System and method for determining volume within a microtiter plate

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 a filling volume determination system, and a system for determining the filling volume of at least one liquid-filled receptacle within a carrier plate.

Description

Technology Field

[0001] The present invention relates to a method for determining the filling volume of at least one liquid-filled receptacle of a carrier plate by a filling volume determination system, and a system for determining the filling volume of at least one liquid-filled receptacle within a carrier plate. Background Technology

[0002] Biological experiments are often volume-dependent, meaning that even very small changes in the volume of liquids or mixing ratios can affect experimental results. The transfer of liquid samples between different receptacles, particularly between wells and vessels, is perhaps the most common procedural step in many laboratories, yet it is frequently performed without proper process control or quality management. Whether using manual operations or automated systems, there is often reliance on dispensing and pipetting systems that, while undergoing periodic maintenance and calibration on one hand, are highly susceptible to error on the other.

[0003] The most common errors include complete or partial blockage of dispensing needles or pipette tips, inaccuracies caused by contamination of the product contact area, incorrect positioning of laboratory equipment, particularly carrier plates, particularly microtiter plates, carrier plate receptacles and / or consumables, incorrect configuration of the system or liquid type, and insufficient or missing calibration.

[0004] Therefore, in established procedures characterized by a high degree of automation, it is desirable to provide process control to detect potential volume errors at an early stage. Failure to do so results in unnecessary additional processing of sample materials and experimental equipment, and incurs significant costs because these errors are discovered only after final analysis, even if detected. Therefore, verifying the volume of the dispensed liquid after the transfer step is a critical element of process control in many laboratory procedures.

[0005] In many known methods, such as high-throughput screening (HTS), carrier plates having multiple wells, such as receptacles or recesses, are frequently used on microtiter plates. A microtiter plate with 1,536 wells is known, in which a single well has a diameter of only about 1.7 mm and can hold about 10 μl of liquid. Known measurement methods for determining the volume within a microtiter plate can no longer provide reliable data for such carrier plates.

[0006] The volume of liquid within a microtiter plate can be determined by various known measurement methods. The average value of all volumes within a microtiter plate is typically determined by an analytical balance. At a resolution of 1 mg and a density of approximately 1 g / cm³, this results in a volumetric accuracy of 1 μl. Accordingly, for a 1536-well microtiter plate, the average well volume can be determined with an accuracy of approximately 1 μl / 1536 = 0.65 nl. This procedure is very accurate and allows for the determination of systematic dispensing errors in a simple manner, but it cannot determine well-specific dispensing errors.

[0007] Various spatially resolved measurement methods are known to determine the liquid volume for each well of a microtiter plate.

[0008] For example, in ultrasonic measurement, the liquid surface is detected by an ultrasonic distance sensor, and the liquid volume is determined based on the geometry of the well. The disadvantages of this method are that the measurement accuracy is relatively low and it can only be used for large wells, such as 96-well or 384-well microtiter plates, due to interference reflections from the well walls. However, this method is stable, sufficiently fast, and allows for parallel processing.

[0009] Another example is an optical interferometer. In this case, the liquid surface is detected by the optical interferometer, and the volume of the liquid is determined based on the geometry of the well. For example, US 2017 / 0205270 A1 discloses an apparatus for determining the volume of a liquid sample within a receptacle, wherein it is possible to determine the volume of the liquid sample using known dimensions of the receptacle and the surface topography of the liquid measured by an optical interferometer system (LCOIRS). According to this document, a low-coherence optical interferometer is used to determine the topography of the liquid surface within a well of a microtiter plate. For example, an LED or super-light-emitting diode is used as a low-coherence light source. A Michelson interferometer is used to split and reflect the light beam. The liquid height is determined by the reflection from the liquid surface and the reference mirror. The distance between the sensor and the liquid surface must be set so that the focused light is accurately reflected from the liquid surface. The reflected light beams interfere with each other. The interference pattern generated during this process is highly sensitive to changes in the distance between the liquid surface and the reference mirror.

[0010] However, because a low-coherence light source is used, interference can only detect changes in the range of a few micrometers (μm), specifically about 100 μm. Therefore, it is essential to periodically readjust the interferometer to maintain a constant distance between it and, in particular, between the liquid surfaces of different heights. Since the interferometer must be moved up or down perpendicular to the well (hereinafter also referred to as the z-direction in the Cartesian coordinate system) over each well, particularly wells with different fill levels, to detect surfaces, this method is very slow when there are many wells. However, the measurement accuracy is much better than that of ultrasonic measurement. Nevertheless, it avoids the disadvantages of invasive methods, such as photometric methods or fluorescent dye methods, which cannot be used to determine the stepwise volume change of a sample. It also avoids the disadvantages of gravimetric methods, which require knowing the density of the liquid and cannot be used when the liquid is introduced simultaneously into, for example, multiple associated wells of a multi-well microtiter plate, as is customary in automated methods.

[0011] Pressure-flow measurement is also known. In this case, an air layer above the liquid surface of each well is pressurized by a sealed plunger, and the flow rate of the incoming air is measured. The volume of the air layer is calculated from the amount of air and the resulting pressure, and from this, the volume of the liquid beneath it can be determined. This method is fast and can be parallelized as needed. However, it has the lowest accuracy among the previously mentioned methods.

[0012] WO 2019 / 005744 A1 discloses a system for transferring a volume of liquid into and out of a container configured to receive a liquid, wherein the liquid in the container has a free surface, and the system comprises a liquid transfer mechanism, a non-contact distance sensor, in particular a low-coherence interferometer fill height sensor or an ultrasonic distance sensor, and a control unit.

[0013] WO 2016 / 025057 A1 discloses a high-throughput sample processing system 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 processing stations, a waste management system, and a control system.

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

[0015] US 2008 / 0233009 A1 discloses an apparatus and method for verifying the accuracy of a liquid dispensing volume based on capillary force. This offers more advantages over conventional methods for verifying dispensing volume, such as gravimetric methods or spectrophotometric methods. Gravimetric methods generally require expensive, sensitive equipment that can only be operated by skilled personnel. Furthermore, gravimetric methods are sensitive to various environmental influences, such as vibration and leveling. To verify the accuracy, particularly the uniformity, of a dispensing device by gravimetric methods, the mass of water dispensed by the dispensing device is measured by a weighing device. Spectrophotometric methods for verifying dispensing volume require an additional diluted solution containing chromogen, through which the volume to be verified is calculated, particularly through the absorbance and volume of the diluted solution. Such spectrophotometric methods are time-consuming, often suffer from reduced accuracy due to human error, and cannot be performed in an automated manner as they are performed manually.

[0016] EP 1 761 747 B1 discloses a method for detecting the height of a liquid in a small volume well, the method comprising the steps of: measuring a first distance from a reference point to the upper side of a small volume well in a confocal manner; measuring a second distance from the reference point to the upper side of the liquid in the small volume well in a confocal manner; determining the difference between the first distance and the second distance; and determining the height and 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. Confocal measurement corresponds to a single-focus scanning method. In this method, the measurement is performed at a single focus or a single-focus plane, i.e., in a single-focus manner, which is obtained particularly by a pinhole aperture or a slit. During measurement, the scanner moves back and forth vertically and horizontally in an equidistant arrangement with respect to the carrier and the liquid surface so that the same distance between the measuring device and the liquid surface is always measured in order to be positioned at the focal point or focal plane of the single-focus light, or at the focal distance of the device (these are hereinafter referred to as the z-direction for vertical movement and the x- and y-directions for horizontal movement, respectively, in the Cartesian coordinate system).

[0017] In EP 1 761 747 B1, the term "confocal" does not refer to a confocal microscope. In this single-focus scanning method, a monochromatic light source, such as a laser, is used as the light source to generate a focused beam. The light is focused by an optical system, usually a lens. The sensor generally has a confocal array in which both the light beam directed toward the liquid phase and the reflected light pass through the same point and are guided toward the detector. The light strikes the liquid surface, reflects from there, and returns to the sensor. The highest intensity for the reflected light is obtained when the focal point or focal plane is positioned precisely on the liquid surface, where the distance of the sensor from the liquid surface corresponds to the focal length of the optical system. The distance is set such that the ratio of reflected light is maximized by moving the optical system or the liquid surface to be measured back and forth parallel to the measurement direction, particularly along the z-axis of the Cartesian coordinate system, specifically up and down. This implies that the distance between the liquid surface and the sensor must always be the same. Therefore, the charge level is calculated, particularly during measurement, from the reciprocating movement of the sensor, specifically up-and-down movement, or from reciprocating movement parallel to the measurement direction of the liquid surface to be measured, specifically from movement in the z-direction. Consequently, because the same distance must always exist between the sensor and the liquid surface, particularly between different liquid surfaces, and specifically so that the focal point or focal plane is always located on the liquid surface, the charge level of the liquid within different receptacles is determined from the reciprocating movement of the sensor for liquid surfaces having different heights. The problem to be solved

[0018] All of the previously mentioned methods are used for volume determination in various laboratory systems. However, none of these methods can accurately measure the packing volume of a microtiter plate with 1,536 wells in a short period of time. means of solving the problem

[0019] The fundamental problem of the present invention is to overcome the aforementioned drawbacks of the prior art. In particular, the fundamental problem of the present invention is to provide a system and method that enables measuring at least one filling volume of a carrier plate receptacle in an accurate, cost-effective, and time-efficient manner.

[0020] The present invention solves the underlying technical problem through the provided technical teachings, in particular the teachings of the independent and dependent claims and the preferred embodiments disclosed in the specification.

[0021] 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 a system for determining the filling volume, wherein the system comprises at least one chromatic white light sensor, a support device for a carrier plate, and at least one metering device associated with said support device, wherein the chromatic white light sensor and the support device are configured to be positioned at a defined distance from each other, particularly in the measurement direction of said chromatic white light sensor, said chromatic white light sensor, said support device, or both are movable, and said method comprises the following steps:

[0022] a) a step of providing at least one carrier plate disposed on the support device and having at least one liquid-filled receptacle, and a chromatic white light sensor at a defined distance from each other,

[0023] b) a step of confocal-chromatically measuring the distance from the chromatic white light sensor to the liquid surface within the at least one receptacle to determine the charge level at the distance defined in method step a), and

[0024] c) a step of determining the filling volume of the at least one receptacle by considering the filling level determined in method step b) and the liquid-specific calibration value determined in method step d),

[0025] In step d) of the above method, a liquid-specific calibration value is determined by a metering device.

[0026] Accordingly, the present invention provides a method in the context of providing at least one chromatic white light sensor, a support device for a carrier plate, and a metering device associated with said support device, wherein in method step a), at least one carrier plate having at least one liquid-filled receptacle is provided on said support device, specifically at a defined distance from said chromatic white light sensor, and in method step b), a step of confocally determining the distance from said chromatic white light sensor to the liquid surface within said at least one receptacle is subsequently performed to determine the filling level at the distance defined in method step a), and in method step c), the filling volume of said at least one receptacle is determined by considering, on one hand, the filling level determined in method step b), and on the other hand, additionally considering a liquid-specific calibration value.

