WO2008055613A1

WO2008055613A1 - Fluidic device, and method for the operation thereof

Info

Publication number: WO2008055613A1
Application number: PCT/EP2007/009468
Authority: WO
Inventors: Erik HÖHNE; Nenad Gajovic-Eichelmann
Original assignee: Fraunhofer-Gesellschaft zur Förderung der angewandten Forschung e.V.
Priority date: 2006-11-10
Filing date: 2007-10-31
Publication date: 2008-05-15
Also published as: EP2087362A1; DE102006053096A1

Abstract

Disclosed is a fluidic device (100) comprising a liquid duct (10), the first end (11) of which forms a dosing mechanism (12) designed to receive or discharge a system liquid in a dosing operating zone (20), and the second end (13) of which is provided with a fluid connection (14) designed to receive a cleaning liquid, and a pump mechanism (30) for actuating the dosing mechanism (12). The pump mechanism (30) is arranged between the first and second end (11, 13) of the liquid duct (10) and is designed to conduct liquid in the liquid duct (10) in a selectable direction of travel. Also disclosed is a method for operating said fluidic device.

Description

Fluidikeinrichtung and method for their operation

The invention relates to a Fluidikeinrichtung, which is adapted for handling liquid samples, in particular a Fluidikeinrichtung with the features of the preamble of claim 1, and a method for their operation.

Fluidics techniques have numerous applications, e.g. As in clinical diagnostics, food and environmental analysis and biotechnology research, operations such. Aspiration and dosing of liquids, mixing of various liquids, washing of solid phase reagents or serial dilution steps. In particular, there is an interest in automatic techniques, e.g. As automated immunoassays or automated clinical chemical assays. Typical requirements for fluidic techniques, in particular in analytical instruments and in diagnostics, are the precision in all fluidic operations and the sample throughput with regard to the cleaning and possibly sterilization of the devices used, in particular the flow paths (fluidic paths).

Fluidic techniques known in the art are generally based on the combination of pumps, valves and fluid lines. The pumps include z. As piston pumps or syringe pumps, however, have the disadvantage that typically at least a 3-way valve is required, which connects the pump with the desired fluid lines. In addition to increased complexity, the use of valves generally means an increased risk of contamination. This disadvantage is in complex fluid operations, eg. B. Operations with at least two liquids (eg system solution and Wash solution), particularly critical, as these typically require at least one valve that can switch between the different fluidic pathways. Fully automatic devices, eg. B. for performing immunoanalytical tests have to handle several different operations and therefore often require more than one pump and more than one valve.

For the implementation of fluidic techniques, automatic gantry robots are known in practice, which contain a plurality of diluters in a three-dimensionally constructed rail system, wherein valves are provided for switching between different system liquids and samples are taken or delivered with a dispensing needle mounted on a robot arm. Conventional portal robots are typically designed for a wide range of applications. However, they have the following disadvantages. In general, the fluidic paths are relatively long due to the geometrical dimensions of the robot (distance storage vessel to dispensing needle), without any requirement for the test to be carried out. However, long fluid pathways are difficult to clean. Furthermore, they cause a high consumption of system fluids. Furthermore, such robots are expensive and maintenance-intensive and therefore in particular unsuitable for use in specialized consumer equipment. The conventional fluidic techniques generally have disadvantages in terms of cleaning, especially in fully automatic cleaning processes. Liquid-filled system liquid tanks and hose lines may become contaminated when exposed to prolonged use. B. due to stagnant liquid in the system.

US Pat. No. 4,422,151 describes a valve-free fluidic device with a system fluid tank and a pump, in which samples are addressed sequentially by a 3-axis robotic arm with a dispensing needle mounted. The fluidic device has the disadvantage that only cleaning with system solution (eg water) is possible. However, the system solution tank, which must always be filled with liquid (eg water), is a source of contamination during extended periods of standstill. It must be ensured during operation that no samples can get into the system solution tank. A particular disadvantage is that the system solution tank can not be sterilized during operation.

In US 3,192,968 a further fluidic device is described in which a plurality of system solutions can be switched with a switching valve. Although this allows washing steps, it has the disadvantage that even two liquid tanks are permanently filled with liquid and must be protected against contamination, and are expensive to clean after prolonged standstill. A 3/2-way valve is another source of contamination, as sample remains (eg blood) can remain in the inevitable dead volumes. In addition, the effort for controlling and regulating the system increases since the switching of the valve must be synchronized with the fluid operations.

Other automatic fluidic devices z. No. 5,206,568 or US 4,952,518 comprise a gantry robot and a plurality of separate metering devices which are controlled in parallel. This allows parallel dosing, dilution or washing steps to be carried out. However, due to the group of metering devices, the fluidic device has relatively large dimensions. Furthermore, according to US Pat. No. 5,206,568, positions of the working space are occupied by a washing liquid container, which further increases the dimensions of the system ("footprint", footprint). In the simple variant, without a valve, all eight channels can be connected to the system fluid tank with a passive 8: 1 distributor. A second system temflüssigkeit (eg washing liquid) can thus not be used, but must be presented as a sample. Furthermore, it is disadvantageous that only a limited volume of washing liquid can be aspirated without entering the diul wells or the system liquid tank. The liquid must be released through the tip again, it must be approached to a waste position. During intensive washing processes, repeat this step several times, which increases the processing time.

