Device for determining a fill level of a liquid in a container, apparatus, system and method

Abstract

The present invention relates to a device (1), apparatus, system and method for determining a fill level of a liquid in a container (2), preferably a laboratory container. The device (1) comprises a pressure source (3) to pressurize the container (2), a pressure sensor (4) to detect a gas pressure inside the container and a control unit (5). The pressure source (3) and the pressure sensor (4) are to be fluidically coupled to the container (2). The control unit (5) is configured to activate the pressure source (3), determine a time interval between the container (2) having a first gas pressure and the container having a second gas pressure after activation of the pressure source (3), and determine the fill level of the liquid in the container (2) based on the time interval.

Description

[0001] Device for determining a fill level of a liquid in a container, Apparatus, System and Method

[0002] The present invention relates to a device for determining a fill level of a liquid in a container.

[0003] Further, the present invention relates to an apparatus for a device for determining a fill level of a liquid in a container.

[0004] Further, the present invention relates to a system comprising a device for determining a fill level of a liquid in a container and a container.

[0005] The present invention relates to a method for determining a fill level of a liquid in a container.

[0006] Pneumatic systems are often used in automated laboratory equipment for moving samples, opening and closing valves, or controlling the environment within bioreactors. They can provide precise control over these actions, which is essential for reproducibility in experiments. In the case of microfluidic devices, pneumatic systems are used to control the flow of liquids through a network of microchannels. These devices are used in various biological applications, including single-cell analysis, point-of-care diagnostics, and the study of cellular processes. The typical configuration of a microfluidic device with a pneumatic system involves a reagent container connected to both the pneumatic system and the device. While such configurations often critically depend on the filling level of the reagent container, they typically lack the possibility to monitor these filling levels or require specialized and dedicated sensors.

[0007] In general, different types of sensors can be used to monitor the filling levels of such containers, such as ultrasound sensors, sensors that are based on determining the filling level based on electrical conductivity or based on capacitive measurements, hydrostatic pressure sensors, light sensors, or gas flow sensors. For example, US 2018 / 0264491 A1 provides a fluid dispensing system that uses a flow sensing assembly to measure a gas flow, and to determine both the amount of liquid being dispensed and the container fill level based on the gas flow measurement. The fill level is deduced from an amplitude of a peak of an air pressure measuring curve. However, inclusion of flow sensors may add cost and effort to the respective laboratory setup. Alternatively, fluid fill levels can be estimated by integrating the flow rate, given by a flow sensor, over time. However, such filling level estimations can be inaccurate or completely wrong, because such flow sensors are typically calibrated for an ideal fluid at a given temperature (e.g. 20°C), which in reality is not always maintained (e.g. disturbances due to particles, air bubbles etc.). Jiehong Peng et al.:” A volume measurement method for pneumatic pressure vessels using compressed- air discharge” discusses an approach, in which a volume of a pneumatic pressure vessel is determined by opening a valve for a fixed time t, and calculating the volume of the vessel from the ratio between an initial pressure and a pressure after the valve is closed, a discharge coefficient and an initial temperature of the gas contained in the pneumatic pressure vessel.

[0008] It is an object of the present invention to improve and further develop a device for determining a fill level of a liquid in a container that allows measurement of a fill level of liquid in a container with no or only little additional cost or effort.

[0009] In accordance with the invention, the aforementioned object is accomplished by a device, apparatus, system and method as specified in the independent claims.

[0010] In an embodiment of the invention, the aforementioned object may be accomplished by a device for determining a fill level of a liquid in a container, preferably a laboratory container that may comprise a pressure source to pressurize the container, a pressure sensor to detect a gas pressure inside the container and a control unit. The pressure source and the pressure sensor are to be flu idical ly coupled to the container. The control unit may be configured to activate the pressure source. The control unit may be configured to determine a time interval between the container having a first gas pressure and the container having a second gas pressure after activation of the pressure source. The control unit may be configured to determine the fill level of the liquid in the container based on the time interval. The pressure source, the pressure sensor and / or a valve may be integrated into a cap to be mounted onto the container.

[0011] In another embodiment, the aforementioned object may be accomplished by an apparatus for the device. The apparatus may comprise the pressure source to pressurize the container, the pressure sensor to detect the gas pressure inside the container, a valve, preferably a pneumatic valve, and a cap of the container. The pressure source, the pressure sensor and / or the valve may be integrated into the cap.

[0012] In another embodiment, the aforementioned object may be accomplished by a system comprising the device and the container.

[0013] In another embodiment, the aforementioned object may be accomplished by a corresponding method for determining the fill level of the liquid in the container. The method may comprise fluidically coupling the pressure source and the pressure sensor to the container. The method may comprise activating the pressure source to pressurize the container. The method may comprise determining the time interval between the container having the first gas pressure and the container having the second gas pressure after activation of the pressure source. The method may comprise determining the fill level of the liquid in the container based on the time interval. For example, the method may be, at least partially, performed using the device as described above and below. Features described in connection with the device may likewise be included in the corresponding method.

[0014] The present invention is based on the finding that the time that it takes the pressure within a pneumatic system, e.g., within the container, to change between two pressure levels in response to a controlled pressurization or depressurization of the pneumatic system is indicative of the gas volume of the pneumatic system. As non-gaseous liquids are quasi-incompressible, the volume of a closed pneumatic system that includes a container with a liquid is determined by how much liquid is inside the container, i.e., the fill level of the container. By measuring the time interval between the container having a first gas pressure and the container having the second gas pressure, the fill level of the container can easily be deduced, e.g., based on knowledge on the overall volume of the pneumatic system or based on calibration measurements. To conduct these measurements, only a pressure source, a pressure sensor, and a control unit for evaluating the measurements are required, optionally combined with a valve and / or a vacuum pump (if the measurements are to be performed during depressurization). Using commonly available hardware of a pneumatic system, it is possible to measure the fill level of reagent containers. This way, the fill level of the container can be determined with little additional effort, in particular in laboratory settings, where the pressure inside the containers may be monitored in any case.

