System and method for determining volume in microtiter plates

Abstract

The present invention relates to a method for determining the filling volume of at least one liquid-filled receptacle of a carrier plate by means of a system for determining the filling volume and to a system for determining the filling volume of at least one liquid-filled receptacle in a carrier plate.

Description

[0001] DESCRIPTION

[0002] System and method for volume determination in microtiter plates

[0003] The present invention relates to a method for determining the filling volume of at least one liquid-filled receptacle of a carrier plate by means of a system for determining the filling volume and a system for determining the filling volume of at least one liquid-filled receptacle in a carrier plate.

[0004] Biological experiments are often volume-dependent, meaning even the smallest changes in the volume or mixing ratio of liquids can affect the outcome of the experiment. Although the transfer of liquid samples between different wells and containers is arguably the most common procedural step in many laboratories, it is often performed without proper procedural or quality control. Both manual and automated systems often rely on dispensing and pipetting systems, which, while regularly maintained and calibrated, are highly error-prone.

[0005] The most common errors include the complete or partial clogging of dispensing needles or pipette tips, inaccuracies due to contamination of parts that come into contact with the product, incorrect positioning of laboratory equipment, in particular carrier plates, especially microtiter plates, carrier plate holders and / or consumables, incorrect setting of systems or liquid classes and insufficient or missing calibration.

[0006] In established processes with a high degree of automation, it is therefore recommended to implement process control to detect any volume errors early on. Failure to do so results in high costs, as sample material and laboratory equipment are unnecessarily further processed, and such errors are only discovered after the final analysis, if at all. Controlling the dispensed liquid volume after a transfer step is therefore a crucial component of process control for many laboratory processes.

[0007] In many well-known methods, such as high-throughput screening (HTS), carrier plates with a high throughput capacity, i.e., a large number of wells, also known as depressions, on a microtiter plate, are also frequently used. Microtiter plates with 1536 wells are known, where a single well has a diameter of only approximately 1.7 mm and can hold approximately 10 μl of liquid. Conventional measurement methods for determining volumes in microtiter plates can no longer provide reliable data with such carrier plates.

[0008] Liquid volumes in microtiter plates can be determined using various well-known measurement methods. The average value of all volumes in a microtiter plate is usually determined using an analytical balance. With a resolution of 1 mg, this results in a density of approximately 1 g / cm 3a volume accuracy of 1 pl. For a 1536-well microtiter plate, the average well volume can thus be determined to approximately 1 pl / 1536 = 0.65 nl. This procedure is very precise and allows for easy detection of systematic dispensing errors, but not well-specific dispensing errors.

[0009] Various spatially resolved measurement methods are known for determining the liquid volume for individual wells of a microtiter plate.

[0010] For example, in an ultrasonic measurement, the liquid surface is detected using an ultrasonic distance sensor, and the liquid volume is determined based on the well geometry. The disadvantage is that the accuracy of the measurement method is relatively low and, due to disruptive reflections from the well walls, can only be used with larger wells, such as 96-well or 384-well microtiter plates. The method is robust, sufficiently fast, and can be parallelized.

[0011] Another example is optical interferometry. This involves detecting the liquid surface using an optical interferometer, and determining the liquid volume based on the well geometry. For example, US 2017 / 0205270 A1 discloses a device for determining the volume of a liquid sample in a well. The known dimensions of the well and the surface topography of the liquid, measured using an optical interferometric system (LCOIRS), allow the volume of the liquid sample to be determined. According to this document, a low-coherence optical interferometer is used to determine the topography of the liquid surface in wells of a microtiter plate. LEDs or superluminescent diodes, for example, are used as low-coherence light sources. A Michelson interferometer is used to split and return light beams.The liquid height is determined by reflection from the liquid surface and from a reference mirror. The distance between the sensor and the liquid surface must be adjusted so that the focused light is reflected precisely from the liquid surface. The returned light beams interfere with each other. The resulting interference patterns are sensitive to even the smallest changes in the distance between the liquid surface and the reference mirror. However, due to the use of low-coherence light sources, only changes in the range of a few pm, in particular approximately 100 pm, can be detected by interference. Regular readjustment of the interferometer to keep the distance between the interferometer and liquid surfaces, especially those of different heights, constant, is therefore essential.Since the interferometer must be moved vertically upwards or downwards relative to each well, especially with different fill levels, in order to detect the surface (hereinafter also referred to as the z-direction of a Cartesian coordinate system), the method is very slow when dealing with many wells. However, the measurement accuracy is significantly better than that of ultrasonic measurement. However, the disadvantages of invasive methods such as photometric or fluorescent dye methods are avoided, since such methods cannot be used to determine the volume change of a sample from one step to the next.It also avoids the disadvantages of gravimetric methods, which require the density of the liquid to be known and which cannot be used when a liquid is added simultaneously to several connected wells, for example, in a multi-well microtiter plate, as is common in automated methods.

[0012] Pressure-flow rate measurement is also known. In this method, the air space above the liquid surface of each well is pressurized using a sealed plunger, and the flow rate of the incoming air is measured. From the amount of air and the resulting pressure, the volume of the air space can be calculated, and from this, the volume of the liquid below can be determined. This method is fast and can be parallelized as required. However, it is the least accurate of the methods mentioned.

[0013] WO 2019 / 005744 A1 discloses a system for transferring a volume of liquid into or from a container configured to hold the liquid, wherein the liquid in the container has a free surface. The system comprises a liquid transfer mechanism, a non-contact distance sensor, in particular a low-coherence interferometric fill level sensor or an ultrasonic distance sensor, and a control unit. WO 2016 / 025057 A1 discloses a system for high-throughput sample processing, comprising a sample dosing device, a non-contact fluid dispensing device, a plurality of non-contact liquid level sensors, a plurality of suction devices, a plurality of non-contact treatment stations, a waste management system, and a control system.

[0014] EP 3 378 563 B1 discloses a droplet dispensing device comprising a droplet ejection assembly having a plurality of nozzles, a sensor configured to measure a value for detecting a liquid amount in a microplate; wherein the sensor is one of a weight measuring device that measures a weight of the microplate, and a transparency sensor.

[0015] US 2008 / 0233009 A1 discloses devices and methods for verifying the accuracy of liquid dispensing volumes based on capillary forces. These are more advantageous than known methods for verifying dispensing volumes, such as gravimetric or spectrophotometric methods. Gravimetric methods require expensive, sensitive equipment that can usually only be operated by skilled personnel. Furthermore, gravimetric methods are sensitive to various environmental influences, such as vibrations and leveling. To verify the precision of a dispensing device, particularly its uniformity, using a gravimetric method, the mass of water dispensed by the dispensing device is measured as a reference using the gravimetric device.Spectrophotometric methods for dispensing volume verification also require a dilution solution containing a chromogen, which is used to calculate the volume to be verified based on, among other things, the absorbance and the volume of the dilution solution. Such a spectrophotometric method is time-consuming, often inaccurate due to potential human error, and performed manually, thus cannot be automated.

[0016] EP 1 761 747 B1 discloses a method for detecting a liquid height in a small-volume well, the method comprising confocally measuring a first distance from a reference point to a top surface of the small-volume well; confocally measuring a second distance from the reference point to a top surface of a liquid in the small-volume well; determining a difference between the first distance and the second distance; and determining a height of the liquid and a volume of the liquid in the small-volume well based on the difference between the first distance and the second distance. In particular, a scanner is used for this purpose. The confocal measurement corresponds to a monofocal scanning method.The measurement is taken at a single focal point or focal plane, i.e. monofocal, which is achieved in particular using a pinhole or a slit. During the measurement, the scanner is moved back and forth vertically and horizontally, hereinafter also referred to as the z-direction for vertical and the x- and y-direction for horizontal, each of a Cartesian coordinate system, at an equidistant arrangement from the carrier and liquid surfaces, so that a constant distance is always measured between the measuring device and the liquid surface in order to be at the focal point or focal plane of the monofocal light or the focal length of the device. The term "confocal" in EP 1 761 747 B1 does not refer to confocal microscopy.In such a monofocal scanning method, a monochromatic light source, such as a laser, is used to generate a focused light beam. The light is focused by an optical system, usually a lens. The sensor typically has a confocal arrangement, in which both the light beam onto the liquid and the reflected light are directed through the same point to the detectors. The light hits the liquid surface, is reflected there, and returns to the sensor. The highest intensity for the reflected light is obtained when the focus point or focal point or focal plane lies exactly on the liquid surface, whereby the distance from the sensor to the liquid surface corresponds to the focal length of the optics.By moving the optics or the liquid surface to be measured back and forth, particularly upwards and downwards, parallel to the measuring direction, particularly along the z-axis of a Cartesian coordinate system, the distance is adjusted so that the proportion of reflected light is maximized. This means that the distance between the liquid surface and the sensor must always be the same. A fill level is therefore calculated from the back and forth movement, particularly upwards and downwards, of the sensor, or the back and forth movement parallel to the measuring direction, particularly in the z-direction, of the liquid surface to be measured, particularly during the measurement.The liquid levels in different images are therefore determined by moving the sensor back and forth relative to the different liquid surfaces. This is because the same distance must always be maintained between the sensor and the liquid surface, especially between different liquid surfaces. In particular, the focal point or focal plane must always be on the liquid surface. All of these methods are used in various laboratory systems for volume determination. However, none of them can reliably and quickly detect fill levels in microtiter plates with 1536 wells.

[0017] The problem underlying the present invention is to overcome the aforementioned disadvantages of the prior art. In particular, the problem underlying the present invention is to provide a system and a method that enables the precise, cost-effective, and time-efficient measurement of at least one fill volume of a support plate receptacle.

[0018] The present invention solves the technical problem underlying it by the technical teaching provided, in particular the teaching of the independent claims as well as the preferred embodiments disclosed in the dependent claims and the description.

[0019] In particular, the present invention solves the underlying technical problem by a method for determining the filling volume of at least one liquid-filled receptacle of a carrier plate by means of a system for determining the filling volume, wherein the system comprises at least one chromatic white light sensor, a support device for the carrier plate and at least one weighing device associated with the support device, wherein the chromatic white light sensor and the support device are configured such that they are arranged at a defined distance from one another, in particular in the measuring direction of the chromatic white light sensor, and the chromatic white light sensor, the support device or both are movable,and wherein the method comprises: a) providing at least one carrier plate arranged on the support device with at least one liquid-filled receptacle and the chromatic white light sensor at a defined distance from each other, b) confocal-chromatic measurement of the distance of the surface of the liquid in the at least one receptacle to the chromatic white light sensor to determine the fill level at the distance defined in method step a), and c) determining the fill volume of the at least one receptacle taking into account the fill level determined in method step b) and a liquid-specific correction value determined in method step d), wherein in method step d) the liquid-specific correction value is determined by means of the weighing device.

