Gamma-sterilizable chips, specifically designed for impedance flow cytometry.

Abstract

This invention relates to a sensor housing for online fluid measurement, comprising: a body having an interface section configured to connect to a sensor head, the interface section including a measurement channel for receiving the fluid to be measured; and a pump housed within the body, the pump including an actuation member configured to be actuated by the sensor head when the interface section is connected to the sensor head to pump the fluid to be analyzed through the measurement channel. The body further includes inflow and outflow sections connected to the interface section, the inflow and outflow sections including an inflow channel and an outflow channel, the inflow channel being flowably connected to the outflow channel via the measurement channel and the pump, such that the fluid to be measured can be pumped from the inflow channel to the outflow channel via the measurement channel to achieve online fluid measurement. The invention also relates to a gamma-sterilizable chip, particularly for impedance flow cytometry.

Description

Technical Field

[0001] The present invention relates to a sensor box for online fluid measurement, a system including a sensor box and a sensor head according to the present invention, and a method for online fluid measurement. Background Technology

[0002] In particular, such sensor boxes can be used to perform flow cytometry, especially impedance flow cytometry.

[0003] Flow cytometry allows for the analysis and quantification of the characteristics of cells or particles in fluids. It has wide applications in various fields, including immunology, hematology, and microbiology. The basic principle of flow cytometry involves passing individual particles / cells through a laser beam and measuring the light scattering and fluorescence emitted by the cells.

[0004] Impedance flow cytometry is a specific type of flow cytometry that measures the change in electrical impedance as a particle or cell passes through a measurement channel (e.g., an orifice). Electrodes can be positioned on either side of the channel / orifice, and a detector can be used to measure the change in electrical impedance as a single particle or cell passes through the electrode. Specifically, the channel is configured to allow the particle or cell to flow through it in a single-row manner, ideally one particle or cell passing through at a time. Each particle or cell changes the electric field between the electrodes as it passes through the channel. This change in electrical impedance is proportional to the volume of the particle or cell. Larger particles or cells cause a greater change in impedance compared to smaller cells. Changes in electrical impedance can be recorded and analyzed to determine various characteristics of the particle or cell, such as cell size, particle size, and cell count.

[0005] EP3914393A1 discloses a microfluidic chip system (e.g., a cytometry system) with on-chip impedance-based measurement and quantification capabilities. The electronic circuitry includes a printed circuit board configured with slots for housing the microfluidic chip portion. The electronic circuitry may include electronics for signal generators, controllers, and impedance detectors, which can be connected to electrodes on the microfluidic chip.

[0006] In addition, US2003178310A1 also discloses "on-chip" detection with integrated electrodes.

[0007] In addition, US2015024373A1 relates to a microfluidic chip that orients and separates components in a sample fluid mixture through two-step focusing.

[0008] Furthermore, US2003152487A1 discloses a sample analysis instrument for use with a fluid analysis cartridge. The instrument includes a cartridge holder and a flow cytometry measurement device positioned for optical coupling with a flow cytometry measurement region on the cartridge. The cartridge holder may include a pump mechanism for coupling with a pump interface on the cartridge and a valve mechanism for coupling with a valve interface on the cartridge.

[0009] Based on the above, the problem to be solved by the present invention is to provide an improved sensor box that allows for online measurement of fluids containing particles or cells in a user-friendly manner, and is particularly easy to sterilize to reduce waste. Summary of the Invention

[0010] The problem is solved by a sensor box for online fluid measurement, a system including such a sensor box and a sensor head, and a method for online fluid measurement.

[0011] In the context of this invention, "online" measurement refers to a measurement performed directly in or in the immediate vicinity of the corresponding process: the user does not need to provide additional hardware to extract samples or create bypasses.

[0012] Preferred embodiments of these aspects of the invention are set forth in the corresponding dependent claims and described below.

[0013] According to claim 1, a sensor box for online measurement of fluids containing particles or cells is disclosed, comprising: - A body having an interface section configured to connect to a sensor head, the interface section including a measurement channel for accommodating the volume of the fluid to be measured. - A pump, housed within the body, the pump including an actuating member configured to be actuated by the sensor head when the interface section is connected to the sensor head, to pump the fluid to be analyzed through a measurement channel, wherein... - The body also includes inflow and outflow sections connected to the interface section, wherein the inflow and outflow sections include an inflow channel and an outflow channel, the inflow channel being flowably connected to the outflow channel via a measurement channel and a pump, such that the fluid to be measured can be pumped from the inflow channel to the outflow channel via the measurement channel, particularly to achieve online measurement of the fluid.

