Additional unit for a dispensing device

Abstract

The invention relates to an additional unit for a dispensing device (2) which comprises at least one fluid path (40) between a fluid reservoir (20) and an outlet nozzle (42). The additional unit is or can be fluidically and / or mechanically coupled to the fluid path (40) and carries out an additional function during operation of the dispensing device (2).

Description

[0001] Description

[0002] Additional unit for a dispensing device

[0003] The invention relates to an additional unit for a dispensing device. The invention further relates to a cartridge system for a dispensing device, a dispensing device, software on a data carrier, and a use thereof.

[0004] Dispensing devices, such as reagent dispensers, are used to apply precise amounts of chemical reagents, solutions, or other liquids into a target vessel or onto a surface. Such dispensing devices can dispense liquid quantities in the microliter (pl) to nanoliter (nl) range, for example.

[0005] Dispensing devices can be designed for a wide variety of applications, including filling microwell plates (or well plates) for high-throughput screening, adding reagents to reaction mixtures in chemical synthesis, or dispensing cells or culture media in biological cultures. Fully automated dispensing devices are capable of dispensing simultaneously from multiple parallel outlet nozzles (dispensing tips) with high precision and speed.

[0006] Such dispensing devices typically comprise a pressure source as a conveying device for conveying a fluid along a fluid path from a fluid reservoir to at least one outlet nozzle. Such pressure sources can be, for example, diaphragm pumps, acoustic dispensing, positive displacement devices, e.g., syringe pumps or piston pumps, pipettes, or compressed air-operated contact or non-contact dispensing systems. The pressure source of the dispensing device can also be coupled to the reservoir. In such embodiments, the fluid paths between the reservoir and the outlet nozzle are designed, in particular, as channels or fluid lines.

[0007] However, the pressure source is often implemented as a peristaltic pump (hose pump). The peristaltic pump conveys the fluid through compressive movement along a deformable tube as the fluid path. The movement is generated by pins, rollers, or wheels of a pump rotor, which compress the tube in a wave-like motion, thereby moving the fluid forward within the tube.

[0008] The hose is usually part of a dispensing cartridge (also called a dispensing cassette), which is arranged as a consumable in the area of ​​the pump rotor. Such dispensing cartridges have a number of parallel hoses routed between at least two cartridge parts. The cartridge parts serve, among other things, for mounting and holding the dispensing device, with the often largely exposed hoses resting on the pump rotor.

[0009] In such dispensing devices or dispensing cartridges, if the fluid paths have the same flow diameter, the same amount of fluid is delivered in each of the fluid paths, so that the same amount of fluid is dispensed from the connected outlet nozzles. The dispensed fluid amount can therefore only be controlled by the flow diameter of the fluid paths and the pressure source or pump operation. Thus, dispensing cannot be controlled at the level of the individual fluid paths.

[0010] This results in interplate and intraplate variability, particularly when dispensing in microtiter plates. Furthermore, edge effects and other effects that can lead to unequal dispensed fluid volumes cannot be specifically compensated for because the individual tubes or fluid paths cannot be individually controlled. An "edge effect" is understood here and below to mean, in particular, the phenomenon in which the images located at the edge and / or near an edge (edge ​​images) of a microplate exhibit different physical and biological properties compared to the images located centrally (central images).This can lead to variations in temperature, evaporation rate, and other environmental conditions, which in turn can affect the concentration of the solutions or suspensions present in the edge images, cell growth, or reaction kinetics. Such edge effects are particularly relevant for long-term incubations or procedures that require precise control of experimental conditions, as they affect the reproducibility and accuracy of the experimental results.

[0011] "Interplate variation" refers here and below to the variability or fluctuation of experimental results between different microtiter plates treated under apparently identical conditions. This variability can affect the comparability and reproducibility of experimental data and is therefore an important aspect that must be considered when planning and evaluating experiments, especially in high-throughput screening procedures.

[0012] "Intraplate variation" refers here and below, in particular, to the variability or fluctuation of experimental results within a single microtiter plate. This variability can be due to various factors, such as the inconsistent distribution of reagents or samples in the wells, as well as the aforementioned edge effect, which affects edge images differently than central images.

[0013] The invention is based on the object of specifying a particularly suitable add-on unit for a dispensing device. Preferably, the add-on unit should provide extended functionality for the dispensing device, which should, in particular, contribute to reducing edge effects as well as intra- and inter-plate variations. The invention is further based on the object of specifying particularly suitable software, a particularly suitable cartridge system, a particularly suitable dispensing device, and particularly suitable uses.

[0014] The object is achieved according to the invention with regard to the additional unit by the features of claim 1, with regard to the software by the features of claim 12, with regard to the cartridge system by the features of claim 13, with regard to the dispensing device by the features of claim 18, and with regard to the use by the features of claim 20. Advantageous embodiments and further developments are the subject of the respective dependent claims (subclaims).

[0015] The advantages and features mentioned with regard to the additional unit are also transferable to the software and / or the cartridge system and / or the dispensing device and / or the use and vice versa.

[0016] The conjunction “and / or” is to be understood here and in the following in such a way that the features linked by this conjunction can be formed both together and as alternatives to one another.

[0017] The additional unit according to the invention is intended for a dispensing device and is suitable and configured therefor. A dispensing device is to be understood here and below in particular as a device by means of which fluids are dispensed into receptacles of a microtiter plate, preferably with dispensed fluid quantities in the microliter to nanoliter range. The dispensing device has at least one fluid path between a fluid reservoir and an outlet nozzle. In one conceivable embodiment, the fluid reservoir is, for example, part of the fluid path. In an additional or alternative embodiment, the outlet nozzle is, for example, part of the fluid path; in particular, it is possible for the outlet nozzle to be designed as one end of the fluid path. The additional unit is intended and configured to be fluidically and / or mechanically coupled to the fluid path or to be coupled thereto.

[0018] In this context, “fluidically coupled” means in particular that the additional unit interacts or interacts with the fluid path, and thus in particular with the fluid contained therein. For example, the additional unit can be connected at least partially into the fluid path so that a fluid guided in the fluid path flows partially through or along the additional unit. The additional unit can also interact or interact with physical properties, such as pressure or pressure distribution, flow velocity, profile or direction, particle or bubble concentration, color, transparency, refractive index, viscosity, conductivity, etc., of the fluid path or the fluid contained therein. In particular, the additional unit can measure, influence or change these physical properties.

[0019] In this context, "mechanically coupled" specifically means that the auxiliary unit is coupled to the fluid path from the outside. With a purely mechanical coupling, the auxiliary unit essentially has no direct or immediate contact with the guided fluid, but only with the fluid path or its components. The mechanical coupling can be direct or immediate. An indirect mechanical coupling to the fluid path is also conceivable, for example, via the dispensing device or a component thereof.

[0020] In the case of a fluidic and mechanical coupling, the additional unit has sections in which the fluid is guided as well as sections in which the additional unit is coupled to the fluid path from the outside.

[0021] According to the invention, the additional unit is intended and configured to perform at least one additional function during operation of the dispensing device. An "additional function" is understood here and below to mean, in particular, an additional or supplementary function that goes beyond the basic conveying and dispensing of fluids, thus expanding the flexibility and functionality of a dispensing device equipped therewith. The additional function is intended and configured, in particular, to reduce edge effects and / or inter- and / or intra-plate variations.

[0022] The additional unit is therefore designed as an add-on for dispensing devices, by means of which the dispensing devices are equipped (also subsequently) with extended functionality in order to reduce or completely avoid edge effects and / or inter-plate and / or intra-plate variations.

[0023] In an advantageous embodiment, the additional unit has a controller for performing the additional function. In other words, the additional unit has, for example, a controller (i.e., a control unit) by means of which the additional function can be controlled and / or regulated. The controller is generally suitable and configured—in terms of programming and / or circuitry—to perform the respective additional function. If the additional unit implements multiple additional functions, the controller can also be designed to perform several or even all of these additional functions. Alternatively, a separate controller is provided for each additional function.

[0024] In a preferred embodiment, the controller is formed, at least in its core, by a microcontroller with a processor and a data memory, in which the functionality for carrying out the method according to the invention is implemented in the form of operating software (firmware), so that the additional function is automatically carried out when the operating software is executed in the microcontroller—possibly in interaction with a user. Within the scope of the invention, the controller can alternatively also be formed by a non-programmable electronic component, such as an application-specific integrated circuit (ASIC) or an FPGA (Field Programmable Gate Array), in which the functionality for carrying out the respective additional function is implemented using circuitry.The controller is, for example, coupled or can be coupled to the dispensing device in terms of signal technology, so that the operation of the dispensing device, in particular a pressure source or pump operation, can be influenced by the controller or depending on the additional function.

[0025] The controller can be integrated into the additional unit or designed as an external additional device that can be coupled to the additional unit via signal technology.

[0026] Alternatively, the controller can be integrated into an external electronic device that is signal-coupled to the auxiliary unit. The signal-coupled connection between the auxiliary unit and the electronic device is preferably wireless. A wireless communication link, such as a radio connection, in particular a Wi-Fi, RFID, or Bluetooth connection, is thus established between the components. For this purpose, the auxiliary unit and the electronic device have corresponding transceivers for data and signal exchange. Corresponding control commands for triggering or operating the auxiliary function(s) can be transmitted via the transceivers or the signal-coupled connection.

[0027] The electronic device is, for example, a mobile operating and display device, in particular a mobile computer device, preferably a smartphone or a tablet. The additional function(s) can be activated by stored application software (operating software). For this purpose, the application software can preferably be installed or can be installed on the electronic device as a so-called app or mobile app (mobile application, smartphone app).

[0028] This training is based on the consideration that modern operating and display devices, such as smartphones or tablet computers in particular, are widespread in today's society and are generally available and accessible to users at any time. In particular, the user of the additional unit or dispensing device is highly likely to have such an operating and display device. This eliminates the need for an additional, separate operating system to monitor and control the additional function. Instead, it is possible to use their existing smartphone or tablet computer by (subsequently) downloading and / or installing the application software. This advantageously reduces user costs.

[0029] The surfaces of smartphones or tablet computers, which are typically designed as touchscreens (displays), continue to allow particularly simple and intuitive operation of the application software of the control and display device created thereby.

[0030] The external electronic device can also be the dispensing device. In other words, the controller for controlling and / or regulating the additional function of the additional unit can also be integrated into the dispensing device equipped with it.

[0031] In a preferred embodiment, the additional unit comprises a valve unit and / or a fill level sensor unit and / or a particle sensor unit and / or a pressure sensor unit and / or a flow sensor unit and / or a pressure source unit and / or a reservoir unit and / or a fluid temperature unit and / or a fluid distribution unit and / or a one-way valve unit and / or a washing unit. Each of these units (valve unit, fill level sensor unit, particle sensor unit, pressure sensor unit, flow sensor unit, pressure source unit, reservoir unit, fluid temperature unit, fluid distribution unit, one-way valve unit, washing unit) is inventive in itself and thus represents a separate invention. The combination of one or more of these units in an additional unit also represents an independent invention.

[0032] The pressure sensor unit is designed and configured to measure the pressure in the fluid and convert it into an electrical signal that can be read and processed. The pressure sensor unit has a pressure sensor coupled to the hose or the fluid conveyed therein. The pressure sensor is, for example, a piezoelectric, capacitive, piezoresistive, or optical sensor. For example, the pressure sensor can also detect deformation of the hose due to internal pressure and use it to determine the pressure.

[0033] The flow sensor unit is designed and configured to measure a flow rate of the fluid in the respective monitored hose. The flow sensor unit converts the physical properties of the flowing fluid, such as velocity or volume per unit time, into an electrical signal that can be used to monitor, regulate, or control the flow. The flow sensor unit has a corresponding flow sensor. The flow sensor can be a thermal sensor that uses temperature changes to determine the flow. Alternatively, the flow sensor can be a mechanical sensor system that uses, for example, the movement of a wheel or turbine in the flow of the fluid.Also conceivable is, for example, an ultrasonic sensor that measures differences in acoustic signals, or a magnetic-inductive flow sensor that measures the change in a magnetic field due to fluid flow.

[0034] The valve unit, the level sensor unit, the particle sensor unit, the reservoir unit, the pressure source unit, the fluid temperature unit, the fluid distribution unit, the one-way valve unit and the washing unit are explained in more detail below.

[0035] In an advantageous embodiment, the additional unit has a valve unit for controlling a flow diameter of the at least one hose. This extends the dispensing device with a valve functionality.

[0036] The valve unit is provided and configured to change the flow diameter of at least one fluid path, in particular to reduce it or to completely close it. The valve unit thus makes it possible to reversibly close and open a fluid or flow channel. The dispensing device can have a number of fluid paths, i.e., at least two fluid paths. Preferably, the valve unit has a number of valves corresponding to the number of fluid paths, so that the flow diameter of each fluid path can be individually controlled and / or regulated. This enables particularly flexible dispensing using the dispensing device.

[0037] In particular, it is thus possible to individually control and / or regulate the dispensing of the individual fluid paths even in pressure source or pump operation, even if the fluid paths are laid together, for example, as hoses on the same pump rotor. This allows a number of dispensing or fluid paths to be individually controlled and / or regulated in a dispensing device with a single pump rotor, so that the dispensed fluid volume can be individually adjusted for each dispensing channel. This makes it possible, for example, to dispense a larger volume of fluid into peripheral receptacles than into central receptacles to minimize edge effects.

[0038] The valve unit is designed to be normally closing, for example, which means that in the inactive (non-energized, non-controlled) state the valve unit preferably completely closes the flow cross-section so that leaks are avoided in the event of a fault.

[0039] The valve unit comprises a valve coupled to the at least one fluid path. The valve can be, for example, a microvalve or a solenoid valve for precise fluid dispensing in the nanoliter range with a switching speed of up to 4 kHz (kilohertz).

[0040] In a preferred embodiment, in which the or each fluid path of the dispensing device is formed in particular by a flexible hose, for example a silicone hose, the valve unit has a pinch valve which pinches the hose from the outside and thus changes the flow diameter. Due to the pinch valve, the valve unit has no direct contact with the fluid carried in the hose, so that contamination is advantageously avoided. The pinch valve is designed, for example, as a solenoid pinch valve. The pinch valve has a (valve) actuator, for example a solenoid, and a valve body that can be moved or adjusted with it. The valve body is, for example, a pin or bolt which is pressed radially against the outer wall of the respective hose.The valve body is preferably spring-loaded into a closed position, so that the flow diameter is closed when the valve unit is not actuated or inactive. The pinch valve, for example, has a fixed counterbearing, which is arranged on the hose approximately diametrically opposite the valve body, and in the direction of which the valve body is moved to close the hose. The counterbearing can also be pin- or bolt-shaped.

[0041] Preferably, the valve unit or valve body is arranged as close as possible to the outlet nozzle of the fluid path to be switched. In other words, the pinch point or pressure point is positioned as close as possible to the outlet nozzle. However, the installation space is limited in this area. In a preferred development, a movable coupling element for force transmission is arranged between the actuator and the valve body. In particular, the comparatively space-intensive actuator is arranged at a spatial distance from the comparatively space-compact valve body and is connected to it for actuation purposes by means of the coupling element. This makes it possible to position the valve body - and thus the pinch point - closer to the respective outlet nozzle and to actuate it virtually remotely via the coupling element.This further development is particularly advantageous in the case of a magnetically active fluid, for example a liquid with suspended magnetic particles, and a solenoid pinch valve, since the (stray) magnetic field of the actuator does not interact with the fluid to be dispensed.

[0042] The coupling element can be, for example, a pneumatic hose, a chain, a hydraulic hose, a rod, or a Bowden cable. In a particularly preferred embodiment of the valve, the pressure point or pinch point on the hose moves away from the outlet nozzle when compressed or pinched. This creates an equilibrium between the volume displaced from the outlet nozzle and the volume pushed back by the displacement, so that no volume is displaced toward the outlet nozzle when the valve closes.

[0043] This can be achieved, for example, by guiding a valve body, e.g., a metal pin, to the pressure point not perpendicular to the hose, but at an angle or a curve. For this purpose, appropriate kinematics for moving the valve body can be provided. Additionally or alternatively, the valve body guide can be embedded in the valve unit in an arc or at an angle. In other embodiments, the valve can also close at an angle to the hose using a correspondingly designed part, for example, an injection-molded part, 3D-printed part, or milled part.

[0044] A conceivable further development envisages one or more valve bodies being variably mounted at different locations on the hoses or fluid paths, or even on different hoses or fluid paths, depending on the application. Depending on the design and choice of coupling element, the actuator can move along with the valve or remain stationary. This allows the user to flexibly choose where, for a specific process, the at least one valve is positioned.

[0045] An additional or further aspect provides that the pinch valve is designed as a directional valve. This means that multiple fluid paths can be switched or reversible using the pinch valve. This makes it possible with the valve unit to use multiple input fluids from different fluid reservoirs and to switch between them or to direct them into different outlet channels using the directional valve. This allows, for example, a cell solution and a buffer solution to be dispensed in one run. In particular, the valve or pinch valve of the valve unit is designed as a 3 / 2-way valve. In a preferred embodiment, the valve unit has a valve mechanism for a number of parallel fluid paths. The valve mechanism has an elongated axial element with at least one transversely projecting radial element.The at least one radial element is intended and configured either to act as a valve body for at least one fluid path or to be coupled to a valve body in terms of drive technology.

[0046] "Axial" or an "axial direction" is understood here and below to mean, in particular, a direction parallel (coaxial) to the longitudinal axis of the axial element, i.e., perpendicular to the end faces of the axial element. Accordingly, "radial" or a "radial direction" is understood here and below to mean, in particular, a direction oriented perpendicular (transverse) to the axis of rotation of the axial element along a radius of the axial element. "Tangential" or a "tangential direction" is understood here and below to mean, in particular, a direction along the circumference of the axial element (circumferential direction, azimuthal direction), i.e., a direction perpendicular to the axial direction and the radial direction.

[0047] The axial element extends along the axial direction and is mounted so that it can rotate or pivot about it. The axial element is thus essentially designed as a drive shaft for the at least one radial element.

[0048] The axial element has the radial element, which is particularly fixed to the shaft, at at least one axial position. The radial element has at least one radially upstanding radial extension. A "radial extension" is understood here and below to mean, in particular, a mechanical element that converts a rotational movement of the axial element into a linear or reciprocating movement along the radial direction. The radial extension is designed, for example, as a radial elevation, in particular as an upstanding cam or nub, of the axial element.

[0049] The radial element preferably has a number of tangentially distributed radial extensions. The radial element thus has, for example, an approximately star-shaped or gear-shaped cross-sectional shape. The axial element essentially has a shape similar to that of a camshaft, sheepsfoot roller bandage, or music box roller.

[0050] The axial element is preferably driven by a drive or servo motor of the valve mechanism. The drive motor is designed, for example, as a controllable electric motor, in particular as a stepper motor for rotating the axial element in predetermined angular or tangential steps.

[0051] The axial element is particularly suitable for valve units that have valves for multiple fluid paths, in particular eight, twelve, or sixteen fluid paths. The axial element is guided transversely to the parallel fluid paths, so that each fluid path can be assigned an axial position on the axial element. A radial element is positioned at each of these axial positions, at least one of whose radial extensions either itself comes into contact with an associated fluid path as a valve body (pinch valve) upon rotation of the axial element, or which actuates a corresponding valve body by means of the radial extension upon rotation of the axial element. The axial element therefore preferably has a number of radial elements corresponding to the number of fluid paths. The arrangement of the radial extensions on the axial element thus corresponds to different valve positions of the valve unit.This makes it possible to control / operate several valves of the valve unit by rotating the axial element using a common drive motor.

[0052] Preferably, the radial elements each have a plurality of tangentially distributed radial extensions, wherein the tangential distribution dimension is the same for all radial elements, so that the axially and tangentially distributed radial extensions realize a profiling of the axial element with a plurality of discrete tangential positions, which encode the desired valve positions.

[0053] In one conceivable embodiment, for example, four different tangential positions are realized as valve positions of the valve unit on the axial element by the radial extensions of the radial elements. In the first tangential position, all fluid paths are open, which means that the radial elements do not have a valve-effective radial extension at these tangential positions. In a second tangential position, at least one individual fluid path is open and the others are closed. In a third tangential position, a combination of fluid paths, i.e. at least two fluid paths, are open and the others are closed. In a fourth tangential position, only the edge-side fluid paths, i.e. the fluid paths positioned on the two opposite end faces of the axial element, are open and the fluid paths in between are closed.This fourth tangential position is particularly suitable for compensating for edge effects during dispensing. A fifth tangential position, for example, is optionally available, in which all fluid paths are closed.

[0054] The number of possible tangential or valve positions, which is possible using the axial element and the radial elements, scales (for a fixed size of the radial elements) essentially with the circumference or diameter of the axial element. To reduce the size of the valve unit, it is conceivable to arrange several axial elements with different tangential settings in a staggered manner, one behind the other. Preferably, all axial elements are adjustable by the same drive motor, with, for example, a corresponding coupling or switching gear of the valve mechanism being provided between the drive motor and the axial elements.

[0055] In a design in which the radial extensions themselves act as valve bodies, the fluid paths are radially squeezed directly or immediately by the radial extensions upon rotation of the axial element. The radial elements are thus essentially designed as pinch valves for the respective fluid path. For this purpose, the fluid paths are routed between the radial elements and a fixed or counter bearing, for example, a housing of the valve mechanism or the valve unit.

[0056] The rotational or rotary movement of the axial element is preferably such that when a fluid path is closed or squeezed by a radial extension, a small amount of fluid is moved / conveyed away from the outlet nozzle in order to avoid droplet formation at the outlet nozzle.

