Dispensing device and method for filling a reaction vessel unit

Abstract

The application relates to a dispensing device (9) which has: a dispensing unit (10) with at least one dispensing head (11) which has at least one dispensing nozzle arrangement (12) for filling at least one reaction vessel (2) of a reaction vessel unit (1) which can be translationally moved and positioned relative to the dispensing unit (10), wherein the reaction vessels (2) are designed in an approximately trough-like manner with approximately vertical peripheral walls (6), wherein the dispensing nozzle arrangement (12) is designed such that it is designed to discharge one or more dispensing jets (16) which extend at an angle with respect to the vertical (5, 5') such that they can be directed at an angle against one of the peripheral walls (6) of one of the reaction vessels (2). The dispensing device is characterised in that the one or more dispensing jets (16) have a jet pattern (17) extending in the peripheral direction (u) of the peripheral wall (6). The application also relates to a method for filling at least one reaction vessel (2) of a reaction vessel unit (1) by means of the dispensing device (9).

Description

[0001] Dispensing device and method for filling a reaction vessel unit

[0002] The invention relates to a dispensing device. The invention also relates to a method for filling a reaction vessel unit.

[0003] Reaction vessels of reaction vessel units, such as the wells of microtiter plates (MTPs), are often filled with a target substance such as a cell culture, genetic material, or the like, and an auxiliary fluid such as a nutrient medium, reagent, or the like. To exchange the auxiliary fluid, the reaction vessel units are centrifuged, thereby expelling the auxiliary fluid. Suitable measures are taken to ensure that the target substance itself remains in the reaction vessels. After the centrifugation cycle, the reaction vessels are refilled with fresh auxiliary fluid.

[0004] WO 2017 / 125598 A1 discloses a centrifuge with a loading and unloading device which can both bring a reaction vessel unit very precisely into a specific end position and also move a reaction vessel unit with very high precision during the displacement process. This allows the position of the reaction vessel unit to be exactly coordinated with a second device, such as a pipetting unit, detection unit or the like. The pipetting unit has at least one or more nozzles arranged parallel to one another in a row, which open downwards with their nozzle openings. The nozzles are each small tubes which can be arranged slightly inclined to the vertical. This introduces a liquid jet into the reaction vessels at an angle to a vertical. The pipetting unit can be mounted on a wall of the centrifuge orbe mounted adjacent to an opening for loading and unloading the centrifuge with the reaction vessel unit. The precise and step-by-step maneuvering of the reaction vessel unit below the pipetting unit ensures accurate and clean filling of the reaction vessel by the pipetting unit. This enables automatic filling of reaction vessels by a pipetting unit and, at the same time, automatic loading and unloading of a centrifuge with this reaction vessel unit. A similar centrifuge is known from WO 2018 / 234420 A1. Furthermore, the subsequently published German patent application DE 10 2021 121 265.0 discloses a dispensing device on a centrifuge for feeding a reaction vessel unit, in which a plurality of dispensing heads are provided, each with at least one dispensing nozzle, wherein each dispensing head is assigned a pump which can be connected via a valve selectively to a common reagent supply and an individual reagent supply. The nozzles can point vertically downwards (angle = 0° to the vertical) or have an angle of preferably 2°, 5°, 20° or 30° to the vertical (not more than 90°). The nozzles can also be arranged variably or pivotably with respect to the vertical. Each dispensing head can have one or more rows of nozzles, and the rows of nozzles can each comprise the same number of nozzles or a different number of nozzles.The dispensing nozzles in multiple rows can form a regular grid, such as a rectangular, square, or diamond-shaped grid. The arrangement of the dispensing nozzles corresponds to the positions of the reaction vessels on the respective reaction vessel unit, which is in particular a microtiter plate.

[0005] The higher the cycle rates in automated operation, the faster the reaction vessel units should ideally be filled with liquid. This may require the excipient to be introduced into the reaction vessels at high speed. The higher the filling speed, the higher the flow velocity in the dispensing jet must be, and thus the tendency to flush the target substance out of the reaction vessel increases. The larger the individual reaction vessels, the greater the amount of excipient to be added, which, on the one hand, further encourages an increase in the flow velocity and, on the other hand, increases the mass flow, thus leading to an increased tendency to flush out. In a cellular assay, there may also be the problem that the "layer of cells" that has grown at the bottom of the reaction vessel can be perforated or divided if a dispensing jet is applied directly.This problem can occur regardless of whether the cells are grown individually, in a monolayer, or in multiple layers.

[0006] DE 10 2010 005 722 A1 relates to a positioning device for a sample distribution device, such a sample distribution device with a positioning device, and a method for positioning. The sample distribution device is, in particular, a pipetting device. The sample distribution device has a plurality of pipette tips, by means of which several sample receptacles of a microtiter plate can be filled in parallel. The microtiter plate has a plurality of sample receptacles, wherein the pipette tips can be moved by means of the positioning device so that all sample receptacles of the microtiter plate can be filled one after the other (see figures).

[0007] DE 198 54 919 A1 describes a workstation for microbiological testing. The workstation features a dispensing head that can be moved in multiple directions. Small liquid samples can be collected and dispensed using the dispensing head. The workstation also features a movable sample container and a movable microscope slide.

[0008] US 2020 / 0355581 A1 discloses a liquid transport system for an automated slide handling device for treating one or more tissue samples arranged on slides. The slide handling device comprises slide handling modules designed to accommodate individual slides. The liquid transport system further comprises a liquid dosing device that can dispense a plurality of reagents to the slides accommodated in the slide modules.

[0009] DE 32 24 077 A1 describes a multi-channel pipette. The pipette comprises several cylinders, each with a piston that can be moved back and forth. The pistons can be used to fill or empty the respective cylinder. A finger-operated slider is provided with which the pistons can be moved and the fill level of the cylinders can be detected.

[0010] An object of the present invention is to provide a dispensing device that enables rapid, efficient, and clean filling of reaction vessels of a reaction vessel unit, particularly with larger reaction vessels, while limiting, minimizing, or preventing the flushing, rinsing, disruption, or perforation of a target substance contained in the reaction vessel. Larger reaction vessels can, for example, be those that are combined in a number of 96 or fewer in a reaction vessel unit.

[0011] The object is achieved by a dispensing device according to claim 1 as well as by a method according to claim 21. Advantageous embodiments and further developments form the subject matter of the subclaims.

[0012] A dispensing device according to one aspect of the invention comprises a dispensing unit with at least one dispensing head. The dispensing head has at least one dispensing nozzle arrangement for filling at least one reaction vessel of a reaction vessel unit, which is translationally movable and positionable relative to the dispensing unit, wherein the reaction vessels are approximately trough-shaped with approximately vertical peripheral walls. The dispensing nozzle arrangement is designed such that it is configured to emit one or more dispensing jets that extend obliquely relative to the vertical, so that they can be directed obliquely against one of the peripheral walls of one of the reaction vessels and have a jet pattern extending in the circumferential direction of the peripheral wall.Because the jet pattern is designed to extend in the circumferential direction of the circumferential wall, it is curved in plan view according to the circumferential wall.

[0013] Such a dispensing nozzle can emit a correspondingly slot-shaped dispensing jet, which forms the jet pattern. If multiple dispensing jets are provided, these can be dispensing nozzles arranged along a line in a top view of the nozzles. Such an arrangement of nozzles can create a linear jet pattern on the peripheral wall of the reaction vessel.

[0014] The reaction vessels of the reaction vessel unit each have an opening arranged in an opening plane, which, within the meaning of the invention, defines a horizontal plane and a vertical direction perpendicular thereto. Within the meaning of the invention, "above" is vertical beyond the opening plane, viewed from the interior of the reaction vessel. This corresponds to a design in which the dispensing head is arranged above the reaction vessel unit and discharges fluid downwards into the reaction vessels. The reaction vessel unit is moved translationally along the dispensing head below the dispensing head, with the translational movement of the reaction vessel unit typically occurring parallel to the opening plane. A transverse direction is defined perpendicular to the direction of movement in or parallel to the opening plane. The approximately vertical peripheral walls of the reaction vessels may have a slight slope and / or curvature in vertical section.If multiple dispensing nozzles are provided, it is expedient for the dispensing nozzles to be arranged along a circular line (circular segment) ("revolver-like") and the impact areas to approximately follow a horizontal section of the reaction vessel. The flow axes of the dispensing nozzles can be fanned out, or in one variant, arranged in parallel, while the nozzle openings are axially offset so that the nozzle openings follow the circular line. Along the peripheral wall means that the jet pattern mimics the shape of the peripheral wall, and the dispensing device is designed such that all dispensing nozzles do essentially the same thing, namely, spray obliquely against the wall at a predetermined angle with the same pressure. The reaction vessels can be arranged in a grid, as is known from microtiter plates. The reaction vessels can have a round cross-section, but the invention is not limited to this.

[0015] Since the jet pattern in the dispensing device according to the invention extends in the circumferential direction of the peripheral wall, a larger area can be covered by the dispensing jet(s) compared to a single point-shaped jet or jet with a circular cross-section (round jet). This allows the flow velocity to be reduced for the same volume flow. This means that the fluid enters the reaction vessel with less momentum and preferably bounces little or not at all off the peripheral wall, but runs down the peripheral wall due to the low momentum and the inclination relative to the wall. This can prevent the fluid from sloshing or splashing out during filling, or from washing out or swirling substances already in the reaction vessel, or from perforating or subdividing a cell layer that has grown on the bottom of the reaction vessel.In other words, the dispensing nozzles are preferably designed and the jet velocity and / or flow rate adjusted so that a film forms on the wall. It is particularly advantageous if the film flows in a laminar fashion. For certain applications, it may also be advantageous if the film adheres to the peripheral wall. Under certain circumstances, the flow rate can even be increased compared to a single point jet, which can be used to fill the reaction vessel more quickly while avoiding the aforementioned difficulties.

[0016] The dispensing nozzle arrangement can comprise a single or multiple dispensing nozzles. In the latter case, the jet pattern can be formed by spacing and / or jet directions and / or positions in the direction of movement and / or in the transverse direction of the individual nozzles. In particular, the dispensing nozzle arrangement can comprise a plurality of dispensing nozzles arranged in a straight or curved line, or concentrically or axially symmetrically around a vertical axis, so that the dispensing jets can be distributed over the circumference of the peripheral wall of one of the reaction vessels. The curvature can correspond approximately to a circle, a semicircle, or a partial circle, or follow the corners of a polygon. The precise design will have to be adapted to the circumstances and situation, such as the size, shape, and arrangement of the reaction vessels in the reaction vessel unit, the distance of the reaction vessel unit from the dispensing head, or the like.In particular, the plurality of dispensing nozzles form a group of dispensing nozzles for each reaction vessel of a reaction vessel unit, in particular for each reaction vessel in a row or column of reaction vessels in a reaction vessel unit, the dispensing jets of which generate an identical jet pattern for each reaction vessel.

[0017] In embodiments, one, preferably several, of the dispensing nozzles of the dispensing nozzle arrangement can be configured to emit a round jet, preferably having an inner diameter of at least approximately 0.15 or 0.2 or 0.25 mm and / or of at most approximately 0.3 or 0.5 or 0.7 mm. The manufacture of dispensing heads with round nozzles, for example in the form of pipe sections, is known per se, comparatively simple, and well-mastered.