[0027] This liquid-specific calibration value is determined and provided in method step d) within the scope of the method according to the present invention, particularly by a metering device. Accordingly, the determination of the filling volume in method step c) presupposes knowledge of the liquid-specific calibration value, that is, its determination, and accordingly, this must be done at least before method step c) is performed for the first time.

[0028] In a preferred embodiment, the present invention provides not only one but several, particularly a plurality of at least partially liquid-filled receptacles to be present in a carrier plate, and accordingly, method steps b) and c) are performed according to the number of filling volumes to be determined for each individual receptacle.

[0029] Accordingly, the present invention provides that method steps b) and c) be performed several times, particularly many times, corresponding to the number of fillings to be measured in a plurality or multiple liquid-filled receptacles of a carrier plate, wherein method step d) for determining a liquid-specific calibration value must be performed at least once within the scope of the method according to the present invention.

[0030] Therefore, if method steps b) and c) are each performed only once, method step d) must be performed before method step c). If method steps b) and c) are performed several times or multiple times, particularly when subsequent measurements relate to the same liquid, and especially the same carrier plate material and / or the same receptacle geometry, since the determined liquid-specific calibration value can be used for method steps b) and c) according to all subsequent measurements, according to the present invention, it is sufficient to provide that method step d) is performed once, that is, before method step c) is performed for the first time, and that method step d) is not performed again in subsequent processes.

[0031] In a preferred embodiment, after performing method step d) at least once before method step c) by the method according to the present invention, in the subsequent process, method step b) and c) are performed sequentially without performing method step d) again, optionally at a greater temporal and / or spatial distance from the performance of method step d).

[0032] According to the present invention, the method for determining the filling volume of at least one liquid-filled receptacle of a carrier plate is performed by a filling volume determination system. In this context, the liquid-filled receptacle does not necessarily have to be a liquid-filled portion, but may be, for example, a liquid adsorption area on the carrier plate. Thus, within the sense of the present invention, the receptacle is a defined area on the liquid-filled carrier plate.

[0033] According to the present invention, the system comprises at least one chromatic white light sensor, at least one support device for a carrier plate, and at least one metering device associated with the support device, optionally at least one carrier plate. According to the present invention, the chromatic white light sensor and the support device are configured to be positioned at a defined distance from each other, particularly in the measurement direction of the chromatic white light sensor.

[0034] Preferably, "defined distance" should be understood to mean an intentionally selected distance. Preferably, "defined distance" is understood to mean the distance that a light beam generated by a chromatic white light sensor must travel to a reference point, where the reference point is located on a support device.

[0035] In a preferred embodiment, the defined distance between the chromatic white light sensor and the support device is determined by the chromatic white light sensor.

[0036] Preferably, if there is a defined distance between the chromatic white light sensor and the support device, there is also a defined distance between the chromatic white light sensor and the carrier plate.

[0037] In a preferred embodiment, during the execution of the method according to the present invention, a defined distance between the chromatic white light sensor and the support device is further measured by the chromatic white light sensor. Preferably, this ensures that the defined distance between the chromatic white light sensor and the support device is always maintained at the same during the execution of the method according to the present invention.

[0038] Preferably, the measurement direction is aligned parallel to the axis of the light bulb of the light bulb generated by the chromatic white light sensor; in particular, the measurement direction is perpendicular to the liquid surface of the liquid present in the receptacle of the carrier plate, in particular to the center of the liquid surface. In the context of the present invention, "perpendicular" should be 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 the Cartesian coordinate system is assigned to the measurement direction incident on the liquid surface at an angle of exactly 90°.

[0039] In a preferred embodiment, the chromatic white light sensor, the support device, or both can be moved relative to each other at least in a plane perpendicular to the measurement direction, particularly in the x- and y- directions of the Cartesian coordinate system, particularly at a distance defined relative to each other.

[0040] In a preferred embodiment, the chromatic white light sensor and the support device can move only the same distance, particularly simultaneously, while maintaining a defined distance in the measurement direction, particularly in a plane parallel to the z-direction of the Cartesian coordinate system.

[0041] According to the present invention, it is preferable that the chromatic white light sensor, the support device, or both are movable relative to each other in a plane perpendicular to the measurement direction. In a first alternative, the chromatic white light sensor is movable in a plane perpendicular to the measurement direction. In a second alternative, the support device is movable in a plane perpendicular to the measurement direction.

[0042] As a third alternative, the chromatic white light sensor and the support device are movable relative to each other in a plane perpendicular to the measurement direction, that is, the white light sensor or the support device is movable only in one of the spatial directions crossing the plane perpendicular to the measurement direction, and the other is movable in each other spatial directions crossing the plane perpendicular to the measurement direction, or the chromatic white light sensor and the support device are each movable in both spatial directions crossing the plane perpendicular to the measurement direction, or the white light sensor or the support device is movable in one of the spatial directions crossing the plane perpendicular to the measurement direction, and each other is movable in both spatial directions crossing the plane perpendicular to the measurement direction.

[0043] Preferably, the chromatic white light sensor or the support device is movable in both spatial directions across a plane perpendicular to the measurement direction, and the other of each is fixed. In the context of the present invention, the plane perpendicular to the measurement direction extends to the x-direction and the y-direction of the Cartesian coordinate system. The chromatic white light sensor and the support device, or both, may each be configured to be movable relative to each other in at least a plane perpendicular to the measurement direction.

[0044] In the context of the present invention, "movable relative to each other" should be understood to mean that the chromatic white light sensor and the support device are movable in one of the spatial directions across a plane perpendicular to the measurement direction at least.

[0045] Preferably, the chromatic white light sensor or the support device is movable in both spatial directions across a plane perpendicular to the measurement direction. Preferably, both the chromatic white light sensor and the support device are movable in both spatial directions across a plane perpendicular to the measurement direction. Preferably, the chromatic white light sensor is movable in only one spatial direction across a plane perpendicular to the measurement direction, or the support device is movable in each other spatial direction. Preferably, the chromatic white light sensor is movable in only one spatial direction across a plane perpendicular to the measurement direction, and the support device is movable in each other spatial direction.

[0046] This enables the present invention to scan a plurality of liquid-filled or liquid-unfilled receptacles on a carrier plate, particularly within a short time. This also enables determining the filling volume of a plurality of liquid-filled receptacles on a carrier plate.

[0047] Accordingly, according to the present invention, in step a) of the first method, at least one carrier plate disposed on a support device and a chromatic white light sensor is provided. According to the present invention, the carrier plate comprises at least one receptacle filled with liquid. According to the present invention, the support device and the chromatic white light sensor are disposed at a defined distance from each other to determine the filling volume of at least one liquid-filled receptacle.

[0048] Within the scope of step b) of the second method, a confocal chromatic measurement method is performed from the chromatic white light sensor to the distance of the liquid surface within at least one receptacle. Preferably, the distance from the liquid surface to the chromatic white light sensor measured in step b) is different from the defined distance between at least one support device and the chromatic white light sensor, and is, in particular, smaller or larger.

[0049] In this way, the present invention enables determining the filling level of at least one liquid-filled receptacle based on the distance defined in method step a), in particular the distance between at least one support device and a chromatic white light sensor.

[0050] In method step c), the filling volume of at least one receptacle is determined by taking into account the filling level determined in method step b) and the liquid-specific calibration value determined in method step d). According to the present invention, the liquid-specific calibration value is determined by a metering device in method step d).

[0051] A liquid-specific calibration value according to the present invention is a numerical value that takes into account, in particular, the physical, chemical, and / or thermodynamic properties of a specific liquid. Preferably, the liquid-specific calibration value takes into account specific parameters of the liquid, in particular parameters attributable only to the liquid, e.g., viscosity, density, surface tension, temperature change, chemical composition, or a combination thereof, and enables calculation, in particular determination of the filling volume, measurement, or adjustment and / or calibration of the method for the specific properties of the liquid.

[0052] Preferably, the liquid-specific calibration value is a liquid- and material-specific calibration value. Preferably, the liquid- and material-specific calibration value is a numerical value that further takes into account, in addition to the specific physical, chemical, and / or thermodynamic properties of the specific liquid, the geometry of the material, particularly the carrier plate material, the interaction with the receptacle geometry, particularly the receptacle geometry, and the thermal or mechanical conditions of the material constituting the receptacle and in which the liquid exists.

[0053] Preferably, liquid- and material-specific calibration values ​​are used to adjust and / or calibrate at least one calculation, in particular the determination and measurement of the filling volume, and / or at least one process performed with the liquid contained in the receptacle, in order to compensate for effects such as, for example, viscosity, density, thermal conductivity, surface tension, or liquid distribution.

[0054] According to the present invention, a liquid-specific calibration value is determined by a metering device. Preferably, the liquid-specific calibration value according to the present invention is determined based on a specific liquid. Preferably, the metering device is not provided for the purpose of inspecting the accuracy, in particular the uniformity, of a dispensing device. Preferably, a reference substance, in particular water as a reference substance, is not measured by the metering device. Preferably, the term "reference substance" should be understood to mean a substance whose physical, chemical, or optical properties are used as a standard value or comparison value in a measurement or test method.

[0055] Preferably, by using a chromatic white light sensor and a confocal chromatic measurement performed according to method step b), it is possible to determine the filling level of a liquid present in at least one receptacle without the need for the chromatic white light sensor, the support device, or both to be moved up or down while changing the distance, especially without the need for reciprocating movement perpendicular to each other, particularly in the z-direction, while maintaining a defined distance between the chromatic white light sensor and the support device while maintaining a constant distance, in particular compared to single-focus scanning methods or interferometric methods which require readjustment to always maintain the distance between the sensor and the liquid surface and cause a change in the distance between the sensor and the support device.

[0056] In the method according to the present invention, for several liquid-filled receptacles filled to different degrees, different distances are measured according to method step b) while maintaining a constant defined distance between a chromatic white light sensor and a support device, and the respective filling level is determined therefrom.

[0057] In known methods, the same distance between the sensor and the liquid surface must always be maintained, and for this reason, the sensor, the support device, or both are vertically reciprocated, particularly in the z-direction, particularly up or down, while changing the distance, which results in high time consumption, particularly due to the physical reciprocating of the sensor, the support device, or both, and results in greater time consumption than in the method according to the present invention. By combining the consideration of determined liquid-specific calibration values, a method according to the present invention for determining a filling volume is provided that is accurate, cost-effective, and time-efficient, particularly time-efficient than known methods.

