EP1833598B1 - Procede et dispositif de dosage et de melange de petites quantites de liquide - Google Patents

Procede et dispositif de dosage et de melange de petites quantites de liquide Download PDF

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Publication number
EP1833598B1
EP1833598B1 EP05818698A EP05818698A EP1833598B1 EP 1833598 B1 EP1833598 B1 EP 1833598B1 EP 05818698 A EP05818698 A EP 05818698A EP 05818698 A EP05818698 A EP 05818698A EP 1833598 B1 EP1833598 B1 EP 1833598B1
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European Patent Office
Prior art keywords
accordance
reservoir
liquid
metering
filling
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EP05818698A
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German (de)
English (en)
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EP1833598A1 (fr
Inventor
Christoph Gauer
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Olympus Life Science Research Europa GmbH
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Olympus Life Science Research Europa GmbH
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Priority claimed from DE102005000835A external-priority patent/DE102005000835B3/de
Priority claimed from DE102005000834A external-priority patent/DE102005000834B4/de
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Publication of EP1833598A1 publication Critical patent/EP1833598A1/fr
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    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
    • B01L3/00—Containers or dishes for laboratory use, e.g. laboratory glassware; Droppers
    • B01L3/50—Containers for the purpose of retaining a material to be analysed, e.g. test tubes
    • B01L3/502—Containers for the purpose of retaining a material to be analysed, e.g. test tubes with fluid transport, e.g. in multi-compartment structures
    • B01L3/5027—Containers for the purpose of retaining a material to be analysed, e.g. test tubes with fluid transport, e.g. in multi-compartment structures by integrated microfluidic structures, i.e. dimensions of channels and chambers are such that surface tension forces are important, e.g. lab-on-a-chip
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01F—MIXING, e.g. DISSOLVING, EMULSIFYING OR DISPERSING
    • B01F31/00—Mixers with shaking, oscillating, or vibrating mechanisms
    • B01F31/80—Mixing by means of high-frequency vibrations above one kHz, e.g. ultrasonic vibrations
    • B01F31/86—Mixing by means of high-frequency vibrations above one kHz, e.g. ultrasonic vibrations with vibration of the receptacle or part of it
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01F—MIXING, e.g. DISSOLVING, EMULSIFYING OR DISPERSING
    • B01F33/00—Other mixers; Mixing plants; Combinations of mixers
    • B01F33/30—Micromixers
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01F—MIXING, e.g. DISSOLVING, EMULSIFYING OR DISPERSING
    • B01F35/00—Accessories for mixers; Auxiliary operations or auxiliary devices; Parts or details of general application
    • B01F35/71—Feed mechanisms
    • B01F35/717—Feed mechanisms characterised by the means for feeding the components to the mixer
    • B01F35/7172—Feed mechanisms characterised by the means for feeding the components to the mixer using capillary forces
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
    • B01L2200/00—Solutions for specific problems relating to chemical or physical laboratory apparatus
    • B01L2200/06—Fluid handling related problems
    • B01L2200/0605—Metering of fluids
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
    • B01L2200/00—Solutions for specific problems relating to chemical or physical laboratory apparatus
    • B01L2200/06—Fluid handling related problems
    • B01L2200/0621—Control of the sequence of chambers filled or emptied
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
    • B01L2300/00—Additional constructional details
    • B01L2300/08—Geometry, shape and general structure
    • B01L2300/0861—Configuration of multiple channels and/or chambers in a single devices
    • B01L2300/0867—Multiple inlets and one sample wells, e.g. mixing, dilution
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
    • B01L2400/00—Moving or stopping fluids
    • B01L2400/04—Moving fluids with specific forces or mechanical means
    • B01L2400/0403—Moving fluids with specific forces or mechanical means specific forces
    • B01L2400/0406—Moving fluids with specific forces or mechanical means specific forces capillary forces
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
    • B01L2400/00—Moving or stopping fluids
    • B01L2400/04—Moving fluids with specific forces or mechanical means
    • B01L2400/0403—Moving fluids with specific forces or mechanical means specific forces
    • B01L2400/0433—Moving fluids with specific forces or mechanical means specific forces vibrational forces
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