[0018] The jet pattern can also be formed by jet formation means, such as a corresponding cross-sectional shape of the dispensing nozzle. In particular, the dispensing nozzle arrangement can comprise at least one slot-like dispensing nozzle designed to deliver a dispensing jet. The dispensing jet can have an elongated, straight, or curved cross-section. This allows a further increase in the volume flow while largely avoiding point-like pulses and, if necessary, with fewer dispensing nozzles. Flow guidance in the dispensing head and its manufacture can also be simplified under certain circumstances if fewer individual nozzles are to be installed.

[0019] The dispensing nozzles can, for example, be formed by tubular shafts inserted into bores in the dispensing head. Thus, the aforementioned advantages of the invention can be achieved using essentially the same and established manufacturing technology known from the manufacture and assembly of tubular dispensing nozzles. The dispensing nozzles can, however, be individually designed at the discharge end.

[0020] It is also possible for the dispensing nozzles to be formed by hollow passages with corresponding openings on the dispensing head itself, for example, in the form of bores or millings or manufactured in another way. This allows for a reduction in the number of individual components, thus simplifying design and assembly. In this case, the dispensing head itself forms the nozzle arrangements, and deformation of the dispensing nozzles during handling or use is not possible. The nozzle shape and flow guidance can be formed by machining from the outflow end, from an inflow manifold inside the dispensing head, or through an additive manufacturing process.

[0021] The dispensing device can be adapted to the individual shape and arrangement of the reaction vessels of a reaction vessel unit by providing at least one, preferably precisely one, dispensing nozzle arrangement for each reaction vessel of the reaction vessel unit in a row or in several rows transverse to the direction of movement of the reaction vessel unit. Such a row (or column) can, for example, comprise one or more reaction vessels corresponding to a grid of microtiter plates known per se and widely used in the field. The invention can be used particularly advantageously for two to eight reaction vessels in a row in the usual dimensions of a microtiter plate, and is also conceivable for a single reaction vessel (e.g., a Petri dish in microtiter plate format).Due to the small size of each individual reaction vessel, more than eight reaction vessels in a row can increasingly pose manufacturing challenges in the manufacture of the dispensing nozzle assemblies as well as in controlling the dosage of the dispensing fluid. When dispensing nozzle assemblies are provided for multiple rows of reaction vessels, even faster filling of the reaction vessel unit is possible by simultaneously filling several transverse rows.

[0022] Several dispensing nozzles of the dispensing nozzle arrangement can be aligned vertically such that the dispensing jets of each dispensing nozzle impinge on the peripheral wall of a reaction vessel of the reaction vessel unit at the same angle or at different, particularly alternating, angles and / or at the same height or at different, particularly alternating, heights. With the same impingement height, a particularly uniform flow can be achieved. With different impingement heights, which can be achieved, for example, by staggering the dispensing nozzles in the circumferential direction, an even greater volume flow can be achieved.

[0023] In the dispensing device, the dispensing nozzle arrangement or multiple dispensing nozzles of the dispensing nozzle arrangement can be configured on a separate or shared nozzle body with a dedicated fluid connection. This enables, among other things, individual control of the nozzle arrangements, reliable error control, and adaptation to deviations in the filling speed at the dispensing nozzle or nozzle arrangement level, depending on the sensors used. Different filling programs for reaction vessels in a transverse row are also possible.

[0024] The dispensing unit can have multiple dispensing heads that can be detachably coupled to the dispensing device and / or to one another, preferably by means of a magnetic coupling and / or a screwable connection and / or a detachable snap-in connection, and / or are arranged in an interchangeable manner. The dispensing heads can be coupled to one another, in particular, in a form-fitting manner. This ensures that the individual dispensing heads are precisely positioned relative to one another. The dispensing heads preferably also have a detachable hose connection to enable them to be detachably coupled to a fluid line leading to the respective dispensing head.

[0025] A collecting basin can be located below the dispensing head(s) to collect fluids dispensed through the dispensing nozzles. This facilitates cleaning of the dispensing nozzles by rinsing with a rinsing fluid, allowing the rinsing fluid to be collected and disposed of.

[0026] The dispensing device can also have a temperature control device for controlling the temperature of a fluid to be supplied to the dispensing head. This temperature control device can be formed, for example, along a fluid line between a fluid source, such as a pump, and the dispensing head. The temperature control device can be formed, for example, from a thermally highly conductive tube surrounded by a heating or cooling device, such as a Peltier element. The tube can be made of copper, for example. In this case, it can be expedient to coat the inner surface of the tube with an inert material or to additionally provide a thin-walled plastic tube within the tube. Furthermore, a pump valve and / or a respective pump itself can be temperature-controlled.Due to their comparatively large masses, these parts have a high heat capacity, so that the temperature can be kept very stable and the flow of reagents does not lead to any significant temperature change, but the fluid can be cooled by the thermal mass of the component itself. To move the reaction vessel unit, a translational drive can be provided which is designed to move and position the reaction vessel unit translationally along the dispensing unit so that the reaction vessel unit can be arranged below the dispensing nozzles of the dispensing unit in order to fill at least one reaction vessel of the reaction vessel unit, wherein the translational drive has a rigid displacement rod for positioning a reaction vessel unit and a linear drive for moving the displacement rod. The rigid displacement rod can transmit a movement generated by the linear drive very precisely.The displacement rod can be arranged such that it is moved back and forth solely along a horizontal axis by a linear drive, without permitting any deviating movements in other directions during its movement. This makes it possible both to bring the reaction vessel unit very precisely into a specific end position and to move a reaction vessel unit with very high precision during the displacement process. This also ensures that the dispensing jets, which run or are emitted at an angle to the vertical, reliably hit the correct location, particularly at the correct height, on the peripheral wall of the respective reaction vessel, so that the jet pattern extending across the circumferential direction of the peripheral wall is reliably formed and the effects described above can be achieved. This would be considerably more difficult with less precise positioning, for example using an elastic actuating element.

[0027] The translational drive can, but does not have to, be implemented in a loading and unloading device of a centrifuge or be part of such a device. The loading and unloading device can also be part of the centrifuge itself. The displacement rod can be guided out through an interior or rotor chamber of the centrifuge and sealed off from it. This allows the positioning of the reaction vessel unit to be related to the position of the centrifuge itself and precisely coordinated with another device. Such an additional device can be the dispensing device itself, but also, for example, an additional pipetting unit, a detection unit, or the like. This can be movable or stationary and attached to a centrifuge housing.

[0028] By precisely maneuvering the reaction vessel unit beneath the dispensing device, the angled dispensing jets can be directed precisely and reliably onto the walls of the reaction vessels. This greatly reduces or even completely eliminates the risk of contamination, spillage, and liquid loss due to misdispensing. This ensures precise and clean filling of the reaction vessel using the dispensing device. This enables automatic filling of reaction vessels using a dispensing device and, at the same time, the automatic loading and unloading of a centrifuge with this reaction vessel unit. For example,Before loading the centrifuge, the reaction vessel unit is filled with a solution, which is then removed from the vessel by centrifugation around a horizontal axis, with the opening of the reaction vessel unit facing away from the axis. The reaction vessel unit can then be placed again under the dispensing device using the loading and unloading device in order to refill the reaction vessel unit and then empty it again by centrifugation. This method is particularly suitable when several identical steps, e.g. washing steps, have to be carried out. The reaction vessel unit is then filled with a washing solution and then emptied by centrifugation. This process can be repeated several times as required.

[0029] Because the reaction vessel unit can be controlled with very high precision by the translational drive, as described herein, and can therefore be positioned very precisely in relation to a dispensing device, the present invention is particularly suitable for experimental and test arrangements carried out with reaction vessel units that require filling the reaction vessels with very low flow velocities, but nevertheless a practical, in particular as high as possible, volume flow. Due to the limitations in the manufacture and control of the dispensing nozzle arrangements described above, a dispensing device of the present invention is particularly suitable for reaction vessel units that are designed in the form of microtiter plates, which have, for example, 96 or fewer, approximately 48, 24, 12, 6 reaction vessels or wells, or a single reaction vessel.

[0030] It is advantageous if the dispensing unit and / or at least one of the dispensing heads is or can be detachably coupled, in particular positively, to a wall of a centrifuge housing, wherein the wall of the centrifuge housing is configured near an opening for loading and unloading a reaction vessel unit for coupling the dispensing unit and / or one of the dispensing heads. The centrifuge can typically have a rotor arranged in a rotor chamber and rotatably mounted, which in turn has a receiving area for receiving the reaction vessel unit.

[0031] In this case, the translational drive can be implemented by a loading and unloading device of a centrifuge on which the dispensing unit is provided. Such a loading and unloading device is typically designed to position the reaction vessel unit between a loading position, in which the reaction vessel unit is arranged outside the centrifuge, and an unloading position, in which the reaction vessel unit is arranged inside the centrifuge, and wherein the loading position comprises one or more dispensing positions, in which the reaction vessel unit is arranged below the dispensing unit for filling.

[0032] In particular, the loading and unloading device can comprise a sliding rod, which is pulled out of the rotor chamber in the unloading position and extends through the rotor in the rotor chamber in the loading position. In other words, the translational drive is located on the opposite side of a loading and unloading opening, i.e., where the rotor drive itself is located. The reaction vessel unit can therefore be pulled through the loading and unloading opening into the rotor chamber using the sliding rod, or pushed out of the rotor chamber, where it can rest on a balcony and / or be picked up by an optional transport and scheduling system. The translational drive can also position the coupled reaction vessel unit precisely beneath the dispensing heads.

[0033] The use of the shift rod, which is part of the centrifuge's loading and unloading device, can also be considered advantageous because a separate positioning system is not required. Since the shift rod is not located in the area of ​​the rotor chamber during the centrifugation process, which is subject to the rotor's rotation, the escaping contents cannot come into contact with the loading and unloading device, especially with the shift rod, especially when emptying the reaction vessel unit by centrifugation. This minimizes the risk of contamination within the rotor chamber due to a contaminated shift rod.

[0034] The dispensing device can further comprise a detection device for determining the position of the reaction vessel unit or of a part of a translational drive that moves with the reaction vessel unit, such as the above-described displacement rod, in the direction of movement. A corresponding detection device ensures that the position of the displacement rod in the direction of movement can be precisely determined at all times and that the reaction vessel unit or carrier unit can be precisely moved to the desired location. The detection device can, for example, comprise one or more sensors for detecting a position of the displacement rod and / or the reaction vessel unit.