[0057] The free-end contact surfaces of the radial extensions on the fluid paths are preferably designed to reduce friction. In other words, friction between the radial extension and the fluid path is reduced as much as possible to prevent wear and / or damage to the fluid path. For this purpose, the free ends of the radial extensions are designed, for example, with rollers or cylinders as a contact surface on the fluid path. Additionally or alternatively, at least the free ends of the radial extensions are made of a material with low frictional resistance or a material with high sliding properties, for example, polytetrafluoroethylene (PTFE) or polyoxymethylene (POM), or are at least provided with a corresponding coating.

[0058] Furthermore, it is additionally or alternatively conceivable for a lubricant to be introduced between the radial extensions and the fluid paths. The lubricant is, for example, a lubricating oil, a lubricating grease, or preferably a solid lubricant, in particular graphite or a ceramic powder. The lubricant is, for example, guided in the valve mechanism and is used in particular to lubricate the axial element bearings.

[0059] Additionally or alternatively, it is also possible for the or each fluid path to have friction- and / or wear-reducing means with respect to the mechanical crushing stress caused by the at least one radial extension. For example, the fluid path has a thin, abrasion-resistant sheath or coating, for example in the form of a metal foil.

[0060] Furthermore, the fluid path or its cross-section is designed in such a way that the squeezing deformation of the fluid path is supported or promoted by the radial extension. For example, it is conceivable for the fluid path to be asymmetrical in cross-section. This means that the fluid path cross-section has comparatively soft (deformable) side walls and comparatively harder (more stable) bottom and top walls, so that more efficient squeezing of the fluid path along a direction perpendicular to the bottom and top walls is possible. Additionally or alternatively, a change in the fluid path cross-sectional shape in the contact area of ​​the radial extension is conceivable, i.e. that the fluid path has, for example, thicker and / or thinner fluid path walls, a rounder or more angular cross-sectional shape, or a different aspect ratio than the rest of the fluid path so that it can be squeezed more easily by the radial extension.

[0061] In an alternative embodiment, in which the radial extensions act to drive or actuate a valve body, the fluid paths are only indirectly closed upon rotation of the axial element. The valve bodies preferably again pinch the respective fluid path, so that the valves of the valve unit are preferably designed as pinch valves.

[0062] In one conceivable embodiment, the valve body is designed as a displaceable pin arranged between two adjacent fluid paths. The fluid paths between which the pin is arranged are, in particular, stacked. In other words, the fluid paths are arranged one behind the other in the radial direction, for example. The associated radial extension moves the valve body, as the axial element rotates, between a valve position in which one of the fluid paths is closed and a valve position in which the other fluid path is closed. This creates a 3 / 2-way valve.

[0063] In another conceivable embodiment, the valve body is arranged on a pivotable lever. The lever is pivoted by the radial extension upon axial element rotation, thus squeezing the valve body against the fluid path. By appropriately dimensioning the lever lengths and arranging the lever pivot point, high closing or squeezing forces can be exerted by the valve body. The lever - and thus the valve body - can be moved back to an initial position after actuation, for example by additional return elements (springs, pressure in the hose, magnets, etc.). An additional or further aspect provides that the at least one radial element has a magnetic element. The magnetic element is, for example, a permanent magnet. The magnetic element is, for example, arranged at the free end of the radial extension. Alternatively, it is conceivable, for example, for the radial extension to be designed as a magnetic element.The magnetic element interacts with a counter-magnetic element of the valve body, which is designed, for example, as a permanent magnet or as a magnetizable element. Alternatively, it is conceivable for the magnetic element to be designed as a magnetizable element and the counter-magnetic element as a permanent magnet. The valve of the valve unit or valve mechanism is thus designed, in particular, as a magnetic pinch valve for the respective fluid path.

[0064] In an advantageous embodiment, this magnetic pinch valve is designed, in particular, as a 3 / 2-way solenoid valve, which is coupled or can be coupled, for example, to two fluid paths in such a way that they alternately close upon magnetic attraction or repulsion. In particular, the counter-magnetic element of the valve body is arranged between the two fluid paths for this purpose.

[0065] In one conceivable embodiment, the magnetic element and the counter-magnetic element are polarized inversely to each other, so that a magnetic attraction force acts between the magnetic element and the counter-magnetic element. The counter-magnetic element is arranged, for example, such that the valve body is moved into a closed position that squeezes the fluid path when the radial extension or the magnetic element is brought closer together. As a result, the magnetic element and the counter-magnetic element are in contact in the closed position, so that the strongest magnetic force is exerted, thereby improving the pressure-load capacity of the resulting (pinch) valve.

[0066] In an equally conceivable embodiment, the magnetic element and the counter-magnetic element have the same polarity, so that a magnetic repulsion force acts between the magnetic element and the counter-magnetic element. The counter-magnetic element is arranged, for example, such that the valve body is moved into an open position, releasing the fluid path, when the radial extension or the magnetic element is brought closer together.

[0067] This allows for a simpler design of the valve mechanism.

[0068] The counter-magnet element is, for example, spring-mounted and is moved, in particular attracted or repelled, against a (spring) restoring force by the magnetic interaction with the magnetic element of the radial element.

[0069] In a practical embodiment, the counter-magnet element is mounted, in particular, in a linear guide of the valve mechanism so that it can be displaced. The counter-magnet element forms, for example, the valve body for directly or immediately squeezing the fluid path. Alternatively, the counter-magnet element acts indirectly on the valve body. The valve body is, for example, a (valve) pin or a (valve) ball, which can be adjusted or moved relative to the fluid path by means of the counter-magnet element. A design in which the counter-magnet element moves or adjusts the valve body via a pivoting lever is also conceivable.

[0070] In a valve mechanism design with a magnetic element on the axial element side and a counter-magnetic element on the valve body side, magnetic shielding is preferably provided between the individual fluid paths or valves to reduce magnetic crosstalk between the individual valves. For example, magnetic shields made of mu-metal or permalloy are arranged in the valve mechanism between the fluid paths or between the counter-magnetic elements. For example, the shields are arranged between two solenoid pinch valves, in particular between two 3 / 2-way solenoid valves.

[0071] In a preferred embodiment of the valve unit, it is intended for, and suitable and configured to mechanically switch or actuate the valves. In other words, the valve unit is intended and configured to be mechanically switched or actuated.

[0072] The valve unit has a gear mechanism with a mechanical interface. The mechanical interface is designed, for example, as a mechanical switching element that can be manually operated by a user. Preferably, the mechanical interface or the mechanical switching element is intended and configured to be actuated at least indirectly by an external motor, wherein the interface subsequently triggers the gear mechanism, which causes a movement of at least one valve body. An “external motor” is understood here to mean a motor drive which, in addition to actuating the valve or valve mechanism, fulfills at least one further function and is not part of the valve unit (e.g., drive motor of the pressure source, distance adjustment motor for adjusting the distance between the outlet nozzles and the fluid receptacles, etc.).This means that the valve unit is motorless, meaning it does not have its own drive motor. This advantageously reduces the number of motors, allowing for a particularly cost-effective add-on unit.

[0073] The mechanical interface or mechanical switching element can thus be actuated by a movement initiated by the external motor. For example, the mechanical switching element is a mechanical pressure switch that is actuated when the outlet nozzle height is adjusted.

[0074] In a preferred embodiment, a valve mechanism with an axial element and radial elements is coupled to the gear mechanism and the external interface. The gear mechanism is coupled to the valve mechanism, for example, in such a way that, upon actuation, the axial element rotates or turns by a predetermined or adjustable angle of rotation. In other words, the gear mechanism changes the tangential or valve position of the valve mechanism. The gear mechanism is a switching mechanism, for example in the manner of a switching heart or locking tension mechanism, which converts an impulse from the external interface into a discrete rotary movement of the axial element. In particular, the gear mechanism is designed like a click or push mechanism of a ballpoint pen, so that the axial element can be rotated successively step by step via the interface.

[0075] Optionally, the gear mechanism is coupled to an optical display on the outside of the valve unit housing to indicate the current switching or valve position of the valve unit to the user. The optical display is preferably designed as a rotating display roller or disc, which displays a number of optical information items (numbers, words, icons, colors, etc.) corresponding to the number of valve positions, and which rotates according to the actuation of the gear mechanism.

[0076] In one possible embodiment of the additional unit, a valve unit is combined with a fluid reservoir or a reservoir unit; in particular, the valve unit and the fluid reservoir or the reservoir unit are integrated into a common housing. The fluid reservoir is designed, in particular, as a priming reservoir. The “priming reservoir” is understood here and below to mean, in particular, a fluid reservoir which serves to hold the fluid (e.g., a reagent) during priming of the dispensing device. “Priming” is understood, in particular, to mean a pre-dispensing process in which, prior to the actual dispensing process, a defined state is achieved for the at least one fluid path, for example, that the fluid path is filled up to the outlet nozzle, or that a dried-out outlet nozzle is free again. The priming reservoir is, in particular, a reject reservoir for excess (priming) fluid.By connecting the valve unit to a priming reservoir, existing dispensing devices that are not designed for this purpose can be easily retrofitted. This enables, in particular, a change of fluids and / or the opening / closing of individual fluid paths in existing dispensing devices with a reduced number of motors, outlet nozzles, and fluid paths. The resulting reduced complexity results in a very robust add-on unit. In an advantageous embodiment, the add-on unit has a fill level sensor unit for determining a fluid quantity within the at least one fluid path and / or the outlet nozzle coupled thereto and / or the fluid reservoir coupled thereto.This makes it possible, in particular, to detect a liquid level in the fluid paths and / or outlet nozzles and to adapt the dispensing pattern, for example, in such a way that the fill levels between different fluid paths and / or outlet nozzles are balanced, thus increasing precision. In the prior art, dispensing inaccuracies in peristaltic and roller pumps as pressure sources arise in particular from the break-off behavior at the outlet nozzles and, related to this, from the fill level in the outlet nozzle. If this fill level is compensated accordingly, precision can be improved. For this purpose, an additional unit is preferably provided which has both a fill level sensor unit and a valve unit as described above, so that appropriate compensation can be achieved by controlling and / or regulating the individual (hose) valves.For example, such compensation can be achieved by a control system implemented in the controller of the additional unit.

[0077] The fill level sensor unit comprises an optical or electrical sensor element coupled to the fluid path and / or outlet nozzle to be monitored. The controller is provided and configured to detect and evaluate measurement signals from the sensor element during operation, in particular to determine a fill level or fluid quantity. The sensor element is, for example, a camera or a light barrier (light barrier).

[0078] In a further advantageous embodiment, the additional unit comprises a particle sensor unit for determining a particle property of (suspended) particles within a fluid that can be conveyed in the at least one fluid path. The particle sensor unit is therefore used in particular for dispersed liquids, in particular suspensions, to determine at least one particle property of the heterogeneous substance mixture. The additional unit preferably comprises a valve unit as described above, which is coupled to the particle sensor unit. The valve unit is used as a means for adjusting a dosing or dispensing volume in order to achieve an approximate target number of dosed particles in the dispensed volume. Furthermore, this enables real-time adjustment of the dispensed volume based on measured values ​​of the particle concentration and viability (in the case of cells).For example, the specific particle properties are used to control and / or regulate the valve unit.

[0079] The particles can be beads, for example. The beads can be magnetic or magnetizable. The particles can also be (air) bubbles within the fluid, for example. In a preferred application, the particles are, in particular, biological cells, cell clusters, or cell components, e.g., bacteria, plant cells, fungi, animal or human cells, vesicles, or organoids.

[0080] A "particle property" is understood here and below to mean, in particular, a characteristic physical or chemical property of solid particles distributed in a liquid. Particle properties include, for example, particle number, density or concentration of particles in the liquid, particle morphology (size, shape), color, fluorescence, or particle distribution.

[0081] In an expedient further development, the particle sensor unit has in particular a sensor element for detecting the particle property.

[0082] The sensor element can be embodied as an optical sensor element. The optical sensor element has a light source and at least one light or photodetector. The light source emits an input light into the fluid to be examined, with at least one light detector detecting an output light coming from the fluid. The input light is, for example, scattered and / or refracted and / or reflected by the particles of the fluid and is detected as output light by the light sensor. For example, an amplitude of the scattered light (scattering amplitude) is correlated with the particle concentration, so that the particle concentration can be determined by evaluating the scattered output light. The fluid path is expediently designed to be transparent, at least in sections.It is conceivable that the fluid path has a fluid path section, for example in the form of a channel, a microfluidic chip or a capillary, in particular a capillary with a rectangular cross section, as a measuring area for the optical sensor element.

[0083] In the case of fluorescent particles, for example, the input light is used to excite the particles, with the output light being the correspondingly emitted fluorescent light of the particles. Based on the sensor data, the controller determines a respective particle property. Based on the particle property, the dispensing or pump operation is then preferably controlled and / or regulated to dispense fluid with a desired particle property. For this purpose, the particle sensor unit preferably has a valve unit as described above.

[0084] In a particularly preferred further development, the optical or imaging detection of the particle number or the particle concentration takes place at an acute angle of inclination to the fluid path, which means that the optical axis of the optical sensor element is oriented neither parallel nor perpendicular to the flow direction of the fluid (flow direction, flow direction).

[0085] If the optical axis is aligned parallel to the flow direction, i.e., at an inclination angle of 0°, alignment problems would arise, since the flow rate varies depending on the position of the focal plane of the optical sensor element in the fluid path, and particles may not be evenly distributed in the fluid path cross-section (e.g., due to sedimentation or inertial effects). Detection with a perpendicular alignment of the optical axis to the flow direction, i.e., at an inclination angle of 90°, is often not possible or only possible with increased effort in order to avoid collisions with the fluid paths or optical disturbances to the fluid paths. Furthermore, focal depths of the optical sensor element across the entire fluid path lead to low resolution. In particular, complex optics or thin fluid paths are required, the latter having negative effects on the particles (shear rate) or the flow rate.

[0086] Therefore, the reading by the optical sensor element preferably takes place at an acute angle of inclination, i.e. an angle of inclination between 0° and 90°, preferably between 20° and 70°, in particular about 45°, to the flow direction, so that alignment for the optical measurement is simplified.

[0087] A particle concentration (c = nA / ) can be determined, for example, by the optical sensor element taking an image with a known depth of focus. The image area and depth of focus define the measurement volume (V), with the number of particles (n) being counted in the image. Alternatively, the optical sensor element can take a series of images (video), for example, when a defined (fluid) volume (V) is pumped through the fluid path, with the number of particles (n) being counted in the series of images. It is also conceivable that the series of images is taken at different positions of the optical plane in order to capture a larger measurement volume.

[0088] To capture images of the optical sensor element, it is possible to acquire an image over a longer period of time (signal integration), allowing more particles to be captured as they flow through the optical plane. An additional or further aspect of this approach is to use dark-field microscopy for image acquisition, thus improving the signal-to-noise ratio. In this case, the particles appear bright and the background (fluid) dark. The use of phase-contrast microscopy or bright-field microscopy is also conceivable.

[0089] The sensor element can alternatively be designed as an electrical, capacitive or impedance-based sensor.

[0090] Impedance-based sensors for determining particle properties are known, for example, from the publications by Holmes et al. (2010), "Single cell impedance cytometry for identification and counting of CD4 T-cells in human blood using impedance labels" (Analytical Chemistry, 82(4), 1455-1461 , https: / / doi.org / 10.1021 / ac902568p) and Schoendube et al. (2015), "Single-cell printing based on impedance detection" (Biomicrofluidics, 9(1 ), https: / / doi.org / 10.1063 / 1.4907896). The disclosures of these publications are hereby expressly incorporated into the present application.

[0091] A sensor element designed as an electrical sensor can be based on the principle of a Coulter counter. A Coulter counter measures the number of particles, including cells, by detecting changes in electrical conductivity between two electrodes in a conductive liquid containing the particles. The fluid is therefore an electrically conductive liquid. The measurement is taken between two areas separated by a narrow opening, each in contact with an electrode. If at least one particle flows through the narrow opening, the conductivity between the electrodes changes measurably. For example, the two liquid-filled areas could each contain a gold electrode and be part of a glass capillary. The glass capillary can then be tapered between the two areas.Using a specially designed electrical readout unit, changes in electrical resistance can be measured as a particle suspension flows through the glass capillary, thus determining the number of particles. The particle number can be used to determine the particle concentration.

[0092] Such Coulter counters are known, for example, from Hoffman et al. (1979) "Flow-system measurement of cell impedance properties" (Journal of Histochemistry & Cytochemistry, 27(1), 234-240, https: / / doi.org / 10.1177 / 27.1.374580) and Hoffman et al. (1981) "Flow cytometric electronic direct current volume and radiofrequency impedance measurements of single cells and particles" (Cytometry, 1(6), 377-384, https: / / doi.org / 10.1002 / cyto.990010605). The disclosures of these publications are hereby expressly incorporated into the present application. The electrical sensor can be designed to measure the capacitance or impedance of the particle suspension (fluid) between the electrodes. In this case, a tapered or waisted glass capillary tube is unnecessary. The particle property measured is the quantity or volume of all particles in the measuring area.

[0093] Preferably, the sensor element is arranged outside the fluid or outside the fluid path in order to avoid contamination and soiling of the sensor element.

[0094] The sensor element is expediently arranged in a measuring area that is coupled or can be coupled to the fluid path. The measuring area is, for example, a window that is transparent to the measuring light, for example made of glass, in particular a glass capillary, preferably a round, rectangular, or oval glass capillary, so that, in the case of an optical sensor element, no additional noise or measurement artifacts are generated during light entry and exit. The window is arranged, for example, in the outer wall of the fluid path and / or in at least one cartridge part of a cartridge system coupled to the additional unit.

[0095] Due to the throughput during peristaltic conveying using a peristaltic pump as the pressure source, comparatively high shear forces sometimes act on the particles, which can deform the particles, making accurate measurement of the particle properties more difficult. Furthermore, due to the throughput rate, a sufficiently high counting rate (particles / second) is required for the sensor element in order to be able to carry out reliable particle measurements, especially individual measurements. The measuring range of the particle sensor unit is designed as a defined measuring volume coupled to the fluid path. In this development, therefore, not the conveyed fluid volume is measured, but only a portion of it. A defined or reduced amount of fluid is branched off into the measuring range, allowing for simpler and more reliable determination of the particle properties.By means of the controller, a value for a corresponding particle property (e.g. cell density, viability) for the fluid volume conveyed in the fluid path can be calculated based on the determined particle property in the measuring range, for example using an algorithm.

[0096] The measuring area can be a fluid path, for example, a bypass to the fluid path volume. Preferably, the channel has a minimum dimension of less than 1 mm (depth of the optical path).

[0097] The particle sensor unit can be implemented as a microfluidic chip, with the measuring area being, for example, a shallow hollow volume. "Shallow" here refers to a reduced depth, thus reducing the optical path for the sensor element's measurement. The reduced depth is less than 1 mm, ideally less than 500 pm, 300 pm, or 100 pm.

[0098] The microfluidic chip can be constructed from a thermoplastic, ideally polypropylene, polystyrene, or cycloolefin polymer or cycloolefin copolymer. Typically, the microfluidic chip is designed as an injection-molded part. The chip can be sealed or sealed either with a second injection-molded part or with a polymer film. The sealing or sealing is designed in such a way that the microfluidic chip is fluidically tight, except at the outlet and inlet structures. At least the film or the microfluidic chip is designed to be optically transparent.

[0099] The chip can contain one or more channels as integrated tube sections or fluid path sections. The integrated channels are each connected to an inlet and an outlet with associated fluid paths or fluid path sections. The fluid path section at the inlet is connected, for example, to the fluid reservoir, while the tube section at the outlet is routed to the outlet nozzle.

[0100] In a practical further development, the particle count can be determined optically or even by imaging. For this purpose, an optical measurement signal is generated, from which the number of cells in a specific area with a defined volume (measurement area) can be determined. This allows the particle concentration to be determined. Furthermore, a gas and a liquid sample can be alternately drawn into the fluid path. This ensures that the sections containing the liquid sample are separated from each other, preventing mixing.

[0101] In an advantageous embodiment, the additional unit, in particular the particle sensor unit, preferably in the measuring area, has an acoustic unit (sound generator) for acoustically arranging, in particular focusing, the particles. This allows the suspended particles in the measuring area to be concentrated by acoustic focusing. In this case, a standing acoustic field can preferably be applied to the channel. The acoustic unit or the sound generator can be a piezo element. Depending on the acoustic particle properties and the chamber or channel geometry, the particles collect in one or more nodes, one or more node lines, or in the areas in between. In one embodiment, a frequency of 630 kHz is applied to a channel approximately 1 mm wide. This causes typical eukaryotic cells to collect in a node line in the middle. To be more robust against tolerances, the frequency can be slightly (e.g.± 10 kHz). The resulting ordering of the cells facilitates the examination / measurement and counting of the cells, so that the particle or cell properties can be determined more easily and reliably.

[0102] In a practical embodiment, the additional unit has a reservoir unit for providing a fluid to be dispensed and for determining a dispensed fluid quantity. The reservoir unit has a fluid reservoir for providing a fluid to be dispensed and for coupling it to the fluid path, a mixing device for the fluid reservoir (e.g., a stirrer), and / or a sensor element for detecting a dispensed fluid quantity. The mixing device, e.g., a shaker or stirrer, is coupled to the fluid reservoir, for example, it is fluidically and / or mechanically coupled to the fluid reservoir. The sensor element is, for example, part of the reservoir unit. Alternatively, an external sensor element can be used, which is coupled to the reservoir unit. Likewise, embodiments of the reservoir unit without a sensor element are conceivable, which only comprise the fluid reservoir and the mixing device.