[0014] Typically, within the framework of this invention, a fluid carries the particles / cells to be measured, wherein the fluid is preferably a liquid.

[0015] Furthermore, in one particular embodiment of the sensor box, the interface section is configured to be inserted into a slot in the sensor head to connect the sensor box to the sensor head. Specifically, in one possible configuration, the sensor box may also be pressed onto the receiving section of the sensor head by means of, for example, a clip, instead of being inserted.

[0016] Furthermore, as illustrated in one embodiment of the sensor box, the online measurement is a cytological measurement, the measurement channel is configured to contain fluid containing particles or cells, and the pump is specifically configured to pump the fluid containing the particles or cells.

[0017] According to one embodiment of the sensor box, the sensor box is a disposable unit. In the context of this invention, the concept of a disposable unit refers to a unit designed for single use and intended to be discarded after that single use. Therefore, such a unit does not imply reuse or extended lifespan. Advantageously, the fact that the sensor box can be a disposable unit enhances convenience, reduces the risk of contamination, and simplifies the measurement process using the sensor box.

[0018] According to another embodiment of the sensor box, the body of the sensor box is gamma-sterilizable, i.e., capable of being sterilized by gamma radiation. This process is commonly used to sterilize items such as laboratory equipment, medical devices, pharmaceuticals, and other products. Gamma sterilization typically involves exposing the item to ionizing gamma radiation, such as radiation from radioactive isotopes such as cobalt-60 or cesium-137. High-energy gamma rays destroy the DNA and other cellular structures of microorganisms, preventing them from reproducing, thereby sterilizing the item. Preferably, the sensor box is gamma-sterilizable, i.e., capable of being sterilized by gamma radiation.

[0019] According to an alternative embodiment, the sensor box is sterile (e.g., by sterilizing intermediate products of the sensor box during the manufacturing process of the sensor box).

[0020] Furthermore, in one embodiment of the sensor box, the interface segment is formed as a flat plate. Specifically, in the context of this invention, the concept of "flat" specifically refers to the interface segment having a thickness in the thickness direction, which is smaller than the dimensions of the interface segment in two perpendicular directions orthogonal to the thickness direction. In a particular embodiment, the interface segment includes a top side and a bottom side, which are spaced apart from each other by the thickness in the thickness direction and each extends orthogonally to the thickness direction. Specifically, the top side and the bottom side extend parallel to each other.

[0021] According to another embodiment of the sensor box, the inflow and outflow sections include elongated and / or cylindrical shapes.

[0022] Specifically, in one embodiment, the inflow and outflow sections include a proximal end connected to the interface section and an opposite distal end forming the end face of the inflow and outflow sections, wherein an inlet of the inflow channel is disposed on the end face, and wherein an outlet of the outflow channel is disposed adjacent to the inlet on the end face. In particular, the inlet and outlet may be disposed on opposite regions of the end faces of the inflow and outflow sections.

[0023] According to another embodiment of the sensor box, the proximal end is integrally connected to the interface section of the body of the sensor box.

[0024] Furthermore, in one embodiment of the sensor box, the inflow channel extends parallel to the outflow channel.

[0025] According to another embodiment of the sensor box, the pump is a membrane pump, wherein the actuating member is an elastically deformable membrane. Alternatively, the pump may be a gear pump or a peristaltic pump. In the case of a gear pump, the actuating member includes gears. In the case of a peristaltic pump, the actuating member includes an elastically deformable membrane.

[0026] Furthermore, in a specific embodiment of the sensor box, the inflow and outflow sections and / or the interface section are formed of or include one of the following materials: glass, acrylic glass, polyetheretherketone (PEEK), or high-density polyethylene (HDPE). Specifically, the density of HDPE ranges from 930 kg / m³. 3 Up to 970 kg / m 3 The standard method for testing the density of plastics (which can also be used in the context of this invention) is ISO 1183 Part 2 (gradient column method), or ISO 1183 Part 1; both are version 2019-03. In particular, suitable materials for the inflow and outflow sections and / or interface sections of the sensor housing include chemical compatibility with the typical biological process media in which the sensor housing is used. Typical biological process media are, for example, culture media containing water, salt, and a carbon source (e.g., glucose).

[0027] Furthermore, in one embodiment, the interface section of the sensor box includes a transparent window located near the measurement channel, particularly in the form of a transparent portion of the interface section, for optical observation of the fluid to be measured (e.g., for performing cytology).

[0028] In one particular embodiment of the invention, the sensor housing includes at least one pair of electrodes arranged on the interface section on the opposite side of the measurement channel to generate an electric field in the vicinity of the fluid to be measured.

