing, waste dispensing, sipping, and ejecting. This method may include determining whether a bottom position is available for a logical position in a database. If a bottom position is available, this method may proceed to the subsequent pipetting procedure; otherwise, steps a) through b) of the method are performed. Bottoms detected for aspiration and / or sipping, as well as ejecting and / or dispensing, can be stored and reused. For each new consumable, such as a new multiwell plate and / or pipetting tip, the bottom can be detected again and used multiple times until the consumable is replaced again. Storage can allow the bottom position to be reused several times. This can save time because detecting the bottom is slower than moving directly to a given position. The time saved can be several seconds per liquid handling operation.

[0037] For example, if the “bottom detection” function is selected for a pipetting procedure, the control unit and / or user can be configured to perform the method according to the present invention. In the first step, the control unit can determine whether the bottom value is already available in the database. For example, if the bottom value is not available for the first aspiration, the control unit and / or user can select the function for bottom detection by moving the pipetting tip further by a predetermined distance after detection. The requested command may then be executed by the control unit. The received value can be stored in a map along with the logical position key and the bottom value. If the value for the bottom is available in the database, a key with the logical position is found in the map. The command for the pipetting procedure can then be executed directly using the bottom value and / or the sum of the value for the bottom and the predetermined distance. After the pipetting tip has been placed down, the map can be washed (for the next execution).

[0038] This method may include monitoring of a force sensor. As used herein, the term “monitoring of a force sensor” is a broad term and should be given its usual, customary meaning to those skilled in the art, and should not be limited to any special or customized meaning. Specifically, the term may refer to monitoring the behavior of a force sensor, particularly to ensure reliability and / or accuracy. The force sensor may be moved to a defined position where it is subjected to at least one resistive force generated from at least one mechanical spring. For example, two different forces may be applied to the force sensor. For example, the force sensor may be checked for two different forces, for example, 27N and 57N. Monitoring may include checking for an accuracy of approximately + / - 10N.

[0039] The laboratory equipment may include at least one force control check station configured for monitoring force sensors. The laboratory equipment may also include multiple force control check stations, for example, in different modules. This can allow for more precise specification of the tolerances of the force sensors.

[0040] The force control check station may be permanently installed in the laboratory equipment. As used herein, the term “permanently installed” is a broad term, and its usual customary meaning should be given to those skilled in the art, and not limited to any special or customized meaning. Specifically, the term may refer to being integrated into the laboratory equipment and / or not replaceable by the user. The force control check station may be positioned in a fixed location on the laboratory equipment. The force control check station may be part of the work surface of the laboratory equipment and / or positioned to interact with specific elements of the work surface of the laboratory equipment. However, additionally or alternatively, embodiments are possible in which the force control check station is a temporarily integrated element of the laboratory equipment. As used herein, the term “work surface” is a broad term, and its usual customary meaning should be given to those skilled in the art, and not limited to any special or customized meaning. Specifically, the term may refer to a plate mounted within the laboratory equipment that represents the actual surface on which sample, sample container, reagent, and / or reagent container processing steps are performed. For this purpose, the work surface is provided with recessed compartments for accommodating consumables, sample processing equipment, waste containers, activators, and racks necessary for performing sample, sample container, reagent, and / or reagent container processing steps. The work surface may consist of a single piece and can be made from any suitable material (e.g., metal and / or plastic) with sufficient rigidity. The work surface may have different shapes and forms to meet the requirements of the laboratory equipment.

[0041] A force control check station may be configured to exert at least one resistive force on a force sensor, generated from at least one mechanical spring. The force control check station may comprise at least one mechanical spring. For example, the force control check station may comprise a plurality of mechanical springs. For example, the force control check station may comprise a plurality of first mechanical springs having a first elastic property and a plurality of second springs having a second elastic property. As used herein, the term “mechanical spring” is a broad term and should be given its usual, customary meaning to those skilled in the art, and should not be limited to any special or customized meaning. Specifically, the term can refer to any shape of element having elastic properties, but is not limited to these. An elastic element may have linear elastic properties. The elastic element may, in particular, be at least one spring, such as a coil spring. Spring deformation can be ignored.

[0042] Instead of plastic chips, metal tools, also known as teaching tools, can be used to monitor force sensors.

[0043] The force control check station may be part of the laboratory equipment, and therefore the checks can be performed regularly and fully automated. Periodic checks ensure the proper functioning of the force sensor. Using metal tools instead of chips can improve the accuracy of the inspection.

[0044] For example, a force control check station may include a compartment configured to receive a mounting plate. The mounting plate may have a teaching tool support configured to receive a teaching tool. The term “compartment” as used herein is a broad term and should be given its usual customary meaning to those skilled in the art, and should not be limited to any special or customized meaning. Specifically, the term may refer to a dedicated embedded element on the work surface of laboratory equipment, but is not limited to this. The mounting plate may be spring-biased relative to the work surface. For example, the mounting plate may be spring-biased relative to the work surface using four mechanical springs. The mechanical springs may have identical elastic properties. The mechanical springs may be arranged to apply a uniform force to the teaching tool. The force control check station may include a spring-loaded intermediate plate. The intermediate plate may be spring-biased relative to the work surface using four further mechanical springs. The further mechanical springs may have identical elastic properties. The further mechanical springs may have different elastic properties from the mechanical springs of the mounting plate. The further mechanical springs may be arranged to apply a uniform force to the teaching tool. The intermediate plate may be positioned below the mounting plate, for example, between the work surface and the mounting plate. The intermediate plate may be designed to be effective at a certain distance (depth). Thus, it may be possible to apply two different forces to the teaching tool at two different distances.