[0103] By combining the reservoir unit with an additional unit containing a valve unit as described above, it is possible, for example, to determine or measure a tip-to-tip variability by dispensing from individual fluid channels. Based on this tip-to-tip variability, the valve-controlled fluid channels can then be individually controlled, ensuring that the desired amount of fluid is always dispensed from each outlet nozzle. This allows intraplate variations in particular to be reduced.

[0104] In a preferred embodiment, the sensor element of the reservoir unit is designed as a weight sensor for detecting the weight of the fluid reservoir or a quantity of fluid held therein. The weight sensor enables a structurally simple determination of the dispensed fluid quantity, i.e., the quantity of fluid withdrawn from the fluid reservoir. For example, a first weight value is compared with a second weight value after a number of dispensations, for example, after 100 dispensations. To further improve accuracy, a background value or correction value (offset value) for fluid or weight losses due to evaporation can be taken into account, particularly by the controller. This compensation further improves the determination of the dispensed volume.

[0105] As an alternative to the reservoir unit, it is also conceivable, for example, to equip a microtiter plate and / or a waste receptacle into which dispensing takes place with a corresponding weight sensor. For example, the weight of a microtiter plate and / or the waste receptacle is measured before and after a dispensing process, and the dispensed amount is determined. To improve accuracy, evaporation losses can also be compensated for using a background or correction value. Alternatively, the sensor element can also be designed as a pressure sensor coupled to the fluid reservoir, wherein the fluid reservoir is vented via at least one vent. The vent(s) together have a comparatively high fluidic resistance.This resistance prevents the negative pressure in the fluid reservoir caused by dispensing from being equalized within less than 1 ms. "Equalized" means that the resulting pressure difference with the ambient pressure is reduced by at least 80%. The pressure sensor can then be used to determine the dispensed volume. To achieve greater accuracy, the value can be averaged over multiple dispenses.

[0106] In another alternative embodiment of the sensor element, the reservoir unit is coupled to at least one fluid channel, with the fluid reservoir being vented only via a single vent. In this embodiment, this vent is equipped with a flow meter as a sensor element, which measures the gas flow into the fluid reservoir. The sensor element or flow meter can be used to calculate the dispensed fluid volume. To achieve greater accuracy, the value can be averaged over multiple dispensations.

[0107] In a conceivable further development, the fluid reservoir is coupled to a temperature control unit for measuring, adjusting, and / or regulating the temperature of a fluid contained in the fluid reservoir. This allows the fluid to be cooled or heated, for example.

[0108] In a preferred embodiment, the fluid reservoir of the reservoir unit has a fluid outlet to the fluid path, which is positioned at a reservoir base. The fluid outlet is arranged at a lowest point of the fluid reservoir in the direction of gravity, so that a dead volume of the dispensing process is reduced. The fluid reservoir also has, for example, a fluid inlet for a fluid path returned from the pressure source or pressure source unit, via which fluid can be pumped back into the fluid reservoir. This enables mixing of the fluid within the fluid reservoir between dispensing processes during operation of the pressure source (unit). The fluid paths to the outlet nozzles are closed, for example, by a valve unit, so that mixing is possible by pumping the fluid back and forth.

[0109] In a suitable refinement, the pressure source (unit) is driven in a reverse direction for mixing, i.e., with a flow direction from the outlet nozzles toward the fluid reservoir. Air is drawn in through the outlet nozzles, so that gas or air bubbles are introduced into the fluid of the fluid reservoir during mixing. This refinement is particularly advantageous for cell cultures, where the fluid reservoir is, in particular, a cell culture reservoir. Optionally, a fluid sensor is provided on the outlet nozzle, which detects a meniscus or the dispensed fluid volume. This enables a further reduction of the dead volume.

[0110] In a practical embodiment, the additional unit comprises the pressure source unit for conveying a fluid along the fluid path. The pressure source unit comprises a peristaltic pump with a number of individually controllable pump rotors. In particular, the pressure source unit comprises a number of pump rotors corresponding to the number of fluid paths, which are designed, in particular, as hoses. This allows each fluid path to be conveyed and / or controlled individually. The additional function of the additional unit is, in particular, the individual control of the fluid paths or the individual conveyance in the individual fluid paths.

[0111] In a suitable application of the additional unit, a reservoir unit is positioned near the pressure source or a pressure source unit. The pressure source (unit) preferably comprises a pressure source or pump rotor equipped with magnetic elements, in particular permanent magnets. The reservoir unit comprises a magnetic mixing device, in particular a magnetic stirrer (stirring bar).

[0112] Here and in the following, “close positioning” or “positioned close to the pressure source (unit)” is to be understood as meaning in particular a small spatial distance between the reservoir unit and the magnetically equipped pressure source rotor, which is sufficiently small in dimension that the rotating magnetic field caused by the rotating pressure source rotor can be used to drive the magnetic mixing device.

[0113] In other words, the magnetic mixing device is driven by the magnetic interaction with the pressure source (unit), so no separate magnetic drive is required for the magnetic mixing device. This means that the fluid in the fluid reservoir of the reservoir unit is automatically mixed during operation of the pressure source (unit). In a particularly compact design, the reservoir unit is also located close to the outlet nozzle(s). This design further reduces potential losses in the fluid path between the fluid reservoir and the outlet nozzle.

[0114] An additional or further aspect of the invention provides that the auxiliary unit is coupled to at least two fluid reservoirs, a pressure source, at least one particle sensor, and at least one valve. This makes it possible to mix fluids from different fluid reservoirs and dispense them together. However, the following explanations are also applicable, analogously, to an auxiliary unit with at least two reservoir units, a pressure source unit, a particle sensor unit, and at least one valve unit.

[0115] The fluid reservoirs contain fluids with different particle concentrations, which are connected to the outlet nozzle via the (common) pressure source and the at least one fluid path. In particular, in a design with two fluid reservoirs, it is possible, for example, for one of the fluid reservoirs to contain a fluid without particles, and for the other fluid reservoir to contain a fluid with a particle concentration that is higher than a target concentration to be dispensed. For example, the fluid in the first fluid reservoir is a cell culture medium with cells, and the fluid in the second fluid reservoir is a cell culture medium without cells. The valve is designed, in particular, as an adjustable throttle or as an adjustable throttle valve. In particular, the (throttle) valve is designed as an adjustable pinch valve.The (throttle / pinch) valve is connected between the fluid reservoirs or coupled to them in such a way that a ratio of the fluids in the fluid reservoirs can be dispensed by adjusting the degree of throttling or pinching.

[0116] In one embodiment, the fluid path is connected to the fluid reservoirs via branched sub-paths (fluid path sections), wherein the valve has a movable pin that can be moved between the sub-paths such that the flow of the sub-paths from the fluid reservoirs can be controlled and / or regulated. The branching or division of the fluid path into the sub-paths is achieved, for example, by a distributor or Y-piece, in particular in the form of 3 / 2-way proportional valves, or comparable arrangements.

[0117] The valve is designed, for example, as a directional proportional valve. With two partial paths, the valve is particularly designed as a 3 / 2-way proportional valve or throttle. The at least one particle sensor is provided and configured to determine the particle concentration in the conveyed fluid. For example, it is conceivable for a particle sensor to be assigned to each partial path, so that the particle concentration of the individual fluid reservoirs can be determined.

[0118] The valve, the particle sensor, and the pressure source are peripheral devices of a control loop. The control loop preferably comprises a controller of the additional unit, which is signal-linked to the valve and the pressure source as actuators on the one hand, and to the particle sensor as the measuring element on the other. The valve is controlled, for example, via the controller in such a way that a ratio as defined as possible (with possible fluctuation) can be dispensed from the fluid reservoir fluids in each dispensing process. For this purpose, the particle sensor detects the particle concentration or particle number as a controlled variable, based on which the controller controls and / or regulates the valve position of the valve and / or the fluid delivery by means of the pressure source. In one possible embodiment, the valve is arranged between the fluid reservoir and the particle sensor, with the particle sensor positioned between the valve and the pressure source.In another possible embodiment, the particle sensor is arranged between one of the fluid reservoirs and the valve. In a preferred embodiment, the particle sensor is arranged, in particular, between the (proportional) valve and the outlet nozzle, so that the particle sensor detects the actual particle concentration to be dispensed.

[0119] In another possible embodiment, the valve is arranged between the branching of the fluid path into the sub-paths connected to the fluid reservoirs and at least one of the fluid reservoirs. The valve is designed, for example, to regulate the flow through the sub-channel connected to the fluid reservoir, so that the mixing ratio of the fluids in the area between the branching and the outlet nozzle can be regulated.

[0120] In particular, it is conceivable that the valve is provided and configured to completely prevent flow through the partial path, i.e. to close off an inflow from the associated fluid reservoir. This enables real-time adjustment of the dispensed particle concentration using the particle sensor. In particular, it is possible to dispense a target particle number and a target volume in each fluid well of a microtiter plate. This makes it possible to dispense as defined a number of particles as possible (with possible fluctuation in the particle number). For example, it is possible to dispense as constant a number of particles as possible (with possible fluctuation in the particle number) and as constant a fluid volume as possible (within a certain fluctuation) into each column or row or even into all fluid wells of a microtiter plate.

[0121] In an advantageous development, the additional unit comprises a fluid distribution unit, by means of which the fluid path is divided or branched into a number of sub-paths. Depending on the arrangement of the fluid distribution unit in the fluid path, the sub-paths are each connected either to an outlet nozzle or to a fluid reservoir (or a fluid reservoir unit).

[0122] In other words, it is possible, for example, to combine several individual sub-paths, each connected to a fluid reservoir, into a common fluid path via a fluid distribution unit. This is particularly advantageous in combination with the above-described mixing of different fluids from different fluid reservoirs, as it allows for easy merging of the different fluids into the fluid path.

[0123] Furthermore, it is thus possible to distribute a fluid path or the fluid flow guided therein, in particular evenly, across a plurality of outlet nozzles, in particular across 2, 4, 8, 12 or 16 outlet nozzles. This is particularly advantageous in combination with the mixing of different fluids from different fluid reservoirs described above, since the mixed fluid can thus be dispensed in parallel from a plurality of outlet nozzles. In this case, it is conceivable, for example, for a particle sensor to be arranged upstream of the branching by the fluid distribution unit. This results in a particularly cost-effective arrangement in which the particle concentration is determined upstream of the branching into the partial paths. Alternatively, a particle sensor can also be provided in each branched partial path or for each outlet nozzle. This increases the measurement accuracy; in particular, the individual particle sensors can be evaluated together (e.g.averaged) in order to reduce random fluctuations in the detected particle numbers.

[0124] In an advantageous embodiment, the additional unit has a fluid temperature unit for controlling or maintaining a fluid temperature of the fluid in a fluid path and / or in a fluid path section and / or in a fluid reservoir. The fluid temperature unit is coupled to the fluid path reservoir or to the fluid in terms of heat conduction or heat transfer. This is advantageous, for example, for temperature-sensitive fluids and / or particles in order to dispense them at a desired (fluid) temperature. This is particularly advantageous in applications with a basement membrane-like matrix (e.g., Matrigel) as the fluid, since such fluids increase their viscosity / harden / solidify at room temperature and are therefore currently rarely used in reagent dispensing.

[0125] The fluid temperature unit comprises, for example, a (passive) thermal insulation or insulating layer for the fluid reservoir and / or the fluid path, in particular for maintaining a fluid temperature. With thermal insulation of the fluid path, a fluid path section coupled to the pressure source or peristalsis is preferably exposed, i.e., designed without insulation, so that fluid delivery is not impaired by the insulation. Alternatively, the thermal insulation of the fluid path can also be arranged in the fluid path section coupled to the pressure source (unit). At least this section of the thermal insulation is designed such that it has only minimal or no impact on fluid delivery.If the thermal insulation has an influence on the fluid delivery through the pressure source (unit), this influence is preferably constant so that the influence can be taken into account as a known factor for dispensing.

[0126] In one possible embodiment, for example, eight parallel fluid paths are arranged between two insulating mats. This creates a particularly compact, ribbon-cable-like design for thermal insulation. The insulating mats are preferably joined together in a non-destructive, removable manner, for example, using a hook-and-loop fastener. Another conceivable embodiment of the thermal insulation is an insulating tube coaxially surrounding the fluid path.

[0127] The fluid temperature unit additionally or alternatively comprises a temperature control element for controlling the temperature of the fluid or for changing the fluid temperature. The temperature control element is arranged, for example, near the outlet nozzle, in particular between the pressure source and the outlet nozzle, ensuring that the volume to be dispensed can be dispensed at a desired fluid temperature. The temperature control element is designed as a heating and / or cooling element that can be actively controlled and / or regulated. The fluid temperature unit also comprises, for example, a temperature sensor for detecting the fluid temperature in order to control and / or regulate the temperature control element.

[0128] For example, the temperature control element has a temperature control circuit which is thermally coupled to the fluid path.

[0129] The heating element is designed to heat the fluid. The heating element is, for example, a heating wire spiraled around the fluid path. Alternatively, the heating element is designed, for example, as a Peltier element or a heating mat.

[0130] The cooling element is designed to cool the fluid. The cooling element is designed, in particular, for passive cooling and comprises a phase change material (PCM) coupled to the fluid path. Alternatively, the cooling element is designed, for example, as a Peltier element or as a vapor chamber for evaporative cooling. In another conceivable embodiment, the cooling element is designed and configured to use the magnetocaloric effect to cool the fluid.

[0131] The fluid temperature unit further comprises, for example, a heat-conducting element coupled to the fluid path, which is coupled to a heat reservoir (heat source, heat sink) and / or a temperature control element. The heat-conducting element has high thermal conductivity to enable targeted heat / cold transfer between the fluid and the heat reservoir or the temperature control element. The heat-conducting element is preferably made of aluminum, copper, silver, or diamond. The heat-conducting element is alternatively designed as a heat pipe or vapor chamber.

[0132] Preferably, heat is conducted by means of the heat-conducting element into an area with an enlarged surface, wherein this area is surrounded by a larger amount of material with—compared to the heat-conducting element—low ​​thermal conductivity and / or higher heat capacity. This can be achieved, for example, using a cooling pack. For example, an arrangement with non-homogeneous cooling packs as a heat reservoir (heat sink) is conceivable, which cool the fluid via a heat-conducting element. The cooling packs are preferably designed or arranged in such a way that they are easily replaceable during operation of the fluid temperature unit or during operation of the dispensing device.

[0133] In one conceivable embodiment of the fluid temperature unit, a number of fluid paths, for example, eight fluid paths, are surrounded by thermal insulation. The fluid paths lead from a fluid reservoir (heat sink) via the pressure source (peristalsis) into a heat-conducting element designed as a cooling block, and from there back to the fluid reservoir (and not to the outlet nozzles). These fluid paths are designed as temperature control paths, which transport / transfer cold from the fluid reservoir via the cooling block into the fluid paths intended for dispensing. Due to the comparatively high fluid volume, the fluid reservoir has a high heat capacity and can therefore be more effectively insulated and / or actively temperature-controlled (cooled).

[0134] In a possible further development, the fluid temperature unit comprises a temperature control element for controlling the temperature of the dispensed fluid volume, in particular for controlling the temperature of a microtiter plate. The temperature control element is therefore not coupled to the fluid path, but rather to the fluid wells of the microtiter plate. This makes it possible to temperature-control the dispensed fluid and / or the particles. In an application with a basement membrane-like matrix as the fluid, it is thus possible, for example, to heat the well volume so that the dispensed fluid stiffens as a gel in the well. This is particularly advantageous for preparing the wells for three-dimensional (3D) cell cultures.

[0135] In an optional embodiment, the fluid temperature unit has a display unit for visually displaying or indicating the fluid temperature. In a particularly simple design, the display unit is designed as a temperature indicator, in particular as a temperature measuring strip with temperature-variable coloring, which is thermally coupled to the fluid path and / or the fluid. Alternatively, the display unit is designed, for example, as a screen that is signal-connected to a temperature sensor that is coupled to the fluid path and / or the fluid.

[0136] In a practical embodiment, the additional unit has a one-way valve unit for directed guidance of the fluid in the fluid path. The one-way valve unit is coupled to a fluid path in such a way that the fluid can only flow in one direction, and a fluid flow in the opposite direction is reduced, blocked, or shut off. The one-way valve unit is designed, in particular, with passive one-way valves, i.e., fluid flow- and / or fluid pressure-controlled one-way valves. The one-way valve unit preferably has at least one check valve connected to the fluid path.

[0137] A "check valve" is understood here and below to mean, in particular, a backflow preventer, i.e., a device that allows the flow of a fluid (liquid or gas) in one direction and blocks or at least significantly reduces the flow in the opposite direction. This can be achieved by movable one-way valve bodies such as flaps, balls, or diaphragms, which open under fluid pressure in the desired flow direction and close in the opposite direction. Alternatively, in other embodiments, for example, in Tesla valves, higher flow resistances may be present in the opposite direction compared to the flow direction.

[0138] Dispensing devices often have a washing function for cleaning the fluid wells, for example, in a microtiter plate. Fluid is aspirated from the fluid wells and directed, for example, into a fluid reservoir. Dispensing devices with a washing function typically have different fluid paths for washing or rinsing and for dispensing, each controlled by a separate pump. An additional unit with a one-way valve unit makes it possible to implement this washing and dispensing functionality using a single, shared pressure source or pressure source unit.In particular, the one-way valve unit makes it possible, during operation of the pressure source (unit), to convey fluid in one conveying direction (flow direction) from at least one fluid reservoir, and, when the conveying direction (flow direction) is reversed, to convey fluid in the opposite direction into another (or the same) fluid reservoir through the pressure source (unit).

[0139] If a common fluid path is used for the washing and dispensing functionality, a fluid distribution unit or Y-piece is provided, for example, which divides the fluid path into several sub-paths to different fluid reservoirs, wherein the check valves of the one-way valve unit are arranged in the sub-paths.

[0140] With appropriate arrangement of the check valves, it is particularly possible to wash multiple fluid wells of a microtiter plate in parallel using the one-way valve unit and a single pressure source (unit). For example, it is possible to wash all fluid wells, or just a row or column of fluid wells, or a predefined pattern of fluid wells.

[0141] In one conceivable design of the one-way valve unit, for example, two parallel fluid paths are provided, each with an outlet nozzle. One fluid path is used for dispensing (dispensing path), and the other fluid path is used for washing (washing path, suction path). The one-way or check valves for the fluid paths are oriented in opposite directions to each other, so that depending on the flow direction of the pressure source (unit), only one of the fluid paths is active.

[0142] The one-way valve unit is positioned, for example, between the at least one fluid reservoir and the pressure source (unit). Preferably, the one-way valve unit is placed between the pressure source (unit) and the outlet nozzles so that no fluid can drip from the wash path during dispensing or pumping back. In one possible embodiment, the additional unit has a one-way valve unit and a first fluid distribution unit for branching a fluid path into a number of parallel sub-paths, each with an outlet nozzle. The one-way valve unit and the fluid distribution unit are arranged, in particular, between at least one fluid reservoir and the pressure source (unit), so that the sub-paths are each routed via the pressure source (unit).The additional unit comprises, for example, a second fluid distribution unit, by means of which several sub-paths from different fluid reservoirs are bundled or combined into a common fluid path, which is then divided into the parallel sub-paths for dispensing by means of the first fluid distribution unit. The one-way valve unit comprises, for example, a number of check valves corresponding to the number of sub-paths, which are interconnected in the sub-paths.

[0143] In an advantageous embodiment, the additional unit has a washing unit for performing a washing function for a fluid receptacle. The washing unit is provided and configured to wash or clean a fluid receptacle, in particular a fluid receptacle of a microtiter plate (well), or to at least partially remove a fluid in the fluid receptacle and replace it with a new fluid. In particular, the washing unit is provided and configured to remove fluid from the fluid receptacle, in particular to aspirate it. Such a washing unit is particularly desirable for applications in cell-based assays, immunoassays, purification of molecules and / or particles in suspension or other biochemical assays, and for changing the medium in cell cultures.The washing unit of the additional unit makes it possible to implement washing processes or washing functionalities even for dispensing devices that are not set up for a washing process.

[0144] The washing unit is or can be coupled, for example, to a pressure source (unit) and / or one-way valve unit of the additional unit, so that a particularly small number of pressure sources, outlet nozzles and fluid paths (partial paths) are required. In a first embodiment, the washing unit has a distance adjustment for adjusting a distance between an outlet nozzle and at least one fluid receptacle. In particular, the outlet nozzle is lowered by means of the distance adjustment during a washing process such that the outlet nozzle at least partially engages in the fluid receptacle to be cleaned or washed. Preferably, the outlet nozzle can be lowered to a bottom of the fluid receptacle so that any fluid contained therein can be sucked out as completely as possible.

[0145] The washing unit is preferably provided and configured for free-jet dosing and / or suction. In particular, the washing unit is configured for free-jet dosing against a chamber wall of the fluid receptacle. For example, the outlet nozzle is designed to be angled or curved in order to dispense / dose against the chamber wall. This protects the floor of the fluid receptacle. Furthermore, the angled or curved outlet nozzle enables simplified suction of the fluid from corners of the fluid receptacle. The outlet nozzle can also be curved in more than one spatial dimension; in particular, a spiral-shaped outlet nozzle is possible, for example. In one conceivable embodiment, an inclination or angle of attack of the outlet nozzle is adjustable or changeable. For this purpose, the outlet nozzle is coupled, for example, to a corresponding servomotor.Alternatively, the outlet nozzle is connected to an adjustment mechanism which can be adjusted to three different angles of inclination when lowered by adjusting the distance, for example.