    • B01L2400/00—Moving or stopping fluids
    • B01L2400/06—Valves, specific forms thereof
    • B01L2400/0677—Valves, specific forms thereof phase change valves; Meltable, freezing, dissolvable plugs; Destructible barriers
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
    • B01L2400/00—Moving or stopping fluids
    • B01L2400/06—Valves, specific forms thereof
    • B01L2400/0688—Valves, specific forms thereof surface tension valves, capillary stop, capillary break
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
    • B01L2400/00—Moving or stopping fluids
    • B01L2400/06—Valves, specific forms thereof
    • B01L2400/0694—Valves, specific forms thereof vents used to stop and induce flow, backpressure valves
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
    • B01L3/00—Containers or dishes for laboratory use, e.g. laboratory glassware; Droppers
    • B01L3/50—Containers for the purpose of retaining a material to be analysed, e.g. test tubes
    • B01L3/502—Containers for the purpose of retaining a material to be analysed, e.g. test tubes with fluid transport, e.g. in multi-compartment structures
    • B01L3/5027—Containers for the purpose of retaining a material to be analysed, e.g. test tubes with fluid transport, e.g. in multi-compartment structures by integrated microfluidic structures, i.e. dimensions of channels and chambers are such that surface tension forces are important, e.g. lab-on-a-chip
    • B01L3/502738—Containers for the purpose of retaining a material to be analysed, e.g. test tubes with fluid transport, e.g. in multi-compartment structures by integrated microfluidic structures, i.e. dimensions of channels and chambers are such that surface tension forces are important, e.g. lab-on-a-chip characterised by integrated valves
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
    • B01L3/00—Containers or dishes for laboratory use, e.g. laboratory glassware; Droppers
    • B01L3/50—Containers for the purpose of retaining a material to be analysed, e.g. test tubes
    • B01L3/502—Containers for the purpose of retaining a material to be analysed, e.g. test tubes with fluid transport, e.g. in multi-compartment structures
    • B01L3/5027—Containers for the purpose of retaining a material to be analysed, e.g. test tubes with fluid transport, e.g. in multi-compartment structures by integrated microfluidic structures, i.e. dimensions of channels and chambers are such that surface tension forces are important, e.g. lab-on-a-chip
    • B01L3/502746—Containers for the purpose of retaining a material to be analysed, e.g. test tubes with fluid transport, e.g. in multi-compartment structures by integrated microfluidic structures, i.e. dimensions of channels and chambers are such that surface tension forces are important, e.g. lab-on-a-chip characterised by the means for controlling flow resistance, e.g. flow controllers, baffles
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y10—TECHNICAL SUBJECTS COVERED BY FORMER USPC
    • Y10T—TECHNICAL SUBJECTS COVERED BY FORMER US CLASSIFICATION
    • Y10T436/00—Chemistry: analytical and immunological testing
    • Y10T436/10—Composition for standardization, calibration, simulation, stabilization, preparation or preservation; processes of use in preparation for chemical testing
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y10—TECHNICAL SUBJECTS COVERED BY FORMER USPC
    • Y10T—TECHNICAL SUBJECTS COVERED BY FORMER US CLASSIFICATION
    • Y10T436/00—Chemistry: analytical and immunological testing
    • Y10T436/25—Chemistry: analytical and immunological testing including sample preparation
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y10—TECHNICAL SUBJECTS COVERED BY FORMER USPC
    • Y10T—TECHNICAL SUBJECTS COVERED BY FORMER US CLASSIFICATION
    • Y10T436/00—Chemistry: analytical and immunological testing
    • Y10T436/25—Chemistry: analytical and immunological testing including sample preparation
    • Y10T436/2575—Volumetric liquid transfer

Definitions

  • the invention relates to a method for metering and mixing small amounts of liquid, a device and an apparatus for carrying out the method and a use.
  • Diagnostic assays are now largely automated.
  • defined volumes of sample liquid and reagents are pipetted into a cuvette or into the well of a microtiter plate and mixed.
  • a first reference measurement is carried out in which, for example, the optical transmission through the cuvette is determined.
  • a second measurement of the same parameter is made. By comparing the two measured values results in the concentration of the sample with respect to a particular ingredient or even the presence of the ingredient.
  • Typical volumes are in the sum of a few hundred microliters, whereby necessary mixing ratios of sample to reagent between 1: 100 and 100: 1 can occur.
  • reagents may be provided for mixing with a sample.