[0020] The present invention therefore provides a method in which at least one chromatic white light sensor, a support device for a carrier plate and a weighing device associated with the support device,and wherein, in a method step a), at least one carrier plate with at least one liquid-filled receptacle is provided on the support device, specifically at a defined distance from the chromatic white light sensor, and wherein, in a method step b), a confocal chromatic measurement of the distance of the surface of the liquid in the at least one receptacle from the chromatic white light sensor subsequently takes place to determine the fill level at the distance defined in method step a), and wherein, in a method step c), the fill volume of the at least one receptacle is determined, on the one hand, taking into account the fill level determined in method step b) and, on the other hand, additionally taking into account a liquid-specific correction value. This liquid-specific correction value is determined and provided in a method step d) within the scope of the method according to the invention,This is done by means of the weighing device. The determination of the filling volume in process step c) therefore requires knowledge and therefore the determination of the liquid-specific correction value, which must therefore have been performed at least before the first execution of process step c).

[0021] In a preferred embodiment, the present invention provides that the carrier plate contains not just one, but several, in particular a large number of at least partially liquid-filled receptacles, so that method steps b) and c) are to be carried out accordingly in accordance with the number of filling volumes to be determined for the respective individual receptacles. The present invention accordingly provides for method steps b) and c) to be carried out multiple times, in particular multiple times, in accordance with the number of fillings to be measured for the multiple or large number of liquid-filled receptacles of the carrier plate, wherein method step d) for determining the liquid-specific correction value must be carried out at least once within the scope of the method according to the invention. Method step d) is therefore to be carried out before method step c), provided that method steps b) and c) are each carried out only once.If method steps b) and c) are carried out several times or multiple times, it is sufficient according to the invention to carry out method step d) once, namely before the first execution of method step c) and not to provide for any further execution of method step d) in the further course, since the determined liquid-specific correction value can be used for all subsequent measurements according to method steps b) and c), in particular if the subsequent measurements involve the same liquid and in particular the same carrier plate material and / or the same recording geometry.In a preferred embodiment, it is conceivable to carry out process step d) at least once before process step c) by means of the process according to the invention and then to carry out process steps b) and c) sequentially in the further course without further carrying out process step d), if necessary also at a greater temporal and / or spatial distance from the carrying out of process step d).

[0022] According to the invention, the present method for determining the fill volume of at least one liquid-filled receptacle of a carrier plate is carried out using a system for determining the fill volume. A liquid-filled receptacle is not necessarily a recess filled with a liquid, but can also be, for example, a liquid-adsorbing region on a carrier plate. Thus, in the context of the present invention, a receptacle is a defined region on a carrier plate that is filled with a liquid.

[0023] According to the invention, the system comprises at least one chromatic white light sensor, at least one support device for the support plate, and at least one weighing device associated with the support device, as well as optionally at least one support plate. According to the invention, the chromatic white light sensor and the support device are configured such that they are arranged at a defined distance from one another, in particular in the measuring direction of the chromatic white light sensor. A "defined distance" is preferably understood to mean a deliberately selected distance. A "defined distance" is preferably understood to mean the distance that must be covered by a light beam generated by the chromatic white light sensor to a reference point, wherein the reference point lies on the support device.

[0024] In a preferred embodiment, the defined distance between the chromatic white light sensor and the support device is determined by means of the chromatic white light sensor. Preferably, a defined distance between the chromatic white light sensor and the support device also exists between the chromatic white light sensor and the support plate.

[0025] In a preferred embodiment, the defined distance between the chromatic white light sensor and the support device is additionally measured by means of the chromatic white light sensor during the implementation of the method according to the invention. This preferably ensures that the defined distance between the chromatic white light sensor and the support device always remains constant during the implementation of the method according to the invention.

[0026] Preferably, the measuring direction is aligned parallel to the light cone axes of the light cones generated by the chromatic white light sensor. In particular, the measuring direction is perpendicular to the liquid surface, in particular to the center of the liquid surface, of a liquid present in a receptacle of a carrier plate. In the context of the present invention, perpendicular is understood to mean an angle of 80 to 100°, in particular 85 to 95°, in particular 90°. In the context of the present invention, the z-direction of a Cartesian coordinate system is assigned to the measuring direction, which strikes the liquid surface at an angle of exactly 90°.

[0027] In a preferred embodiment, the chromatic white light sensor, the support device or both are movable relative to each other, at least in the plane perpendicular to the measuring direction, in particular the x- and y-direction of a Cartesian coordinate system, in particular at the defined distance from each other.

[0028] In a preferred embodiment, the chromatic white light sensor and the support device, in particular during the implementation of the method according to the invention, can be moved solely by the same distance, in particular simultaneously, in the plane parallel to the measuring direction, in particular the z-direction of a Cartesian coordinate system, while maintaining the defined distance.

[0029] According to the invention, the chromatic white light sensor, the support device or both are preferably movable relative to one another, at least in the plane perpendicular to the measuring direction. In a first alternative, the chromatic white light sensor is movable at least in the plane perpendicular to the measuring direction. In a second alternative, the support device is movable at least in the plane perpendicular to the measuring direction. In a third alternative, the chromatic white light sensor and the support device are movable relative to one another at least in the plane perpendicular to the measuring direction, which means that the white light sensor or the support device can each be moved in only one of the spatial directions spanning the plane perpendicular to the measuring direction and the(or) the respective other is movable into the respective other spatial direction spanning the plane perpendicular to the measuring direction, or that the chromatic white light sensor and the support device are each movable in both spatial directions spanning the plane perpendicular to the measuring direction, or that the white light sensor or the support device is each movable in one of the spatial directions spanning the plane perpendicular to the measuring direction and the respective other is movable in both spatial directions spanning the plane perpendicular to the measuring direction. Preferably, the chromatic white light sensor or the support device is movable in both spatial directions spanning the plane perpendicular to the measuring direction, and the respective other is stationary. In connection with the present invention, the plane perpendicular to the measuring direction is spanned by the x-direction and the y-direction of the Cartesian coordinate system.The chromatic white light sensor and the support device, or both, can be configured such that they are movable relative to one another, in each case at least in the plane perpendicular to the measuring direction. In the context of the present invention, “movable relative to one another” is understood to mean that the chromatic white light sensor and the support device are movable in at least one of the spatial directions spanning the plane perpendicular to the measuring direction. Preferably, the chromatic white light sensor or the support device is movable in both spatial directions spanning the plane perpendicular to the measuring direction. Preferably, the chromatic white light sensor and the support device are movable in both spatial directions spanning the plane perpendicular to the measuring direction. Preferably, the chromatic white light sensor is movable in only one of the spatial directions spanning the plane perpendicular to the measuring direction, or the support device is movable in only the other one.Preferably, the chromatic white light sensor is movable in only one of the spatial directions spanning the plane perpendicular to the measuring direction, and the support device is movable in only the other direction. This enables the invention to travel across a plurality of liquid-filled or liquid-unfilled receptacles on a support plate, particularly in a short time. This also makes it possible to determine the fill volume of a plurality of liquid-filled receptacles on a support plate. According to the invention, it is accordingly provided that in a first method step a) at least one support plate arranged on the support device and the chromatic white light sensor are provided. According to the invention, the support plate has at least one receptacle filled with a liquid.According to the invention, the support device and the chromatic white-light sensor for determining the fill volume of the at least one liquid-filled receptacle are arranged at a defined distance from one another. Within the scope of a second method step b), a confocal-chromatic measurement of the distance between the surface of the liquid in the at least one receptacle and the chromatic white-light sensor is carried out. Preferably, the distance measured in method step b) from the surface of the liquid to the chromatic white-light sensor is a different distance, in particular a smaller or larger distance, than the defined distance between the at least one support device and the chromatic white-light sensor.The invention thus makes it possible to determine the fill level of the at least one liquid-filled receptacle based on the distance defined in method step a), in particular between the at least one support device and the chromatic white light sensor. In a method step c), the fill volume of the at least one receptacle is determined taking into account the fill level determined in method step b) and a liquid-specific correction value determined in a method step d). According to the invention, the liquid-specific correction value is determined in a method step d) using a weighing device. The liquid-specific correction value according to the invention is in particular a numerical value that takes into account the physical, chemical and / or thermodynamic properties of a specific liquid.Preferably, the liquid-specific correction value takes into account specific parameters of the liquid, in particular those that can be assigned solely to the liquid, for example viscosity, density, surface tension, temperature behavior, chemical composition or combinations thereof, and enables adaptation and / or calibration of the calculation, determination, in particular of a filling volume, measurement or method to the specific properties of the liquid.

[0030] Preferably, the liquid-specific correction value is a liquid- and material-specific correction value. Preferably, the liquid- and material-specific correction value is a numerical value that, in addition to the specific physical, chemical, and / or thermodynamic properties of a particular liquid, also takes into account its interaction with a geometry, in particular the receptacle geometry, a material, in particular the carrier plate material, and the thermal or mechanical conditions of the material of which the receptacle is made and in which the liquid is present.Preferably, the liquid- and material-specific correction value is used to adapt and / or calibrate at least one calculation, determination, in particular a filling volume, measurement and / or at least one process that is carried out with the liquid contained in the receptacle in order to compensate for influences such as viscosity, density, thermal conductivity, surface tension or liquid distribution.

[0031] According to the invention, the liquid-specific correction value is determined using the weighing device. Preferably, the liquid-specific correction value according to the invention is determined based on the specific liquid. Preferably, the weighing device is not intended for checking the precision of a dispensing device, in particular its uniformity. Preferably, no reference substance, in particular water as a reference substance, is measured with the weighing device. Preferably, "reference substance" is understood to mean a substance whose physical, chemical, or optical properties are used as a standard or comparison value in a measuring or testing method.

[0032] Preferably, the use of a chromatic white light sensor and the confocal chromatic measurement carried out according to method step b) enables the determination of a fill level of a liquid present in at least one receptacle, with a constant defined distance between the chromatic white light sensor and the support device, without either the chromatic white light sensor, the support device or both having to be moved back and forth vertically, in particular in the z-direction, to change the distance from one another, in particular having to be moved upwards or downwards, in particular in comparison to a monofocal scanning method or an interferometry method, in which readjustment is necessary in order to always maintain the same distance between the sensor and the liquid surface, which in the monofocal scanning method and the interferometry method results in a change in the distance between the sensor and the support device.In the method according to the invention, for several differently filled liquid-filled receptacles according to method step b), different distances are measured while maintaining a constant, defined distance between the chromatic white light sensor and the support device, and a respective fill level is determined from this. In known methods, the same distance between the sensor and the liquid surface must always be maintained, which is why either the sensor, the support device, or both are moved back and forth vertically, in particular in the z-direction, in order to change the distance, in particular by moving them upwards or downwards. This results in a high expenditure of time, particularly due to the physical back and forth movement of the sensor, the support device, or both, and in particular results in a higher expenditure of time than in the method according to the invention.In combination with the consideration of the determined liquid-specific correction value, a method according to the invention for determining a filling volume is provided, which is precise, cost-effective and involves little time expenditure, in particular less time expenditure than with known methods.