[0146] The outlet nozzle is preferably made of a hydrophobic or superhydrophobic material or coated with such a material, in particular only on the outside.

[0147] The washing unit expediently comprises a cleaning unit for the outlet nozzle, by means of which the outlet nozzle can be cleaned, in particular decontaminated, after a washing process. For this purpose, the outlet nozzle and / or the cleaning unit are designed to be movable or adjustable relative to one another, so that the outlet nozzle at least partially engages or dips into the cleaning unit for cleaning. The cleaning process of the outlet nozzle by means of the cleaning unit is preferably implemented as an automated protocol, which is carried out automatically, for example, by a controller of the additional unit.

[0148] In a preferred embodiment, the cleaning unit is arranged adjacent to a waste disposal receptacle for disposing of excess or unused fluid. In particular, the cleaning unit and the waste disposal receptacle are designed as a single component, for example, in the form of a two-part container.

[0149] The cleaning unit is, for example, an ultrasonic device or ultrasonic bath into which the outlet nozzle can be immersed for cleaning. The ultrasonic bath contains, for example, water and / or solvents (e.g., ethanol) as the cleaning fluid.

[0150] The cleaning unit is alternatively designed, for example, as a UV unit for irradiating the outlet nozzle with ultraviolet (UV) light. The outlet nozzle is preferably designed such that the interior of the outlet nozzle can be easily cleaned / decontaminated with UV light. In particular, the outlet nozzle is made of a UV-transparent plastic material, such as polymethyl methacrylate (PMMA) or polyamide (PA).

[0151] The cleaning unit can also be configured for heat treatment or heat cleaning of the outlet nozzle, in which contaminants in the outlet nozzle are removed using heat. For example, the cleaning unit comprises a heat source in the form of a light or laser source.

[0152] In a preferred embodiment of the washing unit, a collecting device is provided for guiding or moving the fluid within the fluid receptacle, which collects the fluid at a desired location within the fluid receptacle. The collecting device ensures that fluid can be completely removed from the corners of a fluid receptacle during the washing process. The collecting device is designed, for example, as a tilting table (tilt station) for inclining or tilting the fluid receptacle. Alternatively, the collecting device is designed, for example, as a sonic unit, which drives liquid within the fluid receptacle into the center and / or into a corner / edge / rim of a fluid receptacle through the action of sound.

[0153] An additional or further aspect of the invention provides that the washing unit has at least a first fluid path for dispensing (dosing channel, dispensing channel) and at least one second fluid path for a washing process (suction channel), wherein the first and second fluid paths are conveyed via a common pressure source (unit). The first and second fluid paths each have an outlet nozzle, wherein the outlet nozzle of the suction channel is also referred to below as a suction nozzle for the purpose of differentiation. The first fluid path is coupled to a fluid reservoir, wherein the second fluid path is coupled to a disposal receptacle. In other words, the first fluid path connects the fluid reservoir to the outlet nozzle and the second fluid path connects the suction nozzle to the disposal receptacle. The outlet nozzle and / or the suction nozzle is designed, for example, to be oblique or curved.

[0154] The second fluid path is arranged in the opposite direction to the first fluid path at the pressure source (unit), so that during operation of the pressure source (unit), fluid is conveyed in different directions in the fluid paths. In other words, the flow direction in the first and second fluid paths is inverted, so that in one fluid path, fluid is conveyed from the (outlet / suction) nozzle to the reservoir (fluid reservoir / disposal receptacle), and in the other fluid path, fluid is conveyed from the reservoir to the nozzle.

[0155] For example, the fluid paths are parallel to each other, with the arrangement of reservoir and nozzle interchanged between the two fluid paths. In other words, at one end, the first fluid path is coupled to the fluid reservoir and the second fluid path to the outlet nozzle, while at the other end, the first fluid path is coupled to the outlet nozzle and the second fluid path to the disposal receptacle. As a result, the flow or conveying direction in the two fluid paths is reversed, so that in one fluid path, fluid is conveyed forward (reservoir to nozzle) and in the other fluid path, fluid is conveyed backward (nozzle to reservoir).

[0156] Alternatively, one of the fluid paths is guided in a crossing or skewed manner to form a loop section, wherein the loop section and the other fluid path are guided or can be guided around a pressure source rotor in such a way that, during pressure source operation, fluid is conveyed in the fluid paths in opposite directions.

[0157] By routing the first and second fluid paths in opposite directions, only one pressure source (unit) is required, yet it is still possible to perform rapid washing, even in parallel if necessary. Furthermore, the back-and-forth pumping for dispensing and washing occurs simultaneously, allowing for shorter operation of the pressure source (unit). In other words, it is possible to perform both aspiration and dispensing in pressure source mode. Preferably, the entire first and / or second fluid paths are designed to be removable, allowing for easy cleaning (autoclaving or similar).

[0158] Preferably, the outlet nozzle of the first fluid path and the suction nozzle of the second fluid path address the same fluid intake. In particular, the suction nozzle is washed by the freshly dispensed fluid, which can reduce contamination. In one conceivable embodiment, the suction nozzle of the second fluid path extends, at least temporarily, further downward than the outlet nozzle of the first fluid path.

[0159] For example, a one-way valve unit or a check valve is connected to the second fluid path upstream of the waste receptacle, ensuring that no waste fluid returns to the pressure source (unit) or the fluid receptacle. Alternatively, it is conceivable that a one-way valve unit or a check valve is connected upstream and downstream of the pressure source (unit) in the second fluid path. A method for operating such a washing unit is described in more detail below.

[0160] At the start of the process, a fluid receptacle is at least partially filled with a fluid, for example, a spent cell culture medium. The at least one first fluid path is not primed, i.e., not completely filled with fluid.

[0161] In a first method step, the suction nozzle of the second fluid path is moved into the fluid of the fluid receptacle and the pressure source (unit) is operated (forward) such that the fluid is suctioned out of the fluid receptacle through the suction nozzle. Fluid, e.g. fresh cell culture medium, is conveyed from the fluid reservoir into the first fluid path. The first fluid path is preferably dimensioned and / or primed such that the conveyed fluid does not reach the outlet nozzle. This makes it possible to suction as much of the fluid to be removed from the fluid receptacle as possible before new fluid is dispensed into the fluid receptacle. The suction nozzle is expediently lowered sufficiently deep into the fluid receptacle that essentially all of the fluid can be suctioned out of the fluid receptacle.

[0162] In a subsequent second process step, the pressure source (unit) continues to operate (forward). Since the suction nozzle essentially no longer extends into the fluid, air is sucked into the second fluid path. New fluid, however, is metered into the fluid receptacle via the first fluid path and the outlet nozzle. Preferably, the suction nozzle is raised or moved upward, or the fluid receptacle is moved downward.

[0163] The method thus enables a partial or essentially complete exchange of a fluid in a fluid receptacle. The final fluid quantity in the fluid receptacle is controlled either by the amount of fluid conveyed via the first fluid path or by the last position of the suction nozzle, by moving the suction nozzle to a height of the desired fluid level. To prepare the washing unit for the next washing process, the direction of rotation or conveyance of the pressure source (unit) is reversed (backwards) in a third method step. This empties the first fluid path and fills it with air from the outlet nozzle. The one-way valve unit or check valve prevents waste fluid from being conveyed to the suction nozzle. If necessary, an additional pressure relief valve is provided to release any pressure that builds up.In particular, the pressure source (unit) can also be designed in such a way that it stops delivering above a certain back pressure.

[0164] An additional or further method for operating the washing unit is explained in more detail below. This method can optionally be combined with the method described above, for example, it can be installed upstream or downstream of it.

[0165] According to the method, the suction nozzle of the second fluid path extends at least partially into the fluid of the fluid receptacle, wherein the first fluid path is essentially completely filled with fluid. Thus, when the pressure source (unit) is operated forward, the fluid in the fluid receptacle is continuously exchanged, thus washing the fluid receptacle and any particles or cells possibly contained therein. The final fluid quantity in the fluid receptacle is again controlled either by the quantity of fluid conveyed via the first fluid path or by the final position of the suction nozzle, by moving the suction nozzle to a height of the desired fluid level or fluid mirror.

[0166] The washing unit and the methods described above are not limited to a single fluid receptacle, but can also be applied in parallel to several fluid receptacles, for example 8, 12, 16, 96 or 384.

[0167] In an advantageous development of the washing unit, it is designed to wash magnetic particles in the fluid receptacle. The magnetic particles are suspended in the fluid. The washing unit has a controllable or switchable magnetic field unit in the area of ​​the fluid receptacle, which, during operation, generates a magnetic holding field that concentrates and holds the magnetic particles in an area of ​​the fluid receptacle so that they are not sucked away by the suction nozzle during a washing process. The magnetic field unit is designed, for example, as an electromagnet or as an electromagnetic coil or as a permanent magnet movable relative to the fluid receptacle.

[0168] The cartridge system according to the invention is intended for, and is suitable and configured for, a dispensing device. The cartridge system comprises a dispensing cartridge and at least one additional unit as described above.

[0169] The dispensing cartridge is designed for coupling to a pressure source. The pressure source can be, for example, a peristaltic pump, such as a pressure source unit of the auxiliary unit or the dispensing device. In the following, the pressure source (unit) is described and referred to as a peristaltic pump without restriction of generality.

[0170] The dispensing cartridge has two cartridge parts (cartridge bars) which are coupled in a dimensionally stable manner, for example in the shape of a cuboid or a bar, and at least one fluid path arranged therebetween.

[0171] When assembled, the dispensing cartridge is arranged as a connecting element between a fluid reservoir, from which a quantity of fluid to be dispensed is withdrawn, and a fluid receptacle into which the fluid is dispensed. The fluid receptacle is, for example, a microtiter plate or a microtiter plate receptacle.

[0172] The fluid used as a dispensing agent can be a liquid, in particular a reagent, emulsion, solution, or suspension. For example, the fluid or liquid contains suspended particles, in particular biological cells (living and dead). However, the particles can also be beads, nanoparticles, or the like. The fluid can also be a gas, in particular air, for example.

[0173] In this embodiment, the fluid path is provided as a hose for conveying a fluid that can be guided therein by means of the pressure source (unit), which is designed in particular as a peristaltic pump, and is suitable and configured for this purpose. A "hose" here and below essentially refers to any (fluid) line, channel, or pipe that has a sufficiently deformable, soft, or elastic (hose) outer wall to enable peristaltic fluid conveyance through the pump rotor of the peristaltic pump. Such a hose thus forms the fluid path for guiding the fluid, whereby the hose can also be formed from several coupled individual hose sections. The hose is preferably made of a material that is chemically inert towards the fluid being conveyed or to be conveyed. The hose is designed, for example, as a silicone hose.

[0174] In one conceivable embodiment, the at least one fluid path or tube is designed to be phobic or superphobic on the inside. The fluid path or tube has a corresponding (internal) coating or is made of a corresponding material. A cartridge system with at least one such phobic or superphobic fluid path is inventive in itself and thus represents a separate invention (even without an additional unit).

[0175] "Phobic" is understood here and below to mean, in particular, a contact angle with a liquid fluid of greater than 100°, in particular greater than 110°, preferably greater than 130°. "Superphobic" is understood here and below to mean a contact angle with the fluid of greater than or equal to 150°.

[0176] The phobic or superphobic hoses or fluid paths ensure that no or as little liquid as possible remains in the hose (fluid path) and / or the outlet nozzles when pumping a liquid back and forth. This minimizes dead volume in the fluid path or hose, reducing cleaning effort and the risk of cross-contamination when changing the fluid.

[0177] The fluid paths are designed to be phobic or superphobic, particularly with regard to the (liquid) fluid being conveyed. If the fluid is oil or oil-based, the fluid paths are lipophobic (oleophobic) or superlipophobic (superoleophobic). If the fluid is water or water-based, the fluid path is designed to be hydrophobic or superhydrophobic. A hydrophobic or superhydrophobic design of the fluid path or hose is possible, for example, by an internal coating based on silane, PFA (perfluoroalkoxy), PTFE (polytetrafluoroethylene), Fluoropel, carbon black, combinations of these or similar substances, or by manufacturing the fluid path from a suitable material, such as polyurethane or PTFE or a particularly hydrophobic silicone.

[0178] In a suitable refinement, the or each fluid path is designed to be omniphobic or superomniphobic, so that essentially any liquid can be conveyed through the fluid path. This allows the fluid path to be used in the same way for several different liquids.

[0179] During dispensing or pumping operation, the at least one tube of the dispensing cassette can be guided at least partially adjacent to the pump rotor, for example, with an approximately 180° deflection. The at least one tube is stretched onto or around the pump rotor with a specific tension to enable the deformation of the outer wall by the pump rotor, which is desired for peristaltic conveying.

[0180] The at least one tube runs from one cartridge part to the other cartridge part, with the cartridge parts ideally being dimensionally stable. Between the cartridge parts, for example, at least one dimensionally stable connecting element is arranged, which mechanically connects the cartridge parts to one another. The term “dimensionally stable” is understood here and below to mean in particular a property of the connecting element to keep its specified dimensions (e.g. dimensions, shape, volume, ...) constant under normal operating conditions. This includes in particular the resistance to expansion, shrinkage or change in length under influences such as temperature changes, humidity, mechanical stress or aging. The dimensionally stable connecting element thus retains its specified properties over a long period of time.This ensures that the distance between the cartridge parts is limited, especially when not mounted on the pump rotor, so that undesirable high mechanical loads on the hose are avoided.

[0181] The dimensionally stable connecting element can, for example, be designed to be movable. In such a movable or flexible design, the connecting element is designed, for example, as a wire, a steel cable, a Bowden cable, a chain, or a cable. Dimensionally stable here means, in particular, that the length and flexibility of the connecting element are maintained under typical operating conditions. Alternatively, the dimensionally stable connecting element can, for example, be designed to be flexible, elastic, or spring-elastic. The connecting element can, for example, be U- or C-shaped in the manner of a clasp or clip. The connecting element can also have an articulated connection and / or a folding or pivoting mechanism.

[0182] The cartridge parts are designed and configured to be attached or mounted to the dispensing device, particularly in the area of ​​the peristaltic pump, and thus to maintain the necessary tension in the tubing during operation. Each cartridge part includes a retaining frame for holding and guiding the tubing. One of the cartridge parts can be coupled to at least one fluid reservoir (reservoir cartridge part), while the other cartridge part has a dispensing nozzle connected to the tubing for dispensing a fluid conveyed in the tubing (outlet cartridge part).

[0183] The outlet nozzle is made of plastic or metal, for example. The material of the outlet nozzle is selected to be chemically inert to the fluid to be dispensed. With a sufficiently small hose diameter (flow diameter), it is conceivable, for example, for one hose end to form the outlet nozzle. Which hose diameter is considered sufficient and how large the hose diameter actually is is initially irrelevant. This depends, for example, on the fluid to be dispensed and can be determined, for example, from past dispensing data or from corresponding tests or trials.

[0184] The outlet nozzle can be integrated into the outlet cartridge part, i.e., be part of the outlet cartridge part. Alternatively, the outlet nozzle can be designed separately from the outlet cartridge part, for example. The outlet nozzle is described below—without limiting its generality—specifically as part of the outlet cartridge part.

[0185] Preferably, a number of parallel tubes (fluid paths) are arranged between the cartridge parts, each of which is coupled to an associated outlet nozzle of the outlet cartridge part. "A number of tubes" here and below refers in particular to several tubes, i.e., at least two tubes, for example, 8, 16, or 32 tubes. This makes it possible to fill several wells of the microtiter plate simultaneously using the dispensing cartridge, which is particularly advantageous for high-throughput applications.

[0186] The hoses are each connected to an associated fluid reservoir on the reservoir cartridge side, for example, so that a different fluid is conveyed, or at least can be conveyed, through each hose during dispensing. It is also conceivable, for example, for one or more hoses to be fed from a common fluid reservoir, with a distribution system (distribution comb) being provided, for example, which evenly divides or splits a supply line leading into the fluid reservoir into the hoses. The distribution system (fluid distribution unit) can, for example, be fully or partially integrated into the reservoir cartridge part. Combinations of these are also possible, i.e., some of the hoses are fed via a distribution system and others individually.

[0187] The additional unit can be mechanically or fluidically coupled to at least one of the cartridge parts. In other words, the additional unit can be mechanically or fluidically coupled to the reservoir cartridge part and / or the outlet cartridge part.

[0188] For example, the additional unit can be coupled or attached to and / or to at least one of the cartridge parts. In other words, the additional unit is attached or attachable, for example, to the reservoir cartridge part and / or the outlet cartridge part. Alternatively, the additional unit can also be designed as a third cartridge part (additional cartridge part), which can be arranged in front of the reservoir cartridge part, between the reservoir cartridge part and the outlet cartridge part, or behind the outlet cartridge part.

[0189] An additional unit with a valve unit is arranged, for example, on or in front of the reservoir cartridge part, i.e. in front of the pressure source or peristaltic pump or the pump rotor, so that when the flow diameter is closed, any fluid still in the hose is pumped out and dispensed through the outlet nozzle.

[0190] Preferably, an additional unit with a valve unit is arranged on the outlet cartridge part or behind it, i.e. behind the peristaltic pump or the pump rotor. When the flow diameter is closed during pump operation, increasing (fluid) pressure builds up within the tube. By briefly or partially opening the flow diameter, this pressure can be used to dispense extremely precise, very small amounts of fluid, in particular less than 500 nl, preferably 100 nl, and particularly preferably 10 nl. The opening time in this case is, for example, less than 1 ms (millisecond), preferably approximately 300 ps (microseconds). Such short opening times can be achieved, for example, by accelerating a plunger and striking the valve's closing mechanism with momentum. The plunger is then preferably braked by a stop and moved back by a mechanism.This allows the return force of the valve's closing mechanism to close it again after a very short time. The opening time correlates with the volume of fluid to be dispensed.

[0191] The add-on unit creates a particularly suitable cartridge system. In particular, the additional functionality it provides makes it possible to retrofit existing dispensing devices or adapt them for specific applications. In particular, it makes it possible to use different cartridge systems interchangeably with the same dispensing device depending on the application, thus leveraging each of the advantageous functions.

[0192] The additional unit can be permanently attached to at least one of the cartridge parts, i.e. integrated into the at least one cartridge part or designed integrally with it, so that the dispensing cartridge and the additional unit form a common assembly.

[0193] Alternatively, the additional unit can be attached to and / or coupled to the at least one cartridge part. The additional unit is therefore designed separately from the at least one cartridge part or separately from the dispensing cartridge. In an advantageous embodiment, the additional unit is designed in particular in a modular manner with the dispensing cartridge. Preferably, the additional unit is designed as an exchangeable additional module so that the dispensing cartridge - and thus the dispensing device - can be flexibly adapted to different requirements or applications. With such a modular design, for example, several different additional modules are provided, which differ in particular with regard to the additional functions they can implement, and can be flexibly attached to or coupled to the at least one cartridge part, depending on the desired application.

[0194] While the dispensing cartridge is specifically designed as a consumable, the add-on unit is designed to be at least partially recyclable due to its modular design and / or interchangeability. An add-on unit can therefore be used with several different dispensing cartridges.

[0195] In such a modular design, the additional unit is inventive in itself and thus represents a separate invention independent of the dispensing cartridge. The additional unit is intended, suitable, and configured in particular for a dispensing cartridge of a cartridge system described above.

[0196] The possible fastening of the additional unit or the additional module to the at least one cartridge part is preferably carried out in a form-fitting and / or force-fitting manner.

[0197] A "positive connection" or a "positive connection" between at least two interconnected parts is understood here and below in particular to mean that the interconnected parts are held together at least in one direction by a direct interlocking of the contours of the parts themselves or by an indirect interlocking via an additional connecting part. The "blocking" of mutual movement in this direction is therefore due to the shape.

[0198] A "positive connection" or a "positive connection" between at least two interconnected parts is understood here and below in particular to mean that the interconnected parts are prevented from sliding against each other due to a frictional force acting between them. If a "connecting force" causing this frictional force (this means the force that presses the parts against each other, for example, a screw force or the force of gravity itself) is missing, the positive connection cannot be maintained and can therefore be released.

[0199] The fastening is designed, for example, as a plug-in connection, snap-in connection, or clip connection. Additionally or alternatively, a magnetic connection is provided. For this purpose, a self-aligning magnet is integrated into the additional unit, for example, which interacts with a magnetic or magnetizable counterpart, for example, a magnetic metal, of the at least one cartridge part during the fastening process.

[0200] For example, in a modular design of the add-on unit with a valve unit, it is conceivable that the counter bearing for the valve body is integrated into the cartridge part, and only the actuator and the valve body are part of the replaceable add-on module. This means that the valve unit, in particular part of the pinch valve, is also at least partially integrated into the dispensing cartridge.

[0201] In one conceivable embodiment, the hose has at least two hose sections, wherein the additional unit is arranged between a first hose section, which is guided into the fluid reservoir, and a second hose section, which opens into the outlet nozzle.

[0202] If the additional unit is designed as a valve unit with a 3 / 2-way valve, a third hose section is preferably also led to the additional unit. The 3 / 2-way valve has a first connection for the first hose section coupled to the fluid reservoir, a second connection for the second hose section coupled to the outlet nozzle, and a third connection for the third hose section, thus coupling them together. The third hose section can be led past the pump rotor. The third hose section therefore has a lower preload and a greater play. The third hose section can be connected to a second fluid reservoir, so that fluid from both the first and the second fluid reservoir can be dispensed from the outlet nozzle by means of the 3 / 2-way valve.