[0015] Further features, advantages and preferred embodiments are disclosed or may become apparent in the following.

[0016] The term “container” refers in particular in the claims, preferably in the description to any kind of container, preferably the container may be laboratory container, such as a test tube, or a centrifugal tube or a reagent tube. For example, the container may have a volume of at least 1 ml (or at least 2 ml, or at least 5 ml, or at least 10 ml) and at most 10000 ml (or at most 5000 ml, or at most 2000 ml, or at most 1000 ml, or at most 500 ml).

[0017] According to a preferred embodiment, the pressure source, the pressure sensor and / or a valve, preferably a pneumatic valve, may be integrated into a cap to be mounted onto the container. By integrating the components into the cap of the container, the volume of the resulting pneumatic system is known, which obviates the need for calibration measurements. Moreover, a compact construction of the device is enabled.

[0018] According to a preferred embodiment, the pressure source, the pressure sensor, a pneumatic valve and / or a vacuum pump may be coupled to the container, preferably to a cap of the container, via a tubing. The tubing is used to connect the respective components to the container. For example, the tubing may be attached to connection ports of the containers cap.

[0019] According to a preferred embodiment, the control unit may be configured to activate the pressure source during a pressurization phase to increase the gas pressure in the container from a baseline gas pressure, in particular an ambient gas pressure, to a target gas pressure. By pressurizing the container from a baseline pressure to a known target gas pressure, a controlled pressurization and / or depressurization setup is created, which may improve the accuracy of the fill level measurements.

[0020] According to a preferred embodiment, the control unit may be configured to determine the time interval between a start and an end of the pressurization phase. This way, the fill level can be determined without requiring a controlled depressurization phase and without imposing constraints on the depressurization.

[0021] According to a preferred embodiment, the first and second gas pressure may be greater than the baseline gas pressure and smaller than the target gas pressure. For example, the first gas pressure may be a first pre-defined pressure between 25% and 45% (or between 30% and 40%, or between 33% and 40%, such as 37%) of a difference between the baseline gas pressure and the target gas pressure, the second gas pressure may be a second pre-defined pressure between the 55% and 75% (or between 60% and 70%, or between 63% and 70%, such as 67%) of the difference between the baseline gas pressure and the target gas pressure. By taking a sufficiently large pressure interval that is towards the middle of the pressure range, the linearity of the measurements can be improved, which may increase the accuracy of the fill level determination, e.g., in case interpolation is used.

[0022] According to a preferred embodiment, the control unit may be configured to affect a depressurization phase, and in particular a controlled depressurization phase, for depressurizing the container following the pressurization phase. The control unit may be configured to determine the time interval between a start of the depressurization phase and the container having the second gas pressure during the depressurization phase. By measuring the time interval relative to the start of the depressurization phase, only one additional point in time has to be determined, which may improve accuracy of the measurement. Moreover, during a controlled depressurization phase, there is a more linear relationship between time and pressure level, which may increase the accuracy of the fill level determination, e.g., in case interpolation is used.

[0023] According to a preferred embodiment, a valve, preferably a pneumatic valve, may be fluidically coupled to the container. The control unit may be configured to control the valve to be closed during the pressurization phase and to open the valve to affect the depressurization phase. A controllable valve allows for a simple and yet precise start of the depressurization phase. Additionally, or alternatively, a vacuum pump may be fluidically coupled to the container. The control unit may be configured to control the vacuum pump to depressurize the container to affect the depressurization phase. By using a vacuum pump, the depressurization phase, and thus the overall time required for the fill level determination, can be reduced. Moreover, the linearity of the depressurization can be improved.

[0024] According to a preferred embodiment, the first gas pressure may be the target gas pressure and the second gas pressure may be a gas pressure between the baseline gas pressure and the target gas pressure. In particular, the second gas pressure may be a gas pressure between 25% and 50% (or between 30% and 40%, or between 33% and 40%, such as 37%) of a difference between the baseline gas pressure and the target gas pressure. By using the target gas pressure, which is the result of the pressurization phase, as first gas pressure, only one additional point in time needs to be determined. A second gas pressure that is sufficiently offset from the target gas pressure but is still towards the middle of the pressurization range, is within a range of linear depressurization during the depressurization phase.

[0025] In the present concept, the time interval required for the gas pressure changing from a first level to a second level is determined, via measurements, and used to derive the fill level of the container. In general, this time interval depends both on the fill level (and thus volume) of the container, and on the flow rate of the gas entering or exiting the container. In general, during the pressurization phase, the flow rate depends on the properties of the pressure source. During the depressurization phase, the flow rate depends on the size of the orifice through which the gas exits the pneumatic system. In both cases, but particularly during the depressurization phase, the flow rate can be actively controlled by adjusting the flow resistance of the gas entering or exiting the container. According to a preferred embodiment, the device may comprise a pneumatic element for adjusting a flow resistance during a pressurization or depressurization phase. The control unit may be configured to determine the determine the fill level of the liquid in the container based on the flow resistance being applied by the pneumatic element. The pneumatic element acts as an actively controllable orifice, i.e. an active component that can stepwise increase or decrease the flow resistance. By controlling the flow resistance, the time it takes for the gas pressure to change from a first level to a second level can be scaled according to preference. For example, if the flow resistance is increased, the time required for the gas pressure to change from a first level to a second level increases, if the flow resistance is decreased, the time required decreases. This effect can be used to scale the time intervals, providing choice between fast (less accurate) and more accurate (longer measurement time) filling level readings.

[0026] According to a preferred embodiment, the control unit may comprise a memory with information on a plurality of characteristic time intervals associated with different fill levels of liquid. The control unit may be configured to determine the fill level based on the time interval and based on the information on the plurality of characteristic time intervals. This way, the control unit can translate between the measured time interval and the corresponding fill level of the container.