[0033] The invention thus makes it possible to determine the volume of the liquid present in a receptacle precisely, cost-effectively, and with little time expenditure by means of a confocal-chromatic distance measurement from a chromatic white-light sensor to a liquid surface of a liquid present in a receptacle, taking into account a certain liquid-specific correction value determined using a weighing device. The invention is based on the use of a chromatic white-light sensor, in particular a confocal sensor, with the aid of which, in method step b), the distance from the chromatic white-light sensor to the liquid surface of the liquid present in at least one receptacle is detected in order to determine the fill level of the liquid present in the at least one receptacle, knowing the defined distance between the chromatic white-light sensor and the support device.

[0034] In a preferred embodiment, the liquid is present in more than one receptacle, in particular in at least two, in particular a plurality or multiplicity of, receptacles, wherein the chromatic white light sensor measures the distance from the chromatic white light sensor to the respective liquid surface in the receptacles, wherein the respective fill level of the liquid present in the at least two, in particular the plurality or multiplicity of, receptacles is determined, in particular with knowledge of the defined distance between the chromatic white light sensor and the carrying device.Preferably, at different fill levels of the liquid in the at least two, in particular the plurality or multiplicity of, images, two, in particular several or many, different distances between the chromatic white light sensor and the respective liquid surface of the liquid present in the at least two, in particular the plurality or multiplicity of, images are measured. Preferably, the same liquid-specific correction value is used to determine the volumes of the liquid in the at least two, in particular the plurality or multiplicity of, images.

[0035] According to method step c), the volume of the liquid in the at least one receptacle, in particular the at least two, in particular the plurality or multiplicity of, receptacles, is determined on the basis of the determined distance, in particular the determined distances, and taking into account the liquid-specific correction value determined in method step d) by means of the weighing device, in particular which takes into account the volume occupied by the liquid in the at least one receptacle.

[0036] Advantageously, the method or system according to the invention, in particular the chromatic white light sensor, provides a contactless, particularly non-invasive, measurement, whereby no contamination or carryover occurs in the liquids to be measured. Due to the movability, i.e. the back-and-forth movement, of the chromatic white light sensor, the support device, or both relative to one another, at least in the plane perpendicular to the measurement direction, high sampling rates of the chromatic white light sensor, in particular the confocal sensor, in particular up to 100 kHz, are achieved, thus ensuring rapid measurement of multiple or a large number of liquid-filled or liquid-unfilled wells of the support plate, for example, approximately 1 minute, abbreviated to "min," for 1536 wells of a microtiter plate. Furthermore, the method according to the invention achieves high measurement accuracy.The method according to the invention is less susceptible to shadowing in small image frames, particularly well frames, for example, a 1536-well frame, than known methods. Advantageously, by combining the spatially resolved measurement data obtained by the confocal chromatic measurement, which exhibits high relative accuracy, with the measurement data obtained from the average measurements using the weighing device, which exhibits high absolute accuracy for all liquid-filled images combined, taking into account the liquid-specific correction value, a high measurement accuracy is achieved, in particular a higher measurement accuracy than with known methods.

[0037] Preferably, in contrast to interferometric and monofocal measurements, a distance-changing vertical back and forth movement, in particular a back and forth movement parallel to the measuring direction, in particular in the z-direction, of the support device comprising the support plate comprising the liquid present in at least one receptacle with the liquid surface to be measured or of the chromatic white light sensor, in particular the chromatic confocal sensor, is not necessary in the method according to the invention.Without being bound to theory, this is achieved because the chromatic white light sensor refracts the white light parallel to the measuring direction into different wavelengths, in particular with different intensities. Consequently, at a defined distance between the chromatic white light sensor and the support device of the carrier plate, in particular a fixed arrangement of the chromatic white light sensor and the support device of the carrier plate to one another, and thus also between the white light sensor and the carrier plate itself, wavelength-dependent focal points or focal planes are present. Preferably, a spectrometer is used to detect at which wavelength the focus of the light beam, in particular which focal plane, lies exactly on the liquid surface to be measured. This preferably eliminates the need for distance-changing back and forth movement of the chromatic white light sensor and / or the support device of the carrier plate in the z-direction, which leads to considerable time savings.This is advantageous compared to, for example, interferometric or monofocal measurements, in which the distance between the sensor and the liquid surface to be measured must always be readjusted so that it remains constant and, in particular, the focal point or focal plane is always on the liquid surface in order to determine the fill level. The method according to the invention preferably achieves high sampling rates, in particular higher ones than with interferometric and / or monofocal measurements.

[0038] In a preferred embodiment, the chromatic white light sensor is a confocal sensor.

[0039] In a preferred embodiment, before or during the implementation of method steps a), b), c), in particular a), b), c), and d), or after the implementation of method steps a), b), in particular a), b), d), the distance from the chromatic white light sensor to an unfilled receptacle, in particular a bottom of an unfilled receptacle, in particular a closed end which is opposite an open end, of an unfilled receptacle, is determined, in particular measured, in particular by means of a confocal-chromatic measurement, in particular with the chromatic white light sensor.

[0040] In a preferred embodiment, process step d) is carried out before carrying out process step a), after carrying out process step b), or before carrying out process step a) and after carrying out process step b). Preferably, process step d) is carried out once, in particular before carrying out process step a) or after carrying out process step b). Preferably, process step d) is carried out twice, in particular before carrying out process step a) and after carrying out process step b).

[0041] Preferably, therefore, in a series of measurements in which the same liquid is present in a, in particular identical, receptacle of a, in particular identical, carrier plate, in particular made of the same material, the liquid-specific correction value determined once can be used for each measurement within the series of measurements. Preferably, in such a series of measurements, the liquid-specific correction value is determined in a first measurement of the series of measurements according to method step b). Preferably, the first measurement contains a process step sequence a), b), d), c). Preferably, the liquid-specific correction value determined in the first measurement can also be used for the second measurement of the series of measurements, in particular without repeat determination of the liquid-specific correction value. Preferably, the second measurement contains a process step sequence d), a), b), c.If the liquid-specific correction value is preferably determined in each measurement within the measurement series, a process step sequence d), a), b), d), c) is available for the second measurement.

[0042] Preferably, process step d) must be carried out at least once for a specific liquid, in particular in combination with a specific carrier plate material and / or receiving geometry.

[0043] Preferably, the liquid-specific correction value must be determined at least once for a specific liquid, in particular a specific combination of carrier plate material and / or recording geometry and liquid. Preferably, the liquid-specific correction value must be determined at least once within a measurement series in which the liquid-specific correction value is determined for the first time, in particular during the first measurement, and for subsequent measurements, the determination of the liquid-specific correction value is optional. Preferably, for a measurement or measurement series in which an already determined liquid-specific correction value can be used, a further determination of the liquid-specific correction value is not necessary, wherein the process step sequence d), a), b), c) is present for each measurement.Preferably, the liquid-specific correction value can be determined once for a, in particular specific, liquid and used locally and temporally independently of the determination in a method for determining a filling volume, wherein the method step sequence d), a), b), c) is always present for each subsequent use. Accordingly, it is preferably possible, for example, to determine the liquid-specific correction value within a series of measurements or for a specific liquid, in particular in combination with a specific carrier plate material and / or recording geometry, at a first location and / or at a first time, in particular according to method step d), and then to carry out method steps a) to c) at a second location and / or at a second time that is independent of the first measurement at the first location, wherein this embodiment also falls under the method according to the invention.

[0044] In a preferred embodiment, process step d) is carried out before process step c), in particular before the first execution of process step c).

[0045] According to the invention, method step d) must be carried out at least once in order to be able to determine a filling volume of the, in particular specific, liquid in at least one liquid-filled receptacle according to the method according to the invention.

[0046] In a preferred embodiment, method step d) comprises the following method steps: v) determining the total filling mass of the carrier plate having at least one liquid-filled receptacle by means of the weighing device, w) determining the filling mass and the filling volume of the liquid in the at least one filled receptacle, x) confocal chromatic measurement of the distance of the surface of the liquid in each of the liquid-filled receptacles to the chromatic white light sensor to determine the respective filling level at a defined distance between the carrier device and the white light sensor, y) determining the respective filling volume of the liquid-filled receptacles taking into account the filling level determined in method step x), and z) determining the correction value from the filling volumes determined in method steps w) and y).

[0047] In a preferred embodiment, process step d) comprises the following

[0048] Method steps: v) Determination of the total filling mass of a carrier plate having at least one liquid-filled receptacle by means of the weighing device, w) Determination of the filling mass and the filling volume of the liquid in the at least one filled receptacle, yl) Determination of the respective filling volume of the liquid-filled receptacles taking into account the filling level determined in method step b) and z) Determination of the correction value from the filling volumes determined in method steps w) and yl).

[0049] In method step d) of the method according to the invention, it is accordingly provided to determine the liquid-specific correction value. For an inventive determination of the fill volume of a liquid-filled receptacle in a carrier plate, a liquid-specific correction value is preferably always taken into account, which must be determined at least once for the liquid. The method steps for determining the liquid-specific correction value are preferably carried out in the method according to the invention.

[0050] Preferably, in method step d), the liquid-specific correction value is determined using the values ​​from a, in particular further, confocal-chromatic measurement according to method step x) or using the values ​​from the confocal-chromatic measurement according to method step b).

[0051] In a preferred embodiment, the process according to the invention is carried out with a process step sequence v), w), x), y), z), a), b), c) or a), b), v), w), x), y), z), c) or v), w), x), y), z), a), b), v), w), x), y), z), c) or a), b), v), w), yl), z), c) or v), w), x), y), z), a), b), v), w), yl), z), c) or v), a), b), w), yl), z), c).

[0052] Accordingly, the liquid-specific correction value is preferably determined completely before method step a) or after method step b), in particular once during a method according to the invention, or before method step a) and after method step b), in particular twice during a method according to the invention, or part of the determination of the liquid-specific correction value is carried out before method step a) and the remaining part after method step a) or part of the determination of the liquid-specific correction value is carried out before method step b) and the remaining part after method step b).

[0053] In a preferred embodiment, the confocal chromatic measurement according to method step b) is also used to determine the liquid-specific correction value. Preferably, two separate confocal chromatic measurements are performed, in particular a first confocal chromatic measurement according to method step x) and a second confocal chromatic measurement, in particular after the first measurement, according to method step b).