[0045] For example, the procedure at the force control check station may be as follows: The teaching tool can be placed on the spring load mounting plate (parking position). The pipetting head can be coupled to the teaching tool. The force control check station, in particular the pipetting head, can be moved to at least one first depth value, e.g., -1 mm, such that resistance force is accumulated through one or more springs of the force control check station. A minus sign may indicate that the direction of movement is downward. A force sensor can measure the force. The control unit can compare the measured value to at least one expected value. The force control check station can be moved to at least half a depth value, e.g., -2.5 mm, such that the intermediate plate becomes effective. A force sensor can measure the force. The control unit can compare the measured value to at least one expected value.

[0046] The force control check station may be configured to provide control points for force-distance measurement. The pipetting station may be configured to provide a force-distance function of the pipetting head, e.g., 100N with a specified distance, or an additional second specified force N. As outlined above, monitoring may include applying two different forces by approaching two different depths. The control unit may be configured to interpolate a line passing through a first point (no force), a first depth value, and a second depth value, thereby determining the goodness of the curve.

[0047] The control unit may be configured to determine whether the deviation from the expected value is within a predetermined tolerance. For example, the predetermined tolerance may be ±10%. If the deviation from the expected value is within the predetermined tolerance, the force sensor is considered to be functioning correctly. Otherwise, a malfunction of one or more of the force sensor, pipetting head, and pipetting station is assumed. The control unit may perform at least one action in the event of an assumed malfunction. For example, the action may include checking a specified component. For example, the action may include issuing at least one warning, issuing at least one request, such as calibrating the pipetting head as needed, performing a retry to determine the deviation, or stopping the pipetting device until the force sensor is replaced or repaired.

[0048] The control unit may be configured to perform operations via at least one communication interface and / or user interface. As used herein, the term “communication interface” is a broad term, and its usual and customary meaning should be given to those skilled in the art, and should not be limited to any special or customized meaning. Specifically, the term can refer to an item or element forming a boundary configured to transfer information, but is not limited to this. A communication interface may be configured to transfer information from a computing device, such as a computer, for example, to transmit or output information to another device. Additionally or alternatively, a communication interface may be configured to transfer information to a computing device, such as a computer, for example, to receive information. Specifically, a communication interface can provide means for transferring or exchanging information. In particular, a communication interface can provide data transfer connectivity, such as Bluetooth®, NFC, or inductive coupling. As an example, a communication interface may be, or include, at least one port, including one or more of a network or internet port, a USB port, and a disk drive. A communication interface may be at least one web interface. As used herein, the term “user interface” is a broad term and should be given its usual, conventional meaning to those skilled in the art, and should not be limited to any special or customized meaning. The term can refer to, but is not limited to, features of laboratory equipment configured to interact with its environment for purposes such as exchanging information unidirectionally or bidirectionally, such as for the exchange of one or more data or commands. For example, a user interface may be configured to share information with a user and to receive information by a user. A user interface may be a feature that interacts with the user visually, such as a display, or a feature that interacts with the user acoustically, such as speaking.A user interface may include, for example, one or more of the following: a graphical user interface, a data interface such as a wireless and / or wired data interface.

[0049] In a further embodiment, a pipetting apparatus is disclosed comprising a pipetting head configured to be coupled to a plurality of pipetting tips. The pipetting apparatus is configured to perform a method for detecting the bottom of at least one well of a multiwell plate according to the present invention. The pipetting apparatus comprises at least one force sensor configured to measure a resistance force corresponding to the force exerted on the pipetting tip by the bottom. The pipetting apparatus is as follows: i. A step of measuring resistance while one pipetting tip moves downstream from a starting position toward the bottom of the well, and stopping the movement at the bottom position, wherein the bottom position is the position where a predetermined resistance force is reached, and measuring resistance and stopping the movement at the bottom position, ii. The step of storing the bottom position, along with the corresponding logical position of the well in the multiwell plate, in at least one database of, for example, a control unit. It comprises at least one control unit configured to perform the following:

[0050] For details, options, and definitions, please refer to the methods described above.

[0051] The control unit may be configured to consider the stored bottom position for at least one subsequent pipetting procedure. The control unit may also be configured to determine whether the bottom position is available in a logical position in the database. If the bottom position is available, the control unit is configured to execute the subsequent pipetting procedure; otherwise, steps i) through ii) are performed.

[0052] In further embodiments, laboratory equipment for processing and / or analyzing samples is disclosed. The laboratory equipment comprises at least one pipetting apparatus according to the present invention. The laboratory equipment is one or more of a pre-analysis instrument, an analytical instrument, or a post-analysis instrument. For details, options, and definitions, refer to the pipetting apparatus and methods described above.