[0035] Furthermore, an optical detection unit can be provided. This can be designed and arranged such that it can scan the reaction vessel unit adjacent to the dispensing unit in the movement range of the reaction vessel unit. For optical detection, a detection device is preferably provided which comprises at least one optical sensor (= a camera) and preferably a light source. The optical sensor can be designed as a line sensor or as an area sensor. The optical detection unit can have a line camera which is designed and arranged to scan reaction vessel units in a line-like manner. A scanning line can be aligned approximately at right angles to the direction of movement of the reaction vessel unit. The optical detection device can also have a color camera which is designed and arranged to spectrally scan a reaction vessel unit.The optical detection device can also be designed and arranged for 3D scanning of the reaction vessel unit. Methods for 3D scanning are known, for example, from WO 2011 / 060769 A1, DE 10 2009 040 081 A1, DE 10 2008 036 275 A1, DE 197 21 688 A1, DE 103 09 544 A1, DE 43 01 538 A1, DE 195 32 767 C2, and DE 44 39 307 C2. These and other optical methods for 3D scanning can be used to simultaneously scan the fill level of one or more reaction vessels. Reference is therefore made to these documents in their entirety. Using suitable methods, the optical detection can detect and evaluate the fill level of the reaction vessels and the type of liquid contained in the reaction vessel.The optical detection device can advantageously be arranged parallel and adjacent to a row of dispensing nozzles of the dispensing device, so that the individual reaction vessels into which a solution is supplied via the dispensing nozzles can be optically scanned before and / or during and / or immediately after dispensing. Furthermore, such an optical detection device can be designed to detect the position of a reaction vessel unit or a carrier unit. The position of the reaction vessels or carrier unit determined by the optical detection device can be used in a closed control loop to control a drive for moving the carrier unit or the reaction vessel unit. This also makes it possible to use external drive mechanisms, such as a robot arm, whose control is coupled to the optical detection device of the centrifuge.Detecting the position of the reaction vessel unit also allows automatic control of the dispensing of liquids into the individual reaction vessels, whereby the position of the reaction vessels relative to the dispensing nozzles is recorded and aligned. This makes it possible, for example, to automatically fill several rows of reaction vessels sequentially with liquid. The optical detection device can also automatically detect the type of reaction vessel unit (e.g. 1, 6, 12, 24, 48 or 96 reaction vessels). For this purpose, known types of reaction vessel units can be stored in a database. This can be done using a CAD drawing or in another way, such as labeling with a barcode, QR code, color code, or hologram. Using optical scanning in one, two, or three dimensions, the geometry or other features, such as optically recognizable markings, can be recognized and assigned to a known type.Alternatively, an electromagnetic identifier, such as an RFID, can be attached to the reaction vessel unit and scanned via electromagnetic coupling. Dispensing can be controlled accordingly. The optical evaluation also allows for control of the loading and operation of the associated centrifuge for cleaning or emptying the reaction vessel unit. Pre-stored control programs can be called up depending on the detected type of reaction vessel unit and / or the detected contents of the reaction vessels.

[0036] Furthermore, a control device can be provided and configured to control a / the translational drive to move and / or position the reaction vessel unit based on a detected position and / or to control actuating elements of the dispensing nozzles to fill the reaction vessels of the reaction vessel unit based on fixed specifications and / or detected parameters, wherein the control signal describes the position of the displacement rod with an accuracy of at least 0.2 mm or at least 0.1 mm. Such accuracy can be achieved with the previously described translational drive with a rigid rod. Positioning accuracy is important for the present dispensing device due to the oblique beam alignment so that the beam hits the peripheral wall at the correct location (height).

[0037] One aspect of the invention also relates to a method for filling at least one reaction vessel of a reaction vessel unit by means of a dispensing device. The dispensing device can advantageously be designed as described above, wherein the reaction vessel unit is positioned below dispensing nozzles of a dispensing unit of the dispensing device in order to fill at least one reaction vessel of the reaction vessel unit. According to the invention, the reaction vessel unit is positioned such that a jet or jets from at least one of the dispensing nozzles of the dispensing device impinge on a peripheral wall of the reaction vessel at an angle, preferably in an upper half, in particular in an upper third.

[0038] The method may be designed such that the jet or jets form a jet pattern extending in the circumferential direction of the peripheral wall of the reaction vessel.

[0039] The method can provide for the reaction vessel unit to be positioned below the dispensing device with an accuracy of at most 0.2 mm or at most 0.1 mm, preferably by a loading and unloading device with translational drive belonging to a centrifuge on which the dispensing unit is arranged. The dispensing nozzles of the dispensing device can be supplied with fluid during the method in such a way that the fluid runs off the peripheral wall without bouncing off. For this purpose, a flow rate per dispensing nozzle can preferably be at least 10 or 20 or 40 pl / s and / or at most 400 or 200 or 100 pl / s. Bouncing can also include lateral spraying. This can ensure that the fluid largely loses its flow energy from the jet and runs downwards only under gravity, possibly further inhibited by surface forces.This prevents a target substance from being washed out, flushed out, or excessively disturbed in the reaction vessel. The angled impact on the peripheral wall also prevents the dispensing jet from directly hitting the target substance, such as a cell layer growing at the bottom, and perforating it. Due to the limited volume flow per dispensing nozzle, it is particularly useful for relatively large reaction vessels, such as a microtiter plate-format reaction vessel unit with a few reaction vessels, to provide multiple dispensing nozzles per reaction vessel in order to keep filling times within limits.

[0040] In order to achieve acceptable filling times for the entire reaction vessel unit, which results from the filling time for a row of simultaneously filled reaction vessels in the reaction vessel unit multiplied by the number of rows plus respective interruptions in the translational movement of the reaction unit between the respective rows, it can be provided that a volume flow per row of simultaneously filled reaction vessels in a reaction vessel unit is at least 0.8 ml / s or 1.0 ml / s or 1.2 ml / s or 1.5 ml / s or 2 ml / s.

[0041] On the other hand, to prevent the adverse effects described above, it can be provided that a flow velocity at the outlet end of each dispensing nozzle (13) is at most 2 m / s or at most 1 m / s or at most 0.85 m / s or at most 0.7 m / s or at most 0.55 m / s or at most 0.4 m / s or at most 0.25 m / s or at most 0.1 m / s or at most 0.05 m / s or at most 0.01 m / s. For this purpose, the control elements of the dispensing nozzles can be controlled accordingly. With regard to the device of the first aspect, the nozzle cross-sections and / or the number of dispensing nozzles can be selected such that the flow velocity adheres to the above-mentioned limit while maintaining the desired volume flow per row of simultaneously filled reaction vessels in a reaction vessel unit.

[0042] A centrifuge having a rotor and a rotor chamber in which the rotor is arranged and rotatably mounted, wherein the rotor has a receiving area for receiving the reaction vessel unit and wherein the rotor chamber is delimited by a housing, and which has the dispensing device described above, is also encompassed by the invention.

[0043] The figures show:

[0044] Figures 1A, 1B show a dispensing device according to an embodiment of the invention on a reaction vessel unit in a cross-sectional view in a plane AA in Figure 1B and a plan view in a plane BB in Figure 1A, respectively;

[0045] Figures 2A-2D show variants of dispensing nozzle arrangements in respective plan views in a plane ll-ll in Figure 1A;

[0046] Figures 3A, 3B show a dispensing head of a dispensing device with a further variant of a dispensing nozzle arrangement in a bottom view and a cross-sectional view in a plane BB in Figure 3A, respectively, wherein the sectional plane follows the oblique course of dispensing nozzles in the dispensing head, but a perspective distortion is ignored;

[0047] Figure 4 shows a dispensing device with a supply unit and a dispensing unit with a dispensing head in a schematic block diagram according to a further embodiment of the invention; Figure 5 shows a dispensing device with a supply unit and a dispensing unit with multiple dispensing heads in a schematic block diagram according to a further embodiment of the invention;

[0048] Figure 6 shows a further dispensing device with a supply unit and a dispensing unit with several dispensing heads in a schematic block diagram according to a further embodiment of the invention;

[0049] Figure 7 shows a centrifuge with a dispensing unit of a dispensing device and a

[0050] Loading and unloading device in a schematic cross-sectional view according to a further embodiment of the invention;

[0051] Figure 8 shows the loading and unloading device of the centrifuge of Figure 7 in a schematic perspective view;

[0052] Figure 9 is a plan view of a reaction vessel unit designed as a microtiter plate;

[0053] Figure 10 Variants of reaction vessel units designed as microtiter plates;

[0054] Figures 11A, 11B diagrams for the design of dispensing nozzles based on flow cross-section, volume flow, cross-sectional area and flow velocity;

[0055] Figure 12 shows another variant of a dispensing device.

[0056] The figures serve to illustrate embodiments of the invention and are purely schematic.

[0057] A reaction vessel unit 1 comprises a plurality of reaction vessels 2 (Figs. 1A, 1B). The reaction vessel unit 1 is typically a microtiter plate. Such microtiter plates can be configured with a varying number of reaction vessels. It is common to configure microtiter plates with 6 to 4096 reaction vessels, with microtiter plates with 96, 384, or 1536 reaction vessels being common versions. Fig. 9 shows a reaction vessel unit 1 designed as a microtiter plate according to the usual standard. The rectangular microtiter plates are made of plastic (usually polystyrene, sometimes also polyvinyl chloride). For very specific applications, they can also be made of glass. They contain many mutually insulated wells (cavities, English "wells") as reaction vessels 2 in rows 91, 92.The dimensions (length l x width b x height h) of the base body 90 are 127.76 mm x 85.48 mm x 14.35 mm according to the ANSI standard recommended by the Society for Biomolecular Screening (SBS). The wells are available in various shapes: F-bottom (flat bottom), C-bottom (flat bottom with minimally rounded corners), V-bottom (tapered bottom), and U-bottom (U-shaped recess). Figure 9 shows variants of reaction vessel units 1 designed as microtiter plates with 6, 12, 24, 48, or 96,384 reaction vessels 2, as well as a reaction vessel unit 1 manufactured with the same basic dimensions with a single reaction vessel 2, which can be used, for example, as a Petri dish in microtiter plate format.

[0058] Each reaction vessel 2 has an opening 3, wherein the openings 3 of all reaction vessels 2 are located in a common opening plane 4. A vertical 5 is defined at right angles to the opening plane 4. Each reaction vessel 2 has a peripheral wall 6 and a base 7. In the example shown, the peripheral wall 6 runs approximately vertically at least in a region below an opening edge 8 and has a circular cross-section along the edge 8. In the example shown, the base 7 is approximately spherical and merges into the peripheral wall 6 at a rounded edge. However, the invention is not limited to this; rather, the invention can also be applied or adapted to other shapes of reaction vessels 2. For example, the base 7 can be flat and / or merge into the side wall with sharp edges.The base 7 can also have additional structures such as capillary cavities, beads, or other local depressions or elevations. Such structures can, for example, contribute to controlling the behavior of a content of the reaction vessel 2 during a change in position or movement of the reaction vessel unit 1. The peripheral wall 6 can also be inclined or rounded or curved in the vertical direction. The peripheral wall 6 can also be square, rectangular, oval, hexagonal, or other shaped in horizontal cross-section. The peripheral wall 6 can also have additional structures such as axially or circumferentially extending grooves or ribs or a special design of the rim 8 of the reaction vessel 2.Such structures or designs can, for example, contribute to controlling the behavior of a liquid during filling or the behavior of the already filled contents of the reaction vessel 2 during a change in position or movement of the reaction vessel unit 1. For the purposes of the basic description of the invention, however, the illustrated shape of the reaction vessels 2 will initially be used.