[0054] The correction value is preferably determined using the weighing device assigned to the at least one support device. The support device preferably receives the carrier plate with the at least one liquid-filled receptacle to which the weighing device, in particular a precision balance, is assigned. Preferably, in a method step v), the total fill mass of the carrier plate having at least one liquid-filled receptacle is determined using the weighing device. Preferably, in a method step w), the fill mass and the fill volume of the liquid in the at least one liquid-filled receptacle are determined from the total fill mass of the carrier plate having at least one liquid-filled receptacle. Preferably, if at least two liquid-filled receptacles are present, the average fill mass and the average fill volume of a liquid-filled receptacle are determined.Preferably, in method step x), a confocal chromatic measurement of the distance between the surface of the liquid in each of the liquid-filled receptacles and the chromatic white light sensor is carried out to determine the respective fill level at a defined distance between the support device and the white light sensor. Preferably, in a method step y), the respective fill volume of the liquid-filled receptacles is determined taking into account the fill level determined in method step x). Preferably, in a method step y1), the respective fill volume of the liquid-filled receptacles is determined taking into account the fill level determined in method step b). Preferably, in a method step z), the correction value is determined from the fill volumes determined in method steps w) and y) or w) and y1).

[0055] In a preferred embodiment, method step v) comprises the following method steps: via) measuring the total mass of an unfilled carrier plate by means of the weighing device, v2a) filling at least a portion of the recesses of the carrier plate with equal or unequal volumes of liquid, v3a) measuring the total mass of the filled carrier plate by means of the weighing device and v4a) determining the total filling mass of the carrier plate taking into account the masses measured in method steps via) and v3a).

[0056] In a preferred embodiment, process steps via) and v2a) are carried out before process step a).

[0057] In a preferred embodiment, process step v3a) is carried out before or after process step x) and / or process step y) or process step b) and / or process step yl).

[0058] In a preferred embodiment, process step v4a) is always carried out after process step v3a).

[0059] In a preferred embodiment, method step v) comprises the following method steps: v1b) Providing an unfilled carrier plate on a weighing pan or providing an unfilled carrier plate that is assigned to a lifting element, wherein the weighing pan or the lifting element is arranged at a defined distance from the chromatic white light sensor and wherein the weighing pan or the lifting element is designed such that it is movable vertically relative to the white light sensor, in particular by means of a flexural element assigned to the weighing pan or the lifting element, in a mass-dependent manner, v2b) Confocal-chromatic measurement of the distance of a reference point, in particular on the weighing pan carrying the unfilled carrier plate or on the lifting element assigned to the carrier plate, in particular on the flexural element assigned to the weighing pan or the lifting element, to the chromatic white light sensor,v3b) Filling at least a portion of the recesses of the carrier plate with equal or unequal volumes of liquid, v4b) Confocal chromatic measurement of the distance of the reference point, in particular on the weighing pan carrying the filled carrier plate or on the lifting element associated with the carrier plate, in particular on the bending element associated with the weighing pan or the lifting element, to the chromatic white light sensor, and v5b) Determination of the total filling mass of the carrier plate taking into account the distances measured in process steps v2b) and v4b).

[0060] In a preferred embodiment, process steps vlb) to v3b) are carried out before process step a).

[0061] In a preferred embodiment, process step v4b) is carried out before or after process step x) and / or process step y) or process step b) and / or process step yl).

[0062] In a preferred embodiment, process step v5b) is always carried out after process step v4b).

[0063] In a preferred embodiment, a total of three confocal chromatic measurements are carried out in the method according to the invention, in particular in the method steps v2b, v4b) and b) or x).

[0064] In a preferred embodiment, a total of four confocal chromatic measurements are carried out in the method according to the invention, in particular in the method steps v2b), v4b), x) and b).

[0065] Preferably, the reference point according to method steps v2b) and v4b) lies on a non-fillable part of the carrier plate or on a weighing pan carrying the carrier plate or on a lifting element assigned to the carrier plate or on a bending element assigned to the lifting element assigned to the carrier plate.

[0066] Preferably, the algorithm for obtaining the correction value can be described as follows.

[0067] Preferably, the average well volume Vuptake is determined on average according to process steps v) and w).

[0068] Preferably, the carrier plate is weighed empty, i.e. unfilled, before filling the at least one receptacle with the liquid according to process step via), whereby the mass, also referred to as empty mass, m TP i eer the carrier plate having at least one unfilled receptacle is obtained.

[0069] Alternatively or additionally, the carrier plate having at least one unfilled receptacle is preferably provided on a weighing pan or assigned to a lifting element and provided thereon before filling the at least one receptacle with the liquid according to method step vib). The weighing pan or the lifting element is preferably arranged at a defined distance from the chromatic white light sensor. The weighing pan or the lifting element is preferably designed such that it is movable vertically, in particular in the z-direction of a Cartesian coordinate system, relative to the white light sensor in a mass-dependent manner. The weighing pan or the lifting element is preferably movable in a mass-dependent manner by means of a bending element assigned to the weighing pan or the lifting element.The bending element is preferably movable, in particular deformable, in particular bendable, depending on the mass acting on the bending element, in particular vertically, in particular in the z-direction of a Cartesian coordinate system, relative to the white light sensor. In method step v2b), the distance of a reference point to the chromatic white light sensor is preferably measured confocally-chromatically. The reference point is preferably located on the weighing pan carrying the unfilled carrier plate or on the lifting element assigned to the carrier plate. The reference point is preferably located on the bending element assigned to the weighing pan or the lifting element. The measured distance, also referred to as the empty distance, i.e. ieer is related to the mass, also called empty mass, m TP i eer the carrier plate having at least one unfilled receptacle.

[0070] Preferably, the process step via) or the process steps v1b) and v2b) are carried out once for carrier plates of a series, in particular a production series, in particular if the mass differences of the carrier plates of a series, in particular a production series, are negligibly small, in particular the same.

[0071] Preferably, according to method step v2a) or v3b), at least one unfilled receptacle, in particular all unfilled receptacles, of the carrier plate are filled, in particular by means of a dispensing device, with the same volume of liquid having a known density PLiquid.

[0072] Preferably, according to method step v2a) or v3b), in particular if only method step b) is carried out for the confocal-chromatic measurement of the distance for determining the fill level, in particular if no method step x) is carried out for the confocal-chromatic measurement of the distance for determining the fill level, the at least one receptacle of the carrier plate is filled in the same way as the carrier plate, in particular the one to be filled in method step v2a) or v3b), with which at least one liquid-filled receptacle is provided in method step a).

[0073] Preferably, in process step v2a) or v3b) the receptacles are filled which correspond to the filled receptacles of the carrier plate in process step a).

[0074] Depending on the mass added to the mass of the unfilled carrier plate, the flexural element preferably deforms, in particular bends, further than in the initial state, in which only the unfilled carrier plate is arranged on the weighing pan or assigned to the lifting element. The added mass preferably corresponds to the mass of the liquid with which the unfilled receptacles are filled. The distance between the reference point and the chromatic white light sensor preferably increases or decreases due to the, in particular further, deformation, in particular bending, of the flexural element.

[0075] Preferably, according to method step v3a), the carrier plate having receptacles filled by the dispensing device is weighed by the weighing device, whereby the mass, also referred to as gross mass, n TP be f ü n t the carrier plate containing the filled receptacles is determined.

[0076] Preferably, in method step v4b), the distance of the reference point to the chromatic white light sensor is measured confocally. The reference point is preferably located on the weighing pan carrying the filled carrier plate or on the lifting element associated with the carrier plate. The reference point is preferably located on the bending element associated with the weighing pan or the lifting element. The measured distance d be f ü n t , also called gross distance, is related to the mass, also called gross mass, m TP,ieer the carrier plate having at least one filled receptacle.

[0077] Preferably, according to process step v4a) or v5b), the mass, also referred to as net filling mass, m TP Netto the carrier plate containing the liquid-filled receptacles is calculated using equation (1.1): m TP Net = m TP, filled ~ mTP,empty (1 1) Preferably, according to process step v5b), the distance, also referred to as net distance, d Net to between the position of the reference point during the measurement of the carrier plate having at least one unfilled receptacle according to method step v2b) to the position of the reference point during the measurement of the carrier plate having at least one filled receptacle according to method step v4b) is calculated using equation (1.2): -Net d- filled d-empty (1-2)

[0078] Preferably, in method step v), the total filling mass of the carrier plate having at least one liquid-filled receptacle is determined by means of the weighing device. The total filling mass is preferably determined according to method steps v1a) to v4a) or v1b) to v5b). Preferably, in v1a), the total mass or in v1b) and v2b) the empty distance to the chromatic white light sensor of an unfilled carrier plate is determined by means of the weighing device, wherein the unfilled carrier plate corresponds to the carrier plate provided in method step a) and in which at least one receptacle is filled with the liquid. Preferably, in v2a) or v3b), at least a portion of the receptacles of the carrier plate are filled with equal or unequal volumes of liquid. Preferably, the receptacles that correspond to the filled receptacles of the carrier plate in method step a) are filled.Preferably, in process step v3a), the total filling mass or, in v4b), the gross distance to the chromatic white light sensor of the filled carrier plate is measured using the weighing device. Preferably, in process step v4a) or v5b), the total filling mass of the carrier plate is determined taking into account the masses measured in process steps v5a) and v3a) or the distances measured in v2b) and v4b).

[0079] Preferably, according to process step w), the average net filling mass for each individual liquid-filled receptacle of the carrier plate is determined using equation (2):

[0080] > m TP Net

[0081] '"'On average

[0082] ''Hole VJ, where n is the number of liquid-filled holes in the carrier plate.

[0083] Preferably, according to process step w), the average volume for each filled receptacle is calculated from the mass and the density of the liquid using equation (3): Preferably, according to method step x) or method step b), a confocal chromatic measurement of the distance of the surface of the liquid in each of the liquid-filled receptacles to the chromatic white light sensor is carried out.

[0084] Such a distance measurement often results in a measurement inaccuracy e, the consideration of which is the subject of the present technical teaching and which corresponds to the fluid-specific correction value. Without wishing to be bound by theory, the measurement inaccuracy preferably arises due to the physical properties of the liquid surface of the liquid present in the at least one receptacle and, optionally, the carrier plate material, which form an individual meniscus that leads to the measurement inaccuracy e. This is preferably taken into account using equation (4): where the calculated volume VAU f would take, optically e i neFunction of the measured fill level h + e, where h is the actual fill level of the liquid in the receptacle and e is the measurement uncertainty, and the height-dependent geometry G of the liquid in the receptacle. Preferably, the fill level-dependent mathematical function can be determined without knowledge of the height-dependent geometry of the liquid in the receptacle from the measurement of the fill levels of known liquid volumes, in particular using VReceptacle>average, according to method step y) or yl).

[0085] Preferably, the measurement results from process steps w) and x) or b) are used in equation (5):

[0086] Preferably, according to method step z), the measurement uncertainty e, which corresponds to the fluid-specific correction value, in particular the fluid- and material-specific correction value, is determined by solving a multidimensional system of equations or by iterative approximation. Preferably, the correction value is determined when the above equation (5) is true for a specific e.

[0087] The method according to the invention, namely the combination of confocal measurement technology with a precision balance, advantageously achieves high measurement accuracy. The method according to the invention preferably enables a simplification of system calibration using an integrated method, namely the combination of weighing and optical measurement in one system.