[0053] The laboratory equipment may include a force control check station. The force control check station may be configured to monitor a force sensor. The force control check station may be configured to apply at least one resistive force to the force sensor, generated from at least one mechanical spring. For example, two different forces may be applied to the force sensor.

[0054] Further disclosed and proposed herein are computer programs that, when executed on a computer or computer network, include computer-executable instructions for performing the methods according to the present invention in one or more embodiments included herein. Specifically, computer programs can be stored on computer-readable data carriers and / or computer-readable storage media.

[0055] As used herein, the terms “computer-readable data carrier” and “computer-readable storage medium” may specifically refer to non-temporary data storage means such as hardware storage media on which computer executable instructions are stored. Specifically, a computer-readable data carrier or storage medium may be, or comprise, a storage medium such as random-access memory (RAM) and / or read-only memory (ROM).

[0056] Therefore, specifically, one, more than one, or all of the method steps a) to b) described above can be carried out using a computer or computer network, preferably using a computer program.

[0057] Further disclosed and proposed herein are computer program products having program code means for performing the methods according to the present invention in one or more embodiments included herein when the program is executed on a computer or computer network. Specifically, the program code means may be stored in a computer-readable data carrier and / or computer-readable storage medium.

[0058] Further disclosed and proposed herein is a data carrier storing data structures that, after being loaded into a computer or computer network, such as the working memory or main memory of a computer or computer network, can perform one or more of the methods disclosed herein.

[0059] Further disclosed and proposed herein are computer program products having program code means stored in a machine-readable carrier to perform a method relating to one or more embodiments included herein when the program is executed on a computer or computer network. Where used herein, computer program product refers to a program as a tradable product. Products generally exist in any format, such as paper format, or on a computer-readable data carrier and / or computer-readable storage medium. Specifically, computer program products may be delivered over a data network.

[0060] Finally, disclosed and proposed herein are modulated data signals containing instructions readable by a computer system or computer network for performing one or more of the embodiments disclosed herein.

[0061] Referring to the computer implementation aspects of the present invention, one or more method steps or all method steps of one or more of the embodiments disclosed herein can be performed using a computer or computer network. Therefore, generally, any method step involving data provision and / or manipulation can be performed using a computer or computer network. Generally, these method steps may include any method step, except typically method steps requiring manual intervention, such as in certain embodiments that perform sample provision and / or actual measurements.

[0062] Specifically, this specification further discloses the following: - A computer or computer network comprising at least one processor adapted to perform a method according to one of the embodiments described herein.

[0063] - A computer-loadable data structure adapted to perform a method according to one of the embodiments described herein while the data structure is being executed on a computer.

[0064] - A computer program adapted to perform a method according to one of the embodiments described herein while the program is running on a computer.

[0065] - A computer program comprising programming means for performing a method according to one of the embodiments described herein while the computer program is running on a computer or on a computer network.

[0066] - A computer program comprising the program means according to a prior embodiment, wherein the program means is stored on a storage medium readable by a computer.

[0067] - A storage medium on which a data structure is stored, and which is adapted to perform a method according to one of the embodiments described herein after the data structure has been loaded into the main memory and / or working memory of a computer or computer network.

[0068] - A computer program product having program code means that can store or be stored on a storage medium in order to perform a method according to one of the embodiments described in this specification when the program code means is executed on a computer or computer network.

[0069] The method and apparatus according to the present invention can offer many advantages over similar methods and apparatus known in the art. Specifically, the method can save time, especially when the same well position is used multiple times, whereas the method may only require the detection of the well bottom once. The detected well bottom position can be stored in a database and used in subsequent pipetting procedures. Furthermore, the reliability of force-based measurements can be increased by using a force-controlled check station. Thus, the number of force-controlled movements can be minimized. In addition, the method can minimize dead volume in the well without the potential risk of tip closure at the well bottom. Furthermore, bottom detection may be applicable to one or more functions of laboratory equipment such as aspiration, dispensing and / or sipping, and dispensing procedures.

[0070] In summary, without excluding further possible embodiments, the following embodiments can be envisioned: Embodiment 1. A method for detecting the bottom of at least one well of a multiwell plate for a pipetting apparatus, wherein the pipetting apparatus comprises at least one pipetting head configured to be coupled to a plurality of pipetting tips, and the method comprises using at least one force sensor configured to measure a resistance force corresponding to the force exerted on the pipetting tip by the bottom, a) A step of measuring resistance while one pipetting tip moves downstream from a starting position toward the bottom of the well, and stopping the movement at the bottom position, wherein the bottom position is the position where a predetermined resistance force is reached, and measuring resistance and stopping the movement at the bottom position, b) The step of storing the bottom position, along with the corresponding logical position of the well in the multiwell plate, in at least one database. Methods that include...

[0071] Embodiment 2. The method according to the preceding embodiment, wherein the method includes taking into account a stored bottom position for at least one subsequent pipetting procedure.