[0058] In this way, the present invention makes it possible to determine the volume of liquid in a receptacle in an accurate, cost-effective, and time-efficient manner by measuring the distance from a chromatic white light sensor to the surface of the liquid present in the receptacle by confocal chromatic distance measurement and taking into account a liquid-specific calibration value determined by a metering device. The present invention is based on the use of a chromatic white light sensor, particularly a confocal sensor, and in order to determine the filling level of the liquid present in at least one receptacle with knowledge of the defined distance between the chromatic white light sensor and a support device, in method step b), the distance from the chromatic white light sensor to the surface of the liquid present in at least one receptacle is detected.

[0059] In a preferred embodiment, the liquid is present in a plurality of receptacles, particularly in at least two, particularly in multiple or numerous receptacles, wherein a chromatic white light sensor measures the distance from the chromatic white light sensor to each liquid surface within the corresponding receptacle in each case, and wherein, with knowledge of the defined distance between the chromatic white light sensor and the support device, the respective filling level of the liquid present in the at least two, particularly in multiple or numerous receptacles is determined. Preferably, when the filling levels of the liquid in the at least two, particularly in multiple or numerous receptacles are different, two, particularly in multiple or numerous different distances are measured between the chromatic white light sensor and each liquid surface of the liquid present in the at least two, particularly in multiple or numerous receptacles. Preferably, the same liquid-specific calibration value is used to determine the volume of the liquid in the at least two, particularly in multiple or numerous receptacles.

[0060] According to method step c), the volume of liquid in at least one receptacle, in particular at least two, in particular multiple or numerous receptacles is determined based on the determined distances, in particular the determined distances, and by considering the liquid-specific calibration value determined in method step d) by the metering device, in particular the calibration value that takes into account the volume occupied by the liquid in at least one receptacle.

[0061] Advantageously, the method or system according to the present invention, particularly the chromatic white light sensor, enables non-contact, particularly non-invasive, measurement by preventing contaminants or foreign substances from entering the liquid being measured. Due to the mobility of the chromatic white light sensor, the support device, or both relative to each other—that is, reciprocal movement—at least in a plane perpendicular to the measurement direction, a high sampling rate of the chromatic white light sensor, particularly a confocal sensor, particularly up to 100 kHz is achieved, thereby ensuring rapid measurement of multiple or numerous liquid-filled or unfilled receptacles on a carrier plate, for example, about 1 minute (reduced to "min") for 1,536 wells of a microtiter plate. Furthermore, high measurement accuracy is achieved by the method according to the present invention. The method according to the present invention is less susceptible to shadowing phenomena in smaller receptacle embodiments, particularly in well embodiments, for example, in 1,536-well embodiments, than in known methods. Advantageously, by combining spatially resolved measurement data obtained by confocal chromatic measurement with high relative accuracy while considering liquid-specific calibration values, and measurement data obtained from average measurements by a weighing device with high absolute accuracy for all liquid-filled receptacles, high measurement accuracy, particularly higher measurement accuracy than in known methods, is achieved.

[0062] Preferably, in contrast to interferometers and single-focus measurements, a support device comprising a carrier plate containing a liquid present in at least one receptacle having a liquid surface to be measured, or a chromatic white light sensor, particularly a chromatic confocal sensor, a vertical reciprocating movement changing the distance, particularly a reciprocating movement parallel to the measurement direction, particularly in the z-direction, is not required in the method according to the present invention.

[0063] This is achieved without being bound by theory, because white light is refracted by a chromatic white light sensor into different wavelengths, particularly to different degrees, parallel to the measurement direction, and consequently, wavelength-dependent focal points or focal planes exist at a defined distance between the chromatic white light sensor and the carrier plate support device, particularly in the fixed arrangement of the chromatic white light sensor and the carrier plate support device relative to each other, and accordingly also in the fixed arrangement of the white light sensor and the carrier plate itself.

[0064] Preferably, a spectrometer is used to detect the wavelength at which the focus of the light beam, specifically the focal plane, is precisely located on the liquid surface to be measured. Preferably, this eliminates the reciprocating movement of the chromatic white light sensor and / or carrier plate support device in the z-direction to change the distance, which leads to significant time savings. Preferably, this is advantageous over interferometric or single-focus measurements, for example, where the distance between the sensor and the liquid surface to be measured must always be readjusted to maintain a constant level to determine the charge level, and in particular, the focus, focus point, or focal plane must always be located on the liquid surface. Preferably, high sampling rates are achieved by the method according to the present invention, particularly higher sampling rates than in interferometric and / or single-focus measurements.

[0065] In a preferred embodiment, the chromatic white light sensor is a confocal sensor.

[0066] In a preferred embodiment, before or during the performance of method steps a), b), c), particularly a), b), c), and d), or after the performance of method steps a), b), particularly a), b), and d), the distance from the chromatic white light sensor to the uncharged receptacle, particularly to the bottom of the uncharged receptacle, particularly to the closed end of the uncharged receptacle opposite the open end, is determined particularly by confocal chromatic measurement, particularly by the chromatic white light sensor.

[0067] In a preferred embodiment, method step d) may be performed before method step a), after method step b), or before method step a) and after method step b). Preferably, method step d) is performed once, particularly before method step a) or after method step b). Preferably, method step d) is performed twice, particularly before method step a) and after method step b).

[0068] Preferably, in a series of measurements where the same liquid is present, particularly within a receptacle made of the structurally identical material of a structurally identical carrier plate, a liquid-specific calibration value once determined can be used for each measurement in the series of measurements. Preferably, in such a series of measurements, the liquid-specific calibration value is determined in the first measurement of the series after method step b). Preferably, method-step sequences a), b), d), and c) are present in the first measurement. Preferably, the liquid-specific calibration value determined in the first measurement can also be used for a second measurement in the series, particularly without re-determining the liquid-specific calibration value. Preferably, method-step sequences d), a), b), and c) are present in the second measurement. Preferably, where a liquid-specific calibration value is determined in each measurement within the series of measurements, method-step sequences d), a), b), d), and c) are present for the second measurement.

[0069] Preferably, method step d) should be performed at least once for a specific liquid, in particular in combination with a specific carrier plate material and / or a specific receptacle geometry.

[0070] Preferably, liquid-specific calibration values ​​should be determined at least once for a specific liquid, particularly for a specific combination of the carrier plate material and / or receptacle geometry and the liquid. Preferably, liquid-specific calibration values ​​should be determined at least once, particularly during the first measurement within a series of measurements where the liquid-specific calibration values ​​are determined for the first time, and the determination of liquid-specific calibration values ​​may be optional for subsequent measurements. Preferably, for a measurement or series of measurements where already determined liquid-specific calibration values ​​can be used, further determination of liquid-specific calibration values ​​is not required, wherein each measurement follows method step sequence d), a), b), c). Preferably, liquid-specific calibration values ​​for a specific liquid are determined once and can be used in a method for determining a filling volume regardless of the determination location and time, and method step sequence d), a), b), c) are always present in each subsequent use.

[0071] Preferably, for example within a measurement series or for a specific liquid, in particular in combination with a specific carrier plate material and / or receptacle geometry, it is possible to determine a liquid-specific calibration value according to method step d) at a first position and / or first time, in particular, and then perform method steps a) to c) at a second position and / or second time independent of the first measurement at the first position, and this embodiment is also included in the method according to the present invention.

[0072] In a preferred embodiment, method step d) is performed before method step c), particularly before method step c) is performed for the first time.

[0073] According to the present invention, in particular, to determine the filling volume of a specific liquid among at least one liquid-filled receptacle according to the method according to the present invention, method step d) must be performed at least once.

[0074] In a preferred embodiment, method step d) comprises the following method steps:

[0075] v) a step of determining the total filling mass of a carrier plate having at least one liquid-filled receptacle by a metering device,

[0076] w) a step of determining the filling mass and filling volume of the liquid within at least one filled receptacle,

[0077] x) A step of confocally measuring the distance from the chromatic white light sensor to the liquid surface within each liquid-filled receptacle to determine the respective charge level at a defined distance between the support device and the white light sensor,

[0078] y) a step of determining the respective filling volume of a liquid-filled receptacle by considering the filling level determined in method step x), and

[0079] z) A step of determining a calibration value from the filling volume determined in method steps w) and y).

[0080] In a preferred embodiment, method step d) comprises the following method steps:

[0081] v) A step of determining the total filling mass of a carrier plate having at least one liquid-filled receptacle by a metering device.

[0082] w) a step of determining the filling mass and filling volume of the liquid within at least one filled receptacle,

[0083] y1) a step of determining the respective filling volume of a liquid-filled receptacle by considering the filling level determined in method step b), and

[0084] z) A step of determining a calibration value from the filling volume determined in method steps w) and y1).

[0085] Accordingly, in step d) of the method according to the present invention, a liquid-specific calibration value is determined. Preferably, to measure the filling volume of a liquid-filled receptacle in a carrier plate according to the present invention, a liquid-specific calibration value must always be considered, and this value must be determined at least once for the corresponding liquid. Preferably, steps for determining the liquid-specific calibration value are performed in the method according to the present invention.

[0086] Preferably, in method step d), the liquid-specific calibration value is determined using the confocal chromatic measurement value according to method step x) or the confocal chromatic measurement value according to method step b).

[0087] In a preferred embodiment, the method according to the present invention is performed in the following order of method steps: v), w), x), y), z), a), b), c) or a), b), v), w), x), y), z), c) or v), w), x), y), z), c) or a), b), v), w), y1), z), c) or v), w), x), y), z), a), b), v), w), y1), z), c) or v), a), b), w), y1), z), c) or v), w), a), b), y1), z), c) or v), a), w), b), y1), z), c).

[0088] Preferably, the liquid-specific calibration value is thus completely determined before method step a) or after method step b), and thus particularly during the method according to the present invention, or once before method step a) and after method step b), particularly twice during the method according to the present invention, or part of the determination of the liquid-specific calibration value is performed before method step a) and the remainder is performed after method step a), or part of the determination of the liquid-specific calibration value is performed before method step b) and the remainder is performed after method step b).

[0089] In a preferred embodiment, the confocal chromatic measurement according to method step b) is also used to determine liquid-specific calibration values. Preferably, two separate confocal chromatic measurements are performed, in particular a first confocal chromatic measurement according to method step x), and in particular a second confocal chromatic measurement according to method step b) after the first measurement.

