Device for optically monitoring the dosing of liquids to be pipetted

Abstract

The invention relates to a device (1) for optically monitoring the dosing of a liquid to be pipetted in an automated analysis unit. The device comprises: a dosing device (2) comprising a pipette needle for pipetting the liquid; an illumination device (3) for illuminating a droplet (4) of liquid adhering to the pipette needle; a camera (5) having a set of optical devices for capturing an image of the droplet (4) of liquid; and an evaluation device (6) for characterizing the droplet (4) of liquid by automatically analyzing the image of the droplet (4).

Description

Technical Field

[0001] The invention relates to a device for optically monitoring the metered dispensing of a liquid to be pipetted in an automated analysis unit. Background Art

[0002] A wide variety of tests and analytical methods for determining physiological parameters in samples of body fluids or other biological samples are nowadays performed largely automatically in automated analysis units (also called in vitro diagnostic systems).

[0003] Modern analytical units are capable of performing a wide range of detection reactions and analyses on a single sample. Automating these multiple tests requires various devices for spatially transporting the measuring cells, reaction vessels, and reagent containers, such as transfer arms with gripper functions, conveyor belts, or rotating transport wheels, as well as devices for transferring liquids, such as pipetting devices. These devices include a control unit that, using appropriate software, can largely automatically plan and process the work steps for the desired analysis.

[0004] Many analytical techniques used in such automated analysis units are based on optical methods. These methods enable qualitative and quantitative testing of analytes, i.e., substances to be detected or determined in a sample. The determination of clinically relevant parameters (such as the concentration or activity of an analyte) is typically performed by mixing a portion of the sample with one or more test reagents in a reaction vessel (which may also be a measuring cell), which is a process that, for example, triggers a biochemical reaction or a specific binding reaction, thereby causing a measurable change in the optical or other physical properties of the assay.

[0005] For example, in an automated analysis unit for examining biological fluids, a pipetting device with a pipette needle is used to place the required reagents into a test tube. A robotic arm, part of a robotic station, automatically moves the test tube to different locations via a test tube gripper within the automated analysis unit. After measurement, the used test tube is transported to a waste container via a waste chute for disposal.

[0006] In automated analysis units, this process typically involves transporting liquids in very small quantities, for example using motorized, movable pipettes operated by motor-driven pumps.

[0007] The pump generates a defined overpressure during liquid delivery and a defined underpressure during fluid collection. The pipette is filled with an incompressible system fluid to ensure that the pressure conditions or pressure changes specified by the pump are reproduced at the pipette tip with minimal losses, thus ensuring a high level of pipetting accuracy.

[0008] In medical devices such as diagnostic analyzers for the automated analysis of in vitro samples, errors in liquid dosing and droplet dispensing by pipetting can lead to inaccurate and incorrect measurement results. Such errors in droplet dispensing are caused, for example, by incorrect dosing at the dosing unit.

[0009] Until now, capacitive measurements have typically been used to determine the amount of fluid pipetted during the dispensing of a liquid to be dosed by a pipette or when the pipette needle is immersed in the liquid to be pipetted. This is to detect any deviations in the fill level, for example due to a malfunction of the dosage-dispensing unit, and thus to monitor and subsequently verify the fill level in an automated analyzer. Alternatively, pressure measurements are performed during the dispensing of a liquid to be dosed by a pipette.

[0010] When dispensing, for example, by pipetting reagents onto a sloping wall in a vessel for optimal dispensing of very small amounts of liquid, it can sometimes happen that there is no controlled fluid separation, and some or all of the fluid sticks to the pipette needle and cannot be dispensed correctly. In this case, even capacitive or pressure measurements are difficult to implement because there is no counter electrode due to the lack of grounding. The liquid flows down the sloping wall and is therefore no longer in contact with the pipette. Therefore, for a single dose-dispensing operation, it was previously impossible to subsequently check the changed fill level and, therefore, verify the correct functioning of the dosage-dispensing unit.

[0011] Therefore, devices from the prior art do not always allow reliable monitoring of the dosage dispensing of pipetted liquids in automated analytical units. Summary of the Invention

[0012] It is therefore an object of the present invention to provide an improved device and an improved method for monitoring the dosage dispensing of a pipetted fluid of an automated analytical unit.

[0013] According to the present invention, this object is achieved by the objects and methods described below.