[0072] Embodiment 3. The method according to the preceding embodiment, comprising determining whether a bottom position is available for a logical position in the database, wherein if a bottom position is available, the method proceeds to a subsequent pipetting procedure; otherwise, steps a) through b) of the method are performed.

[0073] Embodiment 4. The method according to any one of the prior embodiments, wherein steps a) and b) are repeated in the case of a new consumable and / or a new pipetting tip.

[0074] Embodiment 5. The method according to any one of the prior embodiments, wherein the force sensor comprises a load cell configured to generate a sensor signal proportional to the resistive force exerted on the pipetting tip.

[0075] Embodiment 6. The method according to any one of the preceding embodiments, wherein the method is performed during aspiration and / or sipping, and during dispensing, specifically during mixing and / or dispensing.

[0076] Embodiment 7. The method according to any one of the preceding embodiments, wherein the method is performed during aspiration and / or sipping and dispensing, and further comprises, after step a), moving the pipetting tip upward until the resistance is reduced to a predetermined residual force, and moving the pipetting tip upward to its final position for aspiration and / or sipping and dispensing by a predetermined distance.

[0077] Embodiment 8. The method according to the preceding embodiment, wherein the predetermined residual force is in the range of 1 to 20 N, specifically in the range of 4 to 10 N.

[0078] Embodiment 9. The method according to any one of the preceding embodiments, wherein the predetermined resistance force in step a) can be in the range of 10 to 120 N, more specifically in the range of 10 to 96 N, and more specifically in the range of 20 N.

[0079] Embodiment 10. The method according to any one of the preceding embodiments, wherein the method includes monitoring a force sensor, the force sensor being moved to a defined position where the force sensor is subjected to at least one resistive force generated from at least one mechanical spring.

[0080] Embodiment 11. The method according to the prior embodiment, wherein two different forces are applied to the force sensor.

[0081] Embodiment 12. The method according to any one of the prior method embodiments, wherein the method is computer-implemented.

[0082] Embodiment 13. A pipetting apparatus comprising a pipetting head configured to be coupled to a plurality of pipetting tips, wherein the pipetting apparatus is configured to perform a method for detecting the bottom of at least one well of a multiwell plate as described in any one of the preceding embodiments, the pipetting apparatus comprises at least one force sensor configured to measure a resistance force corresponding to the force exerted on the pipetting tip by the bottom, and the pipetting apparatus comprises at least one control unit, i. A step of measuring resistance while one pipetting tip moves downstream from a starting position toward the bottom of the well, and stopping the movement at the bottom position, wherein the bottom position is the position where a predetermined resistance force is reached, and measuring resistance and stopping the movement at the bottom position, ii. The step of storing the bottom position, along with the corresponding logical position of the well in the multiwell plate, in at least one database. A pipetting apparatus comprising at least one control unit configured to perform the following:

[0083] Embodiment 14. The pipetting apparatus according to the prior embodiment, wherein the control unit is configured to take into account a stored bottom position for at least one subsequent pipetting procedure.

[0084] Embodiment 15. A pipetting apparatus according to a prior embodiment, wherein the control unit is configured to determine whether the bottom position is available for a logical position in the database, and if the bottom position is available, the control unit is configured to perform a subsequent pipetting procedure; otherwise, steps i) to ii) are performed.

[0085] Embodiment 16. Laboratory apparatus for processing and / or analyzing a sample, wherein the laboratory apparatus comprises at least one pipetting apparatus as described in any one of the preceding embodiments referring to a pipetting apparatus, and the laboratory apparatus is one or more of a pre-analysis apparatus, an analysis apparatus, or a post-analysis apparatus.

[0086] Embodiment 17. The laboratory apparatus according to the prior embodiment, wherein the laboratory apparatus comprises a force control check station, the force control check station is configured for monitoring a force sensor, and the force control check station is configured to exert at least one resistive force generated from at least one mechanical spring on the force sensor.

[0087] Embodiment 18. The laboratory apparatus according to the prior embodiment, wherein two different forces are applied to the force sensor.

[0088] Embodiment 19. A computer program that, when executed by a pipetting apparatus as described in any one of the preceding embodiments that reference the pipetting apparatus, includes instructions causing the pipetting apparatus to perform the method described in any one of the preceding embodiments that reference the method.

[0089] Embodiment 20. A computer-readable storage medium in which, when executed by a pipetting apparatus as described in any one of the preceding embodiments that reference the pipetting apparatus, the program contains instructions causing the pipetting apparatus to perform the method described in any one of the preceding embodiments that reference the method.