[0059] A global coordinate system xyz is defined, where z defines a positively upward vertical direction and x, y are horizontal directions. Without loss of generality, the reaction vessel unit 1 is arranged in the global coordinate system xyz such that the vertical 5 runs along the vertical direction z, so that the opening plane 4 runs horizontally and the openings 3 open upwards. The reaction vessel unit has a length l, a width b and a height h, where the length l extends along the x-axis, the width extends along the y-axis and the height h extends along the z-axis. The reaction vessels 2 have a depth t and a width w at the opening 3. A dispensing device 9 has a dispensing unit 10 (Fig. 7) which is arranged above the reaction vessel unit 1.The dispensing unit 10 has a dispensing head 11, which in the present embodiment has two dispensing nozzle assemblies 12. Each dispensing nozzle assembly 12 has eight dispensing nozzles 13. Each dispensing nozzle assembly 12 can be combined in a dispensing module 14, which are connected to one another in the dispensing head 11. However, this is not mandatory; rather, the dispensing head 11 can be constructed as a monolithic block that carries all dispensing nozzles 13 of all dispensing nozzle assemblies 12.

[0060] The dispensing nozzles 13 are each aligned obliquely at an angle s to a vertical 5' of the dispensing head 11 (Fig. 1A) and, like the vertical 5 of the reaction vessels 5, runs along the vertical direction z. When the dispensing unit 10 is aligned with the reaction vessel unit 1, they are directed obliquely against the peripheral wall 6 of one of the reaction vessels 2. In the present exemplary embodiment, the nozzle openings 15 of the dispensing nozzles 13, each associated with a reaction vessel 2, are arranged along a circular segment and are each designed to emit a dispensing jet 16. The dispensing jets 16 together form a jet pattern 17, which is characterized in that it extends in a circumferential direction u along the peripheral wall 6 (Fig. 1B).In the present embodiment, the dispensing jets are provided in 8 jets per reaction vessel 2, which impinge on the peripheral wall 6 at the same height along an imaginary impingement line 18. After impingement, the liquid can flow down the peripheral wall 6 as a liquid film 19.

[0061] The reaction vessel unit 1 is translationally movable and positionable relative to the dispensing unit 9 in a translation direction T, as will be described in more detail below. The translation direction T is assumed, without loss of generality, to be along the longitudinal axis x. As is clear from Figs. 1A, 1B, each dispensing nozzle arrangement 12 is assigned to precisely one reaction vessel 2 of the reaction vessel unit 1 and is designed to emit one or more dispensing jets 16 with a jet pattern extending in the circumferential direction of the circumferential wall 6 of this one reaction vessel 2. The dispersion nozzle arrangements 12 are arranged along the transverse or width direction y of the reaction vessel unit 1 and thus transversely to the translation direction T. In other words, the dispensing head 11 extends transversely to the translation direction T over the reaction vessel unit 1.A translational drive is so finely controllable that the positioning of the reaction vessel unit 9 is precise enough that the beam pattern 17 along the peripheral wall 6 can be generated reliably and reproducibly.

[0062] In the previous embodiment, the dispensing nozzle arrangement 12 has eight dispensing nozzles 13, which are designed to deliver a circular jet as a dispensing jet 16. In modifications or variants, only one or more than two dispensing nozzles 13 can be present in a dispensing nozzle arrangement 12. The dispensing nozzles 12 can also have other shapes, as long as a jet pattern 17 can be generated that extends in the circumferential direction of the peripheral wall 6 of a reaction vessel 2.

[0063] In one variant, there are several dispensing nozzles 13, which are arranged along a line or along a circular line (circle segment, Fig. 2D) in a top view of the dispensing nozzles 13. The impact areas of the dispensing jets 16 of the dispensing nozzles 13 approximately follow a horizontal section of the reaction vessel 2. In a top view of the nozzle opening 15 of the dispensing nozzles 13, the dispensing nozzles 13 are arranged along a line. Such an arrangement of dispensing nozzles 13 creates a linear jet pattern on the peripheral wall 6 of the reaction vessel 2. In a top view of the reaction vessel 2, the jet pattern is then curved according to the peripheral wall 6 of the reaction vessel 2. The jet pattern adapts to the shape of the peripheral wall 6.

[0064] In a further variant, there is a single dispensing nozzle 13. This dispensing nozzle 13 is a slot-shaped dispensing nozzle (Fig. 2B) that generates a dispensing jet 16 with an elongated cross-section. Such a dispensing nozzle 13 also generates a linear jet pattern on the peripheral wall 6 of the reaction vessel 2 when viewed from the side. In a top view of the reaction vessel 2, the jet pattern is again curved according to the peripheral wall 6 of the reaction vessel 2.

[0065] In a further variant, for example, seven dispensing nozzles 13 are provided, each formed from a tubular body 20 and extending over an angular range of 180° (Fig. 2A). The tubular bodies 20 have a substantially constant and circular flow cross-section 21, which also corresponds to a cross-section of the nozzle opening 15. The dispensing jets 16 thus each have the shape of a circular jet, with the jet pattern 17 resulting from the individual dispensing jets like the spokes of a curved fan. To accommodate the tubular bodies 20, bores can be formed in the drill head 11, which are inclined relative to the vertical in accordance with the direction of the tubular bodies 20 and fanned out from one another in the horizontal direction.In an alternative embodiment, the bores can also be formed parallel to one another in the drill head 11, in which case the tubular bodies 20 are bent at the free end or have deflection devices in the region of the nozzle opening 15 in order to realize the fan-like jet pattern.

[0066] In a further variant, the dispensing nozzle arrangement 12 is formed by a single dispensing nozzle 13 with a flat cone body 22 (Fig. 2B). The flat cone body 22 has a double-walled, flat shape that is arranged around a cone with the helix angle s (cf. Fig. 1A) and widens from the side of the dispensing head 11 to the nozzle end 15. The flow cross-section 21, like the nozzle end 15, thus has the shape of a circularly curved slot and extends over an angle of slightly less than 180°. The dispensing jet 16 emitted by this dispensing nozzle 15 forms the jet pattern 17, which has the shape of the surface of a curved fan.

[0067] In a further variant, three dispensing nozzles 13 are provided with a tubular stem section 23 and a curved, fan-shaped expansion section 24 (Fig. 2C). The curvature corresponds to a cone with the helix angle s (cf. Fig. 1A). The flow cross-section 21 of the dispensing nozzles 13 is thus initially circular and then transitions into the shape of a circularly curved slot, which widens accordingly towards the nozzle end 15. Each of the dispensing nozzles 15 thus emits a dispensing jet 16 that has the shape of the surface of a curved fan. All dispensing jets 16 together thus form a jet pattern 17 that is approximate to that of the previous variant and is interrupted only in short sections.

[0068] In a further variant, which is a modification of the variant in Fig. 2A, five dispensing nozzles 13, each formed from a tubular body 20, are aligned parallel to one another when viewed from below (Fig. 2D). This design is simpler in terms of production technology, since all tubular bodies 20 can be identical and spray in the same direction, and all bores in the drill head 11 in which the tubular bodies 20 are received can be parallel. As can be seen in Figure 2D, the dispensing jets 16, viewed in the circumferential direction, no longer all impinge on the circumferential wall 6 at a right angle, nor at the same angle, but the dispensing jets 16 of the dispensing nozzles 13 located further outwards impinge on the circumferential wall 6 at a shallower angle than the dispensing jets 16 of the dispensing nozzles 13 located further inwards.In order to compensate for the differences in the angles of impact, the dispensing nozzles 13 located further inside can be set flatter in the horizontal direction than the dispensing nozzles 13 located further outside.

[0069] It is understood that the angular range covered by the dispensing jets 16 in each variant along the circumferential direction u of the circumferential wall 6 can be designed arbitrarily and according to requirements. Depending on requirements, dispensing nozzles 13 with slot-like flow cross-sections 21 or nozzle openings 15, which were described above as curved, can also be designed straight, i.e., not curved, in further variants, as long as the angle of incidence and the height of incidence on the circumferential wall 6 are within a range that allows the liquid film 19 to run off the circumferential wall 6. In this sense, a certain scattering range of the angle of incidence of the jet pattern 17 and the position of the line of incidence 18 can be tolerated.If the peripheral wall has a profile deviating from the vertical 5, the dispensing nozzle arrangement 12 can be adapted so that the dispensing jets 13 or the dispensing jet 13 impinge on the peripheral wall 6 at a suitable angle and at a suitable height. In a further variant, eight dispensing nozzle arrangements 12, each with two dispensing nozzles 13, are provided, each formed from a tubular body 20 and arranged opposite one another in the direction of the longitudinal axis x and protruding from a bottom wall 30 of the dispensing head 11 (Fig. 3A).

[0070] In connection with this variant, the basic structure of the dispensing head 11 is explained below, which can be applied with modifications to all embodiments and variants (Figs. 3A, 3B).

[0071] The dispensing head 11 has an upper part 31 and a lower part 35. The upper part 31 has a fluid chamber 32 extending in the transverse direction y, which is closed at one end by a first connecting piece 33 and at the other end by a sealing plug 34. The lower part 35 has a cleaning chamber 36 extending in the transverse direction y, which is closed on both sides by a second connecting piece 37 and a third connecting piece 37'. The tubular bodies 20 of the dispensing nozzles 12 extend through respective bores from the underside 30 of the dispensing head 11 through the lower part 31 and the upper part 31, crossing the cleaning chamber 36 of the lower part 32 and opening into the fluid chamber 31 of the upper part 31.The tubular bodies 20 above the cleaning chamber 36 sit tightly in their bores, while the bores 38 below the cleaning chamber 36 are drilled somewhat wider than the outer diameter of the tubular bodies 20 and annular cleaning channels 38 are formed around the tubular bodies 20, which open in a cleaning opening 39 on the underside 30.

[0072] The fluid chamber 32 serves to collect a reagent supplied via the connecting piece 33 under pressure, so that the reagent is dispensed via the nozzle openings 15 of the dispensing nozzles 13.

[0073] The cleaning chamber 36 serves to clean the dispensing head 11. For this purpose, the second connection piece 37 is connected to a fluid line for supplying a cleaning solution, which can be, for example, ethanol or an aqueous solution containing surfactants. The third connection opening 37' is connected to a fluid line for extracting air from the cleaning chamber 36. By extracting the air, a corresponding air flow is generated through the cleaning channels 38, which entrains liquid droplets hanging from the free ends or tips of the dispensing nozzles 13 in the area of ​​the nozzle opening 15, sucks them through the cleaning channel 38, and removes them from the cleaning chamber 36. The liquid contained therein can be fed to a waste container.If, however, fluid, in particular the liquid cleaning solution, is supplied to the cleaning chamber 36, it flows along the dispensing nozzles 13 through the cleaning channels 38 to clean the outer surface of the dispensing nozzles 13. The cleaning chamber 36 can also be rinsed, for example, by supplying cleaning solution to the cleaning chamber 36 via the second connection piece 37 and simultaneously withdrawing it via the third connection piece 37'. The lower part 35 thus forms a cleaning adapter with which the dispensing nozzles 33 can be regularly cleaned during operation without the need for manual intervention by an operator.

[0074] The lower part 35 can be attached to the upper part 31 by means of webs not shown in detail in Fig. 3A. The lower part 35, which serves as a cleaning adapter, is optional and can also be omitted in modifications. Holes not shown in detail in Fig. 3A serve to attach the dispensing head in a dispensing device, with other dispensing heads or a support structure, or to another component such as a centrifuge, as will be explained in more detail below.