[0203] Preferably, however, the third hose section forms a circulation line coupled to the first hose section and / or the fluid reservoir of the first hose section. Such a circulation line thus enables repeated circulation or recirculation of the fluid, for example, to ensure a constant temperature, concentration, or other specific properties within the system, or to maintain fluid homogeneity by avoiding sedimentation and ensuring a uniform temperature and concentration during the dispensing process. The circulation line opens, for example, into the fluid reservoir, allowing unused fluid to be pumped back. The third hose section is guided essentially parallel to the first hose section.

[0204] In some applications, the circulation line flows directly into the first hose section to avoid contamination of the fluid reservoir.

[0205] Preferably, the first and second ports are arranged as coaxially as possible, so that a fluid path for dispensing is formed that is as straight as possible to avoid turbulence within the fluid. The third port is arranged transversely for this purpose. When installed in a dispensing device, the first and second ports are arranged substantially horizontally, and the third port is arranged vertically, in particular against the direction of gravity. The recirculation bend is thus directed upwards, so that no residues settle in the bend during normal dosing / dispensing.

[0206] In an advantageous embodiment, a valve unit for controlling a flow diameter of the at least one fluid path and a particle sensor unit for determining a particle property of particles within a fluid that can be conveyed in the at least one fluid path are provided by the at least one additional unit.

[0207] In an advantageous development, a pressure source unit comprising at least one peristaltic pump with a number of individually controllable pump rotors (essentially) corresponding to the number of fluid paths or hoses is provided by the at least one additional unit. The cartridge system is thus suitable and configured to dispense different amounts of fluid from different outlet nozzles using at least two different pressure sources (pump rotors).

[0208] As is known, for example, from EP 0 304 446 B1, the dispensing volume of the individual fluid paths of dispensing cartridges is typically calibrated by the preload of the corresponding tubes. Clamping blocks can be moved using appropriate screws, thereby adjusting the preload in the tube. The screws and clamping blocks are usually located in / on the reservoir cartridge.

[0209] By using an additional unit with a pressure source unit and a number of individually controllable pump rotors, this calibration and the aforementioned screws and clamping blocks can be omitted. This allows for a simpler design of the cartridge components, especially the reservoir cartridge component.

[0210] The dispensing volume can be compensated by adjusting the rotation of the pump rotors. Particularly in combination with one of the sensors described above for measuring the dispensing rate (dispensed fluid quantity), the cartridge system can be designed to be self-calibrating without the need for factory calibration. Additionally or alternatively, it is possible for the cartridge system to readjust itself during operation—particularly via the controller. For example, the additional unit comprises a particle sensor unit as described above in addition to the pressure source unit. The pressure source unit is used as a means for adjusting the dispensing volume in order to achieve (at least approximately) a desired target number of dispensed particles in the dispensed volume.Furthermore, this enables real-time adjustment of the dispensed volume based on measured or determined particle properties, for example, particle concentration or viability (in the case of cells). In other words, the particle properties determined by the particle sensor unit are used to control and / or regulate the pressure source unit.

[0211] Alternatively, optimized pumping parameters for a dispensing cartridge can be determined prior to operation, for example at the factory or by the user, and transferred to the dispensing device for operation, for example via a user interface (e.g. user interface) by the user themselves, or automatically, for example via a barcode or an RFID chip which is delivered with the dispensing cartridge or is installed in or on the dispensing cartridge and can be automatically read out by the controller or the dispensing device. The controller preferably converts the dispensing volumes set by the user via the user interface into a control of the pump rotors in such a way that the desired dispensing volume is dispensed from the outlet nozzles and, for example, delivered into the corresponding fluid receptacle of a microtiter plate.

[0212] The dispensing device according to the invention is designed, for example, as a reagent dispenser. The dispensing device has a pressure source or a connection for a pressure source. For example, the dispensing device has a pressure source designed as a peristaltic pump, for example as a roller pump, and a cartridge system as described above, which is or can be coupled to the pressure source or peristaltic pump. The additional functionality of the additional unit creates a particularly suitable dispensing device. In a particularly preferred embodiment, the dispensing cartridge of the cartridge system has a number of tubes as parallel fluid paths, wherein the dispensing device and / or the cartridge system has an additional unit with a pressure source unit.The pressure source unit comprises a peristaltic pump with a number of individually controllable pump rotors corresponding to the number of tubes, with each tube being guided at least partially around an associated pump rotor. In other words, the peristaltic pump in this embodiment is designed and configured to drive individual, selected tubes, allowing individual dispensing from the tubes.

[0213] For example, the dispensing cartridge has eight (8) parallel tubes, and the peristaltic pump has eight (8) associated pump rotors. The corresponding pump motors could be offset from the drive axis of the or each pump rotor and connected, for example, via a gear, a belt, or a chain. The pump rotors can be mounted on a common axis via ball bearings. The pump rotors can each be driven by a pump motor, for example. It is also conceivable for several pump rotors to be jointly driven by a pump motor via appropriate switchable couplings and gears.

[0214] The design of the peristaltic pump with a number of individually controllable pump rotors, in particular at least two individually controllable pump rotors, is inventive in itself and thus represents a separate invention.

[0215] A corresponding pump unit can also be regarded as part of the cartridge system, whereby the pump unit is signal-linked to a controller of the cartridge system or an additional unit.

[0216] The spacing of the hoses in the cartridge parts can be adjusted to match the spacing of the pump rotors, so that, for example, the distance from one hose to the next roughly corresponds to the distance from one pump rotor to the next. If there is a corresponding gap (clear width) between the pump rotors, the respective hose can be moved through this gap to attach the hose to the corresponding pump rotor. This makes it easier to connect the pump rotors individually to the hoses.

[0217] The distance between the tubes can be maintained at the appropriate distance using one or two locks, allowing the user to connect all tubes to the respective pump rotors in a single movement. The corresponding lock can then be attached to a holder on the peristaltic pump, one of the cartridge components, or the dispensing device. The guide perpendicular to the rotational axis of the pump rotors ensures that each tube rests flat on or against the assigned pump rotor and that tubes located at the edge are not crushed laterally. The version shown with 8 channels can also be implemented for 2, 4, 16, 32, or any desired number of tubes and pump rotors.

[0218] In principle, a distance between the parallel tubes and the associated pump rotors is advantageous, which is particularly similar to the distance between the microtiter plate wells, e.g. about 9 mm for a microtiter plate with 96 wells.

[0219] If multiple pump motors are to be used, it is therefore particularly helpful to use very flat motors, for example so-called pancake motors. Such pancake motors have a height of the motor body in the direction of the shaft, calculated without the shaft, of less than 20 mm, in particular less than 15 mm, preferably less than 10 mm. In one conceivable embodiment, an aspect ratio of an (axial) height of the pump motor to a mean (radial) extension of the pump motor can be dimensioned to be less than 1, in particular less than 0.5, preferably less than 0.3, particularly preferably between 0.2 and 0.3. Ideally, stepper motors with a step angle of less than 2° and a holding force of at least 0.1 N cm (Newton centimeters), in particular at least 0.3 N cm, preferably at least 0.5 N cm are used.A further embodiment of the dispensing device includes a movement unit for moving a fluid receptacle that receives the dispensed fluid. The fluid receptacle is, in particular, a microtiter plate or a fluid receptacle (well) of the microtiter plate. This allows a microtiter plate to be arranged so that each outlet nozzle can dispense into each receptacle.

[0220] If the dispensing device is designed to accommodate more than one microtiter plate, the movement unit is configured to position the or each microtiter plate such that each outlet nozzle can dispense fluid into each of the microtiter plates. In a particularly advantageous variant, either the outlet nozzles of the cartridge system or an additional unit with a pressure source unit or at least one of the microtiter plates can be moved perpendicular to the plane defining the microtiter plate receptacles.

[0221] This allows the outlet nozzles to be immersed in at least one of the fluid receptacles of the microtiter plates to aspirate the liquid contained therein into the fluid paths. The aspirated liquid can then be discharged into a waste container or disposal receptacle (waste) or into other fluid receptacles of the microtiter plates, in particular into fluid receptacles of another microtiter plate.

[0222] The cartridge system according to the invention or the additional unit according to the invention and / or the dispensing device according to the invention enable new possible uses that are not feasible with conventional dispensing devices. If method steps are described in the uses described below, advantageous embodiments for the cartridge system and / or the dispensing device result, in particular, from the fact that they are designed to carry out one or more of these method steps.

[0223] An additional unit or a device described above

[0224] A cartridge system or a dispensing device as described above is used to fill a microtiter plate or to dispense cell suspensions as a fluid.

[0225] In another conceivable application, an additional unit with a valve unit enables a small-volume dispenser with dispensing quantities of, in particular, less than 500 nl, preferably 100 nl, particularly preferably 10 nl. For this purpose, the valve unit is coupled to the outlet cartridge part, and an increased pressure is built up in a fluid path with the peristaltic pump when the valve is closed. The valve is then opened briefly or only partially, resulting in a pulse- or hammer-like dispensing action. The pressure buildup can be measured, for example, by measuring the expansion of the tube.

[0226] Preferably, the fluid path behind the valve, i.e., between the valve and the outlet nozzle, is designed to be mechanically rigid in order to reliably withstand the discharge caused by the increased pressure. For example, it is conceivable to manufacture the fluid path section and / or the outlet nozzle behind the valve from a metal, such as stainless steel, or a mechanically stable plastic, such as a thermoplastic. Additionally or alternatively, it is conceivable, for example, to provide the fluid path behind the valve with a superhydrophobic coating on the exterior.

[0227] In this case, it is possible to partially dose air or oil as a fluid for dispensing a sample fluid by appropriately controlling the valve unit in order to realize a small-volume sample dispensing of the sample fluid.

[0228] In an application using cell solutions as the sample fluid, for example, it is possible to use a buffer solution to separate the sections in the fluid path (fluid path sections) containing cell suspensions. The fluid path section connected to the outlet nozzle can be optionally connected to a cell solution reservoir and a buffer solution reservoir using a valve on the valve unit. A quantity of buffer solution is added between liquid quantities with a target cell number. Buffer solution and cell solution are thus fed into the fluid path alternately. "Fluid packets" of buffer solution-cell solution-buffer solution are dispensed, meaning the desired amount of cell solution is "packed" in buffer solutions. The buffer volumes are dimensioned sufficiently large to prevent the cells of successive cell solution packets from mixing with each other.

[0229] In an additional or further application, a dosing process first doses liquids and then drains them from the fluid channels to a valve position. The valves of the valve unit are opened / closed, allowing open channels to be aspirated and then dosed.

[0230] In one embodiment, the valve unit can be arranged upstream of the pressure source or the pump rotor. Advantageously, this allows the valves to be larger, as they are not positioned at a comparatively short distance from the outlet nozzles. For this purpose, the dispensing cartridge can be equipped with an additional cartridge part as an adapter (adapter cartridge part), which keeps the tubes at a defined distance and can be easily connected to the valve unit. Preferably, the reservoir cartridge part can be easily connected to the valve unit or the additional unit.

[0231] To switch during operation, the fluid is then pumped back through the hoses until the corresponding meniscus has reached the corresponding valve. This can be detected by an appropriate sensor, preferably optical, e.g. with a light barrier or camera, or calculated using the pumping movement or rotation of the pump motor. For example, a fill level sensor unit is integrated into the additional unit for this purpose. The valves whose associated outlet nozzles are not supposed to dispense are closed accordingly. The pump rotor now rotates forwards until the fluid has reached the outlet nozzles of the open valves. This can also be detected or monitored by an appropriate sensor, preferably optical, e.g. with a light barrier or camera, in particular with a fill level sensor unit.If the fluid levels of the outlet nozzles to be dispensed are not equal, or if air bubbles are detected, an initial volume can be drained into the disposal receptacle until a defined level is reached. Subsequently, the fluid can be dispensed from the filled outlet nozzles into the corresponding rows and columns. After the dispensing process, the pump rotor is rotated backward until the respective fluid meniscus of the open valves is again in front of them. The valves can then be switched accordingly, and the next dispensing process is started in the same way.

[0232] In a further application, the outlet cartridge part is movably mounted on the dispensing device, so that at least one outlet nozzle is immersed in a fluid-filled fluid receptacle of a microtiter plate, and by reversing the pumping direction, the fluid is removed from the receptacle. This enables washing or cleaning of the microtiter plate receptacles or transfer of liquid from one fluid receptacle to another. In particular, washing of cells located in the fluid and / or exchange of media in the microtiter plate fluid receptacles is thus feasible.

[0233] In a preferred application, the additional unit according to the invention and / or the cartridge system according to the invention and / or the dispensing device according to the invention are used to reduce edge effects in microtiter plates. In a dispensing cartridge with 8 parallel tubes and a microtiter plate with 96 wells, divided into 12 columns and 8 rows (A to H), one column at a time can be dispensed using the outlet nozzles. According to the application, a larger amount of fluid is dispensed in rows A and H by controlling the valve unit and / or individual pump rotors than in rows B to G. Subsequently, rows B to G are passed over once more, with the channels or valves 2 to 7 closed. This builds up excess pressure in tubes 2 to 7, which is ultimately released into the disposal receptacle or which is reduced by reversing the pump rotor(s).By additionally moving the outlet nozzles along the axis in which the outlet nozzles are aligned, other microtiter plates, in particular those with 384 and 1536 wells, can also be filled.

[0234] In general, in addition to compensating for edge effects, any desired dispensing pattern can also be achieved. For this purpose, each corresponding row would preferably be filled with an outlet nozzle, i.e., for a 96-well microtiter plate, one row per outlet nozzle, for a 384-well microtiter plate, two rows per outlet nozzle, and for a 1536-well microtiter plate, four rows per outlet nozzle. The dispensing or fluid volume can be individually adjusted for each column and row by controlling the pump rotor and / or the valve unit accordingly. This allows for the dispensing volume to be adjusted for each column and the use of only one outlet nozzle, so that a freely selectable volume of liquid can be achieved for each of the fluid wells.

[0235] To speed things up, and if required by the dispensing pattern, two or more of the outlet nozzles can sometimes be operated simultaneously. This can also be advantageous if the corresponding target volumes are not exactly the same. For example, if 1.5 pl are to be dispensed into fluid receptacle A1 and 1.7 pl into fluid receptacle C1, these could be filled in parallel with 1.6 pl. Whether a corresponding procedure is advantageous can be pre-defined by the user in the software and automatically set by the controller. This free filling is particularly useful for normalization, for example for next-generation sequencing (NGS) preparation or for the addition of dimethyl sulfoxide (DMSO) before storing a sample (compound).

[0236] In a further application, automatic cleaning can be implemented. For this purpose, the hose or fluid path section is connected to a second fluid reservoir, so that fluid from both the first and the second fluid reservoir can be dispensed from the outlet nozzle by means of the valve unit or its 3 / 2-way valve. The first fluid reservoir contains a fluid to be dispensed, and the second fluid reservoir contains a washing solution, for example ethanol, deionized water (DI water), or an ethanol / DI water mixture. After the dispensing process with the fluid from the first fluid reservoir is complete, the valve can be switched, and the dispensing cartridge or its hoses can be cleaned using the fluid from the second fluid reservoir. The fluid is expediently pumped into the disposal receptacle, for example, while the pump rotor rotates forward.Ideally, by switching the pump rotor further and pumping backward, the washing solution can be pumped to the first fluid reservoir, thus flushing the entire dispensing cartridge. To ensure the dispensing cartridge is cleaned safely, the washing process can be repeated several times. Finally, by pumping backward and switching the valves, the cleaned dispensing cartridge can be flushed with air to remove any cleaning agent residue.

[0237] An additional or further aspect of the invention provides software on a medium or data carrier for carrying out or executing an additional function or use described above, when the software runs on a computing unit (computer), in particular on the controller of the additional unit. This means that the software is stored on a data carrier and is intended to carry out the method described above, as well as being suitable and designed for this purpose. This results in particularly suitable software for operating an additional unit and / or a cartridge system and / or a dispensing device, with which software the functionality for carrying out the additional functions or uses according to the invention is implemented in programming terms. The software is thus in particular operating software (firmware), wherein the data carrier is, for example, a data memory of the controller.

[0238] The invention relates to a fluid temperature control unit for controlling or maintaining the temperature of a fluid in a fluid path and / or a fluid reservoir, which is or can be coupled to the fluid in a thermally conductive manner, comprising a cooling element for cooling the fluid. The cooling element is particularly designed as a phase-change material. The invention also relates to a washing unit for a dispensing device having at least two fluid paths, each of which is or can be coupled to an outlet nozzle and to at least one fluid reservoir, wherein the fluid paths are or can be guided around a pressure source rotor, in particular a peristaltic rotor, such that, during pressure source operation, fluid is conveyed in opposite directions in the fluid paths. Preferably, a one-way valve unit, in particular a check valve, is arranged in at least one of the fluid paths for directed guidance of the fluid.

[0239] The invention further relates to a washing unit for a dispensing device having at least one fluid path which is or can be coupled to an outlet nozzle and to at least one fluid reservoir, comprising a fluid distribution unit for dividing the fluid path into a number of partial paths, wherein each partial path is or can be coupled to a fluid reservoir, and wherein a valve unit and / or one-way valve unit is arranged in each of at least two partial paths.

[0240] The invention also relates in particular to a particle sensor unit for a dispensing device for determining a particle property of particles within a fluid that can be conveyed in at least one fluid path along a flow direction, wherein the particle sensor unit has an optical or imaging sensor element, and wherein an acute angle, in particular an angle between 20° and 70°, preferably approximately 45°, is formed between an optical axis of the sensor element and the flow direction.

[0241] Exemplary embodiments of the invention are explained in more detail below with reference to a drawing. The drawings show, in schematic and simplified figures:

[0242] Fig. 1 is a plan view of a dispensing device with a peristaltic pump and a cartridge system,

[0243] Fig. 2 shows a side view of the peristaltic pump and the cartridge system with a circulation line in a first embodiment, Fig. 3 shows a side view of the peristaltic pump and the cartridge system with a circulation line in a second embodiment,

[0244] Fig. 4 shows a side view of the peristaltic pump and the cartridge system with a circulation line in a third embodiment,

[0245] Fig. 5 shows a side view of the peristaltic pump and the cartridge system with a circulation line in a fourth embodiment,

[0246] Fig. 6 shows a sectional view of a particle sensor unit of the cartridge system,

[0247] Fig. 7 shows a plan view of a valve of a valve unit of the cartridge system,

[0248] Fig. 8 shows a sectional view of the cartridge system and an additional unit coupled to it,

[0249] Fig. 9 shows a perspective view of a section of the cartridge system with an additional unit with a valve unit,

[0250] Fig. 10 shows a sectional view of the valve unit of the additional unit in a second embodiment,

[0251] Fig. 11 in plan view the valve unit of the additional unit in a third

[0252] Embodiment in an open state,

[0253] Fig. 12 in front view the valve unit according to the third embodiment in the open state,

[0254] Fig. 13 shows in plan view the valve unit according to the third embodiment in a closed state,

[0255] Fig. 14 in front view the valve unit according to the third embodiment in the closed state,

[0256] Fig. 15 shows a second embodiment of the dispensing device in plan view,

[0257] Fig. 16, Fig. 17 in plan view a third embodiment of the dispensing device,

[0258] Fig. 18 shows a sectional view of a particle sensor unit of the cartridge system in a second embodiment,

[0259] Fig. 19 shows a sectional view of a particle sensor unit of the cartridge system in a third embodiment, Fig. 20 shows a sectional view of a particle sensor unit of the cartridge system in a fourth embodiment,

[0260] Fig. 21 shows a fourth embodiment of the dispensing device in plan view,

[0261] Fig. 22 shows a sectional view of a reservoir unit and a valve unit of the cartridge system,

[0262] Fig. 23, Fig. 24 in sectional view a valve mechanism of the valve unit in a first

[0263] embodiment,

[0264] Fig. 25, Fig. 26 in sectional view the valve mechanism in a second embodiment,

[0265] Fig. 27, Fig. 28 in sectional view the valve mechanism in a third embodiment,

[0266] Fig. 29, Fig. 30 in sectional view the valve mechanism in a fourth embodiment,

[0267] Fig. 31 , Fig. 32 in sectional view the valve mechanism in a fifth embodiment,

[0268] Fig. 33 shows a perspective view of an axial element of the valve mechanism in a sixth embodiment of the valve mechanism,

[0269] Fig. 34 shows a plan view of a fifth embodiment of the dispensing device,

[0270] Fig. 35 shows a perspective view of a fluid path with a particle sensor unit,

[0271] Fig. 36 in side view the peristaltic pump and the cartridge system with a fluid distribution unit and a valve unit,

[0272] Fig. 37 to Fig. 40 show a side view of the peristaltic pump and the cartridge system with a fluid distribution unit, a one-way valve unit and a washing unit in a first embodiment, and

[0273] Fig. 41 shows a side view of the peristaltic pump and the cartridge system with a fluid distribution unit, a one-way valve unit and a washing unit in a second embodiment.

[0274] Corresponding parts and sizes are always provided with the same reference numerals throughout the figures. Figure 1 shows a dispensing device 2 for dispensing a fluid 4 into a number of fluid receptacles 6.

[0275] The fluid receptacles 6 are designed as depressions (wells) of a microtiter plate 8, wherein the fluid receptacles 6 are arranged in parallel rows and columns. The fluid receptacles 6 are provided with reference numerals in Fig. 1 merely as an example. The microtiter plate 8 is arranged so as to be displaceable in a horizontal plane. For example, the dispensing device 2 has corresponding adjusting means for moving the microtiter plate 8 along a longitudinal direction x and a transverse direction y arranged perpendicular thereto. In particular, the dispensing device 2 has a corresponding travel table as a travel unit 7 for the microtiter plate 8. The mobility along the directions x, y is indicated in Fig. 1 by means of double arrows. Optionally, the microtiter plate 8 can also be moved along a z-direction, i.e. perpendicular to the directions x and y, by means of the travel unit.