[0090] Brief explanation of the drawing Further optional features and embodiments are disclosed in more detail in subsequent descriptions of embodiments, preferably in conjunction with dependent claims. Here, each optional feature may be implemented independently and in any viable combination, as will be understood by those skilled in the art. The scope of the present invention is not limited by preferred embodiments. Embodiments are schematically shown in the figures, where the same reference numerals in these figures refer to identical or functionally equivalent elements. The diagram is as follows: [Brief explanation of the drawing]

[0091] [Figure 1] Schematic diagrams illustrate embodiments of laboratory equipment and pipetting apparatus for processing and / or analyzing samples. [Figure 2] A flowchart of an embodiment of a method for detecting the bottom of at least one well in a multiwell plate for a pipetting apparatus is shown. [Figure 3A] This shows a location-time diagram. [Figure 3B] This shows a force-time diagram. [Figure 4A] Different perspective views of an embodiment of the force control check station are shown. [Figure 4B] Different perspective views of an embodiment of the force control check station are shown. [Figure 4C] Different perspective views of an embodiment of the force control check station are shown. [Figure 4D] Different perspective views of an embodiment of the force control check station are shown. [Figure 5A] The procedure at the force control check station is shown in a cross-sectional view. [Figure 5B] The procedure at the force control check station is shown in a cross-sectional view. [Figure 5C] The procedure at the force control check station is shown in a cross-sectional view. [Figure 5D] The procedure at the force control check station is shown in a cross-sectional view. [Figure 5E] The procedure at the force control check station is shown in a cross-sectional view. [Figure 6] This shows the force lines of the force sensor. [Modes for carrying out the invention]

[0092] Detailed description of the invention Figure 1 schematically shows exemplary embodiments of laboratory equipment 110 and pipetting apparatus 112 for processing and / or analyzing samples. Laboratory equipment 110 is one or more of pre-analysis equipment, analysis equipment, or post-analysis equipment. Laboratory equipment 110 comprises at least one pipetting apparatus 112 according to the present invention, for example, according to the exemplary embodiments described herein.

[0093] The pipetting device 112 includes a pipetting head 114 configured to be coupled to a plurality of pipetting tips 116. The pipetting device 112 is configured to perform a method for detecting the bottom 118 of at least one well 120 of a multiwell plate 122 according to the present invention, such as an exemplary embodiment of the method shown in Figure 2.

[0094] The pipetting device 112 includes at least one force sensor 124 configured to measure a resistive force corresponding to the force exerted on the pipetting tip 116 by the bottom 118. The force sensor 124 may include a load cell 126 configured to generate a sensor signal proportional to the resistive force exerted on the pipetting tip 116. For example, the load cell 126 may be a beam arrangement of strain gauges. As shown in Figure 1, the force sensor 124 may be located within the pipetting head 114.

[0095] Furthermore, the pipetting device 112 includes the following: i. A step of measuring resistance while one pipetting tip 116 moves downstream from a starting position toward the bottom 118 of the well 120, and stopping the movement at the bottom position, wherein the bottom position is the position where a predetermined resistance force is reached, and measuring resistance and stopping the movement at the bottom position, ii. The step of storing the bottom position, along with the corresponding logical position of the well 120 in the multiwell plate 122, in at least one database 130 of the control unit 128, for example. It comprises at least one control unit 128 configured to perform the following:

[0096] The control unit 128 may be configured to consider the stored bottom position for at least one subsequent pipetting procedure. The control unit 128 may also be configured to determine whether the bottom position is available in a logical position in the database 130. If the bottom position is available, the control unit 128 is configured to execute the subsequent pipetting procedure; otherwise, steps i) to ii) are performed.

[0097] Furthermore, the laboratory apparatus 110 may include a force control check station 132. The force control check station 132 may be configured to monitor the force sensor 124. The force control check station 132 may be configured to apply at least one resistive force to the force sensor 124, generated from at least one mechanical spring. For example, two different forces are applied to the force sensor 124. Exemplary embodiments of the force control check station 132 are described in further detail below in Figures 4A to 5E. Therefore, for a description of the force control check station 132, refer to the description in Figures 4A to 5E.

[0098] Figure 2 shows a flowchart of an exemplary embodiment of a method for detecting the bottom 118 of at least one well 120 of a multiwell plate 122 for a pipetting apparatus 112. The pipetting apparatus 112 comprises at least one pipetting head 114 configured to be coupled to a plurality of pipetting tips 116, and can specifically be embodied as shown in Figure 1. The method includes using at least one force sensor 124 configured to measure a resistive force corresponding to the force exerted on the pipetting tip 116 by the bottom 118.

[0099] The method steps may be performed in a given order, or in a different order. Furthermore, there may be one or more additional method steps that are not listed. Additionally, one, several, or even all method steps can be repeated.

[0100] This method, as follows: a) A step of measuring resistance while one of the pipetting tips 116 moves downstream from the starting position (indicated by reference numeral 134) toward the bottom 118 of the well 120, stopping the movement at the bottom position, where the bottom position is the position where a predetermined resistance force is reached, b) The step of storing the bottom position (indicated by reference numeral 136) in at least one database 130 along with the corresponding logical position of the well 120 in the multiwell plate 122. Includes.