[0090] The calibration value is preferably determined by a weighing device associated with at least one support device. Preferably, the support device accommodates a carrier plate having at least one liquid-filled receptacle, and the carrier plate is associated with a weighing device, in particular a precision balance. Preferably, in method step v), the total filling mass of the carrier plate having at least one liquid-filled receptacle is measured by the weighing device. Preferably, in method step w), the filling mass and filling volume of the liquid within at least one liquid-filled receptacle are determined from the total filling mass of the carrier plate having at least one liquid-filled receptacle. Preferably, if there are at least two liquid-filled receptacles, the average filling mass and average filling volume of each liquid-filled receptacle are determined. Preferably, in method step x), the respective filling level is determined by measuring the distance between the liquid surface of each liquid-filled receptacle and the chromatic white light sensor at a defined distance between the support device and the white light sensor using confocal chromatography. Preferably, in method step y), the filling volume of each liquid-filled receptacle is determined by considering the filling level determined in method step x). Preferably, in method step y1), the filling volume of each liquid-filled receptacle is determined by considering the filling level determined in method step b). Preferably, in method step z), a calibration value is determined from the filling volume determined in methods w) and y) or w) and y1).

[0091] In a preferred embodiment, method step v) includes the following method steps:

[0092] v1a) A step of measuring the total mass of the carrier plate that is not filled by a weighing device,

[0093] v2a) A step of filling at least a portion of the receptacles of the carrier plate with liquids of equal or unequal volumes,

[0094] v3a) A step of measuring the total mass of the carrier plate filled by a weighing device, and

[0095] v4a) A step of determining the total filling mass of the carrier plate by considering the masses measured in method steps v1a) and v3a).

[0096] In a preferred embodiment, method steps v1a) and v2a) are performed before method step a).

[0097] In a preferred embodiment, method step v3a) is performed before or after method step x) and / or method step y) or method step b) and / or method step y1).

[0098] In a preferred embodiment, method step v4a) is always performed after method step v3a).

[0099] In a preferred embodiment, method step v) includes the following method steps:

[0100] v1b) A step of providing an uncharged carrier plate on a metering pan or providing an uncharged carrier plate associated with a lifting element - said metering pan or lifting element is positioned at a defined distance from a chromatic white light sensor, and said metering pan or lifting element is configured to be movable perpendicular to the white light sensor in a mass-dependent manner, particularly by a bending element associated with said metering pan or lifting element -.

[0101] v2b) A step of confocally measuring the distance from a chromatic white light sensor to a reference point, particularly on a weighing pan supporting an uncharged carrier plate or on a lifting element associated with the carrier plate, particularly on a bending element associated with the weighing pan or lifting element,

[0102] v3b) A step of filling at least a portion of each of the carrier plates with liquids of equal or unequal volumes,

[0103] v4b) A step of confocally measuring the distance from a chromatic white light sensor to a reference point, particularly on a weighing pan supporting a charging carrier plate or on a lifting element associated with the carrier plate, particularly on a bending element associated with the weighing pan or lifting element,

[0104] v5b) A step of determining the total filling mass of the carrier plate by considering the distances measured in method steps v2b) and v4b).

[0105] In a preferred embodiment, method steps v1b) to v3b) are performed prior to method step a).

[0106] In a preferred embodiment, method step v4b) is performed before or after method step x) and / or method step y) or method step b) and / or method step y1).

[0107] In a preferred embodiment, method step v5b) is always performed after method step v4b).

[0108] In a preferred embodiment, in the method according to the present invention, a total of three confocal chromatic measurements are performed, particularly in method steps v2b), v4b), and b) or x).

[0109] In a preferred embodiment, in the method according to the present invention, a total of four confocal chromatic measurements are performed, particularly in method steps v2b), v4b), x), and b).

[0110] Preferably, the reference point according to method steps v2b) and v4b) is placed on the unfillable portion of the carrier plate or on the metering pan supporting the carrier plate, or on the lifting element associated with the carrier plate or the bending element associated with the lifting element associated with the carrier plate.

[0111] Preferably, the algorithm for obtaining the calibration value can be described as follows. Preferably, the average well volume V_receptacle,average is determined according to method steps v) and w).

[0112] Preferably, in this context, before filling at least one receptacle with liquid, the carrier plate is weighed in an empty state, i.e., unfilled state, according to method step v1a) to obtain the mass of the carrier plate having at least one unfilled receptacle (also called empty mass, m_TP, empty).

[0113] Alternatively or additionally, before filling the liquid into at least one receptacle, it is preferable that a carrier plate having at least one unfilled receptacle be provided on the metering pan according to method step v1b), or provided thereon in association with a lifting element. Preferably, the metering pan or lifting element is positioned at a defined distance from the chromatic white light sensor. Preferably, the metering pan or lifting element is configured to be movable in a mass-dependent manner relative to the white light sensor in a vertical direction, particularly in the z-direction of the Cartesian coordinate system. Preferably, the metering pan or lifting element is movable in a mass-dependent manner by a bending element associated with the metering pan or lifting element. Preferably, depending on the mass acting on the bending element, the bending element is movable particularly perpendicular to the white light sensor, particularly in the z-direction of the Cartesian coordinate system, particularly deformable, and particularly bendable. Preferably, in method step v2b), the distance from the chromatic white light sensor to a reference point is measured confocally chromatically. Preferably, the reference point is located on the metering pan or the lifting element associated with the carrier plate that supports the unfilled carrier plate. Preferably, the reference point is located on a bending element associated with a weighing pan or lifting element. The measured distance (also called empty distance d_empty) is related to the mass of a carrier plate (also called empty mass m_TP,empty) having at least one unfilled receptacle.

[0114] Preferably, method step v1a) or method steps v1b) and v2b) are performed once for a series of carrier plates, particularly a production series, in particular when the mass difference of the carrier plates is negligibly small or particularly the same.

[0115] Preferably, according to method step v2a) or v3b), at least one unfilled receptacle of the carrier plate, in particular all unfilled receptacles, are filled with an equal volume of liquid having a density ρ_liquid known particularly by the dispensing device.

[0116] Preferably, according to method step v2a) or v3b), if only method step b) is performed, particularly for a confocal chromatic measurement of a distance to determine a fill level, and if method step x) is not performed, particularly for a confocal chromatic measurement of a distance to determine a fill level, at least one receptacle of the carrier plate is filled in the same manner as the carrier plate, and in particular, the carrier plate to be filled in method step v2a) or v3b) is provided with at least one liquid-filled receptacle provided in method step a).

[0117] Preferably, in method step v2a) or v3b), a receptacle corresponding to the filled receptacle of the carrier plate in method step a) is filled.

[0118] Preferably, depending on the mass added to the mass of the uncharged carrier plate, the bending element causes more deformation, particularly bending, than the initial state where only the uncharged carrier plate is placed on the metering pan or associated with the lifting element. Preferably, the added mass corresponds to the mass of the liquid charged in the uncharged receptacle. Preferably, due to the deformation of the bending element, particularly additional deformation, particularly bending, the distance between the reference point and the chromatic white light sensor increases or decreases.

[0119] Preferably, according to method step v3a), the carrier plate having the receptacle filled by the dispensing device is weighed by the weighing device to determine the mass of the carrier plate having the filled receptacle (also called total mass m_TP, filled).

[0120] Preferably, in method step v4b), the distance between the reference point and the chromatic white light sensor is measured confocally chromatically. Preferably, the reference point is located on a weighing pan supporting the charged carrier plate or on a lifting element associated with the carrier plate. Preferably, the reference point is located on a bending element associated with the weighing pan or lifting element. The measured distance d_filled (also called total distance) is related to the mass of the carrier plate having at least one charged receptacle (also called total mass, m_TP,filled).

[0121] Preferably, according to method step v4a) or v5b), the mass of the carrier plate having liquid-filled receptacles (also called the net filled mass m_TP,net) is calculated using Equation (1.1):

[0122] m_TP,net = m_TP,filled - m_TP,empty (1.1)

[0123] Preferably, according to method step v5b), the distance (also called net distance d_net) between the position of the reference point during the measurement of a carrier plate having at least one uncharged receptacle according to method step v2b) and the position of the reference point during the measurement of a carrier plate having at least one charged receptacle according to method step v4b) is calculated using Equation (1.2):

[0124] d_net = d_filled - d_empty (1.2)

[0125] Preferably, in method step v), the total filling mass of a carrier plate having at least one liquid-filled receptacle is measured by a metering device. Preferably, the total filling mass is measured 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 from the chromatic white light sensor of an unfilled carrier plate is determined by a metering device, wherein the unfilled carrier plate corresponds to the carrier plate provided in method step a), and at least one receptacle is filled with liquid. Preferably, in v2a) or v3b), at least a portion of the receptacles of the carrier plate is filled with liquid of equal or unequal volumes, respectively. Preferably, in method step a), the receptacles corresponding to the filled receptacle of the carrier plate are filled. Preferably, in method step v3a), the total filling mass, or in v4b), the total distance from the chromatic white light sensor of the filled carrier plate is determined by a metering device. Preferably, in method step v4a) or v5b), the total filling mass of the carrier plate is determined by considering the mass measured in method steps v1a) and v3a) or the distance measured in v2b) and v4b).

[0126] Preferably, according to method step w), the average net filling mass for each individual liquid-filled receptacle of the carrier plate is determined using Equation (2):

[0127] m_receptacle,average = m_TP,net / n_receptacle (2),

[0128] Here, n is the number of liquid-filled receptacles on the carrier plate.

[0129] Preferably, according to method step w), the average volume of each filled receptacle is calculated from the mass and density of the liquid using Equation (3):

[0130] V_receptacle,average = m_receptacle,average / ρ_liquid (3).

[0131] Preferably, according to method step x) or method step b), a confocal chromatic measurement of the distance from a chromatic white light sensor to the liquid surface within each liquid-filled receptacle is performed.

[0132] In such distance measurements, a measurement error ε frequently occurs; taking this error into account is the subject of this technical teaching and corresponds to a liquid-specific calibration value. Preferably, without being bound by theory, the measurement error is caused by the physical properties of the liquid surface of the liquid present in at least one receptacle and optionally by the carrier plate material, thereby forming individual meniscuses and leading to the measurement error ε. Preferably, this is reflected using Equation (4):

[0133] V_receptacle,optical = f(h, G) (4),

[0134] The volume V_receptacle,optical calculated here is a function of the measured filling level h + ε, where h is the actual filling level of the liquid in the receptacle and ε is the measurement error, and is a function of the height-dependent geometry G of the liquid in the receptacle. Preferably, the mathematical function dependent on the filling level can be determined from the measurement of the filling level of a known liquid volume, particularly using V_receptacle,average according to method step y) or y1), without information on the height-dependent geometry of the liquid in the receptacle.

[0135] Preferably, the measurement results from method steps w) and x) or b) are substituted into Equation (5):

[0136] Σ V_receptacle,average = Σ V_receptacle,optical (5).

[0137] Preferably, according to method step z), the measurement error ε corresponding to the liquid-specific calibration value, particularly the liquid- and material-specific calibration value, is determined by solving a multidimensional equation system or through iterative approximation. Preferably, the calibration value is determined when Equation (5) holds for a specific ε.