[0027] According to a preferred embodiment, the control unit may be configured to interpolate between adjacent fill levels of liquid if the time interval is between two characteristic time intervals of the plurality of characteristic time intervals. This way, fewer data points are required for the information on the plurality of characteristic time intervals associated with the different fill levels.

[0028] According to a preferred embodiment, the memory may comprise a characteristic curve representing the information on the plurality of characteristic time intervals associated with the different fill levels of liquid. The control unit may be configured to determine the fill level based on the time interval and based on the characteristic curve. By using a characteristic curve, no interpolation between levels of liquid of adjacent time intervals may be required.

[0029] According to a preferred embodiment, the information on the plurality of characteristic time intervals associated with the different fill levels of liquid may be based on a calibration measurement. This way, the information on the plurality of characteristic time intervals associated with the different fill levels can be tailored to different measurement devices and containers during a calibration phase preceding the actual fill level determination. Alternatively, or additionally, the information on the plurality of characteristic time intervals associated with the different fill levels of liquid may be based on knowledge on a gas volume of the container (and, optionally, of tubing expanding the volume of the container during the pressurization phase). If the volume of the container and tubing is known, no calibration may be required. According to a preferred embodiment, the control unit may be configured to continuously or quasi-continuously determine the gas pressure in the container using the pressure sensor during a pressurization and / or during a depressurization phase, and to determine the time interval based on the continuous or quasi-continuous determination of the gas pressure. In other words, the control unit may be configured to monitor the gas pressure in the container based on sensor data of the pressure sensor, and determine at least one of the points of time defining the time interval once a threshold defined by the first or second gas pressure has been passed.

[0030] In some applications, it is useful to determine a flow rate of (non-gaseous) liquid flowing into or out of the container. The control unit may be configured to repeat determining the fill level of the liquid in the container over time, and to determine a flow rate of non-gaseous liquid entering or exiting the container based on the repeated determination of the fill level of the liquid in the container. Regular fill level measurements allow to estimate average flow rates of liquid into or out of the container. A higher frequency of measurements resolves average flow rates over shorter time intervals.

[0031] There are several ways how to design and further develop the teaching of the present invention in an advantageous way. To this end, it is to be referred to the patent claims subordinate to patent claim 1 on the one hand and to the following explanation of preferred examples of embodiments of the invention, illustrated by the drawing on the other hand. In connection with the explanation of the preferred embodiments of the invention by the aid of the drawing, generally preferred embodiments and further developments of the teaching will be explained. In the drawing

[0032] Fig. 1 shows a schematic diagram of an apparatus and of a device for determining a fill level of a liquid in a container, and of a system comprising the device and the container;

[0033] Fig. 2a shows a diagram illustrating a theoretical relationship between pressure and time for small and large gas volumes in the reagent container;

[0034] Fig. 2b shows a diagram illustrating a measured relationship between pressure and time for an example container; Fig. 3 shows a diagram of a pressure drop effect on the calibration line for different initial pressures;

[0035] Fig. 4 shows a diagram of a time constant Tau over a liquid volume in a 50 ml container;

[0036] Fig. 5 shows an impact of a flow resistance on a pressure change;

[0037] Fig. 6 shows a flow chart of an example of a method determining a fill level of a liquid in a container;

[0038] Fig. 7a to 7c illustrate, for different container sizes, a precision of the pressure-based fill level determination;

[0039] Fig. 8 illustrates a linearity of the calibration curve for different container sizes;

[0040] Fig. 9 shows a calibration curve for a 1 .5 ml Eppendorf tube; and

[0041] Fig. 10 shows a schematic diagram of an further apparatus and of a further device for determining a fill level of a liquid in a container, and of a further system comprising the device and the container.

[0042] The present disclosure relates to a device, apparatus, system and method to monitor the filling level of reagent containers using only two or three pneumatic components: a pressure source 3, a pressure sensor 4, and an optional pneumatic valve 7 (see Fig. 1 ).

[0043] Fig. 1 shows a schematic diagram of an apparatus and of a device 1 for determining a fill level of a liquid in a container 2 (a reagent container), and of a system comprising the device 1 and the container 2. The device 1 comprises a pressure source 3 to pressurize the container 2, a pressure sensor 4 to detect a gas pressure inside the container 2 and a control unit 5, which is logically and electronically coupled to the pressure source 3, the pressure sensor 4 and an optional (pneumatic) valve 7. The apparatus comprises the pressure source 3 to pressurize the container 2, the pressure sensor 4 to detect the gas pressure inside the container 2, the valve 7, preferably a pneumatic valve, and tubing 6, 6’ for coupling the pressure source 3, the pressure sensor 4 and the pneumatic valve 7 to the container 2, preferably to a cap 8 of the container 2. Thus, the pressure source 3 and the pressure sensor are 4 to be fluidically coupled to the container 2, forming a pneumatic system. In the arrangement shown in Fig. 1 , the pressure source 3 and the pressure sensor 4 are fluidically coupled to the container 2 via tubing 6, which extends through a cap / lid 8 mounted onto the container 2. In particular, the tubing 6 connects the pressure source 3, and the pressure sensor 4 to each other and to the container 2.

[0044] In addition to the pressure source 3 and the pressure sensor 4, the valve 7 (e.g., a pneumatic valve) and / or a vacuum pump (not shown) may also be fluidically coupled to the container 2, via tubing 6’, and may thus also be part of the pneumatic system. In Fig. 1 , the pressure source 3, the pressure sensor 4 and the valve 7 are coupled to the container 2, via the lid / cap 8, through the tubing 6, 6’. As an alternative, at least one of the pressure source 3, the pressure sensor 4 and the valve 7 may be integrated into the cap I lid 8. Fig. 10 corresponds to Fig. 1 with the difference that the pressure sensor 4 is integrated into the cap I lid 8. Additionally or alternatively, at least one of the pressure source 3 and the valve 7 may be integrated into the cap I lid 8. Furthermore, the above and following description of Fig. 1 also applies to Fig. 10.