[0276] For dispensing the fluid 4, the dispensing device 2 has a peristaltic pump 10 and a cartridge system 12.

[0277] In the illustrated embodiment, the peristaltic pump 10 is designed, in particular, as a roller pump and comprises, for example, an electric pump motor 14 and a pump rotor 16 driven thereby. The peristaltic pump 10 is preferably height-adjustable, meaning that a vertical distance between the peristaltic pump 10 and the microtiter plate 8 can be changed. In particular, the peristaltic pump 10 is arranged to be movable along the (height) direction z, which is arranged perpendicular to the longitudinal direction x and the transverse direction y.

[0278] The pump rotor 16 can be driven by the pump motor 14 selectively in a forward direction, in which the fluid 4 is conveyed toward the fluid receptacles 6, and in a reverse direction, in which the fluid 4 is conveyed in the opposite direction. The fluid 4 is provided in a reservoir unit 18 of the cartridge system 12. The reservoir unit 18 has a fluid reservoir 20 as a container for the fluid 4, a mixing device 22 for mixing the fluid 4 within the fluid reservoir 20, a sensor element 24 designed as a weight sensor for detecting a dispensed fluid quantity, in particular by monitoring the fluid reservoir weight, and a temperature control unit 26 for controlling the fluid temperature in the fluid reservoir 20.

[0279] In the illustrated embodiment, the cartridge system 12 further comprises a dispensing cartridge 28 and two additional units 30, 32 coupled thereto, as well as a controller 34. The additional units 30, 32 are provided and configured to provide additional functions for the dispensing device 2, wherein the controller 34 is provided and configured to execute these additional functions or to control and / or regulate them. The controller 34 can also be part of one or both additional units 30, 32. In other words, the controller can be integrated into at least one of the additional units 30, 32.

[0280] The dispensing cartridge 28, embodied, for example, as a consumable, comprises two dimensionally stable cartridge parts 36, 38 and a number of fluid paths 40. The fluid paths 40 are designed, in particular, as hoses and are also referred to as such below. In the exemplary embodiment shown, a hose system running between the cartridge parts 36, 38 is provided with a number of parallel hoses 40. In the exemplary embodiment of Fig. 1, the hose system comprises eight hoses 40 shown in dotted lines, which are provided with reference numerals merely as an example.

[0281] The hose system or hoses 40 can be mounted in the area of ​​the peristaltic pump 10 by means of the cartridge parts 36, 38, for example, in such a way that they are height-adjustable together with the peristaltic pump 10. Furthermore, the hoses 40 are guided between the cartridge parts 36, 38 in the installed or assembled state, at least in sections, adjacent to the pump rotor 16, for example, with an approximately 180° deflection.

[0282] The reservoir-side cartridge part 36 is also referred to below as the reservoir cartridge part 36 and the microtiter plate-side cartridge part 38 is also referred to as the outlet cartridge part 38.

[0283] In the assembled state, the cartridge parts 36, 38 are arranged stacked one above the other in the height direction z, with the hoses 40 being guided with a loop around the pump rotor 16.

[0284] The reservoir cartridge part 38 arranged at the top has a holder for parallel guidance of the tubes 40 and the additional unit 30. The additional unit 30 is designed, for example, as a means for calibrating or adjusting a dispensing volume, i.e., a dispensed fluid quantity. The additional unit 30 is designed, for example, to adjust a tube tension.

[0285] The outlet cartridge part 38 arranged at the bottom has a number of outlet nozzles 42 corresponding to the number of hoses 40 for dispensing or delivering the fluid 4 or the amount of fluid to be dispensed into the fluid receptacles 6, with each hose 40 opening into one of the outlet nozzles 42. The outlet nozzles 42 are provided with reference numerals in the figures merely as examples. The additional unit 32 is also arranged on the outlet cartridge part 38.

[0286] The hoses 40 are guided with one hose end into the fluid reservoir 20 and at least partially submerged in the fluid 4. It is also conceivable, for example, for each hose 40 or groups of hoses 40 to be submerged in different fluid reservoirs containing different fluids 4. The other hose end opens into the respective outlet nozzle 42 in the outlet cartridge part 38. A hose section located between the hose ends is at least partially guided around the pump rotor 16 with a certain mechanical tension.

[0287] The dispensing device 2 further comprises a waste container or disposal receptacle 44 (Waste) for disposing of excess or unused fluid. The disposal receptacle 44 is preferably movable relative to the dispensing cartridge 28, so that dispensing can be performed as needed into the fluid receptacles 6 of the microtiter plate 8 or into the disposal receptacle 44.

[0288] The controller 34 is signal-coupled to the reservoir unit 18 and the additional units 30, 32. The controller 34 has, for example, an interface 46. The interface 46 is, for example, a user interface, such as a user interface or a display unit (screen). However, the interface 46 can also be designed as a signal-coupled connection between the controller 34 and an external device, for example, a control unit of the dispensing device 2 and / or the peristaltic pump 10.

[0289] The additional units 30, 32 can be integrated into the respective cartridge part 36, 38. Preferably, however, the additional units 30, 32 are interchangeably attached to the cartridge parts 36, 38 as modular units. It is also conceivable for the additional units 30, 32 to be designed as additional cartridge parts; for example, in the embodiment of Figures 16 and 17, the additional unit 32 is designed as a separate cartridge part.

[0290] The additional unit 30 has a valve unit 48 for controlling or adjusting a respective flow diameter of the hoses 40. The additional unit 32 has a particle sensor unit 50 for determining a particle property of particles 52 (Fig. 2) within the fluid 4 to be dispensed. The fluid 4 is therefore, in particular, a suspension with suspended particles 52. The valve unit 48 and the particle sensor unit 50 can also be integrated into a common additional unit, which is arranged on one or both cartridge parts 36, 38. The additional unit 30 and / or the additional unit 32 can further have a fill level sensor unit (not shown in detail), by means of which a fluid quantity within the at least one hose 4 and / or the outlet nozzle 42 coupled thereto can be determined.The fill level sensor unit comprises an optical sensor element coupled to the hose 40 and / or outlet nozzle 42 to be monitored. The controller 34 is provided and configured to detect and evaluate measurement signals from the sensor element during operation, in particular to determine a fill level or fluid quantity. The sensor element is, for example, a camera or a light barrier (light barrier).

[0291] Furthermore, the additional unit 30 and / or the additional unit 32 can also have a pressure sensor unit and / or flow sensor unit not shown in detail.

[0292] In the embodiment shown in Fig. 1, the valve unit 48 has eight valves 54, each of which is coupled to one of the hoses 40. The valves 54 are preferably designed as pinch valves. The valves 54 are provided with reference numerals in Fig. 1 merely as an example.

[0293] In the embodiment shown in Fig. 1, the particle sensor unit 50 has eight optical or electrical sensor elements 56, by means of which the particle properties of the fluid 4 or the particles 52 within the tubes 40 are determined or monitored. The sensor elements 56 are provided with reference numerals in Fig. 1 merely as an example.

[0294] Different designs and applications of the cartridge system 28 and the additional units are explained in more detail below with reference to Figures 2 to 9. The designs and applications are explained here by way of example for one fluid path. Preferably, however, the cartridge system 12 has several parallel fluid paths, for example 8 fluid paths; the explanations for the individual fluid paths can be applied analogously to several fluid paths. Figs. 2 and 4 each show an application of the cartridge system 28 with a hose section guided into the fluid reservoir 20 and a cartridge system 28 with an additional unit comprising a valve unit 48. The valve 54 in this design is designed as a directional valve, in particular as a 3 / 2-way valve. Preferably, the valve 54 is designed as a pinch valve, for example as a solenoid pinch valve.

[0295] In this embodiment, the valve unit 48 or valve 54 couples three hose sections (fluid path sections) 58, 60, 62. The hose sections 58 and 60 form a hose 40 from the fluid reservoir 20 to the outlet nozzle 42, with the hose section 58 running between the fluid reservoir 20 and the valve 54, and the hose section 60 running between the valve 54 and the outlet nozzle 42. The hose section 58 is guided at least partially over the pump rotor 16 of the peristaltic pump 10. This means that the valve unit 48 or the associated additional unit is arranged on the outlet cartridge part 38.

[0296] The hose section 62 is designed as a circulation line which leads from the valve 54 back to the fluid reservoir 20.

[0297] In a first valve position of valve 54, the hose sections 58 and 60 are connected, so that during pump operation, a quantity of fluid is dispensed from the outlet nozzle 42. In the second valve position, the hose sections 58 and 62 are connected, so that during pump operation, the fluid 4 circulates from the fluid reservoir 20 via the hose sections 58 and 62 back into the fluid reservoir 20. The circulation of the fluid 4 can therefore be driven by the same peristaltic pump 10 as the dispensing unit.

[0298] The embodiment of Fig. 3 shows a design with a valve 54 that couples the hose sections 58 and 60 and a hose section (fluid path section) 64. The valve 54 is again designed, for example, as a 3 / 2-way valve. Preferably, the valve 54 is designed as a pinch valve, for example, a solenoid pinch valve.

[0299] The hose section 64 is also designed as a circulation line. However, unlike the hose section 62 of the previously described embodiment, the hose section 64 does not lead back into the fluid reservoir 20, but rather opens into the hose section 58. The connection between the hose sections 58 and 64 is arranged, for example, in the reservoir cartridge part 36. The hose section 58 is thus led from a peristaltic pump outlet back to a peristaltic pump inlet.

[0300] In a first valve position of valve 54, hose sections 58 and 60 are connected, so that during pump operation, a quantity of fluid is dispensed from outlet nozzle 42. In the second valve position, hose sections 58 and 64 are connected, so that during pump operation, the fluid 4 essentially circulates within hose 40. This prevents contamination of the fluid reservoir 20.

[0301] The illustration in Fig. 5 shows an extension of the above-described embodiment of Fig. 4. In this embodiment, a second additional unit with a valve unit 48 is arranged on the reservoir cartridge part 36. In other words, in this embodiment, both the reservoir cartridge part 36 and the outlet cartridge part 38 are each equipped with a valve unit 48. The valve units 48 each have a valve 54 designed as a 3 / 2-way valve. The valves 54 are preferably designed as pinch valves, for example as a solenoid pinch valve.

[0302] The reservoir-side valve 54 couples three hose sections (fluid path sections) 64, 66, 68, with the outlet-side valve 54 coupling hose sections 66, 60, and 62. Hose section 64 extends into the fluid reservoir 20. Hose section 66 extends between the cartridge parts 36, 38 around the pump rotor 16 from the reservoir-side valve 54 to the outlet-side valve 54. The hose sections 64, 66, and 60 form a hose 40 of the cartridge system for dispensing. Hose section 68 leads into a second fluid reservoir 70 containing a second fluid 72.

[0303] In a first valve position of the reservoir-side valve 54, the hose sections 64 and 66 are connected, so that a quantity of fluid is pumped from the fluid reservoir 20 during pump operation. In the second valve position, the hose sections 68 and 66 are connected, so that a quantity of fluid is pumped from the fluid reservoir 70 during pump operation.

[0304] In a first valve position of the outlet-side valve 54, the hose sections 66 and 60 are connected, so that during pump operation, a quantity of fluid is dispensed from the hose section 66 out of the outlet nozzle 42. In the second valve position, the hose sections 66 and 62 are connected, so that during pump operation, the fluid 4 circulates from the fluid reservoir 20 via the hose sections 58 and 62 back into the fluid reservoir 20.

[0305] Depending on the valve position combination, there is, for example, a dead volume in hose section 66 and / or hose section 60.

[0306] In a conceivable further development, it is possible, for example, that the valve unit 48 of the reservoir cartridge part 36 and / or the outlet cartridge part 38 has more than one valve 54 per fluid path.

[0307] For example, the reservoir-side valve unit 48 has a second 3 / 2-way valve at point 74, which divides the hose section 68. This makes it possible to connect additional fluid reservoirs containing different fluids and dispense them using the cartridge system 12. This is shown in dotted lines in Fig. 5. Additionally or alternatively, the outlet-side valve unit 48 has a second 3 / 2-way valve in the hose section 62, for example, to enable circulation of the fluid 72 back into the fluid reservoir 70.

[0308] The switching or control of the valve units 48 is carried out by means of the controller 34 in a predetermined or adjustable switching pattern.

[0309] Fig. 6 shows the particle sensor unit 50. The particle sensor unit 50, embodied, for example, as a microfluidic chip, has a hollow volume for guiding the fluid 4. The hollow volume is introduced into the fluid path or hose 40 and forms, at least in sections, the guide for the fluid 4. The hollow volume has a stepped basic shape in cross-section with a main channel 76 and a measuring area 78.

[0310] The main channel 76 is dimensioned such that, during pump operation, the majority of the fluid flow, for example, approximately 99%, flows through the main channel 76. The measuring area 78 is designed as a secondary channel running parallel to the main channel 76, through which only a small portion of the fluid flow, for example, approximately 1%, flows. The hollow volume is sealed, for example, by means of a seal 80, for example in the form of a flexible film or foil, so that only the end faces are open for the inflow and outflow of the fluid 4.

[0311] An optical sensor element 82 is arranged on the comparatively flat measuring area 78 in order to detect a particle property of the particles 52 suspended in the fluid 4 in the measuring area 78. The optical sensor element 82 has a light source and at least one light or photodetector. The light source emits an input light into the fluid 4 to be examined, wherein at least one light detector detects an output light coming from the fluid 4. Preferably, the light detector essentially detects output light from the measuring area 78. The flat measuring area 78 has a depth of less than 1 mm, for example. The input light is, for example, scattered and / or refracted and / or reflected by the particles 52 of the fluid 4, and is detected as output light by the light sensor.Preferably, the sensor element 82 is arranged outside the fluid 4 or outside the measuring area 78 in order to avoid contamination and soiling of the sensor element 82.

[0312] By means of the controller 34, a corresponding value for the fluid 4 of the main channel 76 is calculated using an algorithm based on the particle property determined for the measuring range 78.

[0313] The particle sensor unit 50 may optionally have an acoustic unit 84 for acoustically arranging the particles 52 in the measuring area 78.

[0314] The structure of valve 54 of valve unit 48, particularly in the form of a 3 / 2-way valve, is explained below with reference to Fig. 7. Valve 54 is designed as a pinch valve. The structure is explained using an example for a valve 54 between hose sections 58, 60, 62, but is also transferable to other hose sections or hose section combinations.

[0315] The hose section 58 coming from the fluid reservoir 20 branches at a branch point 86 into the hose section 60 and the hose section 62. The valve 54 has two fixed valve bodies 88 and one movable valve body 90. In this embodiment, the valve bodies 88, 90 are bolt- or pin-shaped, i.e., approximately (round) cylindrical, so that when the hose sections 58, 60, 62 are squeezed, no sharp corners press against the outer walls.

[0316] The valve bodies 88, 90 are arranged outside the hose 40, i.e., outside the hose sections 58, 60, 62, so that the valve bodies 88, 90—and thus the valve 54 or the valve unit 48—do not have direct fluid contact. The valve bodies 88, 90 are arranged at a linear distance from one another, with the valve body 90 positioned centrally between the externally arranged valve bodies 88. Thus, a clear width is formed between the movable valve body 90 and each of the valve bodies 88, through which the hose section 60 and the hose section 62 are guided.

[0317] The valve body 90 is mounted for linear displacement in the direction of the valve body 88. The (displacement) mobility is shown in Fig. 7 by a double arrow 92.

[0318] If the valve body 90 is moved upward—referring to the illustration in Fig. 7—the hose section 60 is clamped between the valve bodies 88 and 90, thus closing its flow diameter. Thus, the fluid 4 flows from the hose section 58 into the hose section 62. If the valve body 90 is moved downward—referring to the illustration in Fig. 7—the hose section 62 is clamped between the valve bodies 88 and 90, thus closing its flow diameter. As a result, the fluid 4 flows from the hose section 58 into the hose section 60 to the outlet nozzle 42.

[0319] For example, the valve body 90 is spring-loaded toward the upper valve body 88, so that the valve 54 is normally designed to be either blocking or closing. In the event of a fault, the fluid path to the outlet nozzle 42 is closed, preventing fluid 4 from being dispensed.

[0320] In a preferred embodiment, the adjustment path of the valve body 90 is inclined at an angle relative to the straight connecting line of the valve bodies 88, 90. This inclined mobility of the valve body 90 is shown in Fig. 7 by means of a double arrow 94. Instead of the adjustment path represented by the arrow 92, the valve body 90 in this embodiment has the inclined adjustment path along the double arrow 94. This creates an obliquely oriented pinching direction, so that when the hose section 60 is pinched, the pinch point on the hose section 60 gradually moves toward the branch point 86. In other words, the pressure point on the hose section 60 moves away from the outlet nozzle 42 when compressed.This results in an equilibrium between the volume displaced from the outlet nozzle 42 and the volume pushed back by the displacement, so that when the flow diameter of the hose section 60 is closed, no volume is pushed and dispensed in the direction of the outlet nozzle 60.

[0321] A modular coupling between a cartridge part 36, 38 and an additional unit 30, 32 is explained in more detail below with reference to Fig. 8 and Fig. 9. The following explanations can also be applied to other additional units.

[0322] The cartridge part 36, 38 is designed as a support frame with an approximately U-shaped cross-section for holding and guiding the hoses 40. The additional unit 30, 32 is placed on top as an additional module and fastened to the cartridge part 36, 38. For this purpose, the cartridge part 36, 38 and the additional unit 30, 32 have complementary fastening elements 96, 98. The fastening elements 96, 98, which can be joined together, realize a positive and / or non-positive fastening of the additional unit 30, 32 to the cartridge part 36, 38 when joined. To improve the reproducibility of the fastening, the fastening elements 96, 98 are also designed, for example, for the relative alignment of the additional unit 30, 32 to the cartridge part 36, 38.

[0323] In one conceivable embodiment, the fastening element 98 of the additional unit 30, 32 is designed as a self-aligning magnetic element, while the fastening element 96 of the cartridge part 36, 38 is a magnetic or magnetizable element. For example, the fastening element 96 is designed as a metal element or as a (second) magnetic element or as a ferroelement, i.e., as an element made of a ferromagnetic material.

[0324] Fig. 9 shows an embodiment of the outlet cartridge part 38 and the modular additional unit 32, wherein the additional unit 32 in this embodiment has a valve unit 48 and a particle sensor unit 50. The attachment of the additional unit 32 to the outlet cartridge part 38 has, for example, an articulated connection, so that the additional unit 32 can be folded or pivoted relative to the outlet cartridge part 38 (indicated by the double arrow 100). The hose sections 58 and 62 are guided parallel to one another, at least in sections, by means of a number of locks 102. The peristaltic pump 10 is designed, for example, as a roller pump in this embodiment.

[0325] The valve unit 48 has a valve 54, wherein the structure of the valve unit 48 or of the valve 54, which is designed in particular as a 3 / 2-way pinch valve, essentially corresponds to the embodiment described above in Fig. 7. The two fixed valve bodies 88 can be part of the outlet cartridge part 38.

[0326] The particle sensor unit 50 has, for example, the structure described above with reference to Fig. 6. The particle sensor unit 50 is fluidically connected behind the valve 54 in the hose section 60.

[0327] Optionally, the additional unit 32 can also include a fill level sensor unit. The above statements can also be applied analogously to an additional unit 30 that can be attached to the reservoir cartridge part 36.

[0328] An alternative embodiment of the valve unit 48 is explained in more detail below with reference to Fig. 10. Fig. 10 shows a plan view of two valves 54, each with a movable valve body 104. The valve bodies 104 are each guided in a displaceable manner in a groove- or slot-like guide 105 of the valve unit 48, for example. The guide 105 is shown in Fig. 10 merely as an example. Preferably, the guide 105 is oriented obliquely, for example, along the adjustment path 94.

[0329] The valve bodies 104 are each spring-loaded by a spring element 106 and, in particular, pre-tensioned into a respective closed position. In the closed position, a respective flow diameter of a hose 40 that can be switched thereby is closed. The valves 54 are preferably designed as pinch valves, with the respective counter bearings being integrated, for example, into the respective cartridge part 36, 38.

[0330] In this embodiment, a (valve) actuator 107 of the respective valve 54 (valve actuator) is arranged spatially spaced from the valve body 104, so that the valve body 104 (and their counter bearings) can be positioned closer to a respective outlet nozzle 42.

[0331] The valve bodies 104 are each coupled to the respective valve actuator 107 by means of a movable coupling element 108, for example in the form of a pull cable, pull wire, or Bowden cable. The coupling element 108 is attached to the respective valve body 104, for example, by means of a fixing element 109 with an approximately 180° deflection. Alternatively, the coupling element 108 can also be attached directly or immediately to the valve body 104.

[0332] By means of the coupling element 108, an actuating force of the valve actuator 107 is transmitted to the valve body 104, which is thus moved into an open position against the spring force of the respective spring element 106. In the open position, a respective flow diameter of a hose 40 that can be switched thereby is opened.

[0333] The coupling elements 108 are guided to the respective actuator 107, for example, by means of a deflection 110. Alternatively, the coupling elements 108 can also be designed as a Bowden cable over their entire length.

[0334] Figures 11 to 14 show another conceivable embodiment of a valve 54 of the valve unit 48. In this embodiment, the valve 54 comprises a valve body 111 and an actuator 112 movable relative thereto, each of which is coupled to a spring element 114, 116. One spring end of the spring elements 114 and 116 is connected to the respective valve body 111 or actuator 112, respectively, with a respective second spring end being fixedly clamped, in particular to a housing of the valve unit 48.