[0138] Preferably, high measurement accuracy can be achieved by combining confocal measurement technology and a precision balance by the method according to the present invention. Preferably, the method according to the present invention can simplify system calibration by being an integrated method, that is, by combining weighing and optical measurement in a single system.

[0139] Preferably, the support device includes a receiving device for receiving a carrier plate, wherein the carrier plate is positioned within the receiving device to enable movement relative to the chromatic white light sensor.

[0140] Preferably, the metering device includes a lifting element and is configured so that the carrier plate can be lifted from below from the support device by this lifting element.

[0141] Preferably, the support device includes or is composed of a metering pan. Preferably, the metering pan is positioned, in particular, mounted on a load cell movable in the z-direction, i.e., parallel to the measurement direction. Preferably, method steps v1a) to v4a) or v1b) to v5b) are performed with such device embodiments.

[0142] Preferably, the metering pan and the receiving device are in contact with each other.

[0143] Preferably, the mass of the carrier plate is measured by lifting the carrier plate using a lifting element or moving the weighing pan, particularly by reciprocating the load cell in the z-direction.

[0144] Preferably, the bending element is associated with a metering pan or a lifting element. Preferably, the mass of the carrier plate is determined by the bending element, particularly by reversible deformation, especially bending.

[0145] Preferably, a force sensor is placed on the bending element. Preferably, a force sensor is placed on the bending element, and steps v1a) to v4a) are performed with this placement method.

[0146] Preferably, the force sensor is not placed on the bending element, and steps v1b) to v4b), particularly v5b) are performed with this placement method.

[0147] Preferably, the metering pan is placed on the bending element. Preferably, the lifting element is placed on the bending element below the bending element.

[0148] In a preferred embodiment, the support device is configured such that the z-direction displacement of the carrier plate has an intrinsic relationship with the mass of the carrier plate. Preferably, the z-direction displacement of the carrier plate is determined by confocal chromatic measurement. Preferably, the chromatic white light sensor is fixedly mounted on the support device. Preferably, only the z-direction displacement of the chromatic white light sensor is possible. Preferably, the support device has a bending hinge so that it is movable at least in the z-direction, particularly in the x-, y-, and z-directions. Preferably, method steps v1b) to v4b), particularly v5b), are performed with such an embodiment of the device.

[0149] Preferably, when the height-dependent geometry of the liquid, particularly the volume occupied by the liquid within at least one receptacle, is unknown, method steps v1a) to v4a) or v1b) to v4b), particularly v5b) are performed several times. Preferably, in method step v2a) or v3b), at least one portion of the receptacle of the carrier plate is filled with the same volume of liquid. Preferably, when method steps v1a) to v4a) or v1b) to v4b), particularly v5b) are performed several times and the height-dependent geometry of the liquid, particularly the volume occupied by the liquid within at least one receptacle, is unknown, different liquid volumes are used in different measurements. Preferably, this provides pairs of values ​​that serve as support points for determining a mathematical function describing the relationship between the measured distance and the volume. Preferably, the determined mathematical function is reflected in Equation (4).

[0150] In a preferred embodiment, the metering pan can be displaced vertically relative to the white light sensor in a mass-dependent manner.

[0151] In a preferred embodiment, the bending element associated with the metering pan can be deformed in a direction perpendicular to the white light sensor in a mass-dependent manner, and can be bent in particular.

[0152] In a preferred embodiment, the lifting element, particularly the bending element associated with the lifting element, can be displaced vertically relative to the white light sensor in a mass-dependent manner and, in particular, can be bent.

[0153] In a preferred embodiment, the bending element associated with the lifting element can be deformed in a direction perpendicular to the white light sensor in a mass-dependent manner, and in particular, can be bent.

[0154] In a preferred embodiment, the carrier plate is a plate having a plurality of portions, in particular at least 96 portions, in particular 96, 384, or 1536 portions, in particular a microtiter plate.

[0155] In a preferred embodiment, the carrier plate is a microtiter plate having 384 or 1,536 portions.

[0156] In a preferred embodiment, method step b) or b) and c) are performed sequentially for a plurality of receptacles of the carrier plate, and in particular, the carrier plate is displaced at equal intervals with respect to the white light sensor. Preferably, the distance between the support device and the chromatic white light sensor defined in method step a) is maintained equal. Preferably, when there is a displacement parallel to the measurement direction, particularly the z-direction, the chromatic white light sensor and the support device are displaced by the same distance.

[0157] In a preferred embodiment, method step d) is performed once.

[0158] In a preferred embodiment, method step d) is performed before each measurement in the measurement series.

[0159] In a preferred embodiment, a calibration value for different measurements but the same height-dependent geometry of the liquid, particularly the volume occupied by the liquid, is determined once in at least one receptacle, and the same calibration value is used for additional measurements. In a preferred embodiment, a calibration value is newly determined for each measurement of liquid volumes having the same height-dependent geometry of the liquid in at least one receptacle.

[0160] In a preferred embodiment, in method step y) or y1), the filling volume is determined by measuring the filling level of the liquid in at least one receptacle by confocal chromatography at a defined distance between the support device and the white light sensor and taking into account the volume occupied by the liquid in at least one receptacle, or by measuring the filling level of different known filling volumes of the liquid in at least one receptacle by confocal chromatography at a defined distance between the support device and the white light sensor.

[0161] In a preferred embodiment, the method is an automated method. In a preferred embodiment, the method is not a manual method. Preferably, human error can be minimized or prevented by the automated method. Preferably, an accurate method can be implemented through this.

[0162] Another aspect of the present invention relates to a system, particularly an apparatus, for determining the filling volume of at least one liquid-filled receptacle in a carrier plate configured to perform a method according to the present invention, particularly method steps a), b), c), and d), particularly method steps b) and c) repeated several or numerous times, and method step d) performed at least once before method step c) is first performed, comprising at least one chromatic white light sensor, a support device for a carrier plate, and at least one metering device associated with the support device to determine a liquid-specific calibration value, particularly the total filling mass of the liquid-filled carrier plate, wherein the chromatic white light sensor and the support device are disposed at a distance defined from each other, particularly in the measurement direction of the chromatic white light sensor, and the chromatic white light sensor, the support device, or both are configured to be movable. Optionally, the system has at least one carrier plate comprising at least one, preferably a plurality or a number of liquid-filled receptacles.

[0163] In a preferred embodiment, the system according to the present invention is a system for performing at least one confocal chromatic measurement. In a preferred embodiment, the system according to the present invention is not a system for performing an interferometric measurement or a single-focus scanning measurement. In a preferred embodiment, an interferometric method or a single-focus scanning method cannot be performed in the system according to the present invention.

[0164] Preferably, by using a chromatic white light sensor of the system according to the present invention at a constant distance from a support device, the filling level of a liquid in at least one receptacle can be measured without changing the distance between the sensor and the support device, particularly without moving the chromatic white light sensor, the support device, or both perpendicularly to each other, particularly in the z-direction, particularly upward or downward, and without needing to readjust to always maintain a constant distance between the sensor and the liquid surface, in particular, a system for performing a single-focus scanning method or a system for performing an interferometer method—whereby the distance between the sensor and the support device changes—while preventing the distance between the sensor and the support device from changing. In known systems, the same distance between the sensor and the liquid surface must always be maintained. For this reason, when changing the distance, the sensor, the support device, or both must be moved vertically, particularly in the z-direction, and especially upward or downward. This results in high time consumption when performing measurement methods, particularly due to the physical reciprocating movement of the sensor, the support device, or both, and results in even greater time consumption than when performing measurement methods with the system according to the present invention. Therefore, the system according to the present invention is accurate, cost-effective, and time-saving, and consumes significantly less time than existing systems.

[0165] In a preferred embodiment, the system is a system in which an automated method can be performed.

[0166] In a preferred embodiment, step d) of the method according to the present invention is performed by a metering device of the system according to the present invention. Preferably, the calibration value according to steps v) to z) of the method according to the present invention is determined by the metering device of the system according to the present invention. Preferably, the total filling mass is determined by the metering device of the system according to the present invention, particularly according to step v) of the method according to the present invention, and particularly according to steps v1a) to v4a) or v1b) to v5b) of the method according to the present invention. Preferably, the calibration value according to steps v) to z) of the method according to the present invention is determined by the metering device of the system according to the present invention and the chromatic white light sensor of the system according to the present invention. Preferably, by the chromatic white light sensor of the system according to the present invention, particularly according to step x) or b) of the method according to the present invention, the distance from the chromatic white light sensor to the liquid surface within each liquid-filled receptacle is confocally measured to determine each filling level at a defined distance between the support device and the white light sensor.

[0167] Preferably, the metering device of the system according to the present invention is not provided for the purpose of inspecting the accuracy, in particular the uniformity, of the dispensing device. Preferably, the metering device of the system according to the present invention does not measure a reference substance, in particular water as a reference substance.

[0168] In a preferred embodiment, the system includes only one carrier plate.

[0169] In a preferred embodiment, the support device is a separate component or a separate or integral part of the metering device.

[0170] In a preferred embodiment, the metering device includes a force sensor, in particular a load cell and a lifting element, or is a metering device equipped with an electromagnetic force compensation function.

[0171] In a preferred embodiment, the weighing device includes a bending element, particularly a double bending element. In a particularly preferred embodiment, the bending element is a spring. In the context of the present invention, the bending element is reversibly deformable. Preferably, the bending element is used to measure mass by deforming, particularly bending, through the action of a contacting mass. When the bending element is no longer in contact with the mass, the bending element returns to its original geometry. In a preferred embodiment, the bending element is associated with a weighing pan or a lifting element.

[0172] In a preferred embodiment, the force sensor can move relative to the support device, particularly in the vertical direction, particularly parallel to the measurement direction.

[0173] In a preferred embodiment, the support device includes a receiving device for receiving a carrier plate, the receiving device being configured such that the carrier plate, particularly when placed within the receiving device, can move in contact with a lifting element, particularly in a vertical direction, particularly parallel to the measurement direction. Preferably, the carrier plate placed within the receiving device is lifted by the lifting element.

[0174] In a preferred embodiment, the support device is an integral component of the carrier plate, and in particular, the support device corresponds to the bottom of the carrier plate.

[0175] In a preferred embodiment, the carrier plate is in direct contact with the lifting element and can move, particularly in the vertical direction, particularly parallel to the measurement direction. Preferably, the carrier plate is lifted directly by the lifting element.

[0176] In a preferred embodiment, the metering device includes a metering pan, and the chromatic white light sensor is configured to perform method steps b) and / or x) and v2b) and v4b).

[0177] In a preferred embodiment, the bending element is associated with a metering pan or a lifting element.

[0178] In a preferred embodiment, the metering pan can be displaced vertically relative to the white light sensor in a mass-dependent manner, or the bending element associated with the metering pan is configured to deform, in particular, bend vertically relative to the white light sensor in a mass-dependent manner.