[0088] Preferably, the support device comprises a receiving device for the support plate, wherein the support plate is positioned in the receiving device so that a relative movement to the chromatic white light sensor is enabled.

[0089] Preferably, the weighing device has a lifting element and is designed such that it enables the carrier plate to be lifted from the support device by the lifting element from below.

[0090] The support device preferably has a weighing pan or is designed as a weighing pan. The weighing pan is preferably arranged, in particular mounted, on a load cell that can be moved in the z-direction, i.e., parallel to the measuring direction. Method steps v1a) to v4a) or v1b) to v5b) are preferably carried out with such a device embodiment.

[0091] Preferably, the weighing pan and the support device contact each other.

[0092] Preferably, the mass of the carrier plate is determined by lifting the carrier plate by means of the lifting element or by moving the weighing pan, in particular by moving the load cell back and forth in the z-direction.

[0093] Preferably, a bending element is assigned to the weighing pan or the lifting element. The mass of the support plate is preferably determined by the deformation, in particular bending, of the bending element, which is particularly reversible.

[0094] Preferably, a force sensor is arranged on the bending element. Preferably, a force sensor is arranged on the bending element, wherein method steps v4) to v4a) are carried out with such an arrangement.

[0095] Preferably, no force sensor is arranged on the bending element, wherein with such an arrangement the method steps v1b) to v4b), in particular to v5b), are carried out.

[0096] The weighing pan is preferably arranged on the bending element. The lifting element is preferably arranged below the bending element on the bending element. In a preferred embodiment, the support device is designed such that the displacement of the support plate in the z-direction is clearly related to the mass of the support plate. The z-displacement of the support plate is preferably determined by means of a confocal chromatic measurement. The chromatic white light sensor is preferably mounted stationary above the support device. Displacement of the chromatic white light sensor alone in the z-direction is preferably not possible. The support device preferably has flexure joints, whereby it can be moved at least in the z-direction, in particular in the x-, y-, and z-directions. Method steps v1b) to v4b), in particular to v5b), are preferably carried out with such a device embodiment.

[0097] Preferably, if the height-dependent geometry of the liquid, in particular the volume occupied by the liquid, is unknown, the method steps via) to v4a) or v1b) to v4b), in particular to v5b), are carried out multiple times in the at least one receptacle. Preferably, in method step v2a) or v3b), at least one portion of the receptacles of the carrier plate is filled with the same volume of liquid each. Preferably, if the height-dependent geometry of the liquid, in particular the volume occupied by the liquid, is unknown, different liquid volumes are used in the different measurements in the at least one receptacle. Preferably, this results in pairs of values ​​being obtained which serve as support points for determining a mathematical function which describes the relationship between measured distance and volume.Preferably, the specific mathematical function in equation (4) is taken into account.

[0098] In a preferred embodiment, the weighing pan is displaceable vertically relative to the white light sensor depending on the mass.

[0099] In a preferred embodiment, a bending element associated with the weighing pan is deformable, in particular bendable, vertically relative to the white light sensor in a mass-dependent manner.

[0100] In a preferred embodiment, the lifting element, in particular the bending element associated with the lifting element, is vertically displaceable, in particular bendable, relative to the white light sensor depending on its mass.

[0101] In a preferred embodiment, a bending element associated with the lifting element is vertically deformable, in particular bendable, relative to the white light sensor depending on its mass. In a preferred embodiment, the carrier plate is a plate, in particular a microtiter plate, with several or many wells, in particular at least 96 wells, in particular 96, 384, or 1536 wells.

[0102] In a preferred embodiment, the carrier plate is a microtiter plate with 384 or 1536 wells.

[0103] In a preferred embodiment, method steps b) or b) and c) are performed sequentially for a number of recordings of the carrier plate, with, in particular, equidistant displacement of the carrier plate relative to the white light sensor. Preferably, the distance between the support device and the chromatic white light sensor defined in method step a) remains the same. Preferably, during a displacement parallel to the measurement direction, in particular the z-direction, the chromatic white light sensor and the support device are displaced by the same distance.

[0104] In a preferred embodiment, process step d) is carried out once.

[0105] In a preferred embodiment, method step d) is carried out before each measurement of a series of measurements.

[0106] In a preferred embodiment, the correction value for different measurements, but with the same height-dependent geometry of the liquid, in particular the volume occupied by the liquid, is determined once in the at least one image, and the same correction value is used for the subsequent measurements. In a preferred embodiment, the correction value is determined again for each measurement of volumes of liquids with the same height-dependent geometry of the liquid in the at least one image.

[0107] In a preferred embodiment, the filling volume in method step y) or yl) is determined either by confocal-chromatic determination of the filling level of the liquid in the at least one receptacle at a defined distance between the support device and the white light sensor and taking into account the volume occupied by the liquid in the at least one receptacle or by confocal-chromatic measurement of the filling levels of different known filling volumes of the liquid in the at least one receptacle at a defined distance between the support device and the white light sensor.

[0108] In a preferred embodiment, the method is an automated method. In a preferred embodiment, the method is not a manual method. Preferably, the automated method can minimize or prevent human errors.

[0109] This preferably enables a precise process.

[0110] A further aspect of the present invention is a system, in particular a device, for determining the filling volume of at least one liquid-filled receptacle in a carrier plate, in particular designed to carry out a method according to the invention, in particular the method steps a), b), c) and d), in particular in multiple or multiple repetitions of at least the method steps b) and c), as well as at least once the method step d), at least before the first execution of method step c), comprising at least one chromatic white light sensor, a support device for a carrier plate, at least one weighing device assigned to the support device for determining the liquid-specific correction value, in particular the total filling mass of a liquid-filled carrier plate, and wherein the chromatic white light sensor and the support device are configured such that they,The chromatic white light sensor, the support device, or both, are arranged at a defined distance from each other, particularly in the measuring direction of the chromatic white light sensor, and the chromatic white light sensor, the support device, or both are movable. Optionally, the system comprises at least one support plate with at least one, preferably multiple or multiplicity of, liquid-filled receptacles.

[0111] In a preferred embodiment, the system according to the invention is a system for performing at least one confocal chromatic measurement. In a preferred embodiment, the system according to the invention is not a system for performing an interferometry measurement or a monofocal scanning measurement. In a preferred embodiment, no interferometry method or monofocal scanning method can be performed on the system according to the invention.

[0112] Preferably, the use of a chromatic white light sensor of the system according to the invention at a constant, defined distance from the support device enables the determination of a fill level of a liquid present in at least one receptacle, without either the chromatic white light sensor, the support device or both having to be moved vertically, in particular in the z-direction, to change their distance from one another, in particular having to be moved upwards or downwards, in particular in comparison to the system for carrying out the monofocal scanning method or the system for carrying out the interferometry method, in which readjustment is necessary in order to always maintain the same distance between the sensor and the liquid surface,which, in the system for carrying out the monofocal scanning method or the system for carrying out the interferometry method, results in a change in the distance between the sensor and the support device. In known systems, the same distance between the sensor and the liquid surface is always maintained, which is why either the sensor, the support device, or both must be moved vertically, particularly in the z-direction, in order to change the distance, in particular upwards or downwards. This results in a high expenditure of time, particularly due to the physical back and forth movement of the sensor, the support device, or both, when carrying out a measuring method, in particular in a higher expenditure of time than when carrying out a measuring method with the system according to the invention. Accordingly, a system according to the invention is provided which can be carried out precisely, cost-effectively, and with little expenditure of time,in particular less time-consuming than with known systems, is provided.

[0113] In a preferred embodiment, the system is a system with which automated methods can be carried out.

[0114] In a preferred embodiment, method step d) of the method according to the invention is carried out by means of the weighing device of the system according to the invention. The correction value is preferably determined by means of the weighing device of the system according to the invention, in particular according to method steps v) to z) of the method according to the invention. The total filling mass is preferably determined by means of the weighing device of the system according to the invention, in particular according to method step v), in particular according to method steps v1a) to v4a) or v1b) to v5b) of the method according to the invention. The correction value is preferably determined by means of the weighing device of the system according to the invention and the chromatic white light sensor of the system according to the invention, in particular according to method steps v) to z) of the method according to the invention.Preferably, by means of the chromatic white light sensor of the system according to the invention, in particular according to method step x) or b) of the method according to the invention, the distance of a surface of a liquid in each of the liquid-filled receptacles to the chromatic white light sensor is measured confocally-chromatically in order to determine the respective fill levels at a defined distance between the support device and the white light sensor.

[0115] Preferably, the weighing device of the system according to the invention is not intended for checking the precision of a dispensing device, in particular its uniformity. Preferably, no reference substance, in particular water as a reference substance, is measured with the weighing device of the system according to the invention.

[0116] In a preferred embodiment, the system comprises exactly one carrier plate.

[0117] In a preferred embodiment, the support device is a separate component or a separate or integral part of the weighing device.

[0118] In a preferred embodiment, the weighing device comprises a force sensor, in particular a load cell, and a lifting element or is a weighing device with electromagnetic force compensation.

[0119] In a preferred embodiment, the weighing device comprises a bending element, in particular a double bending element. In a particularly preferred embodiment, the bending element is a spring. In the context of the present invention, a bending element is reversibly deformable. The bending element is preferably used for mass determination by being deformed, in particular bent, under the influence of a mass in contact with it. Once the bending element is no longer in contact with the mass, the bending element returns to its original shape. In a preferred embodiment, the bending element is assigned to the weighing pan or the lifting element.

[0120] In a preferred embodiment, the force sensor can be moved relative to the support device, in particular vertically, in particular parallel to the measuring direction.

[0121] In a preferred embodiment, the support device comprises a receiving device for the carrier plate, wherein the receiving device is designed such that the carrier plate, in particular arranged in the receiving device, can be contacted by the lifting element and can be moved, in particular in a vertical direction, in particular parallel to the measuring direction. The carrier plate arranged in the receiving device is preferably lifted by the lifting element.

[0122] In a preferred embodiment, the support device is an integral component of the support plate; in particular, the support device corresponds to the base of the support plate. In a preferred embodiment, the support plate can be directly contacted by the lifting element and can be moved, in particular in a vertical direction, in particular parallel to the measuring direction. The support plate is preferably lifted directly by the lifting element.

[0123] In a preferred embodiment, the weighing device comprises a weighing pan and wherein the chromatic white light sensor is designed to carry out the method steps b), and / or x) and v2b) and v4b).

[0124] In a preferred embodiment, a bending element is associated with the weighing pan or the lifting element.

[0125] In a preferred embodiment, the weighing pan is designed such that it can be displaced vertically relative to the white light sensor in a mass-dependent manner, or a bending element assigned to the weighing pan can be deformed, in particular bended, vertically relative to the white light sensor in a mass-dependent manner.

[0126] In a preferred embodiment, the lifting element is designed such that it is vertically displaceable relative to the white light sensor depending on its mass, or a bending element associated with the lifting element is vertically deformable, in particular bendable, relative to the white light sensor depending on its mass.