[0014] It has been discovered that an improved device for monitoring the dispensing of liquid to be pipetted in an automated analytical unit can be implemented by visually monitoring the dispensing process using a camera, evaluating images of droplets of liquid adhering to the pipette needle, and then characterizing the droplets accordingly. The dispensing process itself is typically monitored by appropriately automatically monitoring the drive motor of the piston of the associated pumping system. However, this does not indicate, for example, whether the entire volume of the liquid to be pipetted has actually been dispensed, for example, into a reaction vessel, whether the dispensing has been performed correctly, or whether a significant amount of residual liquid is still trapped, for example, at the tip of the pipette needle. Optical monitoring offers the advantage of highly precise monitoring of the dispensing process. Monitoring is contactless and independent of the dispensing process, thus avoiding interference variables and inaccuracies, such as those caused by flake separation when the pipette needle emerges from the liquid in capacitive level measurement. In dispensing processes where a single amount of liquid is dispensed and capacitive measurement is not possible, for example because the surrounding medium is not liquid, the device according to the present invention enables, for the first time, precise monitoring of the actual dispensing process being performed. Similar advantages are also achieved with regard to monitoring dosage-dispensing processes, in which liquid is dispensed onto an inclined wall and drops of liquid can therefore slide down the wall.

[0015] In particular, the subject of the invention is a device for optically monitoring the metered dispensing of a liquid to be pipetted in an automated analytical unit, comprising:

[0016] A dosage-dispensing device comprising a pipette needle for pipetting a liquid; an illumination device for illuminating a drop of liquid attached to the pipette needle; a camera having a set of optical devices for capturing an image of the drop of liquid; and an evaluation device for characterizing the drop of liquid by automatically analyzing the image of the drop of liquid.

[0017] Preferably, the evaluation device comprises one or more field programmable gate arrays (FPGA) and / or a computer, wherein the computer preferably comprises one or more graphics cards for image processing.

[0018] The camera is preferably connected to a computer and / or an FPGA and / or a microcontroller or other suitable data processing machine.

[0019] Preferably, the device according to the invention comprises a trigger device which can transmit a trigger signal to a camera for capturing images of the liquid droplets and / or to an evaluation device for characterizing the liquid droplets. Preferably, continuous or quasi-continuous image recording or evaluation can be initiated by the trigger signal.

[0020] Preferably, the triggering device comprises a light barrier (e.g. a fork-type light barrier) and / or a distance sensor, wherein the distance sensor preferably determines the distance by time-of-flight measurement and / or triangulation. Preferably, the distance sensor can also be an ultrasonic distance sensor, an inductive distance sensor and / or a distance sensor based on variable light flux.

[0021] The trigger signal can preferably be initiated by a triggering device in response to the movement of a piece of equipment. The equipment can be, for example, a test tube and / or a pipette needle. The equipment is preferably part of an automated analysis unit.

[0022] In another preferred embodiment, the trigger signal can also be generated, for example, via a device, which in turn controls the movement of another device.

[0023] The triggering device preferably comprises, for example, electronic and / or optical components, which are used for a triggering operation, preferably a switching operation.

[0024] In a preferred design, the lighting device comprises a ring illuminator.

[0025] In another preferred design, the ring illuminator is arranged on the camera and / or the optical device.

[0026] In another preferred design, the lighting device comprises a reflector. Preferably, the reflector is arranged such that the droplets of the liquid can be imaged via the reflector using the optics of the camera.

[0027] In another preferred design, the illumination device comprises a beam splitter. Preferably, the beam splitter is arranged so that the droplets of liquid can be imaged via the beam splitter using the optics of the camera. The illumination of the droplets of liquid is advantageously coupled by the illumination device using the beam splitter.

[0028] In another preferred design, the lighting device includes at least one light source, preferably includes more than one light source, and particularly preferably includes three light sources.

[0029] Another subject of the present invention is a method for optically monitoring the dispensing of a liquid to be pipetted in an automated analysis unit by acquiring images of droplets of the liquid, preferably using the device according to the invention for optically monitoring the dispensing of a liquid to be pipetted, the method comprising the following steps:

[0030] - dosing of liquids by pipetting using a dosing device,

[0031] - after the dose dispensing is complete, the drop of liquid attached to the pipette needle is illuminated using a lighting device,

[0032] - using optics and a camera to acquire an image of a droplet of liquid,

[0033] - Characterizing the droplets by evaluating the device and automatically analyzing images of the droplets of liquid.