  • high throughput instruments which are typically found in specialized laboratories, there are also efforts to make assays decentralized and without much instrumental effort. It would be desirable if the most recently introduced "lab-on-a-chip" technology could be used, in which the processing of liquids is performed on or integrated into a chip can be. Assay times of less than one hour are desirable.
  • microfluidic systems are used to move the liquids, in which liquid is moved by electro-osmotic potentials, see for example Anne Y. Fu, et al. "A micro fabricated fluorescence-activated cell sorter", Nature Biotechnology Vol. 17, November 1999, p. 1109 et seq.
  • a process for liquid mixing, in the microliter range is in DE 103 25 307 B3 described in which small volumes of liquid in microtiter plates are mixed by means of sound-induced flow.
  • Another method of generating motion in small quantities of fluid on a solid surface describes DE 101 42 789 C1 , Here, a liquid is mixed with the help of surface sound waves or mixed several liquids together.
  • an amount of liquid is brought to a region of a substantially planar surface, the wetting properties of which differ from the surrounding surface in such a way that the liquid preferably resides on it, being held together by their surface tension. Movement of the amount of liquid can be generated by the momentum transfer of a surface acoustic wave to the liquid.
  • volume For dosing, it is necessary to precisely define volumes of liquid quantities. This is geometrically feasible, for example.
  • the wetting properties of the surface can determine a volume, as in FIG DE 100 55 318 A1 is described.
  • the volumes are defined by hydrophilic and hydrophobic regions over the wetting angle on a substantially smooth surface. If several volumes have been defined in this way which are to be reacted, the volumes are moved toward one another in order to achieve this.
  • liquid residues or liquid molecules of the analyte or the reagent can adhere to the surface, so that the movement of a volume loss or a concentration reduction of unknown level can not be excluded.
  • provision must be made against the evaporation which can be problematic especially at longer assay times.
  • channels of defined cross-section which are filled with liquid capillary. If the liquid is an aqueous solution, then at the end of the channel a hydrophobic barrier is attached, which can not be filled capillary. Furthermore, there is a lateral branch on this channel with a likewise hydrophobic surface, which can not be capillary filled.
  • the cross-section and length of the channel between the hydrophobic barrier and the hydrophobic branch now define a volume which can be separated and moved by pneumatic pressure through the branch ( Burns et al., An integrated nanoliter DNA analysis device, Science 282, 484 (1998 )). This type of volume definition results in high costs due to the necessary wetting structure of the surface (hydrophilic for filling the channel itself and hydrophobic for the barrier and the branch).
  • the channel cross-section must be small. For large volumes in the range of a few 100 microliters, therefore, long channels are required. This inevitably leads to large unwanted interactions of the molecules in the liquid with the channel wall. An efficient mixing of several quantities of liquid is almost impossible in this geometry.
  • US-A-5,674,742 describes a device for manipulating, reacting and detecting small quantities of liquid with a reservoir for a first quantity of liquid, a reaction reservoir and a connection structure between the first reservoir and the reaction reservoir.
  • the connection structure is dimensioned such that the first liquid does not enter the reaction reservoir due to its surface tension.
  • a device for mixing the liquid in the reaction reservoir is provided.
  • liquid as used herein includes, but is not limited to, pure liquids, mixtures, dispersions and suspensions, as well as liquids containing solid particles, for example, biological material.
  • dosing and mixing liquids may also be two or more solutions that differ only in ingredients dissolved therein that are to be reacted.
  • the object of the present invention is to provide a method and a device with the aid of which a precise metering of liquid quantities in a large dynamic range is easy to carry out and which enable complete mixing of the liquids.
  • the method should be feasible in a compact lab-on-the-chip system.
  • a metering reservoir is completely filled with a first liquid which communicates with a reaction reservoir via at least one connecting structure, wherein the connecting structure is preferably dimensioned in relation to the reservoir such that the surface tension of the first liquid prevents entry into the reaction reservoir.
  • the cross-section of the connection structure may be chosen to be smaller than the cross-section of the reaction reservoir.
  • the reaction reservoir is completely filled with a second liquid, so that the second liquid at the connection structure comes into contact with the first liquid.
  • a flow pattern is generated in the liquid in or on the reaction reservoir, which leads to the mixing of the liquids, wherein the flow pattern is maintained until the complete homogenization of the liquids.
  • a laminar flow pattern is generated.