[0045] The container 2 contains a (non-gaseous) liquid having a liquid volume 9 and a gas having a gas volume 10. The valve 7 is arranged, via the tubing 6’, in a liquid path between the container 2 and a further pneumo-fluidic setup (indicated by arrow 11 ). For example, in the course of an experiment, the fluid may be removed from the container 2 via the tubing 6’ towards the pneumo-fluidic system, e.g., using the pressure source 3.

[0046] In some implementations, the apparatus and device 1 may further comprise a pneumatic element 7b for controlling a flow resistance for gas flowing out of (or into) the container 2. This pneumatic element 7b, which may represent a controllable orifice (i.e. , an orifice with a size that can be actively controlled), can be used to adjust the flow resistance of gas flowing out of (or into) the container. In Fig. 1 , the pneumatic element 7b is used to control the flow resistance of gas flowing out of the container 2. In an alternative implementation, where it is used to control the flow resistance between the pressure source 3 and the container 2 (e.g., to more tightly control the flow rate of the gas being provided by the pressure source), it may be placed between the pressure source 3 and the container 2. In a further alternative implementation, the valve 7 can be used as pneumatic element if it can be operated in a partially closed mode and thus be used for controlling the flow resistance.

[0047] The container 2, e.g., the container’s lid 8, may have at least one, or, if a depressurization phase is to be used for determining the fill level, two connection ports: one connected to the pressure source 3 (and pressure sensor 4) and the other one towards the downstream pneumo-fluidic setup 11 . The measuring approach is based on the fact that gas is compressible while (non-gaseous) liquid is quasi incompressible. This results in a relationship between the time it takes for pressure to build up inside the container 2 and the gas volume 10 of that container 2: a small gas volume 10 takes less time for pressure to build up compared to a large gas volume 10 (see Fig. 2a). To allow for pressure build-up and a simultaneous readout of pressure values with the pressure sensor 4, the pneumatic valve 7 is closed during a pressurization phase, with tubing stub 7a indicating the closed position.

[0048] The measuring concept can be explained in analogy to electrical circuits. Pneumatic circuits can be modeled by electrical components, where hydrodynamic resistance (e.g. tubing) and gas containers are analogous to electrical resistance (R) and capacitance (C), respectively. A resistor in tandem with a capacitor forms an RC circuit and the time it takes to charge a capacitor in this circuit is expressed by a time constant Tau (T). Tau is defined as the time it takes to charge the capacitor (the reagent container) to about 63% of an applied DC voltage (the target pressure), or to discharge this capacitor (the reagent container) to about 37% of its initial voltage (pressure). Having the same resistance, a larger container will have a larger Tau than a small container (Fig. 2a) as it takes longer to charge the container. Fig. 2a shows a diagram illustrating a theoretical relationship between pressure and time for small and large gas volumes in the reagent container. In the diagram of Fig. 2a, the dotted line 12 indicates the target pressure, line 13 corresponds to the change in pressure for a small gas volume, and line 14 corresponds to the change in pressure for a large gas volume. In Fig. 2a, the x-axis represents time and the y-axis represents pressure. In Fig. 2a, Taui is the time interval during the pressurization phase between the pressure being at 37% of the target pressure and the pressure being at 67% of the target pressure for the smaller gas volume. Tau2 is the time interval during the pressurization phase between the pressure being at 37% of the target pressure and the pressure being at 67% of the target pressure for the larger gas volume. Taus is the time interval during the depressurization phase between the start of the depressurization phase (when the pressure equals the target pressure) and the pressure being at 37% of the target pressure for the smaller gas volume. Tau4 is the time interval during the depressurization phase between the start of the depressurization phase and the pressure being at 37% of the target pressure for the larger gas volume. It is evident that Taui is smaller than Tau2, and Taus is smaller than Tau4. In effect, there is a direct and highly linear (see Fig. 4) relationship between the time interval Tau and the respective gas volume.

[0049] In the present invention, this analogy is used to calculate Tau (T) in a container (a 50 mL reagent tube in case of Figs. 2b and 3), containing different volumes of liquid, after setting an initial pressure (300 mbar in Fig. 2b, however, different initial pressure levels are possible, e.g., between 50 mbar and 2000 mbar). Fig. 2b shows a diagram illustrating a measured relationship between pressure and time for an example container (a 50 ml tube container). In Fig. 2b, the x-axis represents time (in seconds) and the y-axis represents pressure (in mbar). Line 15 represents the applied pressure, line 16 represents the measurements for the container being filled with 50 ml liquid, line 17 represents the measurements for the container being filled with 30 ml liquid, and line 18 represents the measurements for the container being empty. As indicated by the dotted arrow, with increasing gas volume, the time it takes for the respective pressure to reach the target pressure from the baseline pressure (and vice versa) increases. Fig. 2b thus shows that larger gas volumes correspond to longer times to reach the target pressure I baseline pressure both on the positive and negative pressure drop. While 300 mbar is used as target pressure in Fig. 2b, any pressure difference delta P can be used to calculate Tau. For example, a larger delta P results in a larger range in Tau, thus enabling better discrimination between capacitances C (for a constant R). In Fig. 3, a pressure drop effect on the calibration line is shown for target pressures of 1000 mbar (line 19), 600 mbar (line 20) and 200 mbar (line 21 ). Fig. 3 shows measurements for a 15 ml Falcon tube, with water as a liquid, at room temperature. It is evident that he pressure drop delta P affects the range of Tau, where a large pressure drop results in a larger range of Tau. This means that for the same container, a finer discrimination between filling levels is possible, if a larger pressure drop is applied.

[0050] To determine the filling level, the following workflow may be used. For example, the following operations may be used to read out the time constant Tau (T):

[0051] 1 ) Closing or keeping the pneumatic valve 7 closed.