The invention has for its object to provide an improved Fluidikeinrichtung and an improved method for operating a Fluidikeinrichtung with which the disadvantages of the conventional fluidic techniques are overcome.

This object is achieved by a Fluidikeinrichtung and a method for operating a Fluidikeinrichtung with the features of the independent claims. Advantageous embodiments and applications of the invention will become apparent from the dependent claims.

With regard to the apparatus, the invention is based on the general technical teaching of a fluidic device with a fluid line extending between a metering device for receiving or dispensing at least one system fluid in a metering working area and a fluid port for receiving a cleaning fluid in a cleaning work area, and to be provided with a pump device for actuating the metering device, wherein the pump device is arranged on the liquid line and adapted for uninterrupted fluid delivery in the liquid line with changing conveying direction. For receiving or delivering the at least one system Liquid and for cleaning, a single, continuous liquid line is used according to the invention. The liquid line forms a branch-free fluidic path between the fluid connection and the metering device.

The term "system liquid" here refers to any liquid which fulfills a system function and / or represents a sample. The system liquid comprises z. B. Test solutions, buffer solutions or wash solutions, which are to be supplied to the samples in the sample vessels, depending on the specific fluidic operation. For the flexible performance of competitive or two-sided ("sandwich") immunoassays, at least two different system fluids may be used alternately (e.g., dilution buffer for sample dilution and wash fluid for rinsing). The term "system liquid" here also includes sample liquids such. As solutions, dispersions or suspensions containing certain sample molecules, eg. As proteins, or biological samples, for. For example, cells, cell groups or cell components.

The invention is characterized in that it is possible to work with a system liquid, which if necessary exclusively comprises a sample liquid, or with a plurality of different system liquids. Only with one sample liquid, ie without an additional system liquid, can precise aspirating and dosing step processes of sample liquids be performed, mixtures of two or more sample liquids, as well as the mixing of a sample or mixture of samples by blowing in air. In addition, dilution and serial dilution operations can be performed with a system fluid, and solid, eg, solid phase reagents (especially powdered samples) can be dissolved in a defined volume. With two In addition, system fluids can be continuously washed and decontaminated throughout the fluidic path, with the wastes collected in a separate waste container to eliminate system solution contamination and fluidic pathways. During the washing or rinsing and decontamination process, continuous conveying takes place in one direction only to prevent sample carryover and deposits.

The term "metering work area" here refers to the spatial area in which the metering device can be moved for dispensing or receiving system fluid. The term "cleaning work area" here refers to the spatial area in which the fluid connection can be moved. The dosing and cleaning work areas are partially overlapped.

Advantageously, the pump device fulfills a dual function. First, the pump means may be operated to receive or dispense at least one system fluid with the metering device. Secondly, the pump device can be operated such that the cleaning fluid is taken up by the fluid connection into the fluid line and flushed by the metering device or that the entire fluid line is ventilated. Between the two operating modes, in particular between the metering mode with the operation of the metering device and the cleaning mode with the cleaning of the metering device can be switched exclusively by the adjustment of the conveying direction and delivery time (delivery volume) of the pump device. According to the invention, a valve-free fluidic path is thus provided between the metering device and the fluid connection. Advantageously, in particular the use of 3/2-way valves and thus potential fouling stoves are avoided. The fluidic device according to the invention is characterized by a simple and efficient, hygienic cleaning and possibly sterilization of the fluidic path and therefore simplifies automatic process sequences. Preferred applications therefore result in the analysis and processing of complex liquids in analytical-chemical instruments, eg. For the purpose of completely cleaning the fluid line of sample residues, continuous one-way purging is allowed, with the cleaning and system liquids being continuously conveyed to a waste position can. The fluidic device, which can be flushed continuously in one direction according to the invention, is superior to a conventional system with a change in direction of liquid transport, in which cleaning fluid is aspirated and re-dispensed through a dispensing needle or switched over between two fluidic paths with a 3/2-way valve got to.

The liquid line of the fluidic device according to the invention preferably has a constant cross-sectional area between the metering device and the fluid connection. In this case, there are further advantages for an efficient cleaning, since the missing or minimal cross-sectional change along the fluidic path can avoid dead volumes and contamination foci, as occur in the conventional technique by connecting hoses or connecting to a pump.