[0127] In a preferred embodiment, the weighing pan is a separate component or a separate or integral part of the support device or weighing device.

[0128] In a preferred embodiment, the support device is an integral part of the weighing device and is designed as a weighing pan. Accordingly, the support device is preferably a weighing pan if the support device is designed to support and weigh the carrier plate.

[0129] In a preferred embodiment, the carrying device is a separate component and the weighing device comprises a lifting element.

[0130] In a preferred embodiment, the system according to the invention comprises a data processing device, preferably comprising at least one control unit and at least one memory unit, wherein the data processing device is designed to control the implementation of a method according to the invention, in particular to control the implementation of a method according to the invention and to evaluate and display the filling volumes determined according to the method.

[0131] In a preferred embodiment, the system according to the invention comprises a control unit designed to control the implementation of a method according to the invention.

[0132] The invention provides that the chromatic white light sensor, the support device, or both, in particular relative to one another, are movable at least in the plane perpendicular to the measuring direction. This achieves high sampling rates for the images of a support plate, wherein, in particular, the at least one plane is spanned by the x- and y-directions of a Cartesian coordinate system. Preferably, when the white light sensor and / or the support device are moved relative to one another in the plane perpendicular to the measuring direction, the defined distance between the chromatic white light sensor and the support device remains the same.If the defined distance changes due to a back-and-forth movement of the white light sensor and / or the support device relative to one another in the plane perpendicular to the measuring direction, the change in the defined distance must be taken into account in the subsequent determination of the filling volume of the at least one liquid-filled receptacle of the carrier plate according to the method according to the invention. The chromatic white light sensor and / or the support device can also be movable in the z-direction of a Cartesian coordinate system, i.e. in the measuring direction, so that they can be moved towards or away from one another and thus increase or decrease the distance between them. When moving in the z-direction after or during a measurement, the previously defined distance between the chromatic white light sensor and the support device must be adjusted by the changed distance.

[0133] In a preferred embodiment, the chromatic white light sensor and the support device are movable relative to one another, in particular movable in all three spatial directions relative to one another. Preferably, the chromatic white light sensor, the support device, or both are movable in all three spatial directions. Preferably, the chromatic white light sensor is movable in the z-direction and the support device in the x- and y-direction and optionally in the z-direction. Preferably, the chromatic white light sensor is movable in the x- and y-direction and optionally in the z-direction and the support device in the z-direction. Preferably, the chromatic white light sensor is movable in the x- and optionally in the z-direction and the support device in the y- and optionally in the z-direction. Preferably, the chromatic white light sensor is movable only in the x- and y-direction. Preferably, the chromatic white light sensor is not movable in the z-direction.Preferably, in the case of a displacement parallel to the measuring direction, in particular z-direction, the chromatic white light sensor and the support device are displaced by the same distance.

[0134] In a preferred embodiment, the system according to the invention consists of a single device. In a preferred embodiment, the system according to the invention comprises more than one device, in particular two devices, in particular consists of these. In a preferred embodiment, a first device has a chromatic white light sensor, a support device for a carrier plate, at least one carrier plate having at least one receptacle, and a second device has a weighing device for determining a liquid-specific correction value, wherein the weighing device of the second device is assigned to the support device of the first device.

[0135] In the context of the present invention, the x-, y-, and z-directions are respectively assigned to the x-, y-, and z-axes of a Cartesian coordinate system, wherein the z-direction is the vertical direction, in particular parallel to the measurement direction, and the x- and y-directions are the horizontal directions, in particular vertical to the measurement direction. The z-direction is thus arranged vertically to a plane spanned by the x- and y-directions. A Cartesian coordinate system to which reference is made is shown in Figs. 1, 5, and 6 to 8.

[0136] In the context of the present invention, “plane perpendicular to the measuring direction” is understood to mean a plane in which the chromatic white light sensor and / or the support device can be moved and which is perpendicular to the measuring direction.

[0137] In the context of the present invention, a "system" is understood to mean, in particular, a single-part or multi-part device, in particular an integral device, which comprises, in one or more units or modules, which may be present in one or more housings, in particular a chromatic white light sensor, a weighing device and the carrying device.

[0138] In the context of the present invention, a "chromatic white light sensor" is understood to mean a sensor that axially spreads the light beam of a white light source into its spectral components, i.e., in the direction of propagation of the light. Preferably, when an object is introduced into the spread light beam, it is reflected, with the different spectral components of the spread light beam being reflected with varying intensities. Preferably, the reflected light beam is picked up again and projected onto a conventional spectrometer, i.e., one known to a person skilled in the art, using a beam splitter. Based on the spectral intensity distribution of the reflected spectral components of the reflected light beam, the position of the object within the spectral range of the spread light beam, and thus its distance from the sensor, is determined.Depending on the sensor design, measurement accuracies in the tens of nanometers can preferably be achieved. In a preferred embodiment, the chromatic white light sensor can be associated with at least one additional optical component, particularly for deflecting the light beam, such as a mirror.

[0139] In the context of the present invention, "confocal chromatic measurement" is understood to mean a measurement method in which the combination of confocal focusing and chromatic dispersion is used to precisely determine the distance, position, shape, surface structure, or other geometric and optical properties of an object along a measurement axis. Preferably, white light or polychromatic light is spectrally dispersed, with different wavelengths being imaged in different focal planes or focal points, particularly along the measurement direction, due to chromatic dispersion. Preferably, the measurement of the reflected or scattered light intensity as a function of the wavelength enables precise assignment of the focal plane or focal point and thus a determination of the distance information or surface structure of the object.Preferably, a confocal chromatic measurement is not understood to mean a monofocal measurement. Preferably, a confocal chromatic measurement is expressly not monofocal, as it is based on the simultaneous evaluation of light of different wavelengths, with each wavelength assigned to a specific focal plane or focal point. By analyzing the reflected or scattered light intensity as a function of the wavelength, the precise assignment of the measurement data to the respective focal planes or focal points is enabled, thereby measuring, in particular, the distance of the object from the sensor.

[0140] In the context of the present invention, "interferometry" refers to a measurement method in which the superposition, also referred to as interference, of two or more coherent waves, in particular light waves, is used to determine physical quantities such as distance, wavelength, refractive index, surface profile, or deformation. Preferably, the phase or intensity changes of the interfering waves caused by differences in path length, propagation direction, or interactions with an object are analyzed.

[0141] In the context of the present invention, "monofocal measurement" refers to an optical method in which light is concentrated into a single focal point or focal plane. Preferably, the imaging is independent of the wavelength of the light used, so that the focal point or focal plane remains the same for all light waves considered.

[0142] In the context of the present invention, a “monofocal scanning method” is understood to mean an optical measuring or scanning method in which a single focal point or focal plane or focal length is used to capture the properties of an object, such as position, shape, surface, or structure. The focal point or focal plane or focal length must remain constant, which is why the distance between different objects or different high liquid surfaces and the sensor must also always remain constant by moving the sensor back and forth during the method. The method is preferably characterized in that the focal point or focal plane or focal length is constant on the liquid surface for all measurements and, in particular, is not altered by chromatic dispersion or spectral decomposition.

[0143] In the context of the present invention, a difference between a confocal chromatic measurement according to the present invention and an interferometric measurement is preferably that the confocal chromatic measurement is based on the spectral decomposition and detection of light from different focal planes or focal points, while the interferometric measurement uses the phase interference of coherent light to determine distances or deformations.

[0144] In the context of the present invention, a difference between a confocal-chromatic measurement according to the present invention and a monofocal scanning method is preferably that the confocal-chromatic measurement takes into account several focal planes or focal points using light of different wavelengths in order to detect the object features, in particular the distance of an object, whereas the monofocal scanning method is based on a fixed focal point or focal point or a fixed focal plane in which the focus remains constant and no spectral decomposition of the light is used.Confocal chromatic measurement uses chromatic dispersion and multiple wavelengths to improve measurement accuracy and resolution, while the monofocal scanning method is based on the precision of a single focus point or focal point or a single focal plane, where the distance between the sensor and the object or different objects, especially liquid surfaces of different heights, must always remain the same, so that the single focus point or focal point or the single focal plane is always on the object or the liquid surface.

[0145] In the context of the present invention, a "receptacle" is a structure, in particular a depression or other structure, capable of spatially fixing a definable, in particular quantifiable, volume of a liquid. Such spatial fixation is also referred to herein as filling. A receptacle can also be a functionally defined area of ​​a flat surface, for example, a liquid-adsorbing area.

[0146] In the context of the present invention, “receptacle” is understood to mean an area that can hold a liquid, for example, can be filled with a liquid. A receptacle is preferably a depression, in particular a well or a structure that spatially fixes a liquid volume, in particular a spatially defined area. A receptacle, in particular a depression or a structure that spatially fixes a liquid volume, preferably has a liquid-adsorbing area. A receptacle is preferably a hydrophilic area, in particular having a different geometry than a depression, or a lipophilic area, in particular having a different geometry than a depression, that absorbs a hydrophilic or lipophilic liquid.Preferably, a receptacle is an area, in particular a flat area, on the surface of a carrier plate on which polar or non-polar molecules, in particular polar molecules, are arranged.

[0147] In the context of the present invention, "liquid-filled receptacle" is understood in particular to mean that a receptacle is filled with a liquid, i.e., the liquid is present in the receptacle or that the receptacle comprises the liquid. The filling volume preferably refers to the liquid held by a receptacle, wherein a receptacle comprises a recess or a structure, in particular a structure that spatially fixes a liquid volume, which can be designed, for example, as a liquid-adsorbing region on a surface of a carrier plate. The liquid-adsorbing region is preferably a flat, hydrophilic, or lipophilic region on a surface of a carrier plate.The term "in a receptacle" therefore means that the liquid is assigned to a receptacle, i.e., that the liquid is fixed to a receptacle and is located, for example, in a recess or adsorbed to a flat receptacle. Mixing of liquids from neighboring receptacles filled with liquid is preferably prevented due to the geometry of the at least one receptacle and the positioning of adjacent receptacles. Overflow of the liquid is preferably prevented due to the geometry of the at least one liquid-filled receptacle.

[0148] In the context of the present invention, “filled” is not only understood to mean that a receptacle designed as a depression is or will be filled with a liquid, but also that a receptacle not designed as a depression contains a liquid.

[0149] In the context of the present invention, the "measurement direction" is understood to mean the direction parallel to the light cone axes of the light cone generated by the chromatic white light sensor. In particular, the measurement direction is perpendicular to the liquid surface, in particular perpendicular to the center of the liquid surface, of a liquid present in a receptacle of a carrier plate. If the beam path is deflected by optical elements between the chromatic white light sensor and the liquid surface, the "measurement direction" is the direction oriented parallel to the light cone axes of the light cones striking or penetrating the liquid surface.

[0150] According to the invention, the term “vertical” is understood to mean a range from 80 to 100°, in particular 85 to 95°, in particular 90°.