[0179] In a preferred embodiment, the lifting element is configured to be displaced relative to the white light sensor in a mass-dependent manner, or, in particular, to be bent so that the bending element associated with the lifting element can be deformed vertically relative to the white light sensor in a mass-dependent manner.

[0180] In a preferred embodiment, the metering pan is a separate component or a separate or integral part of the support device or metering device.

[0181] In a preferred embodiment, the support device is an integral part of the weighing device and is composed of a weighing pan. Preferably, when the support device is configured to support and weigh a carrier plate, the support device is a weighing pan.

[0182] In a preferred embodiment, the support device is a separate component, and the metering device includes a lifting element.

[0183] In a preferred embodiment, the system according to the present invention preferably comprises a data processing device including at least one control unit and at least one memory device, and the data processing device is configured to control the performance of the method according to the present invention, in particular to control the performance of the method according to the present invention and to evaluate and display a filling volume determined according to the method.

[0184] In a preferred embodiment, the system according to the present invention includes a control unit configured to control the performance of the method according to the present invention.

[0185] The present invention provides a chromatic white light sensor, a support device, or both, capable of moving relative to each other, particularly in a plane perpendicular to the measurement direction. As a result, a high sampling rate for the receptacles of a carrier plate can be achieved, and in particular, said at least one plane extends to the x- and y- directions of a Cartesian coordinate system. Preferably, when the white light sensor and / or support device are moved relative to each other in a plane perpendicular to the measurement direction, a defined distance from the chromatic white light sensor to the support device is maintained constant. If the defined distance changes as the white light sensor and / or support device reciprocates relative to each other in a plane perpendicular to the measurement direction, such change in defined distance must be taken into account when subsequently determining the filling volume of at least one liquid-filled receptacle of the carrier plate according to the method according to the present invention. The chromatic white light sensor and / or support device can be moved in the z- direction of the Cartesian coordinate system, i.e., the measurement direction, so that they can move toward each other or away from each other, and thus the distance between them can increase or decrease. When moving in the z-direction after or during measurement, the predefined distance between the chromatic white light sensor and the support device must be adjusted by the change in mutually relative distance.

[0186] In a preferred embodiment, the chromatic white light sensor and the support device are movable relative to each other, particularly movable relative to each other in all three spatial directions. 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 is movable in the x- and y-directions, and optionally in the z-direction. Preferably, the chromatic white light sensor is movable in the x- and y-directions, and optionally in the z-direction, and the support device is movable in the z-direction. Preferably, the chromatic white light sensor is movable in the x-direction, and optionally in the z-direction, and the support device is movable in the y-direction, and optionally in the z-direction. Preferably, the chromatic white light sensor is movable only in the x- and y-directions. Preferably, the chromatic white light sensor is not movable in the z-direction. Preferably, when a displacement occurs in the measurement direction, particularly parallel to the z-direction, the chromatic white light sensor and the support device should be displaced by the same distance.

[0187] In a preferred embodiment, the system according to the present invention comprises a single device. In a preferred embodiment, the system according to the present invention comprises a plurality of devices, particularly two devices, and is particularly composed of these. In a preferred embodiment, the first device comprises a chromatic white light sensor, a support device for a carrier plate, and at least one carrier plate having at least one receptacle, and the second device comprises a metering device for determining a liquid-specific calibration value, and the metering device of the second device is associated with the support device of the first device.

[0188] In the context of the present invention, the x-, y-, and z- directions correspond to the x-, y-, and z- directions of the Cartesian coordinate system, respectively, where the z- direction is a vertical direction, particularly a direction parallel to the measurement direction, and the x- and y- directions are horizontal directions, particularly perpendicular to the measurement direction. Thus, the z- direction is positioned perpendicular to the plane spanning the x- and y- directions. The Cartesian coordinate system referenced is shown in FIGS. 1, FIGS. 5, and FIGS. 6 through 8.

[0189] In the context of the present invention, "plane perpendicular to the measurement direction" should be understood to mean a plane perpendicular to the measurement direction in which the chromatic white light sensor and / or support device is movable.

[0190] In the context of the present invention, the term "system" should be understood to mean a single-component or multi-component device, particularly an integral device, comprising one or more units or modules that may exist in one or more housings, particularly a chromatic white light sensor, a metering device, and a support device.

[0191] In the context of the present invention, the term "chromatic white light sensor" should be understood to mean a sensor that fan-shaped a beam of light from a white light source into its spectral components along the axial direction, that is, in the direction of light propagation. Preferably, when an object is introduced into the fan-shaped light beam, the light beam is reflected, and the different spectral components of the fan-shaped light beam are reflected to different degrees. Preferably, the reflected light beam is received again and projected through a beam splitter onto a conventional spectrometer, that is, a spectrometer known to those skilled in the art. Based on the spectral intensity distribution of the reflected spectral components of the reflected light beam, the position of the object, that is, the distance from the sensor, is determined within the spectral range of the fan-shaped light beam. Depending on the design of the sensor, measurement accuracy in the double-digit nanometer range can be achieved. In a preferred embodiment, at least one additional optical component, such as a mirror, for deflecting the light beam may be associated with the chromatic white light sensor.

[0192] In the context of the present invention, "confocal chromatic measurement" should be understood to mean a measurement method in which a combination of confocal focusing and chromatic dispersion is used to accurately 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 split, and due to chromatic dispersion, different wavelengths are imaged at different focal planes or foci, particularly along the measurement direction. Preferably, measuring the back-reflected or scattered light intensity as a function of wavelength enables the accurate assignment of focal planes or foci, thereby enabling the determination of distance information or surface structure of the object. Preferably, confocal chromatic measurement should not be understood as meaning monofocal measurement. Preferably, confocal chromatic measurement is not monofocal because it is based on the simultaneous evaluation of light of different wavelengths, and each wavelength is assigned to a specific focal plane or specific foci. By analyzing the back-reflected or scattered light intensity as a function of wavelength, the accurate assignment of measurement data to each focal plane or foci becomes possible, thereby specifically measuring the distance of the object from the sensor.

[0193] In the context of the present invention, "interferometer" should be understood to mean a measurement method in which the superposition of two or more coherent wavelengths, particularly light waves (also referred to as interference), is used to determine physical quantities such as distance, wavelength, refractive index, surface profile, or deformation. Preferably, changes in the phase or intensity of the interfering wavelengths caused by differences in path length, propagation direction, or interaction with an object are analyzed.

[0194] In the context of the present invention, "single-focus measurement" should be understood to mean an optical method in which light is focused only on a single focal position, focal point, or single focal plane. Preferably, since imaging is independent of the wavelength of light used, the single focal position, focal point, or focal plane remains the same for all light waves considered.

[0195] In the context of the present invention, the term "single-focus scanning method" should be understood to mean an optical measurement or scanning method that uses a single focus, focal plane, or focal length to detect characteristics such as the position, shape, surface, or structure of an object. The focal position, focal plane, or focal length must be kept constant, and the distance between the sensor and an object or liquid surface at different heights must also always be kept constant, even if the sensor is moved back and forth during the method. Preferably, the method is characterized in that the focus, focal plane, or focal length is positioned constant on the liquid surface during all measurements and is not altered, in particular, by chromatic dispersion or spectral splitting.

[0196] Preferably, in the context of the present invention, one difference between confocal chromatic measurement and interferometric measurement according to the present invention is that confocal chromatic measurement is based on the spectral splitting and detection of light emanating from different focal planes or foci, whereas interferometric measurement determines distance or deformation using phase interference of coherent light.

[0197] Preferably, in the context of the present invention, one difference between the confocal chromatic measurement method and the single-focus scanning method according to the present invention is that the confocal chromatic measurement method considers multiple focal planes or focal points using light of different wavelengths to measure the characteristics of an object, particularly the distance to the object, whereas the single-focus scanning method is based on a fixed focal position or focal point or fixed focal plane where the focus is maintained constant and spectral splitting of light is not applied. While the confocal chromatic measurement method improves measurement accuracy and resolution by utilizing chromatic dispersion and multiple wavelengths, the single-focus scanning method is based on the accuracy of a single focal position or focal point or single focal plane, where the distance between the sensor and the object or multiple objects, particularly liquid surfaces of different heights, must always be maintained constant, so the single focal position or focal point or single focal plane must always be located on the object or liquid surface.

[0198] In the context of the present invention, a “receptacle” is a structure, particularly a recess or other structure, capable of spatially immobilizing a liquid of a configurable, particularly quantifiable, volume in a configurable manner. Such spatial immobilization is also referred to herein as “filling.” Additionally, the receptacle may be a functionally confined area of ​​a planar surface, for example, a liquid adsorption area.

[0199] Accordingly, in the context of the present invention, "receptacle" should be understood to mean a region capable of receiving a liquid, such as one that can be filled with a liquid. Preferably, the receptacle is a structure that spatially fixes a portion, particularly a well or a liquid volume, particularly a spatially limited region. Preferably, the receptacle, particularly the portion or the structure that spatially fixes the liquid volume, has a liquid adsorption region. Preferably, the receptacle is a hydrophilic region having a geometry different from the portion or a lipophilic region having a geometry different from the portion, which receives a hydrophilic or lipophilic liquid. Preferably, the receptacle is a region on the surface of a carrier plate on which polar or non-polar molecules, particularly polar molecules, are arranged, particularly a planar region.

[0200] Accordingly, in the context of the present invention, "liquid-filled receptacle" should be understood to mean, in particular, that the receptacle is filled with liquid, that is, that liquid is present within the receptacle or the receptacle holds liquid. Preferably, the filling volume relates to the liquid received by the receptacle, wherein the receptacle has a portion or structure, in particular a structure that spatially fixes the liquid volume, which may be composed, for example, of a liquid adsorption area on the surface of a carrier plate. Preferably, the liquid adsorption area is a hydrophilic or hydrophobic planar area on the surface of the carrier plate. Thus, "within the receptacle" means that the liquid is allocated to the receptacle, that is, the liquid is fixed to the receptacle, and is, for example, located within a portion or adsorbed on a planar receptacle. Preferably, due to the geometry of at least one receptacle and the arrangement of adjacent receptacles, mixing of liquids in adjacent liquid-filled receptacles is prevented. Preferably, due to the geometry of at least one liquid-filled receptacle, liquid overflow is prevented.

[0201] In the context of the present invention, "filled" should be understood to mean not only that a receptacle composed of a portion is filled with liquid or is being filled, but also that a receptacle not composed of a portion holds liquid.

[0202] In the context of the present invention, the “measurement direction” should be understood to mean a direction aligned parallel to the optical axis of the light cone generated by the chromatic white light sensor; in particular, the measurement direction is perpendicular to the liquid surface of the liquid present in the receptacle of the carrier plate, and in particular perpendicular to the center of the liquid surface. Where the light path is refracted by an optical element between the chromatic white light sensor and the liquid surface, the “measurement direction” is a direction oriented parallel to the optical axis of the light cone striking or penetrating the liquid surface. According to the present invention, the term “perpendicular” should be understood to mean a range of 80° to 100°, in particular 85° to 95°, in particular 90°.