The fluidic device is preferably equipped with a cleaning device. The cleaning device is set up to receive a cleaning liquid. Advantageous- With the cleaning device, the cleaning liquid is provided in the cleaning operating region of the fluidic device, so that the fluidic device can have relatively small dimensions. According to a preferred variant, the fluid connection is detachably arranged on the cleaning device. The fluid connection can be temporarily connected to the cleaning device, z. B. inserted into a cleaning liquid in the cleaning device, in particular submersible. It is preferably provided that the fluid connection is changed from a state coupled to the cleaning device, in which the fluid connection protrudes into the cleaning fluid and the cleaning fluid can be flushed through the fluid line, into a free state, in which the fluid connection forms an open end Liquid line forms. In this case, there are advantages for different cleaning modes, in which z. B. a permanent flushing of the liquid line or a pressurization of the liquid line with air or a gas for cleaning or drying purposes is hen provided. With the fluid connection in the free state according to the invention, the entire liquid line including the metering device can be ventilated. The settling of liquid residues is avoided, so that the risk of contamination decreases.

The separability of the fluid connection of the cleaning device, in particular of the cleaning liquid in the cleaning device is an important feature of the invention that, as it significantly facilitates the decoupling of the dosing and cleaning modes of Fluidikeinrichtung is

According to a further preferred embodiment of the invention, the fluidic device is provided with a manipulator device. equipped with which the metering device can be moved and positioned. Advantageously, with the manipulator device, the position of the metering device in the metering operating range can be set. The interaction of the manipulator and pump devices allows system fluids to be transported within the metering work area. Preferably, the manipulator device for positioning the metering device is set up in all three spatial directions. Particularly preferred is a linear translation z. B. along rails provided in the

Spatial directions extend. Advantageously, the manipulator device has the geometry of a conventional gantry robot.

With the gantry robot, the z. B. has three independent translation paths or simplified two coupled translation paths and an independent translation path, the metering device can be advantageously positioned in all three spatial coordinates. This allows different types of Probengefäßen, z. For example, tubes, miniature reaction vessels (e.g., so-called Eppendorf tubes, PCR tubes), beakers, and bottles typically up to 20 cm in height are started up with the metering device.

According to a further advantageous embodiment of the invention, the manipulator device is additionally set up for adjusting the position of the fluid connection. The fluid connection of the fluid line can be moved with the manipulator device within the cleaning work area to the cleaning device and connected to it. Advantageously, the manipulator device thus fulfills a dual function during the positioning of the metering device and of the fluid connection. The operation of the Manipu- latoreinrichtung can be simplified if the metering device and the fluid connection with the manipulator device are jointly movable. Preferably, the fluid connection and the metering device are mechanically coupled. For this purpose, the ends of the liquid line are generally attached to a common carrier, which is movable with the manipulator device.

According to a particularly preferred embodiment of the invention, the dosing device and the fluid connection are arranged offset on the carrier in the vertical direction. The vertical distance is selected so that the fluid connection is located above the sample vessel or adjacent sample vessels when the metering device is actuated in the metering working area, in particular when dispensing or picking up a system fluid on a sample vessel. The vertical distance may be selected as a function of the specifically realized geometry of the sample vessel in the dosing work area and is typically at least 1 cm, preferably at least 2 cm, such. B. 4 cm.

Particularly preferred is a variant of the invention, in which the metering device and the fluid connection both through hollow conduits, z. As hollow needles are formed, which are vertically aligned attached to the carrier and open at the bottom. The opening of the metering device, which is set up to receive or discharge the system liquid, protrudes downwards in the vertical direction relative to the opening of the fluid connection, which is set up to receive the cleaning liquid.

If the cleaning device according to a further preferred embodiment of the invention comprises a storage vessel for receiving the cleaning liquid and a washing vessel, is set up for external cleaning of the metering device, the functionality of the cleaning device is advantageously improved. The storage and washing vessels are arranged side by side in the cleaning work area. The provided on the storage and washing vessels openings for receiving the fluid connection and the metering device have a predetermined distance accordingly. Preferably, the fluid connection and the metering device are fastened to the support of the manipulator device at a horizontal distance which is equal to the horizontal distance of the receptacles of the storage and washing vessels. Advantageously, the fluid connection and the metering device can thus be transferred into the cleaning mode with a single movement of the carrier, in which the fluid connection to the storage vessel of the cleaning fluid and the metering device to the washing vessel are connected. Preferably, the washing vessel comprises an overflow vessel having a closed bottom and an overflow opening. The overflow vessel is adapted to receive the cleaning fluid, with which the metering device is rinsed, and to allow it to flow to the overflow opening via the outside of the metering device.

According to a further, particularly preferred embodiment of the invention, the storage vessel of the cleaning device is an open-topped container, which is arranged in the cleaning working area of the fluidic device. The storage vessel is in the cleaning work area z. B. placed on a base block of Fluidikeinrichtung. The container has on its upper side an opening through which the fluid connection can be inserted and submerged in a cleaning liquid in the container. The storage vessel is exchangeable, preferably a disposable container is used. For cleaning and decontamination of the fluidic device is of particular advantage Part of the fact that the storage vessel assumes the function of a permanently installed cleaning liquid tank, which is a risk of contamination in conventional systems.