[0034] Preferably, the acquisition of the image of the drop is initiated by a trigger signal from the trigger device, which is transmitted to the camera by the trigger device. Alternatively, the acquisition can also be performed continuously, independently of the trigger signal.

[0035] Preferably, the characterization of the droplets by means of the evaluation device is started by a trigger signal from the trigger device, which trigger signal is transmitted by the trigger device to the evaluation device. Alternatively, the characterization of the droplets can also be performed continuously, independently of the trigger signal.

[0036] Preferably, continuous or quasi-continuous image recording or evaluation can be started by a trigger signal. Preferably, the image recording and / or evaluation is performed until another trigger signal triggers a corresponding termination, or until a predetermined time period has elapsed.

[0037] Preferably, the trigger signal is activated by the triggering means in response to movement of a piece of equipment. The equipment may be, for example, a test tube and / or a pipette needle. The equipment is preferably part of an automated analysis unit.

[0038] In another preferred embodiment, the trigger signal is generated via one device which in turn controls the movement of another device.

[0039] In a preferred embodiment of the method, the characterization of the droplet of the liquid comprises determining a profile of the droplet.

[0040] In another preferred embodiment of the method, the characterization of the droplet of the liquid comprises determining the volume of the droplet.

[0041] In another preferred embodiment of the method, the determination of the volume of the drop of liquid comprises at least one assumption about the symmetry of the drop. Preferably, it is assumed that the drop is symmetric about at least one axis of rotation.

[0042] In another preferred embodiment of the method, the characterization of the droplets of liquid comprises contactlessly detecting the amount of liquid in the droplets. Preferably, the amount of liquid in the detected droplets is also used to determine whether the dosage distribution of the liquid has been performed correctly and / or to determine the quality of the dosage distribution, which is preferably performed by means of an evaluation device. For example, if the detected liquid volume exceeds a predefined absolute limit or a predefined variable limit (which depends, for example, on the amount of liquid to be pipetted), the liquid dosage distribution has not been performed correctly; otherwise, it has been performed correctly. If the dosage distribution has not been performed in an appropriate manner, an appropriate characterization of the dosage distribution process is advantageously performed automatically and communicated to the laboratory personnel, for example, via a corresponding display on a monitor or a paper printout. Alternatively, for example, the corresponding measurement process can also be automatically terminated and restarted.

[0043] Alternatively, the liquid volume of the detected droplet can be advantageously used as a correction value, and the actual dose dispensed can be determined by subtracting the liquid volume in the detected droplet from the planned dose. Alternatively, an appropriate additional dose can then advantageously be dispensed, which accounts for the missing amount of liquid. This has the advantage of preventing and / or identifying incorrect measurements.

[0044] In a preferred embodiment of the method, determining whether the liquid dosage was performed correctly and / or the quality of the dosage is achieved by machine learning and / or comprises the use of a machine learning system.

[0045] In a preferred embodiment, the volume of a droplet attached to a pipette tip is determined by first weighing the corresponding amount of liquid and then comparing it using image data of multiple droplets. The image data includes images of the droplets. Therefore, a pre-calibration is preferably performed. This is preferably followed by using machine learning to assign an appropriate mass to the liquid for dispensing.

[0046] Preferably, the method according to the invention is partially or completely performed with the aid of the device according to the invention.Preferably, this involves capturing an image of a droplet of a liquid using the device according to the invention.

[0047] Another subject matter of the present invention is an analysis unit comprising the above-described device according to the invention for optically monitoring the dispensing of a liquid to be pipetted and / or being configured such that it can carry out the method according to the invention. The analysis unit advantageously also comprises an automatic test tube holder and / or an automatic pipette.

[0048] A further subject matter of the present invention is the use of the device according to the invention for optically monitoring the metered dispensing of a liquid to be pipetted in an automated analysis unit, wherein the automated analysis unit preferably comprises an automated cuvette gripper and / or an automated pipette.

[0049] For the purposes of the present invention, "sample" refers to a material that is assumed to contain the substance (analyte) to be detected. In particular, the term "sample" encompasses biological fluids of humans or animals, such as blood, plasma, serum, sputum, exudates, bronchoalveolar lavage fluid, lymph, synovial fluid, semen, vaginal mucus, feces, urine, CSF, and encompasses appropriately prepared tissue or cell culture samples, for example, by homogenization or cell lysis, photometric analysis, preferably turbidity analysis. In addition, for example, liquids or tissues of vegetable origin, forensic samples, water and sewage samples, food, medicines may also be used as samples, which may require appropriate pretreatment thereof before analysis.