[0203] In the context of the present invention, "defined distance" should be understood to mean a deliberately selected distance. Preferably, particularly in relation to the arrangement of a chromatic white light sensor and a support device, "defined distance" refers to the path along which a light beam generated by the chromatic white light sensor travels to a reference point, wherein the reference point is located on an object for which the distance from the chromatic white light sensor is to be determined. The path may be particularly straight or oblique. Preferably, the object is a liquid-filled receptacle of a carrier plate within the support device, a lifting element, a bending element, an unfilled portion of the carrier plate, or a liquid present in the support device, particularly in a metering pan. Preferably, the reference point on the liquid is located at the center of the liquid surface. The defined distance can be accurately measured and determined at any time and can be reflected in subsequent measurements.

[0204] In the context of the present invention, "correction value" should also be understood to mean a calibration value. Preferably, the correction value is a value that compensates for measurement uncertainty ε.

[0205] In the context of the present invention, "liquid-specific calibration value" should be understood to mean a numerical value that takes into account the physical, chemical, and / or thermodynamic properties of a specific liquid. Preferably, the liquid-specific calibration value is used to adjust and / or calibrate at least one calculation, in particular the determination of a filling volume, and / or at least one process, in particular a method according to the present invention. Preferably, the liquid-specific calibration value takes into account specific parameters of the liquid, in particular parameters attributable only to the liquid, such as viscosity, density, surface tension, temperature change, chemical composition, or combinations thereof, and enables calculation, measurement, or adjustment and / or calibration of the process regarding specific properties of the liquid.

[0206] In the context of the present invention, "liquid- and material-specific correction values" should be understood to mean numerical values ​​that take into account not only the specific physical, chemical, and / or thermodynamic properties of a specific liquid, but also the geometry of the material, particularly the carrier plate material, and its interaction with the receptacle geometry, and the thermal or mechanical conditions of the material constituting the receptacle and in which the liquid exists. Preferably, the liquid- and material-specific correction values ​​are used to adjust and / or calibrate at least one calculation, particularly the determination and measurement of the filling volume and / or at least one process performed with the liquid contained in the receptacle, in order to compensate for effects such as viscosity, density, thermal conductivity, surface tension, or liquid distribution.

[0207] In the context of the present invention, "height-dependent geometry" should be understood to mean the volume occupied by the liquid present in the liquid-filled receptacle. Preferably, the meniscus formed by the liquid within the receptacle is taken into account in the height-dependent geometry.

[0208] In the context of the present invention, the term "weighing device" should be understood to mean a device configured to determine the mass of an object. Preferably, the mass of an object is measured using confocal chromatography with a chromatic white light sensor or by using a balance, for example, a precision balance.

[0209] In the context of the present invention, the term "support device" should be understood to mean a device configured to position a carrier plate at a defined distance from a white light sensor.

[0210] In the context of the present invention, the term "carrier plate" should be understood to mean a plate having a body having a substantially cubic geometry and, preferably, two or three different side lengths, at least one, preferably a plurality or multiple, receptacle. The receptacle may be integrally disposed with the body and completely penetrate the body, or it may be enclosed by a separate wall and fixed to a holder of the body. The receptacle is preferably located on the widest outer surface of the body having a substantially cubic geometry.

[0211] Preferably, "carrier plate" should be understood to mean a plate comprising at least one receptacle, particularly a well, wherein the at least one receptacle has an open end and a closed end opposite the open end. Preferably, the carrier plate is a multi-well plate comprising at least one receptacle, particularly a well. Preferably, the carrier plate comprises a frame portion that functions as a holder for at least one receptacle. Preferably, the receptacle is enclosed by a wall. Preferably, the carrier plate is a device comprising a plurality or multiple receptacles, particularly wells, arranged in a regular grid shape and secured in place by the frame portion. Preferably, the carrier plate has standardized dimensions such as ANSI / SLAS standards. Optionally, an identifier, marking, or RFID tag may be integrated into the top surface of the carrier plate or the top surface of the frame portion to ensure clear identification and traceability. Brief explanation of the drawing

[0212] The drawing is as follows: FIG. 1 is a schematic diagram of a device according to the present invention. FIG. 2 is a schematic diagram of a chromatic white light sensor, a carrier plate having a liquid-filled receptacle, and an incident angle range of a chromatic white light sensor light beam defining the measurement direction. FIG. 3 is a schematic diagram of a carrier plate having a chromatic white light sensor and a liquid-filled receptacle, wherein the light beam of the chromatic white light sensor is refracted by a mirror. FIG. 4 is a schematic diagram of a chromatic white light sensor and a carrier plate having a liquid-filled receptacle, wherein the carrier plate has a planar liquid-adsorbent receptacle. FIG. 5 is a schematic diagram of one embodiment of a device according to the present invention. FIG. 6 is a schematic diagram of one embodiment of a device according to the present invention. FIG. 7 is a schematic diagram of a metering device equipped with a chromatic white light sensor. FIG. 8 is a schematic diagram of a device according to the present invention. FIG. 9 is an exemplary flowchart of a method according to the present invention. Specific details for implementing the invention

[0213] FIG. 1 shows a schematic diagram of an apparatus according to the present invention. The apparatus according to the present invention according to FIG. 1 includes a chromatic white light sensor (3) that is movable parallel to the measurement direction, i.e., in the z-direction, as indicated by a bidirectional arrow on the chromatic white light sensor (3). The apparatus according to the present invention according to FIG. 1 further includes a support device (4) for a carrier plate (2) and a metering device (5) associated with the support device (4) for determining a calibration value, in particular, the total filling mass of the carrier plate (2) having at least one liquid-filled receptacle (1). According to FIG. 1, the chromatic white light sensor (3) and the support device (4) are configured to be positioned at a defined distance from each other, in particular in the measurement direction of the chromatic white light sensor (3). The carrier plate has a liquid-filled receptacle (1) composed of a recess. The receptacle (1) is filled with liquid of different volumes. The liquid surface is composed of a meniscus and exhibits a height-dependent geometry of the volume occupied by the liquid within the receptacle, particularly the volume of the liquid occupied by the liquid within the receptacle. The light beam generated by the chromatic white light sensor, having an axial wavelength-dependent spectral fan shape, is illustrated by three triangles (for three different wavelengths) tapering toward the receptacle. According to FIG. 1, the support device (4) is movable in the x-direction or y-direction in a plane perpendicular to the measurement direction of the chromatic white light sensor (3), which is illustrated by a double arrow for the x-direction and by directional arrow symbols pointing inward and outward of the paper plane for the y-direction. 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 within the liquid-filled receptacle (1).

[0214] FIG. 2 shows a schematic diagram of a carrier plate (2) having a chromatic white light sensor (3) and a liquid-filled receptacle (1), wherein the chromatic white light sensor (3), together with a light beam outlet (8), is positioned at a distance defined perpendicularly to the liquid surface of the liquid in the liquid-filled receptacle (1) within the carrier plate (2). The light beam generated by the chromatic white light sensor is illustrated by triangles tapering toward the receptacle and strikes perpendicularly to the liquid surface of the liquid within the receptacle to define the measurement direction. The dashed line shown on the left side of FIG. 2 indicates the optical axis and measurement direction of the sensor. According to FIG. 2, the measurement direction forms an angle of less than 10° indicated by a double arrow with respect to the line perpendicular to the liquid surface (the dashed line shown on the right side of FIG. 2), wherein the perpendicular according to the present invention is an angle in the range of 80° to 100°, particularly 85° to 95°, particularly 90°.

[0215] FIG. 3 shows a schematic diagram of a carrier plate (2) having a chromatic white light sensor (3) and a liquid-filled receptacle (1), wherein the chromatic white light sensor (3) is positioned at a defined distance parallel to the liquid surface of the liquid-filled receptacle (1) within the carrier plate (2) along with a light beam outlet (8). The light beam generated by the chromatic white light sensor (3) is emitted parallel to the liquid surface from the light beam outlet (8) of the white light sensor, is refracted through a mirror (7) associated with the white light sensor, strikes the liquid surface perpendicularly, thereby defining a measurement direction perpendicular to the liquid surface.

[0216] FIG. 4 shows a schematic diagram of a carrier plate (2) having a chromatic white light sensor (3) and a liquid-filled receptacle (1), wherein the chromatic white light sensor (3) is positioned at a distance defined perpendicularly to the liquid surface of the liquid-filled receptacle (1) within the carrier plate (2), together with a light beam output portion (8). In FIG. 4, the liquid-filled receptacle (1) is a planar liquid adsorption area that is not a portion according to FIG. 1 to 3.

[0217] FIG. 5 shows a schematic diagram of one embodiment of a device according to the present invention. The device comprises at least one chromatic white light sensor (3) not shown in FIG. 5, a support device (4) for a carrier plate (2), and at least one metering device (5) associated with the support device (4), wherein the metering 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 in a vertical direction, i.e., in the z-direction, relative to the support device (4). The support device (4) has a receiving device (11) for the carrier plate (2), and the carrier plate (2) is placed in the receiving device (11). The receiving device (11) is configured so that the carrier plate (2) placed within the receiving device (11) can move in a vertical direction, i.e., in the z-direction, by contacting the lifting element (10). FIG. 5 shows the stationary state of this embodiment in which the lifting element (10) has not yet come into contact with the carrier plate (2) present in the receiving device (11).

[0218] FIG. 6 shows a schematic diagram of the same embodiment of the device according to the present invention according to FIG. 5. FIG. 6 shows the operating state of this embodiment, wherein the lifting element (10) contacts the carrier plate (2) and moves it in a vertical direction, i.e., the z-direction, and thereby lifts the carrier plate (2) from the receiving device (11) by reversible deformation of the double bending element (13) in particular to determine the total filling mass of the carrier plate. According to the embodiment of the device according to the present invention shown in FIG. 5 and FIG. 6, method step v) is performed according to method steps v1a) to v4a).

[0219] FIG. 7 shows a schematic diagram of another embodiment of the device according to the present invention. The device comprises a chromatic white light sensor (3), a support device (4) for a carrier plate (2), and a metering device (5) associated with the support device (4). The support device (4) is an integral part of the metering device (5) and is composed of a metering pan (12), wherein the metering pan (12) is placed on a double bending element (13). The metering pan (12) is configured to be movable in a mass-dependent manner in a vertical direction, i.e., the z-direction, relative to the white light sensor. In this embodiment, the chromatic white light sensor is configured to perform method steps b), x), and v2b) and v4b). When a light beam generated by the chromatic white light sensor (3) strikes the support device (4), the mass-dependent vertical displacement of the metering pan (12), specifically the displacement of a reference point on the metering pan (12), is measured due to the reversible deformation of the double bending element (13).