[0101] This method may include considering, specifically reusing, a stored bottom position for at least one subsequent pipetting procedure (indicated by reference numeral 138), for example, one or more subsequent aspiration, dispensing, waste dispensing, sipping, and ejecting. This method may include determining whether a bottom position is available for a logical position in database 130 (indicated by reference numeral 140). If a bottom position is available (indicated by reference numeral 142), the method may proceed to the subsequent pipetting procedure (indicated by reference numeral 144); otherwise (indicated by reference numeral 146), steps a) through b) of the method are performed. Bottoms detected for aspiration, and / or sipping, as well as ejecting and / or dispensing, can be stored and reused. For each new consumable, e.g., a new multiwell plate 122 and / or pipetting tip 116, the bottom 118 can be detected again and used multiple times until the consumable is replaced again. Storage may allow the bottom position to be reused several times. This can save time because the detection of the bottom 118 is slower than moving directly to a given position. The time saved can be several seconds per liquid processing operation.

[0102] This method can be performed during aspiration and / or sipping, as well as during dispensing, particularly during mixing and / or dispensing. Examples of the method performed during aspiration and / or sipping, as well as during dispensing, are shown in Figures 3A and 3B. Figures 3A and 3B show position-time diagrams (Figure 3A) and force-time diagrams (Figure 3B) for a method for detecting the bottom 118 of at least one well 120 of a multiwell plate 122 for a pipetting device 112. Specifically, the position 148 and resistance force 150 of one moving pipetting tip 116 are shown as a function of time 152.

[0103] As outlined above, the method includes, in step a), measuring the resistance force 150 while one of the pipetting tips 116 moves downstream from the starting position 154 toward the bottom 118 of the well 120, and stopping the movement at the bottom position 156. The bottom position 156 is the position where a predetermined resistance force 158 is reached. The predetermined resistance force 158 at which the movement of the pipetting tip 116 is stopped can be in the range of 10 to 120 N, more specifically in the range of 10 to 96 N, and more specifically 20 N.

[0104] Furthermore, the method may include, after step a), moving the pipetting tip 116 upward until the resistance force 150 decreases to a predetermined residual force 160, and moving the pipetting tip 116 upward by a predetermined distance to its final position for aspiration and / or slurping, and dispensing (not shown). Specifically, the pipetting tip 116, which has been moved upward until the resistance force 150 decreases to a predetermined residual force 160, may be at the actual bottom position 162. The predetermined residual force may be in the range of 1 to 20 N, specifically in the range of 4 to 10 N. The predetermined distance may be an offset. The detected bottom 118 may be stored for future use. The final position can be reached within an accuracy range of ±0.25 mm. The proposed method can enable handling hardware and consumable intolerances which may be >1 mm. The proposed method may be advantageous when the residual volume in the well 120 must be minimized, for example, <7 μl. The proposed method can also ensure that the pipetting tip 116 does not come into contact with the bottom 118, and that the end of the tip 116 remains fully open for liquid handling.

[0105] As seen in Figures 3A and 3B, while one of the pipetting tips 116 moves downstream from the starting position 154 toward the bottom 118 of the well 120, the pipetting tip 116 can make contact with the bottom 118 of the well 120 at a first time point 164, and the resistance force 150 can begin to increase. The pipetting tip 116 and / or the well 120 may be bent until a predetermined resistance force 158 is reached at a second time point 168 (indicated by reference numeral 166). This movement of the pipetting tip 116 is sometimes referred to as “increase in force transfer” 170. At a third time point 172, the pipetting tip 116 may be moved upward until the resistance force 150 decreases to a predetermined residual force 160, specifically referred to as “decrease in force transfer” 174. The pipetting tip 116 and / or well 120 do not need to be bent to reach a predetermined residual force 160 at the fourth time point 178 (indicated by reference numeral 176).

[0106] This method may include monitoring of a force sensor 124. The force sensor 124 may be moved to a defined position where it is subjected to at least one resistive force generated from at least one mechanical spring. For example, two different forces may be applied to the force sensor 124. For example, the force sensor 124 may be checked for two different forces, for example, 27N and 57N. Monitoring may include checking for an accuracy of approximately + / - 10N.

[0107] As described above, the laboratory apparatus 110 may include at least one force control check station 132 configured for monitoring the force sensor 124. Figures 4A to 4D show different perspective views of exemplary embodiments of the force control check station 132. The force control check station 132 may be configured to exert at least one resistive force on the force sensor 124, generated from at least one mechanical spring. The force control check station 132 may include at least one mechanical spring. For example, the force control check station 132 may include a plurality of mechanical springs, for example, a first plurality of mechanical springs having a first elastic property and a second plurality of springs having a second elastic property.

[0108] Figure 4A shows a perspective view of the assembled force control check station 132. The force control check station 132 may be permanently installed on the laboratory equipment 110. The force control check station 132 may be positioned in a fixed location on the laboratory equipment 110. The force control check station 132 may be part of the work surface 179 of the laboratory equipment 110 and / or may be positioned to interact with specific elements of the work surface 179 of the laboratory equipment 110. As seen in Figure 4A, instead of a plastic tip, a metal tool 180, also referred to as a teaching tool 182, may be used to monitor the force sensor 124.

[0109] Figure 4B shows a perspective view of the force control check station 132 without the teaching tool 182. In this example, the force control check station 132 may include a compartment 184 configured to receive a mounting plate 186. The mounting plate 186 may have a teaching tool support 188 configured to receive the teaching tool 182.