  • the laminar flow pattern can be generated directly in the reaction reservoir. It is also possible that the laminar flow is generated in at least one connecting structure in the direction of the reaction reservoir and in this way acts in the reaction reservoir. Finally, it is also possible to excite the laminar flow in the metering reservoir with a corresponding geometric configuration, so that it acts on the connection structure in the reaction reservoir.
  • the amount of the first liquid to be metered is determined in the metering reservoir.
  • the first liquid is prevented from entering the reaction reservoir.
  • the surface tension prevents the liquid from entering the reaction reservoir. Only when the first liquid With the second liquid comes into contact, which was placed in or on the reaction reservoir, a liquid exchange can take place. In this case, due to the smaller cross section of the connecting channel structure, the liquid exchange due to diffusion is negligible. Only by generating a corresponding flow pattern in the reaction reservoir effective mixing is effected.
  • the amount of the second liquid is determined by the size of the reaction reservoir.
  • the mixing ratio between reagents and sample liquid may be set between 1: 100 to 100: 1.
  • the flow pattern can be generated by irradiation of sound waves into the liquid on or in the second reservoir or in the direction of the second reservoir.
  • surface acoustic waves can be used, which can be generated in a conventional manner by means of an interdigital transducer on a piezoelectric chip which is attached to the device. It is used either the momentum transfer of surface acoustic waves directly or by means of the surface acoustic wave generated sound waves.
  • surface acoustic waves in the present text also includes interfacial sound waves at the interfaces between two solids.
  • the reservoirs and the connection structures can be designed in three dimensions or two dimensions. So can the reservoirs and Connecting structures be correspondingly shaped depressions in a surface. Other configurations are correspondingly shaped cavities.
  • the reservoirs and connecting structures are formed by correspondingly shaped areas of a surface, which are wetted by the liquids more preferably than the surrounding areas of the surface.
  • surfaces that are hydrophilic compared to their environment are selected for the reservoirs and interconnect structures.
  • Such wetting-modulated surfaces are, for example, in DE 100 55 318 A1 described. The liquids are held together on the preferably wetted areas by their surface tension as drops.
  • connection structure may be a correspondingly dimensioned opening between the metering reservoir and the reaction reservoir.
  • a particularly precise procedure uses the capillary force in a connecting capillary structure, which is wetted by the first liquid and by the capillary forces from the metering reservoir is filled.
  • the capillary forces abruptly decrease due to the enlarged cross-section, so that leakage of the first liquid from the connecting capillary structure into the reaction reservoir is prevented. Only when the second liquid is introduced into the reaction reservoir or is applied to the reservoir surface, does the second liquid enter into contact with the first liquid, so that thorough mixing can take place.
  • the reservoirs are filled by filling openings in an embodiment of the metering, which are preferably in the upper end of the reservoir.
  • the metering reservoir can be formed by a correspondingly dimensioned volume.
  • a reservoir capillary structure is used as the metering reservoir, which has at least two openings along its extent. Through an opening, the capillary structure can be filled. Liquid enters through the first opening and, driven by the capillary force, moves to the second opening.
  • the reservoir capillary structure is selected as a capillary structure such that the liquid front of the moving liquid occupies the entire cross-section of the capillary structure. Apart from the filling opening and the second opening, no further openings are opened in the system. At the second opening the liquid stops its movement.
  • an exact volume in the reservoir capillary structure is defined by the distance between the two ports to allow accurate metering.
  • two second openings arranged symmetrically with respect to the filling opening are used. The liquid volume of the liquid metered in such a reservoir capillary structure then corresponds to the distance between these two second openings.
  • a further development uses a reservoir capillary structure with a plurality of such selectable openings, which are opened depending on the desired metering volume of the first fluid. If further openings are opened from the opening used as the filling opening, the liquid can enter these openings and occupy a larger volume.
  • the metering reservoir in this process corresponds to the volume of the reservoir capillary structure filled with the first fluid.
  • the remaining part of the reservoir capillary structure is part of the reaction reservoir.
  • open filling structures can be used, which are connected via feeds to the metering reservoir or the reaction reservoir.
  • the respective liquid can be introduced manually or automatically, for example by means of a pipette. Through the respective supply, the liquid enters the respective reservoir.
  • the filling structures are also selected accordingly.
  • the feeds may then be, for example, appropriately sized channels.
  • the feed or the feeders are selected as a capillary structure.