[0050] Quantitative tests measure the amount, concentration, or activity of an analyte in a sample. The term "quantitative test" also includes semi-quantitative methods, which can only measure the approximate amount, concentration, or activity of an analyte in a sample, or can only be used to indicate a relative amount, concentration, or activity. Qualitative tests are the detection of the presence or absence of an analyte in a sample, or an indication that the amount, concentration, or activity of an analyte in a sample is above or below one or more specific thresholds.

[0051] For example, the measuring cuvette is a cuvette or reaction vessel made of glass, plastic or metal. The measuring cuvette is advantageously made of an optically transparent material, which can be particularly advantageous when using optical analysis methods.

[0052] The terms "measuring cuvette" and "cuvette" are used interchangeably and refer to the same object.

[0053] The terms "analyzing unit" and "analyzer" are used interchangeably herein and refer to the same object.

[0054] A droplet of liquid is a quantity of liquid that can be present, for example, in the form of a film of liquid, a shape similar to that of a light bulb, or a spherical droplet of liquid. The quantity of liquid is preferably a very small amount of liquid, which can be, for example, in the range of 1 to 100 microliters, preferably in the range of 5 to 10 microliters.

[0055] The camera preferably comprises a digital recording device comprising a charge coupled device (CCD) chip or a plurality of CCD chips. The digital recording device is particularly preferably based on complementary metal oxide semiconductor (CMOS) technology and / or comprises a CMOS chip. The camera can also preferably be a digital recording device. BRIEF DESCRIPTION OF THE DRAWINGS

[0056] Examples of the present invention will now be described in more detail with reference to the accompanying drawings, in which:

[0057] Figure 1 、 Figure 2 、 Figure 3 and Figure 4The structure of different advantageous embodiments of a device for optically monitoring the metered dispensing of a liquid to be pipetted in an automated analysis unit is schematically shown. DETAILED DESCRIPTION

[0058] Throughout the drawings, identical parts are marked with the same reference numerals.

[0059] according to Figures 1 to 4 The device (1) is embedded in an analysis unit (not shown in detail) which is designed to perform a wide range of analyses of a sample. To this end, the automated analysis unit comprises, in addition to a control unit for the automated evaluation of the analyses and an evaluation device (6) for characterizing the droplets (4) of liquid adhering to the dosage-dispensing device (2) by automated evaluation of the image of the droplets (4), a plurality of pipetting devices and transport devices (not shown). Each device (1) is designed to optically monitor the dosage of the liquid to be pipetted by the automated analysis unit.

[0060] exist Figure 1 In the embodiment of the device (1) shown, a droplet (4) of a liquid is pipetted by a dosing device (2). The droplet (4) is attached to the tip of a pipette needle. A camera (5) with a set of optical components is arranged below the droplet (4). The droplet is illuminated directly from below at an angle by an illumination device (3), wherein the illumination device (3) includes a light source (10).

[0061] exist Figure 2 In the embodiment of the device (1) shown, a droplet (4) of a liquid is pipetted by a dosing device (2). The droplet (4) adheres to the tip of a pipette needle. A camera (5) with an optical system is arranged on the side at the height of the droplet (4). The droplet is illuminated from the side by an illumination device (3) designed as a ring illuminator (7). The ring illuminator (7) is arranged on the optical device of the camera (5).

[0062] exist Figure 3 In the embodiment of the device (1) shown, a droplet (4) of a liquid is pipetted by a dosing device (2). The droplet (4) is located at the tip of a pipette needle. A camera (5) with a set of optical devices is arranged on the side slightly below the height of the droplet (4). The droplet is illuminated from the side by an illumination device (3), which includes a ring illuminator (7) and two other light sources (10) arranged on the optical system of the camera (5). The ring illuminator (7) and the two other light sources (10) both directly illuminate the droplet (10). In addition, an optical reflector (8) is located below the droplet (4) at an angle to the optical axis of the camera (5). The droplet is imaged by the optical devices of the camera (5) via the reflector (8).

[0063] exist Figure 4In the embodiment of the device (1) shown, a droplet (4) of a liquid is pipetted by a dosing device (2). The droplet (4) adheres to the tip of a pipette needle. At the height of the droplet (4), a camera (5) with an optical system is positioned on one side. A beam splitter (9) is arranged between the droplet (4) and the camera (5). Above the beam splitter (9), an illumination device (3) is provided, which includes a light source (10). Light emitted from the light source is deflected by the beam splitter (9) and strikes the droplet (4) along the optical axis of the camera (5), illuminating the droplet. The droplet (4) is imaged through the beam splitter (9) using the camera's optics.