An essential further advantage of the fluid device according to the invention is the ability to process a large number of samples sequentially and in freely selectable order without any limitation in terms of cleanliness and avoiding cross-contamination. According to a preferred embodiment of the invention, the metering working area of the fluidic device is set up to receive a plurality of sample vessels. The dosing work area has a holder for the sample containers, such. B. on a support platform. Two or more (eg, 10, 50, 100, 400, or even over 1000) sample cups are provided. The sample vessels comprise individual compartments or compartment arrays, such. B. a 384 microtiter plate.

If, according to a further variant of the invention, at least one system liquid reservoir is arranged in the dosing work area, further advantages for an effective handling of liquids for different fluidic operations can result. In contrast to conventional fluidic devices, the metering device is not connected to a permanently installed system fluid tank via the fluid line, but is set up to receive system fluids by movement to the system fluid reservoir and actuation of the pump device. In addition to the simplified adaptation to different fluidic operations, there are advantages in avoiding long fluidic paths (reduced consumption of the system fluid) and the risk of contamination of the system fluid. Because of the short transport paths of the metering device and the intake of the system fluid from one or more system fluid reservoirs. Servoiren and not as in conventional techniques by long tubes, the operating speed and the sample throughput will be increased.

As a system liquid reservoir, an open-topped container is preferably provided, which in the metering work area z. B. is placed on the base block of Fluidikeinrichtung. The container has on its upper side an opening through which the metering device can be inserted and submerged in a system liquid in the container. The container is like the storage vessel preferably arranged interchangeable, it is z. B. uses a disposable container. Advantageously, a permanently installed system liquid tank is avoided, which would represent a risk of contamination of the system liquid.

However, the system fluid reservoir is not necessarily provided. When processing samples through mutual interaction, an additional system liquid is not required in addition to the sample liquids.

The fluid conduit of the fluidic device according to the invention can in principle be made in any shape and with any material that is selected as a function of the specific application. Preferably, the liquid line consists of a flexible material, at least in some areas. Advantageously, the pump device of the fluid line can thus be arranged in a stationary manner, while the fluid connection and the metering device can be positioned freely in the metering and cleaning work areas, in particular using the manipulator device. Preferably, the liquid line is formed in the respective sections by a flexible hose. Particularly preferably, the entire fluid line consists of see the metering device and the fluid connection from the flexible hose or two pieces of tubing with the pump means, since in this case advantages for the simplification of the structure of Fluidikeinrichtung, the availability of inert tubing materials and the effectiveness of the pump device result.

The pump device preferably comprises a positive displacement pump, which acts on the fluid line from the outside. Advantageously, parts of the pumping device are separated from the cleaning system or sample liquids by the wall of the liquid line so that contamination of the pumping device is avoided. Particularly preferred is a diaphragm pump or a peristaltic pump provided, which have advantages in terms of easy cleaning, low risk of contamination and large, continuously to be pumped volumes. Another advantage is the high precision in all fluidic operations, especially when used in analyzers. During aspirations, dosing, washing and incubation, the variance in volume or flow rate of system or cleaning fluids can be minimized.

If the fluidic device according to the invention is equipped with a sensor device according to a further preferred embodiment of the invention, the field of application of the fluidic device can advantageously be extended. The sensor device is provided for measuring at least one property of liquids in the liquid line, in particular in the metering device or an adjacent part of the liquid line. Preferably, the sensor device is set up to detect system fluids. Advantageously, a particularly simple construction results when the sensor device is introduced into the liquid keitsleitung is integrated, ie forms part of the liquid line. For example, an optical sensor, possibly in combination with a lighting device in the liquid line may be provided.

In terms of method, the invention is based on the general technical teaching, in a method for operating a fluidic device, in particular the fluidic device according to the invention, a transport of at least one system liquid in a metering operating range with a metering device which has a first end of a fluid line and is provided with a pump device, and a recording of a cleaning liquid in the liquid line by a fluid connection, which forms a second end of the liquid line to provide, during transport (delivery or recording) of the at least one system liquid or for receiving the cleaning liquid, the conveying direction Pump means which is arranged between the first and second ends of the liquid line is changed.

For transporting the at least one system liquid, the metering device is moved sequentially to at least one sample vessel in the metering working area and the pump device is actuated with repeatedly changed conveying direction such that the at least one system liquid is taken up by the metering device (sucked in) or at least one sample vessel is delivered. Advantageously, in Dosiermodus all typical operations of liquid handling, such. As aspiration, dosing, conveying with predetermined, z. B. constant flow rate, dilution, in particular serial dilution, washing and / or mixing of the at least one system liquid in the at least one sample vessel provided. For cleaning the metering device in a cleaning mode, a cleaning fluid is preferably taken up by a cleaning device through the fluid connection into the fluid line and flushed by the metering device and / or the fluid line is vented through the fluid connection. The cleaning mode has the advantage that the fluid line and in particular the metering device is free of system fluids in idle mode.