[0052] 2) Applying a pressure step function to the container 2 using the pressure source

[0053] 3) Recording the pressure values from the pressure sensor 4 over time

[0054] 4) Extracting Tau (T) from these measurements (see Fig. 2a)

[0055] To measure the filling level in container, the following operations may be used:

[0056] 1 ) For a given reagent container 2, measuring Tau (T) for two or more different fill levels

[0057] 2) Computing a calibration curve (i.e., a characteristic curve) from these two or more values

[0058] 3) Measuring unknown filling levels using Tau (T) and the calibration curve

[0059] In some implementations, such a calibration curve or characteristic curve does not have to be measured. Calibration-free filling level detection is possible if the gas volume in the system around the container (tubing 6, 6’ etc.) is known, and / or if the necessary components are integrated into the container cap 8, thereby removing tubing 6, 6’ and their void volume.

[0060] Fig. 4 shows a diagram of a time constant Tau (T) over a liquid volume in a 50 ml container. In Fig. 4, Tau (T) is plotted as a function of different liquid levels in a 50 mL test tube (n=5). Line 22 indicates the fitted calibration curve. Here, a pressure drop from 300 to 0 mbar was applied. A linear correlation (y=-0.0642x + 4.0251 ) between Tau (T) and filling level with R2=0.99 was determined.

[0061] The measurement principle and pneumatic system shown in connection with Fig. 1 to 3 is employed by the present invention. Returning to Fig. 1 , in the present invention, the control unit 5 is configured to activate the pressure source 3 during a pressurization phase, to increase the pressure in the container 2 from the baseline pressure (e.g., ambient pressure or vacuum) to the target pressure (e.g., a predefined positive pressure level, such as 300 mbar in Fig. 2b). Thus, the container 2, and optional tubing 6, 6’ is being pressurized during the pressurization phase between activation and subsequent deactivation of the pressure source 3 (once the target pressure has been reached). For example, the control unit 5 may be configured to deactivate the pressure source 3 once the target pressure has been reached, e.g., based on pressure sensor data provided by the pressure sensor 4. Alternatively, the pressure source 3 may be parametrized, e.g., by the control unit 5, with a pre-defined target pressure and automatically deactivate once the target pressure has been reached.

[0062] The control unit 5 is configured to determine a time interval between the container 2 having a first gas pressure and the container 2 having a second gas pressure after activation of the pressure source 3. In particular, the control unit 5 uses the pressure sensor 4 to determine the gas pressure within the container 2, and uses the determined gas pressure to measure the time interval. The control unit 5 may be configured to start a timer when the gas pressure is the first gas pressure (e.g., according to the pressure sensor 4, or upon affecting the depressurization phase), and to stop the timer when the gas pressure is the second gas pressure (e.g., according to the pressure sensor 4). The time interval may be the time between start and stop of the timer.

[0063] For example, the control unit 5 may be configured to obtain (e.g., receive or read out) pressure sensor data from the pressure sensor 4, and to determine a current gas pressure within the container 2 based on the obtained pressure sensor data. For example, the control unit 5 may be configured to continuously or quasi-continuously (e.g., according to a pre-defined schedule set by a sampling interval of the pressure sensor 4 or by a processing interval of the control unit 5) determine the gas pressure in the container 2 using the pressure sensor 4 (e.g., using the pressure sensor data) during the pressurization and / or during the depressurization phase, and to determine the time interval based on the continuous or quasi-continuous determination of the gas pressure. For example, the control unit 5 may be configured to log (i.e., store in a memory of the control unit 5) the pressure within the container 2 at a plurality of points in time during the pressurization and / or during the depressurization phase.

[0064] As is evident from Figs. 2a and 2b, both the pressurization phase and the depressurization phase may be used for determining the time interval. In a first approach, the depressurization phase is used for determining the time interval. The control unit 5 may be configured to affect the depressurization phase for depressurizing the container 2 following the pressurization phase, e.g., by controlling the valve 7 or a vacuum pump (not shown) to depressurize the container 2, i.e. , to reduce the pressure form the target pressure to the baseline pressure. By adding a vacuum pump, the measurement time can be reduced. The time interval may be determined within the depressurization phase. For example, the time interval may be determined between the start of the depressurization phase and the container 2 having the second gas pressure during the depressurization phase. Alternatively, the time interval may be determined, during the depressurization phase, between the container 2 having the first gas pressure that is lower than the target pressure and the container 2 having the second gas pressure that is lower than the first gas pressure. As a result, the first gas pressure may be the target gas pressure or a gas pressure that is lower than the target gas pressure (but higher than the second gas pressure), e.g., between 55% and 75% (or between 60% and 70%, or between 63% and 70% of the difference between the baseline gas pressure and the target gas pressure. The second gas pressure may be a gas pressure between the baseline gas pressure and the target gas pressure or the first gas pressure, in particular a gas pressure between 25% and 45% (or between 30% and 40%, or between 33% and 40%) of the difference between the baseline gas pressure and the target gas pressure. Alternatively, the second gas pressure may be the baseline gas pressure, e.g., the ambient gas pressure. In Fig. 2a, a gas pressure level of 37% of the difference between the baseline gas pressure and the target gas pressure was used as second gas pressure for the depressurization phase.