[0335] The valve body 111, coupled to the spring element 114, is approximately bolt-shaped, with a bolt end facing the actuator 112 being domed. The bolt end forms the pressure point of the valve body 111 on the outer wall of the hose 40. The valve body 111 is thus approximately finger-shaped. A stationary counterbearing 118 is arranged on a side of the hose 40 opposite the valve body 111 to form the pinch point.

[0336] A plate element 120 is arranged on the spring-side end of the valve body 111, which protrudes from the valve body 111 in a collar-like or flange-like manner transversely to the adjustment direction.

[0337] The actuator 112 coupled to the spring element 116 is made of a magnetizable material and has an approximately U-shaped groove-like recess or depression 122 on the end face facing the valve body 111. The actuator 112 is surrounded by a coil 124, in particular a solenoid coil (cylindrical coil), acting as an electromagnet.

[0338] When the coil 124 is not energized (Fig. 11, Fig. 12), the valve 54 is closed, meaning the flow diameter of the hose 40 is squeezed. The spring element 114 is, in particular, a compression spring that presses the valve body 111 against the counter-bearing 118, so that the flexible hose 40 is squeezed (pinched) between the valve body 111 and the counter-bearing 118. The spring element 116 is, in particular, designed as a tension spring that holds the valve body 112 in a position spaced apart from the valve body 111.

[0339] When current is applied to the coil 124, the actuator 112 is magnetized and, as a plunger or piston, is moved out of the coil 124 in the direction of the valve body 111 against the spring force of the spring element 116. The actuator 112 thereby engages the free end of the hose 40, the counterbearing 118, and the valve body 111, so that the valve body 111 engages at least partially into the recess 122. The free ends of the vertical U-legs of the actuator 112 come into contact with the plate element 120 during extension. With a sufficiently high coil current, the actuator or actuating force of the actuator 112 and / or the momentum of the actuator 112 overcomes the spring force of the spring element 114, so that the spring element 114 is compressed and the plate element 120, together with the valve body 111, is pushed away from the counterbearing 118—and thus from the hose 40—by the actuator 112. This opens the valve 54 or the flow diameter (Fig.13, Fig. 14). The movement of the actuator 112 is braked by an impact on the counter bearing 118, so that the spring force of the spring element 114 can quickly close the flow diameter again.

[0340] Fig. 15 shows a further embodiment of the dispensing device 2. In this embodiment, the valve unit 48 and the particle sensor unit 50 as well as the controller 34 are part of the dispensing device 2. In other words, the valve unit 48 and the particle sensor unit 50 as well as the controller 34 are integrated into the dispensing device 2 itself. The valve unit 48 and the particle sensor unit 50 as well as the controller 34 are therefore not part of the cartridge system 28 in this embodiment. The additional units 30, 32 or the valve unit 48 and the particle sensor unit 50 can be reusably attached to the dispensing cartridge 28 designed as a consumable, wherein the controller 34 also controls and / or regulates the operation of the peristaltic pump 10 and the movement unit 7 for the microtiter plate 8.

[0341] A further exemplary embodiment of the dispensing device 2 is explained in more detail below with reference to Figures 16 and 17. In this embodiment, the dispensing device 2 has a pressure source unit 126. The pressure source unit 126 can also be part of an additional unit or of the cartridge system 12, and can in particular also be coupled to the controller 34. Figure 16 shows a partially assembled state of the dispensing cartridge 28, while Figure 17 shows the assembled state.

[0342] In the illustrated embodiment, eight tubes 40 are routed parallel to one another by means of the dispensing cartridge 28 or by means of the reservoir cartridge part 36 and the outlet cartridge part 28. An additional unit 32 with a valve unit 48 and eight integrated valves 54 can be attached behind the outlet cartridge part 28, wherein, in the illustrated embodiment, the outlet nozzles 42 are shown as part of the additional unit 32. The additional unit 32 is designed in particular as a third cartridge part, which is coupled to the dispensing cartridge 28.

[0343] In this embodiment, the pressure source unit 126 comprises, for example, eight separate peristaltic pumps, each with a pump motor 128 and a pump rotor 130 driven or drivable by the pump motor. The peristaltic pumps, or in particular the electric pump motors (electric motors) 128, can be individually controlled and / or regulated in this embodiment. A gap 132 is provided as a clear width between the peristaltic pumps, or between the pump motors 128 and pump rotors 130 of adjacent peristaltic pumps. The pump motors 128, pump rotors 130, and gaps 132 are provided with reference numerals in the figures merely as examples.

[0344] The distribution or spacing of the cartridge parts 36, 38 by means of which the tubes 40 are held is preferably adapted to the distribution of the gaps 132. In other words, the tubes 40 are preferably held in such a way that they can be moved together by means of the dispensing cartridge 28 through the gaps of the pressure source unit 126 formed by the gaps 132 in order to wind the tubes 40 around the respective pump rotors 130 and subsequently fix them by mounting the cartridge parts 36, 38 (Fig. 17). Two further embodiments of the particle sensor unit 50 are explained in more detail below with reference to Figures 18 and 19.

[0345] Fig. 18 shows an embodiment of the particle sensor unit 50 in which the sensor element 82 is arranged in an approximately U-shaped coupling element 134, which partially encompasses the seal 80. The horizontal U-leg is arranged along the surface of the seal 80. The sensor element 82 is designed as a camera, which is integrated into the horizontal U-leg of the coupling element 134. To improve the image data recorded by the sensor element 82, at least one exposure element 136 is arranged in the coupling element 134, which in particular exposes the measuring area 78 during the camera recordings. In the embodiment shown, the exposure element 136 is designed in particular as a ring exposure.

[0346] Fig. 19 shows a particle sensor unit 50 with sensor elements 82 designed as scattered light sensors. For example, three sensor elements 82 are provided, which detect scattered light from the measuring area 78. Two sensor elements 82 are arranged in the horizontal U-leg of the coupling element 134, with one sensor element 82 being arranged in the vertical U-leg, which is arranged adjacent to the measuring area 78. The sensor elements 82 can thus detect light scattered in the direction of the coupling element 134 from the measuring area 78, in particular in two measuring directions oriented perpendicular to one another.

[0347] The particle sensor unit 50 has a light source 140 coupled to a cavity 138. During operation, the light source 140 preferably emits a light signal with a fixed wavelength or frequency. The light source 140 can be operated in a pulsed or continuous mode. For example, the light source 140 is designed as a light-emitting diode (LED), a laser diode, or a laser. The cavity 138 is a depression or recess in the coupling element 134 that is open toward the measuring area 78. The light source 140 is arranged at a bottom of the cavity 138, which is arranged parallel to the surface of the seal 80. The sensor elements 82 are arranged outside the cavity 138 and distributed around it, so that the light signal from the light source 140 cannot shine directly onto the sensor elements 82, and the amount of scattered light that does not originate from the measuring area 78 is reduced.

[0348] The sensor elements 82 are arranged in particular in such a way as to detect scattered light from the measuring area 78 caused by the light signal in different directions, in particular the sensor elements 82 in the horizontal U-leg detect a backscattered light signal, wherein the sensor element 82 in the vertical U-leg detects light signals scattered in the 90° direction.

[0349] Optionally, one or more sensor elements 82 can have an optical filter (not shown in detail) that only transmits light signals in a defined wavelength range. This is particularly advantageous for fluorescence measurements of particles 52.

[0350] In the embodiments of Figures 6, 18, and 19, the measuring region 78 is designed as a microfluidic channel. However, the above explanations are also applicable to measuring regions 78 designed as glass capillaries. The glass capillary has, for example, a round or rectangular cross-section.

[0351] Fig. 20 shows a particle sensor unit 50 with such a glass capillary as the measuring area 78. In this embodiment, the sensor element 82 is designed as an electrical sensor in the manner of a Coulter counter.

[0352] The measuring range 78 or the glass capillary is in this version in

[0353] Series connected in the fluid path 40, and has an hourglass-like taper or waist, the flow diameter of which is approximately one to ten times as large as the particles 52 of the fluid 4 to be measured.

[0354] The sensor element 82 comprises a counting unit 142 and two electrodes 144 connected thereto. The electrodes 144 extend upstream and downstream of the taper into the fluid path 40 and into the measuring area 78, respectively. The electrodes 144 are thus in contact with the fluid 4.

[0355] In this embodiment, the fluid 4 is an electrically conductive liquid, with the particles 52 being, in particular, non-electrically conductive. The particles 52 are, in particular, cells. The counting unit 142 has a voltage source (not shown in detail), by means of which an electrical measuring voltage is applied between the electrodes 144—and thus across the tapered measuring area 78.

[0356] As a result, an electric current flows through the fluid 4 in the measuring area 78. If at least one of the particles 52 flows through the narrowing, the electric current flow between the electrodes 144 is changed, in particular reduced. The counting unit 142 detects this current change.

[0357] The counting unit 142 can measure the number and / or amplitude of the current changes, whereby the counting unit 142 or the controller 34 determines the number and / or volume of the particles 52 flowing through the taper as a particle property.

[0358] Fig. 21 shows an embodiment of the dispensing device 2 in which a reservoir unit 18 or a fluid reservoir 20 with a mixing device 22 is arranged spatially close to a pump rotor 16 of the peristaltic pump (pressure source) 10 or a pressure source unit 126. The pump rotor 16 is equipped with a magnetic element 146, and the mixing device 22 of the fluid reservoir 20 has a magnetic stirrer 148.

[0359] The reservoir unit 18 and the pressure source unit 126 can alternatively be part of one or both additional units 30, 32, either individually or in combination. The mixing device 22 itself does not have a drive for the magnetic stirrer 148. The magnetic stirrer 148 is driven by the rotating magnetic field generated by the magnetic element 146 during the rotation of the pump rotor 16. As a result, the fluid 4 in the fluid reservoir 20 is automatically mixed during operation of the peristaltic pump 10.

[0360] Fig. 22 shows an application of the cartridge system 28 with a reservoir unit 18 and a valve unit 48 with a valve mechanism 150. The fluid reservoir 20 has a fluid outlet 152 at its bottom leading to the fluid path 40. The reservoir unit 18 further comprises a sensor element 24 designed as a pressure sensor. The reservoir unit 18 and the valve unit 48 can alternatively be part of one or both additional units 30, 32, individually or in combination.

[0361] The valve mechanism 150, explained in more detail below with reference to Figures 22 to 33, is designed for a number of parallel fluid paths 40. The valve mechanism 150 of the valve unit 48 has an elongated axial element 154 with at least one transversely projecting radial element 156. The at least one radial element 156 is provided and configured either to act as a valve body itself for at least one fluid path 40 or to be coupled to a valve body for drive purposes.

[0362] The axial element 154 extends along an axial direction A and is mounted so as to be rotatable or rotatable about it. The axial element 154 is thus essentially designed as a drive shaft for the at least one radial element 156. The axial element 154 has the radial element 156, which is in particular fixed to the shaft, at at least one axial position. The radial element 156 has at least one radial extension 158 projecting upward in the radial direction R.

[0363] The axial element 154 is preferably driven by a drive or servo motor (not shown in detail) of the valve mechanism 150. Alternatively, in an embodiment (not shown in detail), the valve mechanism 150 is designed for mechanical actuation and has a mechanical interface and a gear mechanism coupling this to the axial element 154. In particular, the gear mechanism can be designed in the manner of a click or push mechanism of a ballpoint pen.

[0364] The radial element 156 preferably has a number of radial extensions 158 distributed along a tangential direction T. The radial element 156 thus has, for example, an approximately star-shaped or gear-shaped cross-sectional shape (Fig. 22). The axial element 154 essentially has a shape similar to that of a camshaft, sheepsfoot roller bandage, or music box roller.

[0365] The axial element 154 is arranged transversely to a number of parallel fluid paths 40, so that each fluid path 40 can be assigned an axial position on the axial element 154. At each of these axial positions, a radial element 156 with at least one radial extension 158 is arranged, which, upon rotation of the axial element 154, either itself comes into contact with an associated fluid path 40 as a valve body (pinch valve) (Fig. 22 to Fig. 26), or which, upon rotation of the axial element 154, actuates a corresponding valve body by means of the radial extension 158 (Fig. 27 to Fig. 33). The axial element 154 preferably has a number of radial elements 156 corresponding to the number of fluid paths 40. The valves 54 of the valve unit 48 are thus essentially formed by the radial elements 156 and, if appropriate, valve bodies coupled thereto, wherein the valves 54 can be adjusted jointly by the axial element 154 of the valve mechanism 150.

[0366] In embodiments in which the radial extensions 158 themselves act as valve bodies, the fluid paths 40 are directly or immediately radially squeezed by the radial extensions 158 upon rotation of the axial element 154. The free-end contact surfaces of the radial extensions 158 on the fluid paths 40 are preferably designed to reduce friction. Furthermore, it is additionally or alternatively conceivable for a lubricant to be introduced between the radial extensions 158 and the fluid paths 40. In embodiments in which the radial extensions 158 act to drive or actuate a valve body, the fluid paths 40 are only indirectly closed upon rotation of the axial element 40.

[0367] Figures 23 and 24 show an embodiment of the valve mechanism 150 with a camshaft-like axial element 156. The radial elements 156 are designed as, for example, oval-shaped cams with two radially upstanding radial extensions 158.

[0368] Fig. 23 shows an open position 0 of the valve 54, in which none of the radial extensions 158 squeezes the fluid path 40. Fig. 24 shows a tangential position of the axial element 156 rotated by approximately 90°, in which one of the radial extensions 158, as the valve body, directly squeezes the fluid path 40. This corresponds to the closed position S of the valve 54.

[0369] Figures 25 and 26 show a further embodiment of the valve mechanism 150, in which two fluid paths 40a, 40b arranged one behind the other in the radial direction R are switched by a single radial element 156, in particular in the manner of a 3 / 2-way valve.

[0370] The radial element 156 has at least two cam-like radial extensions 158a, 158b, which are positioned, for example, diametrically opposite each other on the axial element 154. The radial extensions 158a, 158b have different axial widths and radial heights. In particular, the radial extension 158a is longer in the axial direction A and shorter in the radial direction R than the radial extension 158b.

[0371] In this embodiment, the valve mechanism 150 or the valve 54 further comprises a valve body 160 which is mounted for linear displacement along the radial direction R and has an approximately U-shaped cross-section in an axial and radial sectional plane. The horizontal U-leg of the valve body 160 is pressed against the outer circumference of the axial element 156 in the radial direction R, for example by means of two spring elements 162, wherein the free ends of the vertical U-legs bear against the axial element 156 or are supported thereon. The axial distance between the vertical U-legs of the valve body 160 is dimensioned such that the vertical U-legs are arranged axially outside the radial extension 158b, and that the vertical U-legs are still located within the axial extension region of the radial extension 158a.

[0372] In the tangential position of the axial element 156 shown in Fig. 25, the radial extension 158a is rotated toward the valve body 160. As a result, the valve body 160 is moved radially against the spring force of the spring elements 162, so that the horizontal U-leg of the valve body 160 squeezes the fluid path 40b. The radial length of the vertical U-legs of the valve body 160 is dimensioned such that the fluid path 40a is essentially not squeezed.

[0373] Upon rotation of the axial element 156 by 180°, the tangential position shown in Fig. 26 is realized, in which the valve body 160 laterally engages the radial extension 158b, whereby the fluid path 40a is squeezed between the spring-loaded valve body 160 and the radial extension 158b engaging therein. The fluid path 40b is opened by the relaxation of the spring elements 162.

[0374] In the embodiment of Fig. 27 and Fig. 28, the radial extensions 158 are designed as magnetic elements, in particular as permanent magnets. The valve body 164 for squeezing the fluid path 40 is drive-coupled to a (counter) magnetic element 166. In this embodiment, the valve 54 is designed for a tensile closure; in other words, the fluid path 40 is squeezed when the magnetic element 166 is attracted to the magnetic radial extension 158.

[0375] In the embodiment shown, the radial element 156 has, for example, four tangentially distributed magnetic radial extensions 158, wherein two radial extensions 158 have their magnetic north pole oriented radially outwards and two radial extensions 158 have their magnetic south pole oriented radially outwards, so that by rotating the axial element 154 either a north or south pole can be moved in the direction of the magnetic element 166 in order to control the two valve positions S, 0 of the valve body 164.

[0376] In the embodiment shown in Fig. 29 and Fig. 30, the magnetic element 166 itself forms the valve body of the valve 54. In other words, in the closed position S, the magnetic element 166 essentially itself or directly squeezes the fluid path 40. In this case, the valve 54 is designed, for example, to close under pressure, so that the magnetic element 166 is moved into the closed position S when a radial extension 158 with the same polarity is approached, so that the magnetic element 166 is pushed radially away or pressed radially against the fluid path 40 due to the magnetic repulsion. The magnetic element 166 is guided in a linear guide and has, for example, a pin as a contact or pressure point for the fluid path 40.

[0377] The embodiment of Figures 31 and 32 shows a valve 54 in which the valve body 164 and the magnetic element 166 are connected via a pivotally mounted lever 168. The pivot point of the lever 168 is positioned near the magnetic element 166, allowing a longer force arm for moving the valve body 164. The valve body 164 is moved into the open position 0 when the magnetic element 166 is magnetically attracted by the approaching radial extension 158. Correspondingly, the valve body 164 is moved into the closed position S of the valve 54 when a radial extension 158 with the same polarity is approached to the magnetic element 166.

[0378] Fig. 33 shows a perspective view of an axial element 154 with five radial elements 156. Each radial element 156 is shown with two magnetic radial extensions 158. In Fig. 33, the different polarities of the radial extensions 158 are shown by drawing north-polarized radial extensions 158 with solid lines and south-polarized radial extensions with dashed lines. Fig. 34 shows a dispensing device with a fluid temperature unit 170. In an alternative embodiment, the fluid temperature unit 170 is part of one or both of the additional units 30, 32. The fluid temperature unit 170 has thermal insulation hoses 172 in which the fluid paths 40 are guided. The fluid temperature unit 170 further has insulation 174 for the reservoir unit 18 or for the fluid reservoir 20.

[0379] The cartridge system 12, or at least one of the cartridge parts 34, 36, has thermal insulation 176 of the fluid temperature unit 170. At least one of the cartridge parts 34, 36 further has a temperature control element 178 of the fluid temperature unit 170. The temperature control element 178 is designed, in particular, as a cooling element, for example, with a phase change material or a capacitor.

[0380] The microtiter plate 8 is arranged, for example, on a heatable plate 180 of the fluid temperature unit 170.

[0381] The embodiment of Fig. 34 is designed in particular for dispensing a basement membrane-like matrix as fluid 4. The fluid 4 is, for example, poured into the fluid reservoir 20 in a cooled state and then dispensed. The insulating tubes 172 and the insulation 174, 176 enable the fluid 4 to be heated as little as possible during the dispensing process. The temperature control element 178 is arranged in particular in the cartridge part 38 on the outlet nozzle side, thus ensuring that the fluid 4 is dispensed into the fluid receptacles 6 at a desired fluid temperature. The fluid receptacles 6 are heated by the plate 180, so that the dispensed fluid solidifies or hardens in the fluid receptacles 6. The fluid temperature unit 170 thus makes the dispensing device 2 particularly suitable for preparing the fluid receptacles 6 for three-dimensional (3D) cell cultures.

[0382] Fig. 35 shows a further embodiment of the particle sensor unit 50. The particle sensor unit 50 has an optical sensor element 82 and a light source 182, between which an at least partially transparent section of the fluid path 40 is arranged. The light source 182 emits the input light 184 into the fluid path 40, with the sensor element 82 detecting the corresponding output light 186.

[0383] In this embodiment, the optical or imaging detection of the particle count or particle concentration occurs at an acute angle of inclination to the fluid path 40. This means that the optical axis of the optical sensor element 82 is oriented neither parallel nor perpendicular to the flow direction 188 of the fluid 4 (flow direction). In other words, an acute angle is formed between the flow direction 188 and the direction of the output light 186.

[0384] Therefore, the reading by the optical sensor element 82 takes place at an acute angle of inclination, i.e. an angle of inclination between 0° and 90°, preferably between 20° and 70°, in particular approximately 45°, to the flow direction 188.

[0385] Fig. 36 shows an embodiment of the cartridge system 12 and / or the additional units 30, 32 with two fluid reservoirs 20a, 20b, which are, for example, part of a reservoir unit 18. The fluid path 40 is divided into two sub-paths (not further designated) via a valve unit 48 and / or a fluid distribution unit 190, each of which leads into one of the fluid reservoirs 20a, 20b. An optional fluid distribution unit 192 is arranged between the valve unit 48 and / or the fluid distribution unit 190 and the pressure source 10, 126, which divides the fluid path 40, which is consolidated by the valve unit 48 and / or the fluid distribution unit 190, into several parallel sub-paths.

[0386] With this embodiment, it is possible to mix fluids 4 from different fluid reservoirs 20a, 20b and to dispense them together.

[0387] The fluid reservoirs 20a, 20b contain fluids 4 with different particle concentrations, with the fluid reservoir 20a having a higher concentration than the fluid reservoir 20b. The valve unit 48 is designed in particular as a 3 / 2-way proportional valve, so that a ratio of the fluids from the fluid reservoirs 20a, 20b can be dispensed. The outlet nozzle 42 of the fluid path 40 is designed, for example, to be oblique or curved in the illustrated embodiment. Furthermore, the outlet nozzle 42 and the fluid receptacle 6 are adjustable relative to one another along the height direction z, for example by means of a distance adjustment.