[0029] In particular, this facilitates the sensor housing in performing impedance flow cytometry. Preferably, the sensor housing includes two pairs of electrodes arranged sequentially along the measurement channel, adapted to perform impedance flow cytometry using differential measurements of the electrode pairs.

[0030] In particular, at least one pair of electrodes helps the sensor box perform electrophoresis.

[0031] In particular, additional electrode pairs help the sensor housing to shield different electrode pairs from each other.

[0032] In particular, in one embodiment, the sensor housing includes at least one pair of focusing electrodes arranged on the interface section on the opposite side of the measurement channel to align the cell or particle to be measured in the measurement channel.

[0033] According to another embodiment of the sensor box, the sensor box includes an electrical contact portion for electrically connecting electrodes arranged on the interface section to the electronic unit of the sensor head when the interface section is connected to the sensor head (in particular, inserted into the sensor head).

[0034] Furthermore, in one embodiment of the sensor box, the measurement channel of the sensor box includes a first measurement section and a second measurement section.

[0035] Specifically, in one embodiment, the first measuring section is arranged upstream of the pump, between the inflow channel and the pump, and the second measuring section is arranged downstream of the first measuring section and upstream of the pump, or the second measuring section is arranged downstream of the pump, between the pump and the outflow channel. In particular, arranging both measuring sections upstream of the pump allows for the measurement of cells in the fluid before the fluid passes through the pump, thereby reducing the risk of measuring cells damaged by the pump.

[0036] In one embodiment, the sensor box is configured to measure the fluid and / or particles and / or cells in the fluid using a first measurement method and a first measurement segment adapted to the first measurement method, and the sensor box is configured to perform alternative measurements of the fluid and / or particles and / or cells in the fluid using a second measurement segment adapted to the second measurement method. The adaptation of the measurement segment to a particular measurement method specifically includes one or more of the following features or combinations thereof: one or more windows shaped to function as lenses and / or made of a particular material or coated to be transparent, reflective, or absorptive to a particular wavelength; electrodes having a suitable shape, size, and / or arrangement to generate, modify, and / or measure an electric field; and dots containing coatings and / or dyes that respond to the property to be measured.

[0037] In another embodiment, the sensor box is configured to perform impedance cytometry using the first measurement section, and wherein, in particular, the sensor box is configured to perform alternative measurements using the second measurement section, wherein, in particular, the alternative measurements are optical measurements, especially optical microscopy.

[0038] According to another aspect of the invention, a system is disclosed comprising a sensor housing and a sensor head according to the invention, the sensor head including a receiving section, preferably in the form of a slot, wherein an interface section of the sensor housing is configured to connect to the receiving section of the sensor head such that the inflow section protrudes from the sensor head. Specifically, the interface section of the sensor housing is configured to be inserted into the slot to connect the sensor housing to the receiving section. The corresponding insertion direction may coincide with the longitudinal axis along which the inflow and outflow sections, particularly the inflow and outflow channels, extend.

[0039] In particular, in one embodiment of the system, the sensor head includes at least one measuring instrument arranged in the sensor head and designed to observe the properties of the fluid in the measuring channel.

[0040] Preferably, one of the at least one measuring instrument is at least a portion of a microscope for optical observation of cells and particles in the fluid and / or the fluid in the measuring channel, most preferably through a window in the body of the sensor housing. In such an embodiment, the window may be formed by a lens and thus may be part of the measuring instrument, particularly the microscope. Preferably, a portion of the microscope included in the sensor head and a portion of the microscope formed by the lens acting as a window in the body of the sensor housing can be combined by connecting the sensor housing to the receiving section to jointly form a microscope.

[0041] In a preferred embodiment, a second window may be formed, preferably on the opposite side of the measurement channel or adjacent to the first window, and the second window is preferably used to provide illumination to a portion of the measurement channel observed by the microscope.

[0042] Preferably, the at least one measuring instrument or a component of the at least one measuring instrument contained in the sensor head is mounted and configured such that, when the sensor housing is connected to the receiving section, it can be aligned relative to the sensor housing to allow for the desired measurement. If desired, this alignment can be achieved, for example, by applying a spring load to the at least one measuring instrument or a component of the sensor head, and by providing complementary alignment structures (e.g., ball pins and grooves) on the sensor housing and the measuring instrument or its components.

[0043] In particular, in one embodiment of the system, the sensor head includes an electronic unit configured to be electrically connected to the sensor box and / or an additional measuring instrument disposed in the sensor head and intended to observe the fluid properties in the measuring channel when the sensor box is connected to the receiving section, particularly when inserted into the slot. In particular, in one embodiment of the system, the electronic unit is configured to process signals provided by the sensor box to evaluate the impedance or other properties of particles or cells (e.g., for performing impedance flow cytometry or electrophoresis).