[0110] Figure 4C shows a perspective cross-sectional view of the force control station 132. The mounting plate 186 may be spring-biased relative to the work surface 179. For example, the mounting plate 186 may be spring-biased relative to the work surface 179 using four mechanical springs 190, as is best seen in Figure 4D. The mechanical springs 190 may have identical elastic properties. The mechanical springs 190 may be arranged so that a uniform force can be applied to the teaching tool 182. Furthermore, the mounting plate 186 may be attached to the work surface 179 via at least one mounting bolt 192, specifically via four mounting bolts 192, and / or via at least one centering pin 194, specifically via two centering pins 194.

[0111] Furthermore, the force control check station 132 may include a spring-loaded intermediate plate 196. Figure 4D shows a perspective view of the intermediate plate 196 of the force control check station 132. The intermediate plate 196 may be spring-biased against the work surface 179 using four additional mechanical springs 198. The additional mechanical springs 198 may have the same elastic properties. The additional mechanical springs 198 may have different elastic properties from the mechanical springs 190 of the mounting plate 186. The additional mechanical springs 198 may be arranged so that a uniform force can be applied to the teaching tool 182. The intermediate plate 196 may be positioned below the mounting plate 186, for example, between the work surface 179 and the mounting plate 186. The intermediate plate 196 may be designed to be effective at a certain distance (depth). Thus, it may be possible to apply two different forces to the teaching tool 182 at two different distances. Therefore, in this example, the mechanical spring 190 may be a first plurality of mechanical springs having a first elastic property, and the further mechanical spring 198 may be a second plurality of springs having a second elastic property.

[0112] Figures 5A to 5E show the procedure in the force control check station 132 in cross-sectional views. The force control check station 132 shown in Figures 5A to 5E can correspond to the embodiment shown in Figures 4A to 4D. Therefore, for a description of the force control check station 132, please refer to the description in Figures 4A to 4D.

[0113] As shown in Figure 5A, the teaching tool 182 can be positioned on the spring load mounting plate 186 (parking position). The pipetting head 114 can be coupled to the teaching tool 182. The mechanical spring 190 may be preloaded with a load of 22 ± 4 N. The pipetting head 114 may be at a depth value of 0 mm.

[0114] As shown in Figure 5B, the force control check station 132, in particular the pipetting head 114, can approach at least a first depth value, e.g., -1 mm, such that resistance force is accumulated through the mechanical spring 190 of the force control check station 132. A negative sign may indicate that the direction of movement is downward. A force sensor 124 can measure the force. In this configuration, the force may, for example, be 27 ± 6 N. The control unit 128 may compare the measured value to at least one expected value. As seen in Figure 5C, the mounting plate 186 may be spaced, e.g., 0.5 mm, from the intermediate plate 196 at the first depth value of the force control check station 132.

[0115] Furthermore, as shown in Figures 5D and 5E, the force control check station 132 can approach a depth value of at least half the depth at which the intermediate plate 196 becomes effective, for example, -2.5 mm. Force measurement at the depth value in Figure 5D where the mounting plate 186 contacts the intermediate plate 196, for example, -1.5 mm, may be undesirable for tolerance reasons. Therefore, the force sensor 124 can measure the force at a second depth value, for example, -2.5 mm. The combined force at the second depth value from the mechanical spring 190 and the further mechanical spring 198 may, for example, be 57 ± 10 N. The teaching tool 182 may be, for example, only 0.5 mm away from the work surface 179 at the second depth value. The control unit 128 may compare the measured value to at least one expected value.

[0116] The force control check station 132 may be configured to provide control points for force-distance measurement. The pipetting station may be configured to provide a force-distance function of the pipetting head 114, for example, 100N with a specified distance, or an additional second specified force N. As outlined above, monitoring may include applying two different forces by approaching two different depths. The control unit 128 may be configured to interpolate a line passing through a first point (no force), a first depth value, and a second depth value, thereby determining the goodness of the curve.

[0117] Figure 6 shows a graph of force 200 measured using force sensor 124 as a function of depth value 202. Specifically, this graph shows 20 force measurements using force sensor 124 on pipetting apparatus 112 (indicated by reference numeral 204). Furthermore, the graph in Figure 6 shows force measurements obtained using force control check station 132 (indicated by reference numeral 206) of laboratory equipment 110. The force measurements on force control check station 132 can be used as reference measurements. Thus, as seen in Figure 6, the force measurements 204 obtained using force sensor 124 on pipetting apparatus 112 show a high correspondence with the force measurements 206 on force control check station 132, demonstrating the high accuracy of the force sensor 124 and, therefore, the method for detecting the bottom 118 of well 120 using force measurements obtained using force sensor 124. [Explanation of symbols]