[0220] FIG. 8 shows a schematic diagram of another embodiment of the device according to the present invention. The device comprises a chromatic white light sensor (3), a support device (4) for a carrier plate (2), and a metering device (5) associated with the support device (4). The support device (4) and the metering device (5) are separate components, wherein the metering device (5) has a lifting element (10) and a double bending element (13). The lifting element (10) contacts the carrier plate (2) and moves it in a vertical direction, i.e., the z-direction, and the chromatic white light sensor (3) also moves in a vertical direction at equal intervals. In this embodiment, the chromatic white light sensor (3) is configured to perform method steps b), x), v2b), and v4b). When a light beam generated by the chromatic white light sensor (3) strikes a reference point on the double bending element (13), particularly on the double bending element (13), the double bending element (13) is deformed in a mass-dependent manner during equal-distance vertical displacement of the charged carrier plate (2) and the chromatic white light sensor (3), and the chromatic white light sensor (3) measures the distance from the reference point on the double bending element (13), particularly on the double bending element (13), which has changed compared to the measurement of the uncharged carrier plate. The vertical displacement measured by the chromatic white light sensor (3) is subsequently converted into mass.

[0221] FIG. 9 illustrates an exemplary flowchart of a method according to the present invention. The exemplary method is performed, for example, using a system according to the present invention according to FIG. 1.

[0222] In FIG. 9, method steps of an exemplary embodiment are illustrated in chronological order from top to bottom. In the first column from the right, method steps a), b), d), and c) according to the present invention are indicated within a rectangle with angled corners and connected by arrows. In the second column from the right, preferred method steps v), x), y), and z) are indicated within a circle and connected by arrows. In the third column from the right, preferred method steps v1a), v2a), v3a), and v4a) are indicated within a rectangle with rounded corners and connected by arrows. Each method step in each column is connected by an arrow, wherein the tip of the arrow always points to a method step that is chronologically subsequent.

[0223] In method step a), at least one carrier plate having at least one liquid-filled receptacle disposed on a support device and a chromatic white light sensor are provided at a defined distance from each other. In method step b), confocal chromatic measurement of the distance between the liquid surface within at least one receptacle and the chromatic white light sensor is performed to determine the filling level at the distance defined in method step a). Preferably, in the subsequent method step d), the liquid-specific correction value is determined by a metering device. Preferably, method step v), particularly v1a) to v4a), x), y), and z) are performed. Preferably, in method step v), the total filling mass of the carrier plate having at least one liquid-filled receptacle is determined by a metering device. Preferably, this is done according to method steps v1a) to v4a). Preferably, in v1a), the total mass of the unfilled carrier plate is determined by a metering device, wherein the unfilled carrier plate corresponds to the carrier plate provided in method step a) and having at least one receptacle filled with liquid. Preferably, in v2a), at least a portion of the receptacles of the carrier plate is filled with liquid of equal or unequal volumes, in particular, such that the filled carrier plate corresponds to the liquid-filled carrier plate provided in method step a). Preferably, in method step v3a), the total mass of the filled carrier plate is measured by a metering device. Preferably, in method step v4a), the total filled mass of the carrier plate is determined by taking into account the masses measured in method steps v1a) and v3a).

[0224] Preferably, after method step v), particularly method steps v1a) to v4a) are performed, in method step w), the filling mass and filling volume of the liquid in at least one filled receptacle are determined. Preferably, in method step w), for a plurality of single filled receptacles, the average filling mass and average filling volume of the filled receptacles are determined. In method step x), to determine each filling level at a defined distance between the support device and the white light sensor, the distance between the surface of the liquid in each liquid-filled receptacle and the chromatic white light sensor is measured confocally chromatically. Preferably, the carrier plate and / or the white light sensor are moved relative perpendicularly to the measurement direction so that the distance between the surface of the liquid in each liquid-filled receptacle and the chromatic white light sensor can be measured accordingly. Preferably, in method step y), the filling volume of each liquid-filled receptacle is determined in consideration of the filling level determined in method step x). Preferably, in method step z), a correction value is determined from the filling volumes determined in method steps w) and y). After the correction value is determined according to method step d), finally, in method step c), the filling volume of the at least one receptacle is determined by considering the filling level determined in method step b) and the liquid-specific correction value determined in method step d).

[0225] Advantageously, by combining spatially resolved measurement data with high relative accuracy obtained by confocal chromatic measurement according to method step b) and measurement data with high absolute accuracy for all liquid-filled receptacles obtained from average measurements by a metering device according to method step v) while considering liquid-specific correction values, high measurement accuracy, particularly higher measurement accuracy than known methods, is achieved. Explanation of the symbols

[0226] 1 receptacle 2 Carrier plate 3 Chromatic white light sensor 4 Support device 5. metering device 6 Control unit 7 mirror 8 Light beam output section of a chromatic white light sensor 9 force sensor 10 Lifting elements 11 receiving device 12 Measuring pan 13 Double bending element [MT1.1]

Claims

Claim 1 A method for determining the filling volume of at least one liquid-filled receptacle (1) of a carrier plate (2) by means of a system for determining the filling 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 metering device (5) associated with the support device (4), wherein the chromatic white light sensor (3) and the support device (4) are disposed at a defined distance from each other and the chromatic white light sensor (3), the support device (4), or both are configured to be movable, and the method comprises: a) providing at least one carrier plate having at least one liquid-filled receptacle disposed on the support device and the chromatic white light sensor at a defined distance from each other; b) confocal-chromatically measuring the distance from the chromatic white light sensor to the liquid surface within the at least one receptacle to determine the filling level at the distance defined in method step a); and c) the filling level determined in method step b) and the liquid-specific determined in method step d). A method comprising the step of determining the filling volume of at least one receptacle by taking into account a calibration value, wherein in step d) the liquid-specific calibration value is determined by a metering device. Claim 2 In paragraph 1, method step d) is performed before method step a), after method step b), or before method step a) and after method step b). Claim 3 In claim 1 or 2, method step d) comprises the following method steps: v) determining the total filling mass of a carrier plate having at least one liquid-filled receptacle by the metering device; w) determining the filling mass and filling volume of the liquid within the at least one filled receptacle; x) confocally measuring the distance from the chromatic white light sensor to the liquid surface within each liquid-filled receptacle to determine each filling level at a defined distance between the support device and the white light sensor; y) determining the filling volume of each liquid-filled receptacle in consideration of the filling level determined in method step x); and z) determining a calibration value from the filling volume determined in method steps w) and y). Claim 4 In paragraph 3, method step v) comprises the following method steps: v1a) measuring the total mass of an unfilled carrier plate by the metering device; v2a) filling at least a portion of the receptacles of the carrier plate with liquids of equal or unequal volumes, respectively; v3a) measuring the total mass of the filled carrier plate by the metering device; and v4a) determining the total filled mass of the carrier plate by taking into account the masses measured in method steps v1a) and v3a). Claim 5 In paragraph 3, method step v) comprises the following method steps: v1b) providing an unfilled carrier plate on a metering pan or providing an unfilled carrier plate associated with a lifting element - the metering pan or the lifting element is positioned at a defined distance from the chromatic white light sensor, and the metering pan or the lifting element is configured to be movable perpendicular to the white light sensor in a mass-dependent manner, particularly by a bending element associated with the metering pan or the lifting element; v2b) confocally measuring the distance from the chromatic white light sensor to a reference point, particularly on the metering pan supporting the unfilled carrier plate or on the lifting element associated with the carrier plate, particularly on the bending element associated with the metering pan or the lifting element; v3b) filling at least a portion of the receptacle of the carrier plate with liquid of equal or unequal volumes, respectively; v4b) from the chromatic white light sensor, particularly on the metering pan supporting the filled carrier plate or on the lifting element associated with the carrier plate, particularly the A step of confocally measuring the distance to a reference point on the bending element associated with the weighing pan or the lifting element, and v5b) a step of determining the total filling mass of the carrier plate by considering the distances measured in method steps v2b) and v4b). Claim 6 In paragraph 5, the method wherein the metering pan is capable of being displaced vertically relative to the white light sensor in a mass-dependent manner. Claim 7 A method according to any one of claims 1 to 6, wherein the carrier plate is a microtiter plate having 384 or 1,536 recesses. Claim 8 A method according to any one of claims 1 to 7, wherein method step b) or b) and c) is performed sequentially on a plurality of receptacles of the carrier plate while displacing the carrier plate at equal intervals with respect to the white light sensor. Claim 9 A method according to any one of paragraphs 1 through 8, wherein method step d) is performed once. Claim 10 A method according to any one of claims 3 to 9, wherein the filling volume in step y) of the method is determined by confocal-chromatically determining the filling level of the liquid in the at least one receptacle at a defined distance between the support device and the chromatic white light sensor and taking into account the volume occupied by the liquid in the at least one receptacle, or by confocal-chromatically measuring the filling level for a different known filling volume of the liquid in the at least one receptacle at a defined distance between the support device and the chromatic white light sensor. Claim 11 A system for determining the filling volume of at least one liquid-filled receptacle (1) within a carrier plate (2), configured to perform a method according to any one of claims 1 to 10, and comprising at least one chromatic white light sensor (3), a support device (4) for the carrier plate (2), and at least one metering device (5) associated with the support device (4) to determine a liquid-specific calibration value, wherein the chromatic white light sensor (3) and the support device (4) are positioned at a defined distance from each other and configured such that the chromatic white light sensor (3), the support device (4), or both are movable. Claim 12 In claim 11, the above-mentioned metering device (5) comprises a force sensor (9), in particular a load cell and a lifting element (10), or is a metering device (5) of an electromagnetic force compensation function. Claim 13 In paragraph 12, the force sensor (9) is a system that is particularly movable vertically relative to the support device (4). Claim 14 A system according to any one of claims 11 to 13, wherein the support device (4) has a receiving device (11) for the carrier plate (2), and the receiving device (11) is configured such that the carrier plate (2) disposed in the receiving device (11) can move in a particularly vertical direction by contacting the lifting element (10). Claim 15 In claim 11, the metering device comprises a metering pan, and the chromatic white light sensor is configured to perform method steps b) and v2b) and v4b). Claim 16 A system according to claim 15, wherein the metering pan is configured to be displaced perpendicularly with respect to the white light sensor in a mass-dependent manner, or the bending element associated with the metering pan is configured to be deformed perpendicularly with respect to the white light sensor in a mass-dependent manner. Claim 17 In paragraph 15 or 16, the system wherein the metering pan is an integral component of the support device. Claim 18 A system comprising a control unit (6) configured to control the execution of a method according to any one of claims 1 to 10 in any one of claims 11 to 17.

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