The different modes of operation, d. H. the dosing mode, in which the samples are sucked in and output by the metering device, and the cleaning mode in which cleaning solution is continuously sucked through the fluid connection and is discharged again by the metering device in the washing position, represent an essential feature of the method according to the invention. The switching between these modes occurs without the use of a valve, with the advantageous consequence of a particularly easy and thorough cleaning of all fluidic pathways of the system and the avoidance of contamination risks.

The inventors have found that surprisingly with a single liquid line complex liquids such. As milk, handle very well, and that the Fluidikeinrichtung can be completely flushed with a minimum use of cleaning solution. The low consumption of cleaning solutions is an aspect which has particular significance in on-site devices or in dealing with explosive (toxic) liquids because of the associated disposal costs. Surprisingly, it has also been found that the fluidic device according to the invention can be stored for a long time without use, without contamination occurring, for example cyanobacteria or algae growth, dust Entry etc .. When commissioning after a break in operation no special cleaning protocols had to be used.

The use of the fluidics device according to the invention or the associated operating method, in particular in analytical-chemical analyzes, in liquid treatments of biological samples, in clinical diagnostics, in environmental analysis, in food chemistry and / or in the performance of immunoassays represents a further subject of the invention. Preferred applications are in the analytical chemical study of pathogens, eg. B. Botulismuserregern (Clostriudium botulinum), Pesterregern (Y- ersinia pestis), and bacterial varieties that have developed resistance to antibiotics (Streptococcus aureus strains, MRSA etc). This listing of possible applications is without limitation of completeness. The Fluidikeinrichtung can be used as a so-called liquid handling robot z. B. be used as a single device for sample preparation or for sample processing.

The invention has the following further advantages. Since the used in clinical, food chemical and environmental analysis for analysis complex fluids such. As blood, milk, slurries, food samples have a high content of solids, the easy cleaning is an important advantage of Fluidikeinrichtung. The Fluidikeinrichtung works with high precision, d. H. while maintaining given volumes and volume flows and an exact timing of the fluidic operations (timing).

The device according to the invention thus has the potential of conventional technical solutions when used in fully automatic or partially automated analyzers of clinical and veterinary diagnostics, environmental analysis, Food chemistry and biotechnology, particularly in low-cost, on-site analyzers designed to perform complex analytical-chemical processes in the field.

The fluidic device according to the invention is a fluid-handling system which is particularly simple in construction and which is particularly easy to clean and which can process two or more system fluids and up to several hundred sample fluids. It advantageously combines a continuously conveying pump with a single fluidic path consisting of two hollow needles of the fluid connection or the metering device and at least one hose connection, a 3-axis robot and disposable vessels for the supply of all liquids (system fluids and samples). Due to the constructive realization and the switching between two different operating modes (dosing mode or cleaning mode), the use of permanently installed system solution tanks can be dispensed with and no liquid remains in the system during idle operation. The fluidic device is particularly suitable for liquid handling in low-cost on-site analyzers for carrying out complex analytic-chemical analyzes, in particular for carrying out immunoassays.

Further advantageous features of the invention are the short Fluidikweg without branching, the valve freedom, the positioning of the entire Fluidikweges above the level of the vessels (storage vessels, washing vessels, reservoirs), so that a risk of leakage is avoided. All vessels in contact with liquid can be disposable vessels, resulting in high process reliability and a low risk of contamination. No injection port is required to deliver fluids and samples. Finally, the Invention a simple adaptation to analytical-chemical laboratory equipment.

Further details and advantages of the invention will be described below with reference to the accompanying drawings. Show it:

Figure 1: a schematic perspective view of a first

Embodiment of the fluidic device according to the invention,

FIG. 2 shows an illustration of the combination according to the invention of a fluid line with a pump device, and

FIG. 3 shows a schematic perspective view of a further embodiment of the fluidic device according to the invention.

FIG. 1 illustrates a first embodiment of the fluidic device 100 according to the invention with the fluid line 10, the metering work area 20, the pump device 30, the cleaning device 40, the manipulator device 50 and the cleaning work area 60. The components 10 to 30 and 60 are also enlarged in FIG Figure 2 shown. In the dosing working area 20, a multiplicity of sample vessels 21, which contain samples for the treatment or processing with the fluidic device, and a system liquid reservoir 22 are arranged. The sample containers 21 are set up for storage and handling of the liquid samples and z. B. on a support (so-called tray).

The fluidic device 100 has a base block 110, on which the manipulator device 50 is mounted and in which Liquid waste container (not shown) is included. In practice, a Fluidikeinrichtung other components, such. As a controller, a control panel and possibly for automated detection of sample vessels and their posi- tions a camera device, which are known per se and not shown in the figures.