[0044] Preferably, the electronic unit is configured to be electrically connected to the electrical contacts of the sensor housing. Alternatively, according to one embodiment of the system, the electronic unit may be configured to preprocess the signal provided by the sensor housing and provide the preprocessed signal to another means for analyzing the preprocessed signal, particularly for evaluating impedance (e.g., for performing impedance flow cytometry or electrophoresis).

[0045] Specifically, in one embodiment of the system, the electronic unit is configured to provide signals to the electrical contacts of the sensor housing to generate the electric field required for the intended measurement, particularly delivering a desired voltage or current signal to the electrodes for measurement and / or connecting the electrodes to a common ground: For example, to perform impedance measurements in impedance flow cytometry, an AC voltage signal at a desired frequency or a set of frequencies (“drive frequencies”) can be applied to one, two, or more pairs of electrodes, and the phase shift between the drive frequencies and the observed frequencies and / or between the observed frequencies at corresponding pairs can be evaluated to obtain information about the presence and / or properties of particles or cells through the electric field generated by the respective pair of electrodes. In this example, the sensor housing includes one, two, or more pairs of electrodes, and the sensor head includes an electronics unit comprising contacts connected to the different electrodes disposed on the sensor housing.

[0046] For example, to perform electrophoresis, a DC voltage or a low-frequency AC voltage can be applied to a pair of electrodes, and the movement of cells or particles in response to the electric field can be evaluated through a transparent window using an optical device, thereby obtaining information about the presence and / or properties of particles or cells through the field generated by the pair of electrodes. In this example, the sensor housing includes the pair of electrodes and an optical window for observing the measurement channel within the region of the measurement channel through the electric field generated by the pair of electrodes. The sensor head includes an electronic unit with contacts connected to electrodes disposed on the sensor housing, and the sensor head also includes an optical device for observing the measurement channel through the optical window within the region of the measurement channel through the electric field generated by the pair of electrodes.

[0047] Specifically, in one embodiment of the system, the sensor head includes a first measuring instrument and a second measuring instrument or an electronic unit adapted to provide signals to electrical contacts on the sensor housing. In this system, the sensor housing includes a first measuring section adapted to the first measuring instrument and a second measuring section adapted to the second measuring instrument and / or containing electrodes and electrical contacts to the electrodes. This embodiment allows for the observation of the same flow and / or particles and / or cells using at least two different measurement methods: one using the first measuring instrument and the other using the second measuring instrument and / or electrodes.

[0048] The resulting datasets of the same flow and / or particles and / or cells observed using different measurement methods are preferably used to create a training set for a machine learning system. A first group of these different measurement methods (which may include one or more measurement methods) produces measurement results, which are evaluated to become labels. These labels are assigned to the measurement results of a second group of these different measurement methods, which may include one or more measurement methods. The assignment of labels to the measurement results of the second group is done automatically and is preferably based on timestamps: since the pump driving the flow is integrated with the measuring instruments and / or electrodes in the same system, the time difference between observations of the same flow and / or particles and / or cells using different measurement methods is precisely known.

[0049] The training set is preferably then used by a machine learning system or artificial intelligence (AI) to derive a trained AI model that automatically assigns the characteristics described by the label values ​​to measurement results obtained through at least one of the measurement methods in the second group.

[0050] In another embodiment, the training set is evaluated to derive or test an algorithm, and when the algorithm is executed on a computing device, the characteristics described by the label values ​​are automatically assigned to measurement results obtained through at least one of the measurement methods in the second group.

[0051] In a preferred embodiment, the measurement method of the second group is an optical method that generates an image, most preferably a microscopic image. In this embodiment, the trained AI model or algorithm preferably allows for object recognition and / or object segmentation of the image, and preferably for image classification.

[0052] Specifically, the first set of measurement methods is impedance spectroscopy, and the second set is microscopy. In this embodiment, impedance spectroscopy is evaluated to assess the presence and viability of cells. The presence and / or viability of cells are used as labels for the corresponding microscopic images. For example, if impedance spectroscopy is performed symmetrically along the measurement channel before and after the window for acquiring the microscopic image, the impedance spectral measurements of the first set of electrodes at time t-Δt and the impedance spectral measurements of the second set of electrodes at time t+Δt can be evaluated to create labels for the microscopic image acquired at time t. The resulting training set comprises a set of microscopic images labeled with the presence or absence of cells and their respective viability. This training set is fed into a machine learning system or artificial intelligence (AI) to create a trained model that can identify cells and their viability on microscopic images. According to another embodiment of the system, the sensor head includes an actuator configured to actuate a pump of the sensor housing, particularly by deforming the membrane to form a membrane pump or peristaltic pump, or by driving at least one gear of a geared pump.