[0065] Particularly if depressurization from a positive pressure towards ambient pressure is chosen as a mode of action, the flow resistance for the outflowing air has a major impact on the time intervals being measured. As before, we are interested in a time constant Tau resulting from a pressure change during the depressurization phase, e.g., defined as the time between start of depressurization and the time when 37% of the pressure difference is reached. To control the flow resistance, a pneumatic element 7b (e.g., a controllable orifice) that controls the outflux of air may be used. This pneumatic element 7b (controllable orifice) acts as a flow resistance for air, where the length of the orifice and opening area (i.e. inner diameter for a tube) scale with the resulting flow resistance. Again, there is a direct analogy to electronic RC circuits, where R stands for the flow / electrical resistance and C for pneumatic / electrical capacity. Tau, the time constant for such a system can be estimated from R ■ C. Therefore, Tau increases for increasing flow resistance R and increasing capacitance C. In order for a depressurization to happen, air needs to be able to escape through an opening. R in our system can result from the tube length and diameter between container and this opening, and the opening itself. This opening, here also denoted as “orifice”, can dominate the flow resistance of the tubing, if it is very small. In Fig. 1 , such an orifice 7b is shown. R can be very small if the orifice is a large opening (opening area » inner diameter of tube) or very large if the orifice is very small (opening area < inner diameter of tube). Also, a very long tube / connection between container and orifice can lead to a large R, then potentially dominating the flow resistance of the system. Thus, two extreme cases for the flow resistance are R very large (a completely closed orifice) or R very small (a completely open orifice). A very large R allows to discriminate between different C values, at the cost of time. On the other hand, a very small R results in very short measurement times, but (depending on the sampling frequency of the system) does not enable discrimination between different C values.

[0066] Fig. 5 shows an impact of a flow resistance on the pressure change. Fig. 5 shows three cases for different orifice configurations (same filling level of container, i.e. constant capacitance C): closed, partially closed, open, which resembles large, intermediate, and low flow resistances, respectively. Line 23 represents the pressure change for a very large R (a nearly closed system), line 24 represents the pressure change for a very small R (an open system), and line 25 represents the pressure change for a partially closed system. The results show how the time it takes for depressurization increases with flow resistance R. For measurements of Tau, a small R results in fast measurements, but does not allow to discriminate between different capacitances. On the other hand, a large R results in a large measurement range, at the expense of measurement time. By setting an appropriate flow resistance, the time interval can be scaled into a region that provides an adequate tradeoff between fast (less accurate) and more accurate (longer measurement time) filling level readings.

[0067] The flow rate of the gas, and thus the scaling of the time interval, can be actively controlled by adjusting the flow resistance of the gas entering or exiting the container. Thus, as shown in Fig. 1 , the apparatus and device may comprise a pneumatic element for adjusting the flow resistance during a pressurization or depressurization phase. The control unit may be configured to determine the determine the fill level of the liquid in the container based on the flow resistance being applied by the pneumatic element. The pneumatic element acts as an actively controllable orifice, i.e. an active component that can stepwise increase or decrease the flow resistance. For example, the pneumatic element may be a valve that can be partially closed, i.e., a valve that provides an orifice with an adjustable size. If such a pneumatic element is used, the flow rate, and thus temporal scaling of the time interval, depends on the flow resistance being applied by the pneumatic element. Thus, the flow resistance is taken into account when deriving the fill level from the time interval.

[0068] In some cases, an initialization phase may be used to determine a desired flow resistance. For example, the control unit may be configured to determine the time interval between two gas pressure levels for different fill levels of the container. If the measured time intervals fall within a range of acceptable time intervals (e.g., of at least >2 second or at least 1 second and at most 8 seconds or at most 6 seconds), the flow resistance may be kept as is. If one of the measurements falls outside the range of acceptable time intervals, the flow resistance may be adjusted, via pneumatic element 7b, to scale the time intervals until the time intervals measured for different fill levels all fall within the range of acceptable time intervals.

[0069] In a second approach, the time interval is determined while the container 2 is being pressurized during the pressurization phase. In other words, the control unit 5 may be configured to determine the time interval between a start and an end of the pressurization phase, e.g., after the start and before the end of the pressurization phase. To avoid non-linearities that arise at the beginning and the end of the pressurization phase, two pressure levels may be chosen that are sufficiently far apart, but towards the middle range of the pressurization range between baseline gas pressure. In other words, the first and second gas pressure may be greater than the baseline gas pressure and smaller than the target gas pressure. In Fig. 2a, 37% and 67% were used as first and second gas pressure, respectively. In more general terms, the first gas pressure may be a first pre-defined pressure between 25% and 45% (or between 30% and 40%, or between 33% and 40%) of a difference between the baseline gas pressure and the target gas pressure. Additionally, or alternatively, the second gas pressure may be a second pre-defined pressure between 55% and 75% (or between 60% and 70%, or between 63% and 70% of the difference between the baseline gas pressure and the target gas pressure. Again, the flow rate of the gas flowing into the container can be controlled by a pneumatic element, to scale the time it takes for the container to pressurize.

[0070] The determined time interval can then be used to determine the fill level of the liquid in the container 2. To achieve this, a known relationship between time intervals and corresponding fill levels (and, optionally, flow resistances applied by pneumatic element 7b) may be used, which may be represented by information on a plurality of characteristic time intervals associated with different fill levels of liquid. The information on the plurality of characteristic time intervals associated with different fill levels of liquid may represent, for each of the characteristic time intervals (and optionally a given flow resistance), a corresponding fill level of the container 2. Such information on the plurality of characteristic time intervals associated with different fill levels of liquid may be stored in a memory of the control unit 5 and may be used by the control unit 5 to determine the fill level of liquid based on the determined time interval.

[0071] In some implementations, the information on the plurality of characteristic time intervals associated with different fill levels of liquid may be represented as a look-up table, which can be used to look up a fill level for each of the characteristic time intervals. For example, if the determined time interval matches a characteristic time interval, the control unit 5 can look up the fill level directly. In most cases, the determined time interval may be between two characteristic time intervals. In this case, the control unit 5 may be configured to interpolate between adjacent fill levels of liquid if the time interval is between two characteristic time intervals of the plurality of characteristic time intervals.

[0072] As an alternative (or in addition) to the look-up table, the memory may comprise a characteristic curve representing the information on the plurality of characteristic time intervals associated with the different fill levels of liquid. For example, the characteristic curve may be represented as a mathematical function or a set of mathematical functions each covering a range of characteristic time intervals. The control unit 5 may be configured to determine the fill level based on the time interval and based on the characteristic curve, e.g., by inputting the time interval into the mathematical function (covering the respective range of time intervals). In this case, no interpolation may be necessary.