[0075] In a further embodiment, in which the dispensing nozzles 13 of each dispensing nozzle arrangement 12 are arranged in a row transverse to the direction of movement of the reaction vessel unit 1, the dispensing head 11 as a whole can also be oriented obliquely to the vertical. In particular, the inclination of the dispensing head 11 can correspond to an inclination of the dispensing nozzles 13 in space. Since in this case the dispensing nozzles 13 can run at least partially approximately parallel to the side walls of the dispensing head 11, such an embodiment allows the dispensing head 11 to be constructed narrower, since no or less thickness of the dispensing head 11 needs to be provided for the oblique extension of the dispensing nozzles 13 (Figure 12). It is always possible to arrange several dispensing heads 11 in the dispensing unit 10, which can be arranged one behind the other in the translation direction T (along x) in order to be able to fill several columns 92 of reaction vessels 2 simultaneously.This can result in a considerable time saving, particularly for reaction vessel units 1 with a large number of reaction vessels 2.

[0076] To further reduce the filling time for the entire reaction vessel unit 1, several dispensing heads 11 can be arranged one behind the other in the direction of movement of the reaction vessel unit 1 (Figure 12, only two dispensing heads 11 are shown there; for the reaction vessel unit 1 shown, it is advantageous if three dispensing heads 11 are present). Different sets of dispensing heads 11 can be provided for different types of reaction vessel units 1. Alternatively, several dispensing nozzle arrangements 12 can be provided on a dispensing head 11, staggered one behind the other in the direction of movement of the reaction vessel unit 1.

[0077] The dispensing head 11 can be supplied with a reagent from a reagent container 40 (Fig. 4). The reagent container 40 can be connected to a pump 42 via a suction line 41. The pump 42 can be connected to a shut-off or metering valve 41 via a connecting line 43. The metering valve 44 can be connected to the first connection plug 33 of the dispensing head 11 via a connecting line. The dispensing head 11 in this embodiment has three dispensing nozzle assemblies 12. The elements 40 to 45 form a supply unit 46 for the dispensing unit 10 with the dispensing head 11. The dispensing device 9 of this embodiment has the supply unit 46 and the dispensing unit 10.

[0078] The dispensing device 11 can also have multiple dispensing heads 11-1, 11-2, 11-3 (Fig. 5). For example, a first dispensing head 11-1 can have four first dispensing nozzle assemblies 12-1, each with seven dispensing nozzles 13, a second dispensing head 11-2 can have six second dispensing nozzle assemblies 12-1, each with four dispensing nozzles 13, and a third dispensing head 11-3 can have eight third dispensing nozzle assemblies 12-3, each with three dispensing nozzles 13. The dispensing nozzles 13 are assumed to be identical, but this is not mandatory. The dispensing heads 11-1, 11-2, 11-3 each have the same width in the transverse direction y and can be connected and aligned with one another by suitable means, in particular magnetic and / or form-locking means, such that their respective verticals 5' (cf. Fig.1A) are parallel to each other, so that the same and precise alignment to the vertical of a reaction vessel unit to be filled and moved below the dispensing heads 11-1, 11-2, 11-3 is always ensured.

[0079] The first dispensing head 11-1 can be connected to a first dosing valve 44-1 via a first connecting line 45-1, the second dispensing head 11-2 can be connected to a second dosing valve 44-2 via a second connecting line 45-2, and the third dispensing head 11-3 can be connected to a third dosing valve 44-3 via a third connecting line 45-3. The respective connecting lines 43-1, 43-2, 43-3, which lead to the dosing valves 44-1, 44-2, 44-3, can lead to respective pumps or to a single pump or other distribution unit.

[0080] Each of the dispensing heads 11-1, 11-2, 11-3 can be modularly constructed with a connection module 50, a terminal module 51, and dispensing modules 14-1, 14-2, or 14-3, each of which supports the dispensing nozzle arrangement 12-1, 12-2, or 12-3. The dispensing modules 14-1, 14-2, 14-3 can be dimensioned such that all dispensing heads 11-1, 11-2, 11-3 formed by suitable interconnection with a connection module 50 and a terminal module 51 each have the same dimension in the transverse direction y. The dispensing modules 14-1, 14-2, 14-3 can, but do not have to, have the same length in the longitudinal direction x. However, an equal length is advantageous for the design of a connection device and for the exact positioning to a reaction vessel unit to be filled and moved in the longitudinal direction x below the dispensing heads 11-1, 11-2, 11-3.The dispensing modules 14-1, 14-2, 14-3 are designed such that at least respective fluid chambers are aligned with one another to form a continuous fluid chamber 32; the same applies to optional cleaning chambers. The connection modules 50 can each have a connection piece 33 for connecting respective connecting lines 45-1, 45-2, 45-3, and the closing modules close off the fluid chamber 32. The connection module and the closing module can also have respective connection pieces 37, 37' of a cleaning module. The dispensing modules 14-1, 14-2, 14-3 can be connected and aligned with one another and optionally with the connection module 50 or the closing module 51 via suitable means, in particular magnetic and / or form-fitting means, such that their respective verticals 5' (cf. Fig.1A) are parallel to each other, so that the same and precise alignment to the vertical of a reaction vessel unit to be filled and moved below the dispensing heads 11-1, 11-2, 11-3 is always ensured.

[0081] In a further embodiment, five dispensing heads 11 / 1 to 11 / 5 are provided, each coupled to a connecting line 45 / 1 to 45 / 5 to supply the dispensing heads 11 with a liquid reagent, which is dispensed via the dispensing nozzles 13 (Figure 1). The dispensing nozzle assemblies 12 of the respective dispensing heads 11 / 1 to 11 / 5 can, but do not have to, all be designed differently. Rather, this embodiment illustrates the supply of different reagents from a common reagent supply 60 and individual reagent supplies 62, regardless of the type of dispensing nozzle assemblies 12.

[0082] The dispensing heads 11-2 to 11-5 are each connected to a pump module 61 (Figure 2), which can supply liquid reagents to the corresponding dispensing heads 11-2 to 11-5 via a valve, either from the common reagent reservoir 60 or from an individual reagent reservoir 62. The dispensing head 11-1 is connected only to the common reagent reservoir 60 via a connecting line, in which no pump module 61 is arranged, but only a pump 42 and a shut-off valve 44, in the conveying direction to the dispensing head 11-1.

[0083] Each individual reagent supply 62 has a single reagent reservoir 63. The lines between these reagent reservoirs 63 and the pump modules 61 have only connecting couplings and can be kept very short to minimize the volume they delimit. When replacing the reagent reservoirs 63 of the individual reagent supplies 62, these lines must be flushed, which means that the waste is greater the larger the volume of these lines.

[0084] The shared reagent supply 60 has a distribution arrangement 64 with five distribution valves 65, which distribute a provided reagent to the respective consumption points, such as the pump modules 61. With the distribution arrangement 64, a liquid reagent supplied at the inlet of the distribution arrangement 64 can be specifically and individually supplied to one or more of the dispensing heads 11 by enabling the corresponding distribution valves 65. The distribution arrangement 64 thus serves to distribute a specific liquid reagent to one or more of the dispensing heads 11.

[0085] The inlet of the distributor arrangement 64 is connected via a filter 66 to an outlet of a valve arrangement 67, which is connected on the inlet side to five reagent storage containers 69 by means of five valves 68. The reagent storage containers 69 are connected to the individual lines by a detachable coupling (not shown) so that the reagent storage containers can be exchanged. Thus, the reagents located in the various reagent storage containers 69 can be individually supplied to the respective dispensing heads 11 by means of the valve arrangement 67 and distributor arrangement 64. The number of reagent storage containers can vary; the number of valves 68 in the valve arrangement 67 must then be adjusted accordingly. The number of dispensing heads 11 can also vary; in this case, a separate distributor valve 65 would have to be provided for each dispensing head 11 in the distributor arrangement 64.

[0086] With the dispensing device 9 shown in Figure 6, a specific reagent from the individual reagent supply 62 can be supplied to each of the dispensing heads 11-2 to 11-5. These individual reagents can be very expensive reagents, such as reagents containing individually produced biological substances, such as antibodies. These reagents can be automatically dosed to the reaction vessels 2 in the reaction vessel unit 1 via the dispensing heads 11 and the corresponding dispensing nozzles 13 (see Figure 1A).

[0087] To avoid the risk of contamination of the dispensing nozzles 13, they can be regularly rinsed with a cleaning solution. Such a cleaning solution can be stored in one of the reagent reservoirs 69 of the common reagent reservoir 60. Such a cleaning solution is economical compared to the special reagents stored in the individual reagent reservoirs 63. Even if comparatively large quantities of reagent must be rinsed when changing the reagents in the common reagent reservoir 60 in order to safely exchange the reagent in the lines from the reagent reservoirs 69 via the valve assembly 67, the distributor assembly 64, the pump modules 61, and the dispensing heads 11, the economic losses are minimal.The shared reagent supply 60 allows the storage of several different reagents in larger quantities, which can be supplied to the individual dispensing heads as required.

[0088] The pump modules 61 (Figures 1, 2) thus allow the supply of individual reagents from the individual reagent supply 62 with very low waste and the supply of other reagents from the shared reagent supply 60, whereby different reagents can be flexibly selected. This allows the dispensing nozzles to be regularly cleaned with one or different cleaning solutions, enabling continuous operation without the need for manual intervention. Furthermore, the dispensing heads can be used to supply additional reagents from the shared reagent supply 60, such as buffer solutions or the like.

[0089] The dispensing device 9 of this embodiment, in which each dispensing head 11 is assigned a pump 42 which can be selectively connected to a common reagent supply and an individual reagent supply via a valve, is, apart from the arrangement of the dispensing nozzles 13, described in more detail in DE 9 2021 121 265.0, to whose disclosure content in this regard reference is made in full here.

[0090] The reaction vessels are automatically positioned precisely beneath the dispensing nozzles 13 by means of a translational drive. For this purpose, the translational drive can preferably comprise a displacement sensor that detects the displacement of a displacement element and thus the position of the reaction vessel unit 1. From this position, the position of the individual reaction vessels 2 of the reaction vessel unit 1 can be determined.

[0091] A further embodiment of the invention is a centrifuge 70 with a dispensing unit 10 and a loading and unloading device 80 for reaction vessel units 1 (Figs. 7, 8). The centrifuge 70 has a rotor 71, a housing 72, and a drive device 73 for rotating the rotor 71 about a rotation axis R.

[0092] The rotor 71 has at least one receiving area 74 for receiving a reaction vessel unit 1, which can be designed, for example, as a microtiter plate. Such a reaction vessel unit 1 can be inserted alone into a receiving area 74 of the rotor 71 or on a carrier unit 81. Preferably, a carrier unit 81 is used which has a coupling element 83 that can be coupled to a loading and unloading device 80. Such a loading and unloading device 80 is disclosed, for example, in WO 2017 / 125598 A1, which is incorporated herein by reference.

[0093] This loading and unloading device 80 has a rigid displacement rod 82, which can be releasably coupled at its free end to the reaction vessel unit 1 or a support unit 81 on which the reaction vessel unit 1 is located by means of a coupling element 83. The loading and unloading device 80 has a linear drive 85, with which the displacement rod 82 can be moved in its longitudinal direction such that the reaction vessel unit 1 can be moved from a loading position P1 to an unloading position P2, in which the reaction vessel unit 1 is located in the rotor 71. With the loading and unloading device 80, the reaction vessel unit 1 can also be moved from the unloading position P2 to the loading position P1.