[0053] Furthermore, according to one embodiment of the system, the system includes components configured to position and releasably lock a sensor housing and a sensor head relative to each other, wherein, in particular, the components are configured to provide a form-fitting seat (e.g., for the sensor housing) to position the sensor housing and the sensor head relative to each other, and / or wherein, in particular, the components include a releasable lock configured to releasably lock the sensor housing relative to the sensor head at the desired position (e.g., provided by the seat). In particular, the releasable lock may include a latch, especially a movable latch. The components are positioning and / or locking components.

[0054] According to another embodiment of the system, the sensor head and / or the sensor housing includes a coupling device configured to establish, in particular, a fluid-tight connection with a measurement port, specifically a measurement port in a fluid line, or a measurement port in a fluid reservoir or reactor.

[0055] In one embodiment, the coupling device includes a circumferential seal, wherein, in particular, the seal is an O-ring, and wherein, in particular, the seal is configured to form a seal with the inner surface of the measuring port when the inflow and outflow sections are arranged in the measuring port. Specifically, in one embodiment, the inflow and outflow sections include a coupling device, or the coupling device is arranged on the inflow and outflow sections.

[0056] Furthermore, according to another embodiment of the system, the coupling device includes one of the following: a male thread adapted to connect with a corresponding female thread on the inside of the measuring port, a union nut, a female component of a bayonet mount, and a retainer, the retainer being specifically configured to engage with a measuring port in the form of an Eldon-James port.

[0057] According to another embodiment of the system, the system includes a container for containing the fluid to be measured, wherein, as described above, the container may be a fluid line, a fluid reservoir, or a reactor, wherein the sensor housing is part of a closed fluid system including the container and the sensor housing, and wherein the sensor head is liquid-tightly separated from the fluid system (e.g., by liquid-tightly connecting the sensor housing to the container via the coupling device, such that an inflow channel, a measurement channel, and an outflow channel form a conduit leading only to the container, and the sensor head is connected to the sensor housing). Specifically, the sensor housing is part of the fluid system, and the sensor head does not contact the interior of the container. Therefore, specifically, the sensor head need not be sterile; only the sensor housing is sterile.

[0058] According to another aspect of the invention, a method for online measurement of fluid using the system according to the invention is disclosed, wherein inflow and outflow sections of a sensor housing connected to a sensor head are arranged to be flow-connected with the flow of the fluid to be measured, and a portion of the fluid flow is pumped into the sensor housing via an inflow channel by a pump, wherein the portion of the flow is measured in a measurement channel of the sensor housing with the aid of the sensor head, and wherein the portion of the flow is discharged through an outflow channel and merges with the flow of the fluid. Attached Figure Description

[0059] Other features and advantages of the invention, as well as embodiments thereof, will now be described with reference to the accompanying drawings, in which: Figure 1A A perspective view of an embodiment of the sensor box according to the present invention is shown. Figure 1B A partial cross-sectional view of an embodiment of the sensor box according to the present invention is shown.

[0060] Figure 2A perspective view of an embodiment of a system according to the invention is shown, wherein the system includes a sensor housing (e.g., as shown in FIG1) and a sensor head according to the invention, wherein, Figure 2 The sensor housing is shown being released from the sensor head. Figure 3A The system shown is a sensor box inserted into a sensor head. Figure 3B It shows Figure 2 and 3A The schematic cross-sectional view of one embodiment of the system components shown allows for positioning relative to the sensor head and, in particular, releasably locking of the sensor box when it is inserted into the sensor head. Figure 4 Examples are shown, for instance. Figures 2 to 3B The system shown is based on one embodiment of the invention, wherein a sensor housing is positioned in the measurement port of a container of the system, wherein, as an example, the container is a fluid line that guides the fluid to be measured. Figure 5 Details of one embodiment of the system's coupling device are shown, which allows for fluid-tight coupling of the sensor housing to the measurement port of the container (e.g., Figure 4 (fluid pipelines), and Figure 6 Details of another embodiment of the system's coupling device are shown, which allows for fluid-tight coupling of the sensor housing to the container's measurement port (e.g., Figure 4 (fluid pipelines). Detailed Implementation