The liquid line 10 extends between a first end 11 with the metering device 12 and a second end 13 with the fluid connection 14. The liquid line 10 consists of a first piece of tubing extending from the first end 11 to the pump means 30 and a second piece of tubing, the extends between the pumping device 30 and the second end 13. Alternatively, an integral continuous tube may be provided which is integrated into the pump device 30. The pieces of hose or the continuous hose consists z. B. silicone with an outer diameter of 3.2 mm and an inner diameter of 1.6 mm.

The metering device 12 is generally provided for receiving or dispensing liquids and comprises a hollow conduit, in particular a hollow needle and a metering reservoir, which is formed by the interior of the end of the liquid conduit 10. The inner diameter of the hollow needle is preferably equal to the inner diameter of the liquid line. The hollow needle is, for example, a steel cannula with a length of approx. 50 mm, an outer diameter of 2 mm and an inner diameter of 1.6 mm. The fluid connection 14 is preferably also formed by a hollow needle, the z. B. as the hollow needle of the metering device is executed.

The pump device 30 comprises a peristaltic pump 31, which is attached to the manipulator device 50. As peer ristaltikpumpe 31 is z. B. the program-controlled, provided with a stepper motor pump type SR25-S300 (manufacturer: Rietschle Thomas AG) provided.

The manipulator device 50 comprises a three-axis gantry robot. In the illustrated embodiment, the manipulator device 50 comprises a bridge fixedly fixed to the base block 110 bridge 52, on which the carrier 51 of the metering device 12 and the fluid connection 14 with two linear translational drives in the orthogonal y- and z-

Spaced spatial directions, and a platform 53 which is arranged with a further linear translational drive in the x-spatial direction slidably on the base block 110.

The carrier 51 consists of a carrier plate 54 and two laterally protruding needle holders 55. The needle holders 55 each have a receptacle for the hollow needles of the metering device 12 and the fluid connection 14. The receptacles of the needle holder 55 have in the horizontal direction (y-

Direction) a distance corresponding to the horizontal distance of the storage and washing vessels of the cleaning device 40 (see below). The parts of the liquid line 10 which are fastened to the carrier 51 and generally form the ends of the liquid line 10 and, in the example shown, the

Hollow needles of the metering device 12 and the fluid connection 14 include, have a mutual vertical displacement Z ₀ (Figure 2). The vertical displacement Zo is chosen such that, in the case of all movements of interest, the hollow needle of the metering device 12 in the metering working region 20 enters

Penetration of the hollow needle of the fluid connection 14 is excluded in one of the sample container 21. The vertical distance Zo is selected by selecting a suitably sized plate 54 of the carrier 51. Alternatively or additionally a height adjustment may be provided by a displacement of the hollow needles in the receptacles of the needle holder 55 in the vertical direction.

The cleaning device 40 comprises the storage vessel 41 and the washing vessel 42, which are arranged in a cleaning work area 60 next to the metering work area 20 on the base block 110. The storage and washing vessels 41 are located on the base block 110 next to the bridge 52 such that the hollow needles of the metering device 12 and the fluid port 14 by a movement of the carrier 51 in the y and z directions respectively in the storage vessel 41 and the Washing vessel 42 can be introduced. The storage and washing vessels are arranged with a vertical working distance Zi, which is equal to the vertical distance Zo of the hollow needles of the metering device 12 and the fluid connection 14. The washing vessel 42 is designed for passive cleaning by inner and outer rinsing of the dosing device 12.

The vertical displacement of the metering device 12 and the fluid connection 14 and the storage and washing vessels 41, 42 and the vertically uniform orientation of the sample vessels 21, the essential advantage of the invention is achieved that the metering device 12 and the fluidic connection 14 in the metering work area functionally decoupled and functionally coupled in the cleaning workspace 60. Contrary to the intuitive assumption that it is not possible to completely decouple the functions of the two mechanically coupled hollow needles or the dosing mode from the cleaning mode, it has been found that this can be achieved by the shown arrangement of the storage and washing vessels and the sample vessels. As a reservoir 41 and system liquid reservoir 22 are preferably disposable articles such. B. plastic container provided. For example, PP containers with a volume of 125 ml are used.

The sample containers 21 are arranged so that they lie completely in the dosing working area 20. The system fluid reservoir 22 is mounted so that it is at least partially disposed in the metering work area 20. The storage vessel 41 is mounted so that it is at least partially disposed in the cleaning work area of the fluid port 14, and the distance of the fluid port 14 and the metering device 12 is selected so that the metering device 12 is immersed in the washing vessel 42 (overflow) when the Fluid connection 14 immersed in the cleaning liquid in the storage vessel 41.