[0151] In the context of the present invention, a "defined distance" is understood to mean a deliberately chosen distance. Preferably, "defined distance," particularly with regard to the arrangement of a chromatic white light sensor and a support device, is the distance to be traveled by a light beam generated by the chromatic white light sensor to a reference point, wherein the reference point lies on an object for which the distance to the chromatic white light sensor is to be determined. The distance can, in particular, be straight or angled. Preferably, the object is a liquid present in a liquid-filled receptacle of a support plate in the support device, a lifting element, a bending element, a non-liquid-filled part of the support plate, or the support device, in particular the weighing pan. Preferably, the reference point on the liquid is centered on the liquid surface.The defined distance can be precisely measured and determined at any time and can be taken into account for subsequent determinations.

[0152] In the context of the present invention, "correction value" also refers to the calibration value. The correction value is preferably the value that compensates for the measurement inaccuracy e.

[0153] In the context of the present invention, a "liquid-specific correction value" is understood to mean a numerical value that takes into account the physical, chemical, and / or thermodynamic properties of a particular liquid. The liquid-specific correction value is preferably used to adapt and / or calibrate at least one calculation, determination, in particular a fill volume, measurement, and / or at least one process, in particular the method according to the invention. The liquid-specific correction value preferably takes into account specific parameters of the liquid, in particular those that can be assigned solely to the liquid, such as viscosity, density, surface tension, temperature behavior, chemical composition, or combinations thereof, and enables adaptation and / or calibration of the calculation, measurement, or process to the specific properties of the liquid.

[0154] In the context of the present invention, “liquid and material-specific correction value” is understood to mean a numerical value which, in addition to the specific physical, chemical and / or thermodynamic properties of a particular liquid, also takes into account its interaction with a geometry, in particular receptacle geometry, a material, in particular carrier plate material, and the thermal or mechanical conditions of the material from which the receptacle consists and in which the liquid is present.Preferably, the liquid- and material-specific correction value is used to adapt and / or calibrate at least one calculation, determination, in particular a filling volume, measurement, and / or at least one process that is carried out with the liquid contained in the receptacle in order to compensate for influences such as viscosity, density, thermal conductivity, surface tension, or liquid distribution. In the context of the present invention, "height-dependent geometry" is understood to mean the volume in the receptacle occupied by the liquid present in a liquid-filled receptacle. Preferably, the height-dependent geometry takes into account the meniscus formed by the liquid in the receptacle.

[0155] In the context of the present invention, a "weighing device" is understood to mean a device designed to determine the mass of an object. The mass of an object is preferably determined via a confocal chromatic measurement using a chromatic white light sensor or via a scale, for example a precision balance.

[0156] In the context of the present invention, “supporting device” is understood to mean a device which is designed to be able to position the support plate at a defined distance from the white light sensor.

[0157] In the context of the present invention, a "carrier plate" is understood to mean a plate having a base body, preferably with a substantially cuboidal geometry and preferably two or three different edge lengths, which has at least one, preferably multiple or multiplicity of receptacles. The receptacles can be arranged integrally in the base body and completely penetrate the base body, or they can be surrounded by separate walls and fixed in the base body by holders. The receptacles are preferably located in the outer surfaces of the base body, which preferably has a substantially cuboidal geometry and which have the greatest extent.

[0158] The term “carrier plate” is preferably understood to mean a plate which has at least one receptacle, in particular a well, wherein the at least one receptacle has an open end and a closed end opposite the open end. The carrier plate is preferably a multi-well plate which has at least one receptacle, in particular a well. The carrier plate preferably has a frame part which serves as a holder for the at least one receptacle. The receptacle is preferably surrounded by a wall. A carrier plate is preferably a device having several or a plurality of receptacles, in particular wells, which are arranged in a regular grid and held in position by a frame part. The carrier plate preferably has standardized dimensions, such as ANSI / SLAS standards.Optionally, labels, markings or RFID tags are integrated on the top side of the carrier plate or the top side of the frame part to ensure clear identification and traceability.

[0159] The figures show

[0160] Figure 1 is a schematic view of a device according to the invention,

[0161] Figure 2 is a schematic view of a chromatic white light sensor, a carrier plate having liquid-filled receptacles and the angle of incidence range of the light beam of the chromatic white light sensor defining the measuring direction,

[0162] Figure 3 is a schematic view of a chromatic white light sensor and a carrier plate having liquid-filled receptacles, wherein the light beam of the chromatic white light sensor is deflected by means of a mirror,

[0163] Figure 4 is a schematic view of a chromatic white light sensor and a carrier plate having liquid-filled receptacles, wherein the carrier plate has planar liquid-adsorbing receptacles,

[0164] Figure 5 is a schematic view of an embodiment of a device according to the invention

[0165] Device,

[0166] Figure 6 is a schematic view of an embodiment of a device according to the invention

[0167] Device,

[0168] Figure 7 is a schematic view of a weighing device with a chromatic white light sensor,

[0169] Figure 8 is a schematic view of a device according to the invention, and

[0170] Figure 9 shows an example of a flow diagram of a method according to the invention.

[0171] Figure 1 shows a schematic view of a device according to the invention. The device according to the invention according to Figure 1 has a chromatic white light sensor (3) which, illustrated by the forward and backward arrow on the chromatic white light sensor (3), can be moved parallel to the measuring direction, i.e. in the z-direction. The device according to the invention according to Figure 1 also has a support device (4) for a carrier plate (2) and a weighing device (5) assigned to the support device (4) for determining the correction value, in particular the total filling mass of a carrier plate (2) having at least one liquid-filled receptacle (1). The chromatic white light sensor (3) and the support device (4) are configured according to Figure 1 such that they are arranged at a defined distance from one another, in particular in the measuring direction of the chromatic white light sensor (3).The carrier plate has liquid-filled receptacles (1) designed as depressions. The receptacles (1) are filled with different volumes of liquid. The liquid surface is designed as a meniscus and illustrates the volume occupied by the liquid in the receptacle and, in particular, illustrates the height-dependent geometry of the volume of liquid occupied by the liquid in the receptacle. The light beam generated by the chromatic white light sensor with its axial wavelength-dependent spectral dispersion is illustrated by the three triangles tapering towards the receptacle (for three different wavelengths). According to Figure 1, the support device (4) is arranged in the plane perpendicular to the measuring direction of the chromatic white light sensor (3), illustrated by the forward and backward arrows for the x-direction and the symbols for directional arrows into and out of the paper plane for the y-direction.y-direction, movable. The defined distance between the chromatic white light sensor (3) and the support device (4) corresponds to the distance traveled by the light beam generated by the chromatic white light sensor (3) to the center of the liquid surface of the liquid in the liquid-filled receptacle (1).

[0172] Figure 2 shows a schematic view of a chromatic white light sensor (3) of a carrier plate (2) having liquid-filled receptacles (1), wherein the chromatic white light sensor (3) is arranged with its light beam output (8) at a defined distance vertically from the liquid surface of the liquid in the liquid-filled receptacles (1) in the carrier plate (2). The light beam generated by the chromatic white light sensor, which is illustrated by the triangles tapering towards a receptacle and strikes the liquid surface of the liquid in the receptacle perpendicularly, defines the measuring direction. The dashed line on the left in Figure 2 indicates the optical axis of the sensor and the measuring direction.According to Figure 2, the measuring direction is at an angle of less than 10° to the perpendicular (dashed line shown on the right in Figure 2) on the liquid surface, indicated by a double arrow, wherein perpendicular according to the present invention is an angle in the range of 80 to 100°, in particular 85 to 95°, in particular 90°. Figure 3 shows a schematic view of a chromatic white light sensor (3) and a carrier plate (2) having liquid-filled receptacles (1), wherein the chromatic white light sensor (3) is arranged with its light beam output (8) at a defined distance parallel to the liquid surface of the liquid in the liquid-filled receptacles (1) in the carrier plate (2).The light beam generated by the chromatic white light sensor (3) exits at the light beam output (8) of the chromatic white light sensor parallel to the liquid surface and is deflected by a mirror (7) assigned to the white light sensor so that it strikes the liquid surface perpendicularly and thereby defines the measuring direction, which is perpendicular to the liquid surface.

[0173] Figure 4 shows a schematic view of a chromatic white light sensor (3) and a support plate (2) having liquid-filled receptacles (1). The chromatic white light sensor (3) is arranged with its light beam output (8) at a defined distance vertically from the liquid surface of the liquid in the liquid-filled receptacles (1) in the support plate (2). In Figure 4, the liquid-filled receptacles (1) are not depressions as in Figures 1 to 3, but rather flat liquid-adsorbing regions.

[0174] Figure 5 shows a schematic view of an embodiment of a device according to the invention. The device comprises at least one chromatic white light sensor (3) (not shown in Figure 5), a support device (4) for the carrier plate (2), and at least one weighing device (5) associated with the support device (4). The weighing device comprises a force sensor (9), a double bending element (13), and a lifting element (10), and the force sensor (9), the double bending element (13), and the lifting element (10) are movable vertically, i.e., in the z-direction, relative to the support device (4). The support device (4) has a receiving device (11) for a carrier plate (2), in which the carrier plate (2) is arranged. The receiving device (11) is designed such that a carrier plate (2) arranged in the receiving device (11) can be contacted by the lifting element (10) and can be moved vertically, i.e., in the z-direction.Figure 5 shows the rest state of this embodiment, in which the lifting element (10) does not yet contact the carrier plate (2) present in the receiving device (11).

[0175] Figure 6 shows a schematic view of the same embodiment of the device according to the invention shown in Figure 5. Figure 6 shows the active state of this embodiment, in which the lifting element (10) contacts the carrier plate (2) and moves in the vertical direction, i.e. in the z-direction, thus lifting the carrier plate (2) out of the receiving device (11) in order to determine the total filling mass of the carrier plate, in particular by means of the reversible deformation of the double bending element (13). By means of the embodiment of the present device according to the invention shown in Figures 5 and 6, method step v) is carried out in accordance with method steps v1a) to v4a).

[0176] Figure 7 shows a schematic view of a further embodiment of the device according to the invention. The device comprises a chromatic white light sensor (3), a support device (4) for the carrier plate (2), and a weighing device (5) assigned to the support device (4). The support device (4) is an integral part of the weighing device (5) and is designed as a weighing pan (12), wherein the weighing pan (12) is arranged on a double-flexural element (13). The weighing pan (12) is designed such that it can be displaced vertically, i.e. in the z-direction, relative to the white light sensor depending on its mass. In this embodiment, the chromatic white light sensor is designed to carry out method steps b), x) and v2b) and v4b).The light beam generated by the chromatic white light sensor (3) strikes the support device (4), whereby a mass-dependent vertical displacement of the weighing pan (12), in particular of a reference point on the weighing pan (12), is measured due to the reversible deformation of the double bending element (13).