[0118] 110 Laboratory Equipment 112 Pipetting device 114 Pipetting Heads 116 Pipetting Tips 118 Bottom 120 wells 122 multiwell plate 124 Force Sensor 126 load cells 128 Control Unit 130 Databases 132 Force Control Check Station 134 Measuring resistance 136. Remember the bottom position. 138 Consider the stored bottom position for subsequent pipetting procedures. 140 Determine whether the bottom position is available. 142 The bottom position is available. 144 Subsequent pipetting procedure 146 Bottom position is unavailable 148 positions 150 resistance 152 hours 154 Starting position 156 Bottom position 158 Pre-defined resistance 160 Pre-defined residual force 162 Actual bottom position 164 The first point in time 166 Pipetting Tips and / or Well Curves 168 Second point in time 170 Increase in force transfer 172 Third point in time 174 Reduction in force transfer 176 Non-curved pipetting tips and / or wells 178 The fourth point in time 179 Work surface 180 Metal Tools 182 Teaching Tools 184 plots 186 Mounting plate 188 Teaching Tool Support 190 Mechanical spring 192 Mounting bolts 194 Centering pin 196 Intermediate plate 198 Further mechanical springs 200 power 202 Depth Value 204 Force measurement in a pipetting device 206 Force measurement at force control check station

Claims

1. 1. A method for detecting a bottom (118) of at least one well (120) of a multi-well plate (122) for a pipetting device (112), the pipetting device (112) comprising at least one pipetting head (114) configured to be coupled to a plurality of pipetting tips (116), the method comprising using at least one force sensor (124) configured to measure a resistance force (150) corresponding to a force exerted by the bottom (118) on the pipetting tip (116), the method comprising: a) measuring the resistance force (150) while one of the pipetting tips (116) moves downstream from a start position (154) toward the bottom (118) of the well (120) and stopping the movement at a bottom position (156), the bottom position (156) being the position where a predefined resistance force (158) is reached; b) storing said bottom positions (156) together with the corresponding logical positions of said wells (120) within said multiwell plate (122) in at least one database (130).

2. 2. The method of claim 1, wherein the method includes taking the stored bottom position (156) into account for at least one subsequent pipetting procedure.

3. 3. The method of claim 2, wherein the method includes determining whether a bottom position (156) is available for a logical position in the database (130), and if the bottom position (156) is available, the method proceeds to a subsequent pipetting procedure, and if not, method steps a) to b) are performed.

4. 2. The method of claim 1, wherein steps a) and b) are repeated for new consumables and / or new pipetting tips (116).

5. 2. The method of claim 1, wherein the force sensor comprises a load cell configured to generate a sensor signal proportional to the resistive force exerted on the pipetting tip.

6. The method of claim 1 , wherein the method is performed during inhalation and / or sipping and during exhalation and / or dispensing.

7. 2. The method of claim 1, wherein the method is performed during aspiration and / or sipping and dispensing, and the method further comprises, after step a), moving the pipetting tip (116) upward until the resistive force (150) is reduced to a predefined residual force (160), and moving the pipetting tip (116) upward a predefined distance to its final position for aspiration and / or sipping and dispensing.

8. 2. The method of claim 1, wherein the method includes monitoring the force sensor (124), and the force sensor (124) is moved to a defined position where the force sensor (124) is subjected to at least one resistive force generated from at least one mechanical spring.

9. The method of claim 8, wherein two different forces are applied to the force sensor (124).

10. 10. A pipetting device (112) comprising a pipetting head (114) configured to be coupled to a plurality of pipetting tips (116), the pipetting device (112) configured to perform a method for detecting a bottom (118) of at least one well (120) of a multi-well plate (122) according to any one of claims 1 to 9, the pipetting device (112) comprising at least one force sensor (124) configured to measure a resistance force (150) corresponding to a force exerted by the bottom (118) on the pipetting tip (116), the pipetting device (112) comprising at least one control unit (128) comprising: i. measuring the resistive force (150) while one of the pipetting tips (116) moves downstream from a start position (154) toward the bottom (118) of the well (120) and stopping the movement at a bottom position (156), the bottom position (156) being the position where a predefined resistive force (158) is reached; ii. storing said bottom locations (156) together with the corresponding logical locations of said wells (120) within said multiwell plate (122) in at least one database (130); a pipetting device (112) comprising at least one control unit (128) configured to perform the steps of:

11. 11. The pipetting device (112) of claim 10, wherein the control unit (128) is configured to take into account the stored bottom position (156) for at least one subsequent pipetting procedure.

12. 12. The pipetting device of claim 11, wherein the control unit is configured to determine whether a bottom position is available for a logical position in the database, and if the bottom position is available, the control unit is configured to perform a subsequent pipetting procedure; otherwise, steps i) to ii) are performed.

13. A laboratory instrument (110) for processing and / or analyzing samples, said laboratory instrument (110) comprising at least one pipetting device (112) according to claim 10, wherein said laboratory instrument (110) is one or more of a pre-analytical instrument, an analytical instrument, or a post-analytical instrument.

14. 14. The laboratory equipment (110) of claim 13, wherein the laboratory equipment (110) comprises a force control check station (132), the force control check station (132) configured for monitoring the force sensor (124), and the force control check station (132) configured to exert at least one resistive force (150) generated from at least one mechanical spring on the force sensor (124).

15. The laboratory instrument (110) of claim 14, wherein two different forces are applied to the force sensor (124).

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