[0064] Reference Number List

[0065] 1 device

[0066] 2 Dosage dispensing device

[0067] 3 lighting fixtures

[0068] 4 droplets

[0069] 5 cameras

[0070] 6 Evaluation device

[0071] 7 Ring Illuminator

[0072] 8 reflectors

[0073] 9 beam splitter

[0074] 10 light sources.

Claims

1. A device (1) for optically monitoring the dispensing of a liquid to be pipetted in an automated analysis unit, comprising: a dosage-dispensing device (2) comprising a pipette needle for pipetting the liquid, an illumination device (3) for illuminating the droplet (4) of the liquid attached to the pipette needle, a camera (5) having a set of optics for capturing an image of said droplet (4) of said liquid, An evaluation device (6) for characterizing the droplet (4) of the liquid by automatically analyzing the image of the droplet (4) of the liquid, wherein the detected liquid quantity of the droplet is used as a correction value and the actual dose dispensed is determined by subtracting the detected liquid quantity in the droplet from the planned dose, thereby performing an additional dose dispense, wherein the characterization of the droplet (4) of the liquid includes determining the volume of the droplet (4), and the determination of the volume of the droplet (4) of the liquid includes at least one assumption about the symmetry of the droplet (4).

2. The device according to claim 1, wherein The lighting device comprises a ring illuminator (7).

3. The device according to claim 2, wherein The ring illuminator (7) is located on the optical device.

4. The device according to any one of claims 1 to 3, wherein: The lighting device comprises a reflector (8).

5. The device according to any one of claims 1 to 3, wherein: The lighting device comprises a beam splitter (9).

6. The device according to any one of claims 1 to 3, wherein: The lighting device comprises at least one light source (10).

7. The apparatus according to claim 6, wherein The lighting device comprises at least three light sources (10).

8. A method for optically monitoring the dispensing of a liquid to be pipetted in an automated analysis unit by acquiring an image of a droplet (4) of the liquid, the method comprising the following steps: The liquid is dosed by pipetting the liquid using a dose-dispensing device (2), After the dose dispensing is completed, the droplet (4) of the liquid attached to the pipette needle is illuminated using an illumination device (3), using a set of optics and a camera (5) to acquire said image of said droplet (4) of said liquid, The droplet (4) of liquid is characterized by an evaluation device (6) and an automatic analysis of the image of the droplet (4), wherein the detected liquid quantity of the droplet is used as a correction value and the actual dose dispensed is determined by subtracting the detected liquid quantity in the droplet from the planned dose, thereby performing an additional dose dispense, wherein the characterization of the droplet (4) of the liquid includes determining the volume of the droplet (4), and the determination of the volume of the droplet (4) of the liquid includes at least one assumption about the symmetry of the droplet (4).

9. The method according to claim 8, wherein The characterization of the droplet (4) of the liquid comprises determining a profile of the droplet (4).

10. The method according to claim 8, wherein A symmetry of the droplet about at least one axis of rotation is assumed.

11. The method according to any one of claims 8 to 10, wherein By means of said characterization of said droplet (4) of said liquid, the amount of liquid in said droplet (4) is detected in a contactless manner.

12. The method according to claim 11, wherein The detected amount of liquid in the droplet is used to determine whether the metering of the liquid was performed correctly and / or to determine the quality of the metering.

13. The method according to claim 12, wherein: The evaluation device (6) determines whether the metering of the liquid was performed correctly and / or determines the quality of the metering.

14. The method according to claim 12, wherein: The determining is performed by machine learning and / or includes use of a machine learning system.

15. The method according to any one of claims 8 to 10, wherein The image of the droplet (4) of the liquid is acquired by means of a device (1) according to any one of claims 1 to 7 and / or the entire method is performed by means of a device (1) according to any one of claims 1 to 7.

16. An automatic analysis unit, wherein: The automated analysis unit comprises the apparatus (1) according to any one of claims 1 to 7 and / or is configured such that the method according to any one of claims 8 to 15 can be performed, the automated analysis unit having an automated test tube holder and / or an automated pipette.

17. Use of the device (1) according to any one of claims 1 to 7 and / or the method according to any one of claims 8 to 15 in an automatic analysis unit comprising an automatic test tube holder and / or an automatic pipette.

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