[0094] The housing 72 defines a rotor chamber 75. In the present embodiment, the region of the housing 72 defining the rotor chamber 75 is formed from a lower shell 72a, an upper shell 72b, a front end wall 72c, and a rear end wall 72d. Further parts of the housing 72, which are not illustrated in the accompanying figures, adjoin the rear end wall 72d. A ball bearing is located in each of the front end wall 72c and the rear end wall 72d, in which a continuous shaft 76 of the rotor 71 is rotatably mounted. The center line of the shaft 76 forms the rotation axis R. The rotation axis R runs parallel to a base of the centrifuge 70 or dispensing device. In the present embodiment, the base is formed by the underside of the lower shell 72a or the feet 72e formed there (Figure 7).

[0095] The rear end of the shaft 76 is coupled to the drive device 73. The further part of the housing 72, which adjoins the rear end wall 72d, contains the drive device 73, the loading and unloading device 80, and a central control device (not shown) with which all components of the centrifuge 70 or the dispensing device 9 are controlled.

[0096] A balcony 77 is attached to the outside of the front end wall 72c, which serves to accommodate a reaction vessel unit 1. At the level of the balcony 77, a loading and unloading opening 78 is formed in the front end wall 72c, through which a reaction vessel unit 1 can be inserted into the rotor chamber 75 and pushed out again. The loading and unloading opening 78 is provided with a pivoting door so that the rotor chamber 75 can be closed. Instead of a pivoting door, a vertically or horizontally movable door can also be provided.

[0097] The loading and unloading device 80 can move the displacement rod 82 with its free end horizontally through the rotor chamber 75 through a through-opening 79 on the rear end wall 72d. The displacement rod 82 can be coupled to a reaction vessel unit 1 or to a carrier unit 81 using the coupling element 83. Preferably, a carrier unit 81 is provided which has a corresponding counter-coupling element 84. This allows any reaction vessel units 1 to be moved automatically from the balcony 77 through the loading and unloading opening 78 in the rotor chamber 75, wherein the rotor 71 is arranged with a receiving area 74 adjacent to the loading and unloading opening 78, so that the carrier unit 81 or the reaction vessel unit 1 is moved into the receiving area 74 of the rotor 71. The coupling between the displacement rod 82 and the carrier unit 81 orthe reaction vessel unit 1 can be released so that the carrier unit 81 or the reaction vessel unit 1 is freely movable in the rotor 71 and the rotor 71 can be rotated accordingly with this unit.

[0098] The coupling element 83 can, for example, be a magnetic coupling element or be designed as a mechanical hook element. The coupling element 83 can have a locking element that can engage with the counter-locking element provided on the reaction vessel unit 1 or on the carrier unit 81. At least the locking element or the counter-locking element can be elastically mounted, ensuring "smooth coupling" and decoupling, thereby preventing any possible back-and-forth sliding or impact of the reaction vessel unit 1. This prevents contents from possibly escaping from a reaction vessel 2 and either being lost or entering an adjacent reaction vessel 2. The coupling element 83 and the counter-coupling element 84 are designed such that the position of the reaction vessel unit 1 relative to the displacement rod 82 is always precisely and consistently defined in the coupled state.A locking mechanism may be provided to secure the coupled state.

[0099] By means of the sliding rod 82 of the loading and unloading device 80, the carrier unit or the reaction vessel unit 1 can be pushed from the receiving area 74 of the rotor 71 through the loading and unloading opening 78 back onto the balcony 77. The reaction vessel unit 1 can be removed from the balcony 77, for example, by means of a robot.

[0100] If the reaction vessel unit 1 is located on the balcony 77, it is arranged in the loading position P1, in which the centrifuge 70 can be provided with a reaction vessel unit 1 and thus loaded. If the reaction vessel unit 1 is located in the receiving area 74 of the rotor 71, the reaction vessel unit 1 is arranged in the unloading position P2, in which the reaction vessels of the reaction vessel unit 1 can be unloaded by rotating the rotor 71 about the rotation axis R.

[0101] The lower shell 72a has a groove 72f, which runs approximately parallel to the rotation axis R. The groove 27 extends from the rear end wall 72d into the area of ​​the front end wall 72c, wherein it is inclined or sloping towards the front (Figure 72). An outlet opening, into which the groove 27 opens, is formed on the front side of the lower shell 72a. A connection pin, to which a hose can be connected, is arranged at the outlet opening. The hose generally opens into a receiving container (not shown), which receives the liquids that are ejected from the reaction vessels of the reaction vessel unit 1 in the centrifuge 70. The container preferably has a ventilation opening, or the hose extends through the container with some play, so that liquid flowing out of the centrifuge through the hose 30 does not generate counterpressure in the container.

[0102] The housing 72 essentially corresponds to that of WO 2018 / 234420 A1, which is why reference is made to this document in its entirety.

[0103] On the front end wall 72c, in the area above the balcony 77, a dispensing unit 10 of a dispensing device 9 is arranged. The dispensing unit 10 has five dispensing heads 11, each with one or more dispensing nozzle arrangements 12 according to one of the preceding exemplary embodiments or variants. The dispensing heads 11 are preferably magnetically coupled to the dispensing unit 10 or a mounting body thereof and to one another. Furthermore, form-locking elements are preferably provided so that the position of the dispensing heads 11 is precisely aligned with respect to the dispensing module 9 and to one another. The form-locking elements can, for example, be pins and corresponding, precisely fitting recesses. However, the form-locking elements can also have other shapes, such as conical, in particular circular conical, projections with corresponding recesses.Such conical projections and corresponding recesses that are self-centering.

[0104] The dispensing heads 11 are oriented with their dispensing nozzle assemblies 12 facing downward, so that liquid reagents can be introduced from the dispensing nozzles 13 of the dispensing nozzle assemblies 12 into reaction vessels 2 of the reaction vessel unit 1, which are aligned with respect to the dispensing nozzles 13 or the dispensing heads 11 by means of the loading and unloading device 80. The loading and unloading device 80 thus serves as a positioning device for positioning the reaction vessel unit 1 with respect to the dispensing nozzle assemblies 12 or the dispensing heads 11.

[0105] The support frame 86 has a partition 86a attached to the rear wall 72d of the housing 72 of the centrifuge 70, and a guide rail 86b. The displacement rod 82 is mounted for axial displacement on the partition 86a and has a carriage 82a fixedly mounted on the displacement rod, which is mounted for axial displacement on the guide rail 86b. The linear drive 85 has a threaded rod 85a that is rotatable with respect to the support frame 86 but axially fixed. It extends into the formed displacement rod 82, is aligned with it, and engages a nut (not shown in detail) fixedly mounted on the carriage 82a. By rotating the threaded rod 85a, the nut and thus the displacement rod 82 can be moved in the axial direction.To achieve particularly high accuracy, a ball screw can be used, which is enclosed by a nut in which balls rotate in a closed system.

[0106] The position of the displacement rod 82 can be detected by means of a detection device 87 attached to a support frame 86 of the loading and unloading device 80. For this purpose, the detection device 87 is configured to emit a laser beam L perpendicular to the translation direction T. This laser beam is reflected via a first mirror 88, which is fixedly attached to the support frame 86 and oriented at a 45° angle to the laser beam L and the translation direction T, onto a second mirror 89, which is fixedly attached to the displacement rod 82 via a bracket 82b fixedly attached to the carriage 82a and oriented perpendicular to the translation direction T. From there, it is reflected back and guided via the first mirror 88 back into the detection device 87, where it falls onto a sensor (not shown in detail) provided there.Alternatively, instead of the second mirror 89, a sensor can be mounted on the bracket 82b, which receives the laser beam L and is signal-connected to the detection device 87. From the travel time of the laser beam L, the path of the laser beam L and thus the position of the displacement rod 82 relative to the support frame 86 can be precisely determined in a conventional manner. This also enables a precise determination of the position of the support unit 81 and thus of the reaction vessel unit 1 relative to the centrifuge 70 and thus also relative to the dispensing unit 10 attached to the centrifuge 70. This allows each transverse row of reaction vessels 2 of the reaction vessel unit 1 to be precisely positioned and precisely filled under the dispensing nozzles 13 of the dispensing nozzle unit(s) 12 of each dispensing head 11.

[0107] An optical detection device (not shown in detail) can also be arranged near or on the dispensing unit. A large number of experiments are evaluated and analyzed by detecting optical signals. The methods for optical detection can be carried out in different ways. For example, optical signals can be detected by generating fluorescence, by light, or the like. Some reactions used to generate optical signals proceed very quickly, which is why direct measurement after addition of the corresponding reagents may be desirable. For optical detection, a detection device is preferably provided which comprises at least one optical sensor (= a camera) and preferably a light source. The optical sensor can be designed as a line sensor or as an area sensor. When using a color camera, the color of the contents of the reaction vessels can also be analyzed.This represents a spectral analysis of the sample.

[0108] The optical detection device is preferably directed approximately vertically downwards, so that the contents of reaction vessels open at the top can be detected. The viewing direction can be exactly vertical or slightly inclined relative to the vertical. Furthermore, the optical detection device is preferably designed and arranged such that it can scan the reaction vessel unit in a line pattern adjacent to the rotor chamber within the movement range of the reaction vessel unit, with one scanning line being aligned approximately perpendicular to the movement direction of the reaction vessel unit or carrier unit.

[0109] The optical detection unit can comprise one or more light sources that can enable the illumination of reaction vessels on the opposite side of the movement path of a reaction vessel unit. The optical detection device can also comprise a color sensor or a color camera, with which the color of the contents of the reaction vessels in the reaction vessel unit can be detected.

[0110] The optical detection device is preferably designed to detect the fill level of the individual reaction vessels. The fill level can be scanned, for example, using an optical triangulation method, in particular a laser triangulation method. Other methods for optical 3D scanning can also be provided, such as stereoscopy, deflectometry, or white light interferometry. The detection of the fill level can advantageously be used to control the dispensing device 9.

[0111] The optical detection device is preferably arranged parallel and adjacent to a dispensing head 11, so that during or immediately after dispensing, the individual reaction vessels 2, into which a solution is supplied via the dispensing nozzles 13, can be optically scanned. This allows the filling of the individual reaction vessels 2 to be precisely recorded and taken into account during further handling and processing. For example, the concentration of certain compositions may depend on the amount of solvent to be dispensed; different concentrations are generally permissible but must be known. By detecting the fill level, the concentration can then be determined, and this can be taken into account in the subsequent evaluation.

[0112] With an appropriate evaluation device (not shown in detail), the signals obtained with the optical detection device can be automatically evaluated according to the following parameters:

[0113] - colour of the contents of at least one reaction vessel of the reaction vessel unit,

[0114] - Fill level of at least one reaction vessel of the reaction vessel unit,

[0115] - Position of the reaction vessel unit,

[0116] - Type of reaction vessel unit.