At the same time, the fluid port 14 is disposed at a fixed offset in the x and z directions so that it can never penetrate the metering work area 20 when the metering device 12 is moved in the metering work area 20. Depending on the depth (z height) of the sample vessels processed by the metering device 12, it is sufficient to mount the fluid connection 14 correspondingly higher and to correspondingly increase the mounting height of the cleaning fluid storage vessel 41. In the case of particularly deep vessels to be processed by the metering device 12 (with a high aspect ratio), it may additionally be necessary to define gaps in the metering working area into which the fluid connection 14 can dip.

The waste liquid container 111 is arranged so that the liquid wastes entering the passive washing station flow by gravity into the waste liquid container 111, ie it is below the liquid levels the storage vessels and the sample vessels and below the dosing work area and the cleaning work area.

FIG. 3 shows a modified embodiment of the fluidic device 100 with the fluid line 10, the metering work area 20, the pump device 30, the cleaning device 40, the manipulation device 50, the cleaning work area 60 and a sensor device 70. The fluid line 10 is at a vertical distance the end, d. H. the metering device 12 and the fluid connection 14 on the carrier 51 of the manipulator device 50 is attached. The pump device 30 is arranged in the liquid line 10. In contrast to the embodiment described above, in the fluidic device 100 according to FIG. 3, a stationary metering operating region is provided. Accordingly, the manipulator device 50 is equipped with three linear drives (eg, stepper motors) for moving the carrier 51 in all three spatial directions.

The sensor device 70 is integrated in the liquid line 10 in the region of the metering device 12. The sensor device 70 comprises z. B. a fluorescence measuring cell, z. B. with fiber optic sensors.

Figure 3 further illustrates the waste liquid container 111 which is connected to the washing vessel 42 of the cleaning device. The cleaning liquid, which is purged by the liquid line 10 during cleaning, flows from the overflow opening of the washing vessel 42 into the waste liquid container 111.

The operation of the fluidic device according to the invention may comprise, for example, the methods described below. Example 1: Robot for handling liquid samples

The following table shows elementary Fluidikoperationen the Fluidikeinrichtung invention, z. B. Complex fluidic operations such as dilution, serial dilution, etc. can be represented by combining the elementary operations and translational operations of the robot.

Example 2: Immunosensor with flow cell and integrated sample handling robot

The Fluidikeinrichtung for handling liquid samples of Example 1 is by integration of a sensor device 70th (Figure 3) in the fluid path to an immunoassay analyzer with fully automated processing of clinical samples, food samples or environmental samples upgraded. The sensor device comprises a through-sensor, in particular an immunosensor 70, such. B. a fiber optic fluorescence sensor between the metering device and the pump.

The Fluidikeinrichtung is z. For processing and measuring 12 milk samples for antibiotic residues. The milk samples are introduced into the fluidics device in a first group of sample containers (snap-cap bottles, eg from the manufacturer Fisher Scientific) in a sample carrier. 12 further sample vessels (for example manufactured by Eppendorf AG) doped with lyophilized antibody-fluorophore conjugates are also introduced into the fluidic device. The fully automatic processing of the samples is carried out by the following sequence of fluidic operations:

1. Aspiration of milk sample 1

2. Dosing milk sample 1 in sample vessel 1

3. Washing the hollow needle of the metering device 12 and the Fluidikweges with cleaning fluid

4. Aspiration of system liquid 5. Dosing of system liquid in sample vessel 1

6. Mixing milk sample and system fluid by alternating aspirate / dosing

7. Incubation of the reaction mixture (waiting time to wait)

8. conveying the reaction mixture before the immunosensor 70 (aspirate)

9. Incubation of the reaction mixture with the immunosensor 70th

10. Washing the Immunosensor 70 (Aspirate System Fluid)

11. Measuring the fluorescence signal, storing the value 12. Regenerate the immunosensor 70 (continuous rinse with cleaning fluid)

13. Aspirate milk sample 2 and repeat the above steps.

The control of the sequence of operations and the analysis of the measurement results are performed by an external computer or an embedded controller.

The features of the invention disclosed in the foregoing description, claims and drawings may be significant to the realization of the invention in its various forms both individually and in combination.

Claims

A fluidic device (100) comprising:

- A liquid line (10), the first end (11) forms a metering device (12) adapted to receive or deliver a Systeraflüssigkeit in a metering work area (20), and the second end (13) has a fluid connection (14 ), which is adapted to receive a cleaning liquid, and

- A pump device (30), which is adapted to operate the metering device (12), characterized in that - the pump device (30) on the liquid line (10) between the first and second ends (11, 13) arranged and for conveying liquids in the liquid line (10) is arranged with selectable conveying direction.

2. fluidic device according to claim 1, which comprises:

- A cleaning device (40) which is adapted to provide a cleaning liquid for cleaning the metering device (10).

3. Fluidikeinrichtung according to claim 2, wherein the

Fluid connection (14) with the cleaning device (40) is connectable.

4. Fluidics device according to at least one of the preceding claims, comprising:

- A manipulator device (50) which is adapted to adjust the position of the metering device (12) within the metering work area (20).