[0061] Figure 1A An embodiment of sensor housing 1 for online measurement of fluid 2 is shown. For example... Figure 1A As shown, the sensor housing 1 includes a body 10 having an interface section 11, which can be formed, for example, a rectangular flat plate and is configured to connect to a sensor head 100. Figure 1A Not shown in the image, see [link / reference]. Figures 2 to 4Interface section 11 encloses a measurement channel 12 for guiding the flow of the fluid 2 to be measured. For this purpose, sensor housing 1 also includes a pump 13 disposed on body 10, wherein the pump 13 includes an actuating member 130, for example in the form of a membrane 130, configured to be actuated by sensor head 100 when interface section 11 is connected to sensor head 100 to pump the fluid 2 to be analyzed through measurement channel 12. Specifically, sensor head 100 may include an actuator operatively coupled to membrane 130 to move membrane 130, thereby pumping fluid 2 through measurement channel 12. Furthermore, the body 10 includes inflow and outflow sections 14 connected to the interface section 11, wherein the inflow and outflow sections 14 include an inflow channel 15 and an outflow channel 16, the inflow channel 15 being flowably connected to the outflow channel 16 via a measuring channel 12 and a pump 13, such that the fluid 2 to be measured can be pumped from the inflow channel 15 to the outflow channel 16 via the measuring channel 12. Specifically, the inflow and outflow section 14 may include a proximal end 14a connected to the interface section 11 and an opposite distal end 14b forming the end face of the inflow and outflow section 14, wherein the inlet 15a of the inflow channel 15 is disposed on the end face 14b, and wherein the outlet 16a of the outflow channel 16 is disposed adjacent to the inlet 15a on the end face 14b. Furthermore, the inflow channel 15 may extend parallel to the outflow channel 16.

[0062] In particular, the above-described configuration of the inflow and outflow sections 14 supports the possibility of performing online measurements in an advantageous manner, as the fluid 2 to be analyzed can be readily drawn from the container (such as a fluid line or reactor) through the inflow and outflow sections 14 and can be discharged back into the container via the same inflow and outflow sections 14. The inflow and outflow sections 14 may comprise an elongated, and particularly cylindrical, shape, and protrude from the interface section 11, allowing the inflow and outflow sections 14 to readily contact the fluid 2 via a relatively small measurement port of the container and to be effectively sealed relative to the measurement port of the container.

[0063] The interface section 11 of the sensor housing 1 accommodates the measurement channel 12, the pump 13, and, according to one embodiment, accommodates electrodes 18a, 18b and corresponding electrical contacts 19, which allow the sensor housing 1 to make electrical contact with the sensor head 100. The electrodes 18a, 18b, arranged in pairs on opposite sides of the measurement channel 12, allow the sensor housing 1 to perform impedance flow cytometry. Specifically, the sensor housing 1 may include at least one pair of focusing electrodes 18a, arranged on the interface section 11 on the opposite side of the measurement channel 12, to generate an electric field near the fluid 2 for interacting with and aligning the particles / cells to be measured within the measurement channel 12. Furthermore, the sensor housing 1 may include at least one pair of electrodes 18b, arranged on the interface section 11 on the opposite side of the measurement channel 12, for acquiring signals from which the impedance of the particles or cells can be deduced.

[0064] To facilitate different measurement techniques, the measurement channel 12 of the sensor housing 1 may include multiple measurement sections, such as a first measurement section 12a and a subsequent second measurement section 12b, wherein both measurement sections are arranged upstream of the pump 13. This arrangement has the advantage that cells contained in the liquid are measured in said sections 12a and 12b before passing through the pump 13. Specifically, impedance flow cytometry can be performed in the first measurement section 12a, while different measurements, such as optical measurements, can be performed in the second measurement section 12b of the measurement channel 12. However, a second or additional measurement section 12c may alternatively be arranged downstream of the pump 13 (see also above). For optical measurements, the interface section 11 of the sensor housing 1 may include a transparent window 17 adjacent to the measurement channel 12. Specifically, the interface section 11 may be, or at least partially, formed of a transparent material.

[0065] Furthermore, the aforementioned partitions of the sensor housing 1 (preferably along its longitudinal axis) are divided into inflow and outflow sections 14 at one end and an interface section 11 at the other end. This allows for safe and reliable contact with the sensor head 100 using the interface section 11, for example, by connecting the interface section 11 to the receiving section 101 of the sensor head 100. Specifically, the receiving section 101 may be formed by a slot 101 in the housing 102 of the sensor head 100, allowing the interface section 14 to be inserted into the slot 101 to establish all necessary electrical connections between the sensor head 100 and the sensor housing 1. In particular, connecting the sensor housing 1 to the receiving section 101 as intended (e.g., by inserting the sensor housing 1 into the slot 101) also aligns the actuating member 130 of the pump 13 with the actuator included in the sensor head 100, thereby allowing actuation of the pump 13.