[0073] There are different possible sources for the information on the plurality of characteristic time intervals associated with different fill levels of liquid. For example, it may originate from calibration measurements. In other words, the information on the plurality of characteristic time intervals associated with the different fill levels of liquid may be based on a calibration measurement, e.g., based on a plurality of calibration measurements using the different fill levels of liquid and the pneumatic system. Alternatively, the information on the plurality of characteristic time intervals associated with different fill levels of liquid may be calculated or simulated based on knowledge on a gas volume of the container 2 and, if applicable, tubing 6’. In other words, the information on the plurality of characteristic time intervals associated with the different fill levels of liquid may be based on knowledge on a gas volume of the container 2 (and, if applicable, of the tubing 6, 6’).

[0074] In some applications, it is useful to determine a flow rate of (non-gaseous) liquid flowing into or out of the container. The control unit 5 may be configured to repeat determining the fill level of the liquid in the container over time, and to determine a flow rate of non-gaseous liquid entering or exiting the container based on the repeated determination of the fill level of the liquid in the container. For example, if a first measurement at a first point in time results in a first fill level, and a second measurement at a second point in time results in a second fill level, the difference between the first and second fill level may be determined by the control unit 5, and divided by the time passed between the first and second point in time to determine the flow rate of liquid into or out of the container. Preferably, the measurements may be repeated frequently, e.g., according to a schedule, and the flow rate may be averaged over multiple measurements. A higher frequency of measurements resolves average flow rates over shorter time intervals.

[0075] For example, the control unit 5 may be a controller that is used to control the actor and sensor components of the proposed system, such as the pressure source 3, the pressure sensor 4, the optional valve 7, the optional pneumatic element 7b, and the optional vacuum pump. The control unit 5 may comprise circuitry that is used to implement the functionality of the control unit 5. For example, the control unit 5 may comprise interface circuitry configured to communicate with the other components (the pressure source 3, the pressure sensor 4, the optional valve 7 and the optional vacuum pump), processor circuitry or control circuitry configured to perform the functionality ascribed to the control unit 5, and memory circuitry configured to store information (such as a characteristic curve, pressure sensor data, or machine- readable instructions being executed by the processor circuitry or control circuitry). For example, the functionality ascribed to the control unit 5 may be implemented in software, with the processor circuitry or control circuitry being configured to execute machine-readable instructions representing the functionality.

[0076] For example, the pressure source 3 may be an air compressor, e.g., combined with a pressure regulator. Alternatively, the pressure source 3 may be a pre-pressurized gas cylinder.

[0077] For example, the pressure sensor 4 may be a sensor for sensing the gas pressure in the container 2, e.g., the gas pressure in a closed pneumatic system including the container 2. For example, the pressure sensor 4 may be a piezoresistive or capacitive pressure sensor, which both react to a deformation of a material, such as a membrane, in response to the gas pressure.

[0078] In connection with Figs. 1 to 5, the inventive concept has been demonstrated with reference to a device 1 , apparatus and system. The inventive concept may also be embodied by a corresponding method shown in Fig. 6, which may use the device 1 , apparatus and / or system to determine the fill level. Features described in connection with Figs. 1 to 5 may likewise be included in the corresponding method of Fig. 6.

[0079] Fig. 6 shows a flow chart of an example of such a method determining a fill level of a liquid in a container 2. At S1 , the method comprises fluidically coupling the pressure source 3 and the pressure sensor 4 to the container 2. At S2, the method comprises activating, e.g., by the control unit 5, the pressure source 3 to pressurize the container 2. At S3, the method comprises determining, e.g., by the control unit 5, a time interval between the container 2 having a first gas pressure and the container 2 having a second gas pressure after activation of the pressure source 3. At S4, the method comprises, e.g., by the control unit 5, determining the fill level of the liquid in the container 2 based on the time interval. In the following, experimental results are provided that underline the suitability of the proposed concept. Figs. 7a to 7c illustrate, for different container sizes, a precision of the pressure-based fill level determination, with the pressure-based determination of the fill level being compared to pipetting and gravimetric measurements. Fig. 7a shows the results for a 15 mL Falcon tube, Fig. 7b shows the results for a 50 mL Falcon tube, and Fig. 7c shows the results for a 500 mL Falcon tube / flask. These containers (15ml, 50ml, 500ml) are most common in cell culture / bioreactor applications and compared the results from our system to pipetting and gravimetric measurements. The following parameters were used: Pressure calculation: Calibration curve based on three points of a training set: 0, 50%, 100% (N=5); New measurements were performed and fitted to the previously determined calibration curve (N=5). The measurements were performed with water as a liquid and at room temperature.

[0080] Fig. 8 illustrates a linearity of the calibration curve for different container sizes. Solid rectangles indicate measurements of time intervals for an 1.5 mL Eppendorf tube, empty circles indicate measurements of time intervals for a 15 mL Falcon tube, and solid circles indicate measurements of time intervals for a 50 mL Falcon tube. For the 1 .5 mL Eppendorf tube, the fitted curve y = -0.1035% + 0.9797 was determined, with R2= 0.9776. For the 5 mL Falcon tube, the fitted curve y = -0.1075% + 2.5197 was determined, with R2= 0.9991. For the 50 mL Falcon tube, the fitted curve y = -0.1138% + 0.6.9216 was determined, with R2= 0.9992. Experiments were performed with water at room temperature. Result: Even for a 1 .5 ml Eppendorf tube, the R2value reaches 0.98, which speaks to a high linearity of the calibration curve. Fig. 9 shows the calibration curve for a 1.5 ml Eppendorf tube, with y = -9.4482% + 9.1882 and R2= 0.9776 (note that Fig. 8 plots Tau on the y-axis and the volume on the x-axis, while Fig. 9 plots Tau on the x-axis and the volume on the y-axis). The calibration curve was fitted based on measurements of five filling levels. Fig. 9 shows the measurements for the five filling levels and the corresponding calibration curve (linear fit).