[0177] Figure 8 shows a schematic view of a further embodiment of a device according to the invention. The device comprises a chromatic white light sensor (3), a support device (4) for the carrier plate (2), and a weighing device (5) assigned to the support device (4). The support device (4) and the weighing device (5) are separate components, with the weighing device (5) having a lifting element (10) and a double bending element (13). The lifting element (10) contacts the carrier plate (2) and moves it in the vertical direction, i.e., in the z-direction, with the chromatic white light sensor (3) also moving equidistantly in the vertical direction. In this embodiment, the chromatic white light sensor (3) is designed to carry out method steps b), x), and v2b) and v4b).The light beam generated by the chromatic white light sensor (3) strikes the double bending element (13), in particular a reference point on the double bending element (13), whereby, upon equidistant vertical displacement of the filled carrier plate (2) and the chromatic white light sensor (3), the double bending element (13) is deformed in a mass-dependent manner, and the chromatic white light sensor (3) measures the distance to the double bending element (13), in particular to the reference point on the double bending element (13), which has been changed for measuring the unfilled carrier plate. The vertical displacement measured by the chromatic white light sensor (3) is subsequently converted into a mass.

[0178] Figure 9 shows an exemplary flowchart of a method according to the invention. The exemplary method is carried out, for example, with a system according to the invention as shown in Figure 1.

[0179] In Figure 9, the method steps of the exemplary embodiment are shown in chronological order from top to bottom. In the first column from the right, the method steps a), b), d) and c) according to the invention are shown in rectangles with square corners and connected by arrows. In the second column from the right, the preferred method steps v), x), y) and z) are shown in circles and connected by arrows. In the third column from the right, the preferred method steps v1a), v2a), v3a) and v4a) are shown in rectangles with rounded corners and connected by arrows. The respective method steps in the respective columns are connected by arrows, with the arrowhead always pointing to the chronologically subsequent method step.

[0180] In a method step a), at least one carrier plate arranged on the support device with at least one liquid-filled receptacle and a chromatic white light sensor are provided at a defined distance from one another. In a method step b), a confocal-chromatic measurement of the distance between the surface of the liquid in the at least one receptacle and the chromatic white light sensor is carried out to determine the fill level at the distance defined in method step a). Preferably, in method step d), the liquid-specific correction value is then determined using the weighing device. Preferably, method steps v), in particular v1a) to v4a), x), y) and z) are carried out. Preferably, in method step v), the total fill mass of the carrier plate having at least one liquid-filled receptacle is determined using the weighing device. This preferably takes place according to method steps v1a) to v4a).Preferably, in via), the total mass of an unfilled carrier plate is determined by means of the weighing device, wherein the unfilled carrier plate corresponds to the carrier plate that is provided in method step a) and in which at least one receptacle is filled with the liquid. Preferably, in v2a), at least a portion of the receptacles of the carrier plate are filled with equal or unequal volumes of liquid, in particular filled such that the filled carrier plate corresponds to the filled carrier plate that is provided in method step a). Preferably, in method step v3a), the total mass of the filled carrier plate is measured by means of the weighing device. Preferably, in method step v4a), the total filling mass of the carrier plate is determined taking into account the masses measured in method steps via) and v3a).Preferably, after carrying out method step v), in particular method steps v1a) to v4a), the filling mass and the filling volume of the liquid in the at least one filled receptacle are determined in method step w). Preferably, in method step w) the average filling mass and the average filling volume of a filled receptacle are determined for more than one single filled receptacle. In method step x), the distance of the surface of the liquid in each of the liquid-filled receptacles to the chromatic white light sensor is measured confocally-chromatically to determine the respective fill level at a defined distance between the support device and the white light sensor. Preferably, the support plate and / or the white light sensor are therefore moved vertically to the measuring direction such that the distance of the surface of the liquid in each liquid-filled receptacle to the chromatic white light sensor can be measured.Preferably, in a method step y), the respective filling volume of the liquid-filled receptacles is determined taking into account the fill level determined in method step x). Preferably, in method step z), the correction value is determined from the fill volumes determined in method steps w) and y). After determining the correction value according to method step d), the filling volume of at least one receptacle is finally determined, preferably in method step c), taking into account the fill level determined in method step b) and the liquid-specific correction value determined in method step d).

[0181] Advantageously, by combining the spatially resolved measurement data obtained by the confocal chromatic measurement according to method step b), which have a high relative accuracy, and the measurement data obtained from the average measurements using the weighing device according to method step v), which have a high absolute accuracy for all liquid-filled images together, taking into account the liquid-specific correction value, a high measurement accuracy is achieved, in particular a higher measurement accuracy than with known methods.

[0182] 1 recording

[0183] 2 carrier plate

[0184] 3 chromatic white light sensor 4 carrying device

[0185] 5 Weighing device

[0186] 6 Control unit

[0187] 7 mirrors

[0188] 8 Light beam output of the chromatic white light sensor 9 Force sensor

[0189] 10 Lifting element

[0190] 11 Mounting device

[0191] 12 weighing pan

[0192] 13 Double bending element

Claims

CLAIMS 1. A method for determining the fill volume of at least one liquid-filled receptacle (1) of a carrier plate (2) by means of a system for determining the fill volume, wherein the system comprises at least one chromatic white light sensor (3), a support device (4) for the carrier plate (2), and at least one weighing device (5) associated with the support device (4), wherein the chromatic white light sensor (3) and the support device (4) are configured such that they are arranged at a defined distance from one another and the chromatic white light sensor (3), the support device (4), or both are movable, and wherein the method comprises: a) providing at least one carrier plate arranged on the support device with at least one liquid-filled receptacle and a chromatic white light sensor at a defined distance from one another,b) Confocal chromatic measurement of the distance of the surface of the liquid in the at least one receptacle to the chromatic white light sensor to determine the fill level at the distance defined in process step a) and c) Determination of the fill volume of the at least one receptacle taking into account the fill level determined in process step b) and a liquid-specific correction value determined in a process step d), wherein in process step d) the liquid-specific correction value is determined by means of the weighing device.

2. The method according to claim 1, wherein method step d) is carried out before carrying out method step a), after carrying out method step b) or before carrying out method step a) and after carrying out method step b).

3. Method according to claim 1 or 2, wherein method step d) comprises the following method steps: v) Determination of the total filling mass of the carrier plate having at least one liquid-filled receptacle by means of the weighing device, w) Determination of the filling mass and the filling volume of the liquid in the at least one filled receptacle, x) Confocal chromatic measurement of the distance of the surface of the liquid in each of the liquid-filled receptacles to the chromatic white light sensor to determine the respective filling level at a defined distance between the support device and the white light sensor, y) Determination of the respective filling volume of the liquid-filled receptacles taking into account the filling level determined in method step x) and z) Determination of the correction value from the filling volumes determined in method steps w) and y).

4. The method according to claim 3, wherein method step v) comprises the following method steps: via) measuring the total mass of an unfilled carrier plate by means of the weighing device, v2a) filling at least a portion of the receptacles of the carrier plate with equal or unequal volumes of liquid, v3a) measuring the total mass of the filled carrier plate by means of the weighing device and v4a) determining the total filling mass of the carrier plate taking into account the masses measured in method steps via) and v3a).

5. The method according to claim 3, wherein method step v) comprises the following method steps: vlb) providing an unfilled carrier plate on a weighing pan or providing an unfilled carrier plate which is assigned to a lifting element, wherein the weighing pan or the lifting element is arranged at a defined distance from the chromatic white light sensor and wherein the weighing pan or the lifting element is designed such that it is movable vertically relative to the white light sensor, in particular by means of a bending element assigned to the weighing pan or the lifting element, in a mass-dependent manner, v2b) Confocal-chromatic measurement of the distance of a reference point, in particular on the weighing pan carrying the unfilled carrier plate or on the lifting element assigned to the carrier plate, in particular on the bending element assigned to the weighing pan or the lifting element, to the chromatic white light sensor, v3b) Filling at least a portion of the receptacles of the carrier plate with equal or unequal volumes of liquid, v4b) Confocal-chromatic measurement of the distance of the reference point, in particular on the weighing pan carrying the filled carrier plate or on the lifting element assigned to the carrier plate, in particular on the bending element assigned to the weighing pan or the lifting element, to the chromatic white light sensor, and v5b) Determination of the total filling mass of the carrier plate taking into account the distances measured in method steps v2b) and v4b).

6. The method according to claim 5, wherein the weighing pan is displaceable vertically relative to the white light sensor in a mass-dependent manner.

7. Method according to one of the preceding claims, wherein the carrier plate is a microtiter plate with 384 or 1536 wells.

8. Method according to one of claims 1 to 7, wherein method steps b) or b) and c) are carried out sequentially for a number of recordings of the carrier plate with, in particular equidistant, displacement of the carrier plate relative to the white light sensor.

9. The method according to any one of claims 1 to 8, wherein step d) is carried out once.

10. Method according to one of the preceding claims 3 to 9, wherein the filling volume in method step y) is determined either by confocal-chromatic determination of the filling level of the liquid in the at least one receptacle at a defined distance between the support device and the white light sensor and taking into account the volume occupied by the liquid in the at least one receptacle or by confocal-chromatic measurement of the filling levels of different known filling volumes of the liquid in the at least one image is taken at a defined distance between the support device and the white light sensor.

11. System for determining the filling volume of at least one liquid-filled receptacle (1) in a carrier plate (2), in particular designed to carry out a method according to one of the preceding claims 1 to 10, comprising at least one chromatic white light sensor (3), a support device (4) for a carrier plate (2), at least one weighing device (5) assigned to the support device (4) for determining a liquid-specific correction value, and wherein the chromatic white light sensor (3) and the support device (4) are configured such that they are arranged at a defined distance from one another and the chromatic white light sensor (3), the support device (4) or both are movable.

12. System according to claim 11, wherein the weighing device (5) comprises a force sensor (9), in particular a load cell, and a lifting element (10) or is a weighing device (5) with electromagnetic force compensation.

13. System according to claim 12, wherein the force sensor (9) is movable, in particular vertically, relative to the support device (4).

14. System according to one of claims 11 to 13, wherein the carrying device (4) has a receiving device (11) for the carrier plate (2), wherein the receiving device (11) is designed such that the carrier plate (2), arranged in particular in the receiving device (11), can be contacted by the lifting element (10) and can be moved, in particular in the vertical direction.

15. System according to claim 11, wherein the weighing device comprises a weighing pan and wherein the chromatic white light sensor is designed to carry out method steps b) and v2b) and v4b).

16. The system of claim 15, wherein the weighing pan is configured to be vertically displaceable relative to the white light sensor in a mass-dependent manner, or a flexural element associated with the weighing pan is deformable vertically relative to the white light sensor in a mass-dependent manner.

17. System according to claim 15 or 16, wherein the weighing pan is an integral part of the support device.

18. System according to one of claims 11 to 17, comprising a control unit (6) designed to control the implementation of a method according to one of claims 1 to 10.

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