[0388] In an alternative embodiment of the cartridge system 12 and / or the additional unit 30, 32, the particle sensor 50 is arranged between the fluid reservoir 20a and the valve unit 48 and / or the fluid distribution unit 190. In a further alternative embodiment, the particle sensor 50 is arranged between the pressure source 10, 126 and the outlet nozzle 42, so that the particle sensor 50 detects the actually dispensed particle concentration. The alternative sensor positions are shown in dashed lines in Fig. 36.

[0389] In another possible embodiment of the cartridge system 12 and / or the additional unit 30, 32, the valve unit 48 is arranged between the fluid distributor 190 and at least one of the fluid reservoirs 20a, 20b. The alternative valve unit positions are shown in dashed lines in Fig. 36.

[0390] Figures 37 to 40 show a first embodiment of a washing unit 194 for performing a washing process for a fluid receptacle 6 of a microtiter plate 8. The washing unit 194 is in particular part of a cartridge system 12 and / or at least one additional unit 30, 32.

[0391] The washing unit 194 has two fluid reservoirs 20a, 20b, wherein the fluid 4 to be dispensed is held in the fluid reservoir 20a, and a waste fluid 196 is held in the fluid reservoir 20b. The fluid reservoirs 20a and 20b are each coupled to a sub-path, wherein the sub-paths are combined to form the fluid path 40 by means of a valve unit 48 and / or a fluid distribution unit 190.

[0392] The optional fluid distribution unit 192 branches the fluid path 40 into several parallel sub-paths, each sub-path ending in an outlet nozzle 42. The inclination or curvature of the outlet nozzle 42 can be adjusted, for example, by means of an adjusting unit (not shown in detail). Furthermore, the relative height or the relative vertical distance along the height direction z of the outlet nozzle 42 to the fluid receptacle 6 can be adjusted.

[0393] The washing unit 194 is preferably provided and configured for free-jet dosing and / or suction. In particular, the washing unit 194 is configured for free-jet dosing against a chamber wall of the fluid receptacle 6. For example, the outlet nozzle 42 is designed to be height-adjustable. Additionally or alternatively, the fluid receptacle 6 or the microtiter plate 8 and / or the movement unit 7 are designed to be height-adjustable.

[0394] The washing unit 194 further comprises two check valves 198, which are preferably part of a one-way valve unit 200. The first check valve 198 is arranged in the partial path between the fluid reservoir 20a and the valve unit 48 and / or the fluid distribution unit 190, wherein this check valve 198 opens for a flow direction toward the pressure source (unit) 10, 126 and closes for a flow direction toward the fluid reservoir 20a. The second check valve 198 is connected in the partial path between the fluid reservoir 20b and the valve unit 48 and / or the fluid distribution unit 190, wherein this check valve 198 closes for a flow direction toward the pressure source (unit) 10, 126 and opens for a flow direction toward the fluid reservoir 20b.

[0395] In this embodiment, the washing unit 194 further comprises a two-part container 202. The container 202 comprises, on the one hand, a disposal receptacle 44 as a waste container and, on the other hand, a cleaning unit 204. The disposal receptacle 44 comprises, for example, an outlet for discharging the (rejected) fluid 4, 196.

[0396] The cleaning unit 204 is a decontamination area into which the outlet nozzle 42 can be immersed for cleaning and decontamination. In the embodiment shown, the cleaning unit 204 is designed, in particular, as an ultrasonic bath with a cleaning liquid 206. The cleaning liquid 206 is water and / or ethanol. Preferably, the outlet nozzle 42 is made of a hydrophobic or superhydrophobic material or coated with such a material, so that it can be essentially completely cleaned or decontaminated by the cleaning unit 204. The cleaning unit 204 is alternatively designed as a UV unit, heating unit, X-ray unit, or combinations thereof.

[0397] Figure 39 shows a dispensing process in which a volume of fluid 4 is dispensed into a fluid receptacle 6 of the microtiter plate 8. The pressure source (unit) 10, 126 or the pump rotor 16, 128 is driven in the forward direction. This closes the check valve 198 for the fluid reservoir 20b and opens the check valve 198 for the fluid reservoir 20a, so that fluid 4 is conveyed from the fluid reservoir 20a to the outlet nozzle 42 and dosed or dispensed into the fluid receptacle 6.

[0398] During a washing process shown in Fig. 40, the height of the outlet nozzle 42 and / or its inclination and / or bend are adjusted such that the outlet nozzle 42 is immersed in the fluid receptacle 6 to be cleaned. Subsequently, the pressure source (unit) 10, 126 or the pump rotor 16, 128 is driven in the reverse direction. This closes the check valve 198 for the fluid reservoir 20a and opens the check valve 198 for the fluid reservoir 20b, so that the fluid 4 is sucked out of the fluid receptacle 6 and conveyed as reject fluid 196 into the fluid reservoir 20b. The pressure source (unit) 10, 126 is operated until essentially only air is present in the fluid path 40, at least between the outlet nozzle 42 and the fluid distribution unit 192.

[0399] Following the washing process, in a process step shown in Fig. 37, the pressure source (unit) 10, 126 or the pump rotor 16, 128 is driven in the forward direction. This closes the check valve 198 for the fluid reservoir 20b and opens the check valve 198 for the fluid reservoir 20a, so that fluid 4 is pumped (primed) from the fluid reservoir 20a to the outlet nozzle 42. The rejected fluid 196 never leaves the fluid reservoir 20b. Optionally, the fluid 4 can be pumped back again before it reaches the outlet nozzle 42 to flush the fluid distribution unit. The fluid 4 is then pumped further forward. If it is not clear when controlled dispensing actually begins, a test volume of the fluid 4 can be dispensed from the fluid reservoir 20a into the disposal receptacle 44.

[0400] Subsequently, the outlet nozzle 42 is optionally cleaned in a cleaning process shown in Fig. 38. Here, the cleaning unit 204 is positioned below the outlet nozzle 42, and the outlet nozzle 42 is immersed in the cleaning unit 204 or in the cleaning fluid 206. The cleaning unit 204, for example, the ultrasonic bath, is activated, thus cleaning the outlet nozzle 42. During the cleaning process, the pressure source (unit) 10, 126 is in particular inactive or is periodically switched between forward and reverse operation.

[0401] Fig. 41 shows a second embodiment of the washing unit 194. The washing unit 194 has two fluid reservoirs 20a and 20b. The fluid reservoir 20b is filled with fluid 4 to be dispensed, while the fluid reservoir 20a is provided for receiving waste fluid 196.

[0402] The washing unit 194 has a fluid path 40 for dispensing and a fluid path 208 for washing. The fluid path 40 connects the fluid reservoir 20b to the outlet nozzle 42, and the fluid path 208 connects the fluid reservoir 20a to an outlet nozzle referred to as the suction nozzle 210.

[0403] The fluid path 40 has, for example, an optional fluid distribution unit 192 between the pressure source (unit) 10, 126 and the fluid reservoir 20b, by means of which the fluid path 40 is branched into several parallel sub-paths, each with an outlet nozzle 42.

[0404] The fluid path 208 also has, for example, an optional fluid distribution unit

[0405] 190 between the pressure source (unit) 10, 126 and the fluid reservoir 20a, by means of which several parallel partial paths, each with a suction nozzle 210, are combined to form a common fluid path 208 for the fluid reservoir 20a.

[0406] As can be clearly seen in the illustration of Fig. 41, the fluid path 208 is arranged in the opposite direction to the fluid path 40 at the pressure source (unit) 10, 126, so that during operation of the pressure source (unit) 10, 126, fluid can be conveyed in the fluid paths in different directions.

[0407] For example, the fluid path 208 is guided in a crossing or skewed overlapping manner to form a loop section, wherein the loop section and the other fluid path 40 are guided or can be guided around a pressure source rotor 16, 128 in such a way that, in pressure source operation, fluid 4, 196 is conveyed in opposite directions in the fluid paths 40, 208.

[0408] Alternatively, the fluid paths 40, 208 are routed parallel to each other, with the arrangement of reservoir and nozzle being reversed in the two fluid paths 40, 208. In other words, at one end, the fluid path 40 is coupled to the fluid reservoir 20b and the fluid path 208 to the outlet nozzle 210, and at the other end, the fluid path 40 is coupled to the outlet nozzle 42 and the fluid path 210 to the disposal receptacle 20a. As a result, the flow or conveying direction in the two fluid paths 40, 210 is reversed, so that during pressure source operation, fluid 4, 196 is conveyed in the opposite direction in the fluid paths 40, 208.

[0409] In a preferred embodiment, the or each outlet nozzle 42 is arranged on the cartridge part (outlet cartridge part) 38, and the or each suction nozzle 210 is arranged on the cartridge part (reservoir cartridge part) 40. The fluid path section of the fluid path 210 to the disposal receptacle 20a is guided into the cartridge part 38. In the installed state, the cartridge parts 38, 40 are arranged one above the other in particular such that the nozzle of the respective upper cartridge part 40, 38 is guided at least partially past the lower cartridge part 38, 40, so that the outlet nozzle 42 and suction nozzle 210 can engage parallel and adjacent to a common fluid receptacle 6. At least one check valve 198 is connected to the fluid path 208. The check valve 198 is connected between the pressure source (unit) 10, 126 and the fluid reservoir 20a, in particular between the pressure source (unit) 10, 126 and the fluid distribution unit 190.The check valve 198 opens for a flow direction from the pressure source (unit) 10, 126 to the fluid reservoir 20a, and closes in the opposite direction.

[0410] Alternatively, the check valve 198 is connected, for example, at another location on the fluid path 208, with Fig. 41 showing two further installation locations, which are designated as check valves 198' and 198". The check valve 198' is positioned between the fluid receptacle 6 and the pressure source (unit) 10, 126, with the check valve 198" being connected between the pressure source (unit) 10, 126 and the fluid reservoir 20a, in particular between the fluid distribution unit 190 and the fluid reservoir 20a.

[0411] The check valve 198, 198', 198" is preferably part of a one-way valve unit 200.

[0412] As shown in Fig. 41, the outlet nozzle 42 and the suction nozzle 210 address the same fluid receptacle 6. In particular, the suction nozzle 210 is washed by the freshly dispensed fluid 4, thereby reducing contamination. For example, the suction nozzle 210 extends further downward than the outlet nozzle 42. In other words, the suction nozzle 210 penetrates deeper into the fluid receptacle 6 than the outlet nozzle 42, at least during a washing process.

[0413] A method for operating such a washing unit 194 is described in more detail below.

[0414] At the beginning of the process, as shown in Fig. 41, a fluid receptacle 6 is at least partially filled with a fluid, for example, a spent cell culture medium. The at least one fluid path 40 is not primed, i.e., not completely filled with fluid.

[0415] In a first method step, the suction nozzle 210 is immersed in the fluid 4 of the fluid receptacle 6, and the pressure source (unit) 10, 126 is operated (forward) such that the fluid 4 is suctioned from the fluid receptacle 6 through the suction nozzle 210 and conveyed into the fluid reservoir 20a. In this process, fluid 4, e.g., fresh cell culture medium, is conveyed from the fluid reservoir 20b into the fluid path 40. Preferably, the fluid path 40 is dimensioned and / or primed such that the conveyed fluid 4 does not reach the outlet nozzle 42.

[0416] In a subsequent second method step (not shown in detail), the pressure source (unit) 10, 126 is operated further (forward). Since the suction nozzle 42 essentially no longer protrudes into the fluid 4, air is sucked into the second fluid path. New fluid 4 is metered into the fluid receptacle 6 via the fluid path 40 and the outlet nozzle 42. Preferably, the suction nozzle 210 is raised or moved upward during this process.

[0417] To prepare the washing unit 194 for the next washing process, the rotation or conveying direction of the pressure source (unit) 10, 126 is reversed (backward) in a third process step. This empties the fluid path 40 and fills it with air from the outlet nozzle 42. The one-way valve unit 200 or the check valve 198, 198', 198" prevents the conveyance of rejected fluid 196 to the suction nozzle 210.

[0418] In the embodiment of Fig. 41, the washing unit 194 is designed in particular for washing magnetic particles 52' in the fluid receptacle 6. The magnetic particles 52' are suspended in the fluid 4. The washing unit 194 has a controllable or switchable magnetic field unit 212 in the region of the fluid receptacle 6, which, during operation, generates a magnetic holding field that concentrates and holds the magnetic particles 52' in a region of the fluid receptacle 6 so that they are not sucked away by the suction nozzle 210 during a washing process. The magnetic field unit 212 is designed, for example, as an electromagnet or as an electromagnetic coil or as a movable permanent magnet.

[0419] Although exemplary embodiments have been explained in the preceding description, it should be noted that numerous modifications are possible. Furthermore, it should be noted that the exemplary embodiments are merely examples and are not intended to limit the scope of protection, applications, or structure in any way. Rather, the preceding description provides the skilled person with a guide for implementing at least one exemplary embodiment, whereby various modifications, particularly with regard to the function and arrangement of the described components, can be made without departing from the scope of protection as defined by the claims and equivalent combinations of features.

[0420] Thus, the cartridge system 12, the additional units 30, 32 and the valve unit 48, in particular the valve mechanism 150, the particle sensor unit 50, the fill level sensor unit, the pressure source unit 126, the pressure sensor unit, the flow sensor unit, the fluid temperature unit 170, the fluid distribution unit 190, 192, the washing unit 194, the one-way valve unit 200 and the reservoir unit 18 are each inventive in their own right and thus each represent a separate invention.

[0421] Furthermore, it is possible for an additional unit 30, 32 to comprise a valve unit 48 and / or a fill level sensor unit and / or a particle sensor unit 50 and / or a pressure sensor unit and / or a flow sensor unit and / or a pressure source unit 126 and / or a reservoir unit 18 and / or a fluid temperature unit 170 and / or the fluid distribution unit 190 and / or the fluid distribution unit 192 and / or the washing unit 194 and / or the one-way valve unit 200. List of Reference Symbols

[0422] 2 Dispensing device

[0423] 4 Fluid

[0424] 6 Fluid intake

[0425] 7 Traversing unit

[0426] 8 microtiter plates

[0427] 10 Peristaltic pump

[0428] 12 cartridge system

[0429] 14 Pump motor

[0430] 16 Pump rotor

[0431] 18 Reservoir unit

[0432] 20, 20a, 20b Fluid reservoir

[0433] 22 mixing device

[0434] 24 Sensor element, weight sensor

[0435] 26 Temperature control unit

[0436] 28 Dispensing cartridge

[0437] 30, 32 additional unit

[0438] 34 controllers

[0439] 36 Cartridge part, reservoir cartridge part

[0440] 38 Cartridge part, outlet cartridge part

[0441] 40, 40a, 40b Fluid path, hose

[0442] 42 Outlet nozzle

[0443] 44 Disposal recording

[0444] 46 Interface

[0445] 48 valve unit

[0446] 50 particle sensor unit

[0447] 52 particles

[0448] 52' magnetic particles

[0449] 54 Valve

[0450] 56 sensor elements

[0451] 58, 60, 62, 64, 66, 68 Hose section, fluid path section

[0452] Fluid reservoir Fluid location Main channel Measuring range Sealing Sensor element Acoustic unit Branch point , 90 Valve body , 94 Double arrow , 98 Fastening element0 Double arrow 2 Coupling element 4 Valve body 6 Spring element 7 Actuator 8 Coupling element 9 Fixation 0 Deflection 1 Valve body 2 Actuator 4, 116 Spring element 8 Counter bearing 0 Plate element 2 Recess 4 Coil 6 Pressure source unit8 Pump motor 0 Pump rotor 2 Intermediate space 4 Coupling element 6 Illumination element8 Cavity Light source Counting unit Electrode Magnetic element Magnetic stirrer Valve mechanism Fluid outlet Axial element Radial element , 158a, 158b Radial extension

[0453] Valve body Spring element Valve body Magnetic element Lever Fluid temperature unit Insulating hose Insulation Insulation Tempering element Plate

[0454] Light source Input light Output light Flow direction Fluid distribution unit Fluid distribution unit Wash unit Reject fluid , 198', 198" Check valve

[0455] One-way valve unit Container cleaning unit 206 cleaning fluid

[0456] 208 Fluid path

[0457] 210 suction nozzle

[0458] 212 Magnetic field unit

[0459] X Longitudinal direction y Transverse direction z Height direction

[0460] A Axial direction R Radial direction

[0461] T Tangential direction

[0462] 0 Open position

[0463] S Closed position

Claims

Ill Claims 1. Additional unit for a dispensing device (2) with at least one fluid path (40) between a fluid reservoir (20) and an outlet nozzle (42), which is or can be coupled fluidically and / or mechanically to the fluid path (40) and which performs an additional function during operation of the dispensing device (2).

2. Additional unit according to claim 1, comprising a controller (34) for performing the additional function.

3. Additional unit according to claim 1 or 2, comprising - a valve unit (48) for controlling a flow diameter of the at least one fluid path (40) and / or - a level sensor unit for determining a fluid quantity within the at least one fluid path (40) and / or outlet nozzle (42) and / or fluid reservoir (20) and / or - a particle sensor unit (50) for determining a particle property of particles (52) within a fluid (4) that can be conveyed in the at least one fluid path (40) and / or - a reservoir unit (18) for providing a fluid (4) to be dispensed and for determining a dispensed fluid quantity and / or - a pressure source unit (126) for conveying a fluid (4) along the fluid path (40) and / or - a pressure sensor unit for determining a fluid pressure in the fluid path (40) and / or - a flow sensor unit for determining a flow rate in the fluid path (40).

4. Additional unit according to claim 3, characterized in that the valve unit (48) comprises a valve (54) coupled or connectable to the fluid path (40), for example a pinch valve, in particular a Solenoid pinch valve, with an actuator and with a valve body (90, 104, 110, 112) movable thereby, wherein in particular a movable coupling element (108) for force transmission is arranged between the actuator and the valve body (104).

5. Additional unit according to claim 4, characterized in that the valve (54) is designed as a 3 / 2-way valve.

6. Additional unit according to one of claims 3 to 5, characterized in that the particle sensor unit (50) has a measuring area (78) which can be coupled to the at least one fluid path (40) for receiving a defined measuring volume of the fluid (4), and a sensor element (82) which is coupled or can be coupled to the measuring area (78).

7. Additional unit according to one of claims 1 to 6, comprising an acoustic unit (84) for acoustically arranging particles (52) within a fluid (4) that can be conveyed in the at least one fluid path (40).

8. Additional unit according to one of claims 3 to 7, wherein the reservoir unit (18) - a fluid reservoir (20) for providing a fluid (4) to be dispensed and for coupling to the fluid path (40), - a mixing device (22) for the fluid reservoir (20) for mixing the fluid (4), and / or - a sensor element (24) for detecting a dispensed amount of fluid.

9. Additional unit according to claim 8, characterized in that that the sensor element (24) is designed as a weight sensor for detecting a weight of the fluid reservoir (20) or a fluid quantity of the fluid (4) held therein.

10. Additional unit according to claim 8 or 9, characterized in that the fluid reservoir (20) is coupled to a temperature control unit (26) for measuring, adjusting and / or regulating a fluid temperature.

11. Additional unit according to one of claims 3 to 10, characterized in that the pressure source unit (126) has at least one peristaltic pump with a number of individually controllable pump rotors (130).

12. Software on a data carrier for carrying out the additional function of an additional unit according to one of claims 1 to 11, when the software runs on a computing unit of the additional unit.

13. Cartridge system (12) for a dispensing device (2), comprising a dispensing cartridge (28) for coupling to a pressure source (10), and at least one additional unit according to one of claims 1 to 11, - wherein the dispensing cartridge (28) has at least two coupled cartridge parts (36, 38) and at least one hose (40) arranged therebetween as a fluid path for conveying a fluid (4) which can be guided therein by means of the pressure source (10), - wherein one of the cartridge parts (36) can be coupled to at least one fluid reservoir (20), - wherein an outlet nozzle (42) connected to the hose (40) for dispensing a fluid (4) conveyed in the hose (40) is arranged on the other cartridge part (38).

14. Cartridge system (12) according to claim 13, characterized in that that the hose (40) has at least two hose sections, wherein the additional unit is arranged between a first hose section (58), which is guided into the fluid reservoir (20), and a second hose section (60), which opens into the outlet nozzle (42).

15. Cartridge system (12) according to claim 13 or 14, characterized in that the additional unit (30, 32) is designed modularly with the dispensing cartridge (28).

16. Cartridge system (12) according to one of claims 13 to 15, characterized in that the additional unit (30) has a valve unit (48) with at least one valve (54) designed as a 3 / 2-way valve, which is arranged between a first hose section (58) coupled to the fluid reservoir (20) and a second hose section (60) coupled to the outlet nozzle (42) as well as a third hose section (62, 64), wherein the third hose section (62, 64) forms in particular a circulation line which is connected to the first hose section (58) and / or the fluid reservoir (20).

17. Cartridge system (12) according to one of claims 13 to 16, wherein at least one valve unit (48) for controlling a flow diameter of the at least one fluid path (40), and / or a particle sensor unit (50) for determining a particle property of particles (52) within a fluid (4) that can be conveyed in the at least one fluid path (40) is provided by the at least one additional unit (30, 32).

18. Cartridge system (12) according to one of claims 13 to 17, wherein a pressure source unit (126) with at least one peristaltic pump (10) with a number of individually controllable pump rotors (130) is provided by the at least one additional unit.

19. Dispensing device (2) comprising a pressure source (10) or a connection for a pressure source and a cartridge system (12) coupled or coupleable thereto according to one of claims 13 to 18 or at least one additional unit (30, 32) according to one of claims 1 to 11.

20. Use of an additional unit according to one of claims 1 to 11 or a cartridge system (12) according to one of claims 13 to 18 or a dispensing device (2) according to claim 19 for filling a microtiter plate (8) and / or for dispensing cell suspensions as a fluid (4).

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