[0117] The values ​​of these parameters thus recorded can be used to automatically control processes for processing samples contained in the reaction vessels 2 of the reaction vessel units 1. Thus, the following steps can be automatically controlled and executed once or repeatedly in any order:

[0118] - Dispensing

[0119] - Spectral analysis

[0120] - Clean

[0121] Furthermore, a control device can be provided and configured to control the translational drive 85 in order to move and / or position the reaction vessel unit 1 based on a detected position and / or to control actuating elements of the dispensing nozzles 13 in order to fill the reaction vessels 2 of the reaction vessel unit 1 based on fixed specifications and / or detected parameters, wherein the control signal describes the position of the displacement rod 82 with an accuracy of at least 0.2 mm or at least 0.70 mm. Such accuracy can be achieved with the previously described translational drive 85 with a rigid displacement rod 82. The positioning accuracy is important for the present dispensing device 9 due to the oblique beam alignment so that the beam strikes the peripheral wall at the correct location (height).Optionally, a three-dimensional scan of the space within the detection range of the optical detection device can be performed, and the presence and, if applicable, the type or geometry of a reaction vessel unit 1 located there can be recorded. For the purpose of this assignment, a model or CAD drawing of various reaction vessel units 1 can be stored in a database. The type of reaction vessel unit 1 can also be determined by scanning a barcode or RFID label or other identification features present on the reaction vessel unit 1.

[0122] A method for filling at least one reaction vessel 2 of a reaction vessel unit 1 by means of a dispensing device 9 can be carried out in such a way that the reaction vessel unit 1 is positioned below the dispensing nozzles 13 of a dispensing unit 10 of the dispensing device 9 in order to fill at least one reaction vessel 2 of the reaction vessel unit 1, wherein a dispensing jet 16 or dispensing jets 16 of at least one of dispensing nozzles 13 of the dispensing device 9 impinge obliquely, preferably in an upper half, in particular in an upper third, onto a peripheral wall 6 of the reaction vessel 2.

[0123] The method can be designed such that the dispensing jet 16 or the dispensing jets 16 form a jet pattern 17 which extends in the circumferential direction u of the circumferential wall 6 of the reaction vessel 2.

[0124] The method can provide for the reaction vessel unit 1 to be positioned below the dispensing unit 10 with an accuracy of at most 0.2 mm or at most 0.70 mm, preferably by a loading and unloading device 80 with a translation drive 85 belonging to a centrifuge 70 on which the dispensing unit 10 is arranged. During the method, the dispensing nozzles 13 of the dispensing device 9 can be supplied with fluid in such a way that the fluid flows off the peripheral wall 6 without rebounding, with a flow rate per dispensing nozzle 13 preferably being 10 to 400 pl / s. It is understood that the range of the achievable volume flow Q per dispensing nozzle 13 is also predetermined by the design of the supply unit 46.

[0125] In current designs, for example, at maximum pressure, a volume flow of approximately 170 pl / s per dispensing nozzle 13 can be provided. Correspondingly, at minimum pressure, a volume flow of approximately 25% of the maximum rate, or approximately 40 pl / s per dispensing nozzle 13, can be provided. A reaction vessel unit 1 with, for example, six (2x3) reaction vessels 2 in microtiter plate format is typically filled with 3-6 ml per reaction vessel 2. With a volume flow of 40 pl / s and only one dispensing nozzle 13 per reaction vessel 2 (i.e., two dispensing nozzles 13 in a row perpendicular to the direction of movement of the reaction vessel unit 1), filling 6 ml would take 2.5 minutes. Filling the entire reaction vessel unit 1 in three steps, each of which fills two reaction vessels 2 simultaneously, would then take 7.5 minutes. This is too long for many applications.For example, a filling rate of no more than 1 minute, or no more than 0.5 minutes, or no more than 10 seconds per reaction vessel unit might be desirable. This would be possible by increasing the flow rate. However, with a constant nozzle cross-section, this also increases the flow velocity in the dispensing jet or the jet speed, and thus the risk of a reagent in the reaction vessel being washed out, disrupted, or punctured, or of the dispensing liquid splashing or spilling over. This can be counteracted by increasing the number of dispensing nozzles per reaction vessel or by increasing the nozzle cross-section.

[0126] Dispensing nozzles with a round cross-section can, for example, be designed as tubes that are inserted into the nozzle head. Such tubes typically have an inner diameter D of 0.25 to 0.5 mm. Inner diameters D of 0.15 to 0.7 mm are also available. The flow cross-section A is determined from the relationship

[0127] A = nD 2 / 4

[0128] The flow velocity v results from the volume flow Q from the relationship v = Q / A

[0129] In the following Table 1, for the above specified inner diameters d in mm and the corresponding flow cross-section A in mm 2 and selected volume flows Q in pl / s the flow velocity in m / s:

[0130] Table 1: Flow velocity v in m / s

[0131] The relationships given above can also be represented as a diagram in the form of a family of curves of the flow velocity v as a function of the volume flow Q with the flow cross-section A as a parameter, or as a function of the flow cross-section A with the volume flow Q as a parameter. If a round nozzle is used as the dispensing nozzle 13, the inner diameter D, for example, can also be used as an argument or parameter instead of the flow cross-section A.

[0132] A tolerable or maximum flow velocity v max, which roughly corresponds to the impact velocity of the dispensing jet 16, depends on a variety of factors, such as the angle of impact on the peripheral wall 6, the experimental setup, the initial filling of the reaction vessel 2 with a reagent or other target substance, the fill level of the reaction vessel 2 with dispensing liquid, the accuracy requirements, the cross-section of the reaction vessel, or other factors. The shape and cross-section of the dispensing jet 16 can also influence the maximum flow velocity v max The maximum flow velocity v max can be determined or verified based on empirical values ​​and / or fluid dynamics considerations and / or experimentally.

[0133] With the maximum flow velocity v maxSuitable pairings for the nozzle cross-section A or the nozzle inner diameter D and for the volume flow Q can be taken from the table, interpolated if necessary, or read from a corresponding diagram (Figures 11A, 11A).

[0134] With a given volume flow per dispensing nozzle 13 and a predetermined maximum filling time for a reaction vessel 2 or a reaction vessel unit 1, the required minimum number of dispensing nozzles 13 per reaction vessel 2 can also be determined for each format of the reaction vessel unit 1. For example, a reaction vessel unit 1 has X columns 92 and Y rows 91 (see Fig. 9) and thus a number n = X - Y of reaction vessels 2. Each reaction vessel 2 has a volume Vw, which can be a maximum, regular, or experiment-specific filling volume (the index "W" stands for "well"). The filling time for a reaction vessel 2 is tw = Vw / Q.

[0135] The total filling time for a reaction vessel unit 1 is t P = X • t w = X • V w / V assuming that the reaction vessels 2 of a column 92 are filled simultaneously (the index "P" stands for "plate").

[0136] With a maximum filling time t max the minimum number of required dispensing nozzles is 13 with the respective flow cross-section A

[0137] Nmin = tw / tmax, if the maximum filling time t max refers to a reaction vessel 2, or

[0138] Nmin = tp / tmax, if the maximum filling time t m ax refers to the entire reaction vessel unit 1.

[0139] Of course, instead of a minimum number Nmin for the dispensing nozzles 13 with a fixed flow cross-section A, a minimum cross-sectional area for the dispensing nozzles 13 as a whole can also be determined. This minimum cross-sectional area can also be realized by other cross-sectional shapes, such as slot nozzles according to Figure 2B or 2D, and / or correspondingly adapted flow cross-sections of the individual dispensing nozzles 13.

[0140] Conversely, with a specified value for the maximum filling time t m ax is the required volume flow Qmin for a specific filling volume V of a specific reaction vessel 2 from

[0141] Qmin = V / tmax can be determined. Then, with a given value for the maximum flow velocity Vmax, the required total flow cross-section A ges ,min a dispensing nozzle arrangement 17 for the reaction vessel 2 under consideration

[0142] Ages.min= Qmin / Vmax can be determined. Using this value, suitable nozzle configurations, shapes, groupings, and orientations of a dispensing nozzle arrangement 12 can be designed, which also fit into the available space corresponding to the size of the reaction vessel 2 under consideration. Furthermore, the supply unit 46 with its containers, pumps, valves, lines, and other elements can be designed with regard to the required volume flow for all dispensing nozzles 13 of a dispensing unit 10, as well as with regard to the system pressure. The required system pressure can be calculated, for example, from Bernoulli's energy equation, which, in its simplest form, applies to frictionless, incompressible fluids.

[0143] E = v 2 / 2 + p / p + gz, where E is the total energy, v is the local velocity of a streamer, p is the local pressure, p is the density assumed to be constant, g is the gravitational acceleration, and z is the local height. Neglecting vertical flow components and the initial velocity, the required system pressure is roughly calculated as p = p V 2 max / 2, whereby safety margins for pressure losses and dynamic effects must also be taken into account. If several nozzle configurations are included, for example for different reaction vessel units 1 with different numbers and filling volumes of their reaction vessels 2, which are to be served with the dispensing device 9, upper and lower limits for the system pressure p can be determined and the supply unit 46 can be designed accordingly.

[0144] The volume flow can also be specified as a volume flow per row of simultaneously filled reaction vessels in a reaction vessel unit. The nozzle cross-section and / or the number of dispensing nozzles in a row can then be dimensioned so that the flow velocity does not exceed a specified maximum value.

[0145] The method described herein can be modified in many ways or combined with known methods. For example, it is possible to vary the flow velocity during a filling process. In any case, it is possible that the flow velocity is not completely constant during a filling process, but rather has an initial region with increasing flow velocity, a core region with a roughly constant flow velocity, and a decay region with decreasing flow velocity. It is also conceivable to vary the position and / or orientation of the dispensing head 11 in height during a filling process. The flow velocity can also be varied depending on the height of the dispensing head 11 (and thus depending on the height of the nozzle openings 15).For example, it is conceivable to start with a high flow rate when the dispensing head 11 is low, then raise the dispensing head 11 and reduce the flow rate as the height of the dispensing head 11 increases, or conversely, to start with a low flow rate and then increase the flow rate as the height of the dispensing head 11 increases. It is understood that the dispensing device 9, whose dispensing unit 10 is attached to the centrifuge 70, can be any dispensing device 9 covered by the scope of the invention, in particular the exemplary embodiments and variants explained in this description. Any dispensing unit 9 and / or supply unit 46 described herein can be used in any dispensing device 9 described herein. Any dispensing head 11 described herein can be used in any dispensing unit 9 described herein.Each dispensing head 11 described herein may include any of the dispensing nozzle assemblies 12 described herein. Each dispensing nozzle assembly 12 described herein may be used in any method described herein.

[0146] The invention is defined by the appended claims. The independent claims relate to various aspects of the invention. The dependent claims relate to embodiments of the invention or an aspect of the invention. Each combination of features described herein may constitute an independent invention insofar as it solves a technical problem or contributes to solving the problem of the invention.