5. Fluidikeinrichtung according to claim 4, wherein the manipulator means (50) for linear translation of the metering device (12) in all orthogonal spatial directions within the metering work area (20) is arranged.

6. Fluidikeinrichtung according to claim 4 or 5, wherein the manipulator device (50) for adjusting the position of the fluid connection (14) within a cleaning work area (60) of the cleaning device (40) is arranged.

7. Fluidikeinrichtung according to at least one of claims 4 to 6, wherein the manipulator device (50) has a movable support (51) on which the metering device (12) and the fluid connection (14) are attached.

8. fluidic device according to claim 7, wherein the metering device (12) and the fluid connection (14) on the support (51) are fixed with a mutual vertical distance.

9. Fluidikeinrichtung according to claim 8, wherein the metering device (12) and the fluid connection (14) are vertically aligned hollow conduits, wherein the metering device (12) projects relative to the fluid port (14) by the vertical distance in the vertical direction downwards.

10. fluidic device according to at least one of claims 2 to 9, wherein the cleaning device (40) has a supply container (41) and a washing vessel (42).

11. fluidic device according to claim 10, wherein the metering device (12) and the fluid connection (14) has a ho Have a horizontal distance, which is adapted to the distance of the storage and washing vessels (41, 42).

12. Fluidikeinrichtung according to claim 10 or 11, wherein the storage and washing vessels (41, 42) corresponding to the vertical distance of the metering device (12) and the fluidic connection (14) are arranged offset in the vertical direction.

13. Fluidikeinrichtung according to at least one of claims 10 to 12, wherein the washing vessel is an overflow vessel (42) for receiving the metering device (12).

14. Fluidics device according to at least one of the preceding claims, wherein the dosing work area (20) is adapted to receive a plurality of sample vessels (21).

15. fluidic device according to at least one of the preceding claims, wherein in the dosing work area (20) a

System liquid reservoir (22) is arranged.

16. Fluidikeinrichtung according to at least one of the preceding claims, wherein the liquid line (10) at least in some areas of a flexible material.

17. Fluidikeinrichtung according to claim 16, wherein the liquid line (10) consists of a tube at least in some areas.

18. Fluidikeinrichtung according to claim 17, wherein the liquid line (10) consists entirely of a hose.

19. Fluidics device according to at least one of the preceding claims, comprising:

- A sensor device (70) which is adapted to measure a property of the system liquid in the liquid line (10).

20. fluidic device according to claim 19, wherein the sensor device (70) in the liquid line (10) between the metering device (12) and the pump device (30) is arranged.

21. Fluidikeinrichtung according to at least one of the preceding claims, wherein the metering device (12) and / or the fluid connection (14) has a hollow needle (15).

22. Fluidikeinrichtung according to at least one of the preceding claims, wherein the pump means (30) comprises a diaphragm pump or a peristaltic pump (31).

23. A method for operating a fluidic device (100), comprising the step:

- Transport of at least one system liquid in a metering work area (20) of the Fluidikeinrichtung (100) with a metering device (12), which forms a first end (11) of a liquid line (10) and is actuated with a pump device (30) characterized : through the next step

- Receiving a cleaning liquid in the liquid line (10) through a fluid connection (14) which forms a second end (13) of the liquid line (10), wherein

- During transport of the at least one system liquid or for receiving the cleaning liquid, the conveying direction of the pump device (30) on the liquid line (10) is arranged between the first and second ends (11, 13) is changed.

24. The method according to claim 23, wherein in a Dosiermo- dus for transporting the at least one system liquid the

Metering device successively moves to at least one sample vessel (21) in the dosing work area (29) and the pump device (30) is operated with repeatedly changed conveying direction so that the at least one system liquid at the at least one sample vessel (21) from the metering device ( 10) is recorded or delivered.

25. The method according to claim 24, wherein in the metering mode the at least one system liquid is received from at least one system fluid reservoir (22).

26. The method according to claim 24 or 25, wherein in the dosing mode, aspiration, dosing and / or mixing of the at least one system liquid in the at least one sample vessel (21) is provided.

27. The method according to any one of claims 23 to 26, wherein in a cleaning mode, a cleaning liquid from a cleaning device (40) through the Fluidi- kanschluss (14) is received in the liquid line (10) and passed through the metering device (10).

28. The method according to claim 27, wherein for the passage of the cleaning liquid, the metering device is arranged in an overflow washing vessel (42).

29. The method according to any one of claims 27 or 28, wherein in the cleaning mode, the liquid line (10) is vented.

30. The method according to any one of claims 23 to 29, comprising the step:

- Measurement of a property of the at least one system liquid in the liquid line (10).

31. Use of a fluidic device (100) or a method for its operation according to at least one of the preceding claims, for: - analytical-chemical analyzes,

- liquid treatments of biological samples,

- environmental analytical procedures,

- Procedures of clinical diagnostics,

- Methods of food chemistry, and / or - Implementation of immunoassays.