[0066] Figure 1BA cross-sectional view of the sensor housing 1 extending perpendicularly to the measurement channel 12 through a pair of electrodes 18b is shown. The electrodes 18b are arranged on opposite sides of the measurement channel 12, and during measurement, the voltage of the electrodes 18b is controlled or measured by a sensor head that contacts the electrodes 18b via corresponding electrical contacts 19. The electrical contacts 19 are in electrical contact with the corresponding electrodes 18b.

[0067] An embodiment of this system 200, including sensor box 1 and sensor head 100, is in Figures 2 to 6 As shown in the image.

[0068] Figure 2 The sensor head 100 and sensor housing 1 are shown before the sensor housing 1 is inserted into the receiving section / slot 101. The sensor head 100 may include, for example, a cylindrical housing 102 having an end face 103 that provides access to the slot 101. Furthermore, power and communication with other devices can be provided via leads 104 connected to the sensor head 100. Therefore, analysis of the signals measured by the sensor housing 1 can also be performed by a remote device connected to the sensor head 100 via leads 104.

[0069] Figure 3A Sensor housing 1 is shown, wherein the interface section 11 is inserted into the slot 101 of the sensor head. Specifically, as... Figure 3B As schematically shown, system 200, particularly sensor head 100, may include component 201 configured to position and / or releasably lock sensor housing 1 and sensor head 100 relative to each other. For this purpose, component 201 may provide a form-fitting seat 202 to position sensor housing 1 and sensor head 100 relative to each other. Specifically, seat 202 may be defined by slot 101 and / or guide structures arranged in said slot 101. Furthermore, component 201 may include a releasable lock 203 configured to releasably lock sensor housing 1 relative to sensor head 100, particularly at the position provided by seat 202. Figure 3B As shown, lock 203 may include a movable latch that, when engaged with a portion of interface section 11, prevents the sensor housing from being pulled out of slot 101.

[0070] also, Figure 4 An example is shown of how the inflow and outflow sections 14 of sensor housing 1 can be connected to container 207 (here, the fluid line 207 that guides fluid 2) via the measurement port 206 of container 207. Specifically, the inflow and outflow section 14 is inserted forward with its distal end 14b into the measurement port 206, thereby establishing a flow connection between the fluid line 207 and the inlet 15a and outlet 16a of the inflow and outflow section 14 of sensor housing 1.

[0071] In particular, in order to achieve a fluid-tight (i.e. sealed) connection between the inflow and outflow sections 14 and the measurement port 206, the sensor head 100 and / or sensor housing 1 may include a coupling device 205 configured to establish a fluid-tight connection with the measurement port 206 of the container / fluid line 207.

[0072] according to Figure 5 In one embodiment shown, the coupling device 205 may include a male (i.e., external) thread 208 configured to engage with a corresponding female thread formed in the measuring port 206. The coupling device 205 may also include at least one seal 210, particularly an O-ring, disposed on the inflow and outflow sections 14, which may contact the inside of the measuring port 206 to seal the connection between the inflow and outflow sections 14 of the sensor housing 1 and the measuring port 206.

[0073] Figure 6 An alternative embodiment of the coupling device 205 is illustrated, wherein the coupling device 205 includes a retainer 209 that may house the nozzle of the measuring port (e.g., the Eldon-James port) 206. Also here, a seal 210 may be arranged on the inflow and outflow sections 14 of the sensor housing 1, the seal 210 contacting the inside of the measuring port 206 to seal the connection between the inflow and outflow sections 14 of the sensor housing 1 and the measuring port 206.

[0074] This invention provides an advantageous sensor housing capable of enabling online measurement of fluids, particularly based on impedance flow cytometry. Specifically, the particular design of the sensor housing allows its inflow and outflow sections 14 to be conveniently connected to the fluid to be measured in a manner that is convenient (e.g., via small measurement ports), while ensuring an efficient seal between the inflow and outflow sections 14 of the sensor housing 1 and the container (e.g., fluid line, reactor, etc.) containing / guiding the fluid to be measured. The interface sections 11 protruding from the inflow and outflow sections 14 allow for easy and user-friendly operation of the sensor housing 1 with the corresponding sensor head 100, thereby ensuring proper electrical contact between the sensor housing 1 and the sensor head 100 and proper interaction with the functions contained in the sensor head 100 (e.g., actuators of the pump 13). In particular, since the sensor head 100 can be completely separated from the fluid, only the sensor housing 1 needs to be sterile.