[0147] List of reference symbols and formula symbols

[0148] Reaction vessel unit 41 suction line

[0149] Reaction vessel 42 pump

[0150] Opening 43 connecting line

[0151] Opening level 44 Dosing valve, 5' Vertical 45 Connection line

[0152] Peripheral wall 46 supply unit

[0153] Floor 50 connection module

[0154] Edge 51 final module

[0155] Dispensing device 60 common reagent reservoir 0 Dispensing unit 61 Pump module 1 Dispensing head 62 individual reagent reservoir 2 Dispensing nozzle assembly 63 Reagent reservoir 3 Dispensing nozzle 64 Distributor assembly 4 Dispensing module 65 Distributor valve 5 Nozzle orifice 66 Filter 6 Dispensing jet 67 Valve assembly 7 Jet pattern 68 Valve 8 Circumference line 69 Reagent reservoir 9 Fluid film 70 Centrifuge 0 Tubular body (shaft) 71 Rotor 1 Flow cross-section 72 Housing 2 Flat cone body 72a Lower bowl 3 Stem part (shaft) 72b Upper bowl 4 Flared part 72c Front end wall 0 Bottom 72d Rear end wall 1 Upper part 72e Stand 2 Fluid chamber 72f Gutter 3 First connection piece 73 Drive unit 4 Sealing plug 74 Receptacle 5 Lower part 75 Rotor chamber 6 Cleaning chamber 76 Shaft 7 Second connection piece 77 Balcony 7' Third connection piece 78 Loading and unloading opening 8 Cleaning channel 79 Through opening 9Cleaning opening 80 Loading and unloading device 0 Reagent container 81 Carrier unit 82 Sliding bar b Width

[0156] 82a Slide d Distance

[0157] 82b bracket g gravitational acceleration

[0158] 83 Coupling element I Length

[0159] 84 negative feedback element n number of reaction vessels

[0160] 85 Translational drive p pressure

[0161] 85a Threaded rod s helix angle

[0162] 86 support frame t time

[0163] 86a Partition wall and circumferential direction

[0164] 86b Guide rail v speed

[0165] 87 Detection device w opening width

[0166] 88 first mirror x longitudinal direction

[0167] 89 second mirror y transverse direction, width direction

[0168] 90 Basic body z vertical direction, height

[0169] 91 row

[0170] 92 Column A Flow cross-section

[0171] D (inner) diameter

[0172] E Energy

[0173] L laser beam

[0174] N Number of dispensing nozzles per reaction vessel

[0175] Q. Volume flow

[0176] R rotation axis

[0177] T Translation direction

[0178] V Volume

[0179] X number of columns

[0180] Y Number of rows p Density

[0181] The above list is an integral part of the description.

Claims

Patent claims 1. Dispensing device (9), which comprises: a dispensing unit (10) with at least one dispensing head (11) which has at least one dispensing nozzle arrangement (12) for filling at least one reaction vessel (2) of a reaction vessel unit (1), which is translationally movable and positionable relative to the dispensing unit (10), wherein the reaction vessels (2) are approximately trough-shaped with approximately vertical peripheral walls (6), wherein the dispensing nozzle arrangement (12) is designed such that it is designed to emit one or more dispensing jets (16) which run obliquely with respect to the vertical (5, 5') so that they can be directed obliquely against one of the peripheral walls (6) of one of the reaction vessels (2), characterized in that the one or more dispensing jets (16) have a jet pattern extending in the circumferential direction (u) of the peripheral wall (6). (17).

2. Dispensing device (9) according to claim 1, characterized in that the dispensing nozzle arrangement (12) has a plurality of dispensing nozzles (13) which are arranged in a straight or curved line or concentrically or axially symmetrically around a vertical axis (5'), so that the dispensing jets (16) can be emitted distributed over the circumference of the peripheral wall (6) of one of the reaction vessels (2).

3. Dispensing device (9) according to claim 1 or 2, characterized in that at least one, preferably several, of the dispensing nozzles (13) of the dispensing nozzle arrangement (12) are designed to emit a round jet, and preferably have an inner diameter of at least about 0.15 or 0.2 or 0.25 mm and / or of at most about 0.3 or 0.5 or 0.7 mm.

4. Dispensing device (9) according to one of the preceding claims, characterized in that the dispensing nozzle arrangement (12) has at least one slot-like dispensing nozzle (13) which is designed to emit a dispensing jet (16) of elongated, straight or curved cross-section.

5. Dispensing device (9) according to one of the preceding claims, characterized in that for each reaction vessel (2) of the reaction vessel unit (1) at least one, preferably exactly one, dispensing nozzle arrangement (12) is provided in a row (92) or in several rows (92) transverse to the direction of movement of the reaction vessel unit (1).

6. Dispensing device (9) according to one of the preceding claims, characterized in that the dispensing nozzles (13) of the dispensing nozzle arrangement (12) are aligned to the vertical (5') in such a way that the dispensing jets (16) of each dispensing nozzle (13) strike the peripheral wall (6) of a reaction vessel (2) of the reaction vessel unit (1) at the same angle or at different, in particular alternating, angles and / or at the same height or at different, in particular alternating, heights.

7. Dispensing device (9) according to one of the preceding claims, characterized in that the dispensing nozzle arrangement (12) or several dispensing nozzles (13) of the dispensing nozzle arrangement (12) are formed on a separate or common nozzle body with a specially assigned fluid connection.

8. Dispensing device (9) according to one of the preceding claims, characterized in that the dispensing nozzles (13) have tubular shafts (20, 23) which are inserted into bores on the dispensing head (11).

9. Dispensing device (9) according to one of the preceding claims, characterized in that the dispensing nozzles (13) are formed by openings on the dispensing head (11).

10. Dispensing device (9) according to one of the preceding claims, characterized in that the dispensing unit (10) has a plurality of dispensing heads (11) which are detachably coupled to the dispensing device (9) or to one another, preferably by means of a magnetic coupling and / or by means of a screwable connection and / or by means of a detachable locking connection, in particular in a form-fitting manner, and / or are arranged to be interchangeable.

11. Dispensing device (9) according to one of the preceding claims, characterized in that a collecting basin for collecting fluids dispensed with the dispensing nozzles (13) is arranged in the region below the dispensing head (11) or the dispensing heads (11).

12. Dispensing device (9) according to one of the preceding claims, characterized in that a tempering device is provided for tempering a fluid to be supplied to the dispensing head (11), wherein the tempering device is preferably designed for tempering a section of a fluid line leading to the dispensing head (11) and / or for tempering a pump or valve provided on the fluid line.

13. Dispensing device (9) according to one of the preceding claims, characterized in that a translational drive (85) is provided which is designed to move and position the reaction vessel unit (1) translationally along the dispensing unit (10) so that the reaction vessel unit (1) can be arranged under the dispensing nozzles (13) of the dispensing unit (10) in order to fill at least one reaction vessel (2) of the reaction vessel unit (1), wherein the translational drive has a rigid displacement rod (82) for positioning a reaction vessel unit and a linear drive for moving the displacement rod (82).

14. Dispensing device (9) according to one of the preceding claims, characterized in that the dispensing unit (10) and / or at least one of the dispensing heads (11) is or can be detachably, in particular positively, coupled to a wall (72c) of a housing (72) of a centrifuge (70), wherein the wall of the housing of the centrifuge (70) is designed near an opening (78) for loading and unloading a reaction vessel unit (1) for coupling the dispensing unit (10) and / or one of the dispensing heads (11), wherein the centrifuge (70) preferably has a rotor (71) arranged and rotatably mounted in a rotor chamber (75), which rotor has a receiving area (74) for receiving the reaction vessel unit (1).

15. Dispensing device (9) according to claim 14, as far as dependent on claim 13, characterized in that the translation drive (85) is realized by a loading and unloading device (80) of a centrifuge (70) on which the dispensing unit (10) is provided, wherein the loading and unloading device (80) is designed to position the reaction vessel unit (1) between a loading position (PI), in which the reaction vessel unit (1) is arranged outside the centrifuge (70), and an unloading position (P2), in which the reaction vessel unit is arranged inside the centrifuge (70), and wherein the loading position (PI) comprises one or more dispensing positions in which the reaction vessel unit (1) is arranged below the dispensing unit (10) for filling.

16. Dispensing device (9) according to claim 15, characterized in that the loading and unloading device (80) has the displacement rod (82) which is pulled out of the region of the rotor chamber (75) in the unloading position (P2) and extends through the rotor (71) in the rotor chamber (75) in the loading position (PI).

17. Dispensing device (9) according to one of the preceding claims, characterized in that a detection device (87) is provided for determining the position of the reaction vessel unit (1) or of a part of a translation drive (85) moved with the reaction vessel unit (1) in the direction of movement (T).

18. Dispensing device (9) according to one of the preceding claims, characterized in that an optical detection unit is provided, which is preferably designed and arranged such that it can scan the reaction vessel unit (1) adjacent to the dispensing unit (10) in the movement range of the reaction vessel unit (1), and which in particular has a line camera which is designed and arranged to scan reaction vessel units (1) in a line-like manner, wherein a scanning line is aligned approximately at right angles to the direction of movement of the reaction vessel unit (1), and / or a color camera which is designed and arranged to spectrally scan a reaction vessel unit (1) and / or is designed and arranged for 3D scanning of the reaction vessel unit (1).

19. Dispensing device (9) according to one of the preceding claims, characterized in that a control device is provided and designed to control a / the translation drive (85) in order to move and / or position the reaction vessel unit (1) on the basis of a detected position and / or to control actuating elements of the dispensing nozzles (13) in order to fill the reaction vessels (2) of the reaction vessel unit (1) on the basis of fixed specifications and / or detected parameters, wherein the control signal describes the position of the displacement rod (82) with an accuracy of at least 0.2 mm or at least 0.1 mm.

20. Dispensing device (9) according to claim 19, characterized in that the control device is designed to control the actuating elements of the dispensing nozzles (13) such that a flow velocity at the outlet end of each dispensing nozzle (13) is at most 1 m / s or at most 0.85 m / s or at most 0.7 m / s or at most 0.55 m / s or at most 0.4 m / s or at most 0.25 m / s or at most 0.1 m / s.

21. Method for filling at least one reaction vessel (2) of a reaction vessel unit (1) by means of a dispensing device (9) designed in particular according to one of claims 1-20, such that the reaction vessel unit (1) is positioned under dispensing nozzles (13) of a dispensing unit (10) of the dispensing device (9) in order to fill at least one reaction vessel (2) of the reaction vessel unit (1), characterized in that the reaction vessel unit (1) is positioned such that a dispensing jet (16) or dispensing jets (16) of at least one of dispensing nozzles (13) of the dispensing device (9) strikes a peripheral wall (6) of the reaction vessel (2) obliquely, preferably in an upper half, in particular in an upper third.

22. Method according to claim 21, characterized in that the dispensing jet (16) or the dispensing jets (16) form a jet pattern (17) which extends in the circumferential direction (u) of the circumferential wall (6) of the reaction vessel (2).

23. Method according to claim 21 or 22, characterized in that a volume flow per row of simultaneously filled reaction vessels in a reaction vessel unit is at least 0.8 ml / s or 1.0 ml / s or 1.2 ml / s or 1.5 ml / s or 2 ml / s.

24. Method according to one of claims 21 to 29, characterized in that a flow velocity at the outlet end of each dispensing nozzle (13) is at most 2 m / s or at most 1 m / s or at most 0.85 m / s or at most 0.7 m / s or at most 0.55 m / s or at most 0.4 m / s or at most 0.25 m / s or at most 0.1 m / s or at most 0.05 m / s or at most 0.01 m / s.

Images