[0081] Many modifications and other embodiments of the invention set forth herein will come to mind to the one skilled in the art to which the invention pertains having the benefit of the teachings presented in the foregoing description and the associated drawings. Therefore, it is to be understood that the invention is not to be limited to the specific embodiments disclosed and that modifications and other embodiments are intended to be included within the scope of the appended claims. Although specific terms are employed herein, they are used in a generic and descriptive sense only and not for purposes of limitation.

Claims

C l a i m s1 . Device (1 ) for determining a fill level of a liquid in a container (2), preferably a laboratory container, comprising a pressure source (3) to pressurize the container (2), a pressure sensor (4) to detect a gas pressure inside the container (2) and a control unit (5), wherein the pressure source (3) and the pressure sensor (4) are to be fluidically coupled to the container (2), wherein the control unit (5) is configured to activate the pressure source (3), determine a time interval between the container (2) having a first gas pressure and the container having a second gas pressure after activation of the pressure source(3), and determine the fill level of the liquid in the container (2) based on the time interval, wherein the pressure source (3), the pressure sensor (4) and / or a valve (7) is / are integrated into a cap (8) to be mounted onto the container (2).

2. Device according to claim 1 , characterized in that the valve (7) is a pneumatic valve (7), and / or characterized in that the pressure source (3), the pressure sensor(4), the pneumatic valve (7) and / or a vacuum pump is / are coupled to the container (2), preferably to a cap (8) of the container (2), via a tubing (6, 6’).

3. Device according to claim 1 or 2, characterized in that the control unit (5) is configured to activate the pressure source (3) during a pressurization phase to increase the gas pressure in the container (2) from a baseline gas pressure, in particular an ambient gas pressure, to a target gas pressure.

4. Device according to claim 3, characterized in that the control unit (5) is configured to determine the time interval between a start and an end of the pressurization phase.

5. Device according to claim 4, characterized in that the first and second gas pressure are greater than the baseline gas pressure and smaller than the target gas pressure, in particular in that the first gas pressure is a first pre-defined pressure between 25% and 45% of a difference between the baseline gas pressure and thetarget gas pressure, the second gas pressure is a second pre-defined pressure between the 55% and 75% of the difference between the baseline gas pressure and the target gas pressure.

6. Device according to claim 3, characterized in that the control unit (5) is configured to affect a depressurization phase for depressurizing the container (2) following the pressurization phase, and to determine the time interval between a start of the depressurization phase and the container (2) having the second gas pressure during the depressurization phase.

7. Device according to claim 6, characterized in that a valve (7), preferably a pneumatic valve (7), is fluid ically coupled to the container (2), with the control unit (5) being configured to control the valve (7) to be closed during the pressurization phase and to open the valve (7) to affect the depressurization phase, and / or characterized in that a vacuum pump is fluidically coupled to the container (2), with the control unit (5) being configured to control the vacuum pump to depressurize the container (2) to affect the depressurization phase.

8. Device according to claim 6 or 7, characterized in that the first gas pressure is the target gas pressure and the second gas pressure is a gas pressure between the baseline gas pressure and the target gas pressure, in particular a gas pressure between 25% and 50% of a difference between the baseline gas pressure and the target gas pressure.

9. Device according to any one of claims 1 to 8, comprising a pneumatic element (7, 7b) for adjusting a flow resistance during a pressurization or depressurization phase, with the control unit (5) being configured to determine the fill level of the liquid in the container (2) based on the flow resistance being applied by the pneumatic element.

10. Device according to any one of claims 1 to 9, characterized in that the control unit (5) comprises a memory with information on a plurality of characteristic time intervals associated with different fill levels of liquid, with the control unit (5) being configured to determine the fill level based on the time interval and based on the information on the plurality of characteristic time intervals.

11. Device according to claim 10, characterized in that the control unit (5) is configured to interpolate between adjacent fill levels of liquid if the time interval is between two characteristic time intervals of the plurality of characteristic time intervals, and / or characterized in that the memory comprises a characteristic curve representing the information on the plurality of characteristic time intervals associated with the different fill levels of liquid, with the control unit (5) being configured to determine the fill level based on the time interval and based on the characteristic curve, and / or characterized in that the information on the plurality of characteristic time intervals associated with the different fill levels of liquid is based on a calibration measurement, or in that the information on the plurality of characteristic time intervals associated with the different fill levels of liquid is based on knowledge on a gas volume of the container (2).

12. Device according to any one of claims 1 to 11 , characterized in that the control unit (5) is configured to continuously or quasi-continuously determine the gas pressure in the container (2) using the pressure sensor (4) during a pressurization and / or during a depressurization phase, and to determine the time interval based on the continuous or quasi-continuous determination of the gas pressure, and / or in that the control unit (5) is configured to repeat determining the fill level of the liquid in the container (2) over time, and to determine a flow rate of non-gaseous liquid entering or exiting the container based on the repeated determination of the fill level of the liquid in the container.

13. Apparatus for a device (1 ) according to any one of claims 1 to 12, comprising a pressure source (3) to pressurize the container (2), a pressure sensor (4) to detect a gas pressure inside the container (2), a valve (7), preferably a pneumatic valve (7), and a cap (8) for the container, wherein the pressure source (3), the pressure sensor (4) and / or the valve (7) is / are integrated into the cap (8).

14. System comprising a device (1 ) according to any one of claims 1 to 12 and at least one container (2), preferably a reagent container.

15. Method for determining a fill level of a liquid in a container (2), preferably by using a device (1 ) according to any one of claims 1 to 12, the method comprising:- flu idical ly coupling (S1 ) a pressure source (3) and a pressure sensor (4) to the container (2);- activating (S2) the pressure source (3) to pressurize the container (2);- determining (S3) a time interval between the container (2) having a first gas pressure and the container (2) having a second gas pressure after activation of the pressure source (3); and- determining (S4) the fill level of the liquid in the container (2) based on the time interval.

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