Claims

1. A sensor box (1) for online measurement of fluid (2), comprising: - Body (10), the body (10) having an interface section (11) configured to connect to a sensor head (100), the interface section (11) including a measurement channel (12) for accommodating the volume of the fluid (2) to be measured. - A pump (13), housed in a body (10), the pump (13) including an actuating member (130) configured to be actuated by a sensor head (100) when the interface section (11) is connected to the sensor head (100) to pump the fluid (2) to be analyzed through the measurement channel (12), wherein, - The body (10) also includes an inflow and outflow section (14) connected to the interface section (11), wherein the inflow and outflow section (14) includes an inflow channel (15) and an outflow channel (16), the inflow channel (15) being flowably connected to the outflow channel (16) via a measurement channel (12) and a pump (13), so that the fluid (2) to be measured can be pumped from the inflow channel (15) to the outflow channel (16) via the measurement channel (12) to realize the online measurement of the fluid (2).

2. The sensor cartridge of claim 1, wherein, The online measurement is a cytological measurement, the measurement channel (12) is configured to contain a fluid (2) containing particles or cells, and the pump (13) is configured to pump the fluid (2).

3. The sensor cartridge of any one of the preceding claims, wherein, The main body (10), preferably the sensor box, is gamma-sterilizable.

4. The sensor cartridge of any one of the preceding claims, wherein, The inflow and outflow sections (14) include cylindrical shapes.

5. The sensor cartridge of any one of the preceding claims, wherein, The inflow and outflow section (14) includes a proximal end (14a) connected to the interface section (11) and an opposite distal end (14b) forming the end face of the inflow and outflow section (14), wherein the inlet (15a) of the inflow channel (15) is arranged on the end face (14b), and wherein the outlet (16a) of the outflow channel (16) is arranged adjacent to the inlet (15a) on the end face (14b).

6. The sensor box according to any one of the preceding claims, wherein, The interface section (11) of the sensor box (1) includes a window (17) adjacent to the measurement channel (12) for optical observation of the fluid (2) to be measured.

7. The sensor box according to any one of the preceding claims, wherein, The sensor box (1) includes at least one pair of electrodes (18a, 18b) arranged on the interface section (11) on the opposite side of the measurement channel (12) to generate an electric field in the vicinity of the fluid (2) to be measured.

8. The sensor box according to any one of the preceding claims, wherein, The sensor box (1) includes an electrical contact (19) for electrically connecting electrodes (18a, 18b) arranged on the interface section (11) to the electronic unit of the sensor head when the interface section (11) is connected to the sensor head (100).

9. The sensor box according to any one of the preceding claims, wherein, The measurement channel (12) of the sensor box (1) includes a first measurement section (12a) and a second measurement section (12b, 12c).

10. The sensor box according to claim 9, wherein, The sensor box (1) is configured to perform impedance flow cytometry using the first measurement section (12a), and wherein, in particular, the sensor box (1) is configured to perform alternative measurements using the second measurement sections (12b, 12c), wherein, in particular, the alternative measurements are optical measurements.

11. A system (200) comprising a sensor housing (1) and a sensor head (100) according to any one of the preceding claims, the sensor head (100) comprising a receiving section (101), particularly a slot (101), wherein, The interface section (11) of the sensor box (1) is configured to connect to the receiving section (101) of the sensor head (100), such that the inflow and outflow sections (14) protrude from the sensor head (100).

12. The system according to claim 11, wherein, The sensor head (100) and / or the sensor box (1) include a coupling device (205) configured to establish a fluid-tight connection with a measuring port (206) of a container (207) for containing the fluid (2), wherein, in particular, the container is a fluid line (207), or a fluid reservoir, or a reactor.

13. The system according to any one of claims 11 to 12, wherein, The inflow and outflow sections (14) include a connecting device (205).

14. The system according to any one of claims 11 to 13, wherein, The system also includes a container (207) for containing the fluid (2) to be measured, wherein the sensor box (1) is part of a closed fluid system including the container (207) and the sensor box (1), and wherein the sensor head (100) is liquid-tightly separated from the fluid system.

15. A method for online measurement of fluids using the system according to any one of claims 11 to 14, wherein, The inflow and outflow sections of the sensor box (1) connected to the sensor head (100) are arranged to flow into connection with the fluid (2) to be measured, and a portion of the fluid (2) is pumped into the sensor box (1) via the inflow channel (15) by the pump (13), wherein the portion of the flow is measured in the measurement channel (12) of the sensor box (1) with the aid of the sensor head (100), and wherein the portion of the flow is discharged through the outflow channel (16) and merges with the fluid (2).

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