  • the liquid to be introduced then moves independently from the filling structure into the respective reservoir due to the capillary forces.
  • Another advantageous embodiment of the method according to the invention employs a plurality of preferably differently sized metering reservoirs, which communicate with the reaction reservoir via connection structures.
  • the metering reservoirs communicate with a filling opening.
  • the connecting structures between the individual metering reservoirs and the reaction reservoir can initially be closed in one embodiment and be opened to select the desired metering reservoir.
  • the desired metering reservoir with the desired volume is selected by closing the remaining connection structures to the other metering reservoirs.
  • Both the opening and the closing can be effected by a melting process, with suitable selection of the material of the metering device used.
  • a plastic part is suitable as a metering device.
  • Either the connection structures are initially closed, wherein the desired connection structures are melted before use in order to establish a connection.
  • connection structures are initially open and the unnecessary connection structures are closed by a melting process before use.
  • connection between the two liquids is made via a small "bridge drop", which is brought between the two liquids and creates a liquid bridge.
  • the bridge drop has a smaller volume than both the first and the second amount of liquid.
  • connection structure between a metering reservoir and the reaction reservoir.
  • the fluid exchange - driven for example by sound waves - take place in a circuit until a complete homogenization of the liquids has occurred.
  • the inventive method is not limited to the metered addition of a liquid amount to a second amount of liquid.
  • a corresponding number of metering reservoirs and connecting structures which connect these metering reservoirs with the reaction reservoir can be provided simultaneously or successively for metered addition to the liquid in the reaction reservoir a plurality of liquid quantities.
  • a device according to the invention with which the method according to the invention can be carried out, has at least one metering reservoir for a first quantity of liquid. Furthermore, a reaction reservoir for a second amount of liquid and at least one connection structure between the two reservoirs is provided. The connection structure is preferably dimensioned in relation to the reservoir such that the first liquid can not enter the reaction reservoir due to its surface tension. Finally, the device according to the invention has a device for generating preferably a laminar flow pattern for the mixing of liquid in the reaction reservoir.
  • a preferred embodiment has at least one sound wave generating device for irradiating sound waves into the reaction reservoir or in the direction of the reaction reservoir.
  • the at least one sound wave generating device is formed by a surface acoustic wave generating device, in particular by an interdigital transducer on a piezoelectric chip.
  • the reservoirs and the at least one connecting structure may be formed as depressions or cavities in a solid body.
  • the reservoirs and connecting structures are formed by correspondingly shaped regions of a surface, which are wetted by the liquids more preferably than the surrounding regions of the surface.
  • wetting-modulated surfaces are, for example, in DE 100 55 318 A1 described.
  • a three-dimensional embodiment of the metering device according to the invention may comprise wells in a solid which are closed by a lid to form the reservoir or connection structure.
  • the lid can be made in a simple manner from a film, preferably made of plastic.
  • An apparatus according to the invention with which the method according to the invention can be carried out using a device according to the invention comprises a receptacle for a device according to the invention.
  • the at least one device for generating a flow pattern is electrically contacted.
  • the apparatus of the invention further comprises controllable filling devices, for. As pipettes or dispensers, which are arranged in the receptacle inserted device above the filling structures.
  • the apparatus has a control for controlling the timing of a protocol, which performs the control of the device for generating the flow pattern and the filling devices.
  • Preferred embodiments include opening means for opening individual filling structures, vents or barrier structures or means for closing individual barrier structures.
  • the apparatus of the invention can also fulfill other functions with appropriate equipment, if z. B. a heater for Temperature control is provided. Finally, the z. B. electrical or optical evaluation with integrated.
  • the method according to the invention can be carried out simply and automatically. Disposable parts can be used without problems as devices according to the invention for integrated metering and mixing.
  • the method according to the invention, the device according to the invention and the apparatus according to the invention can be used particularly effectively for the metering and mixing of biological fluids in which a precise metering of very small amounts of liquid is necessary.
  • Fig. 1 shows a plastic part 5 with chambers 1, 3.
  • the plastic part 5 can be produced for example by injection molding.
  • the cover of the chamber is effected by a thin laminated plastic film 2, which in Fig. 2 is visible and in Fig. 1 is not shown to illustrate the interior of the plastic part 5.
  • Reference numeral 13 denotes the wall between the chambers 1 and 3.
  • Fig. 1 the positions of the filling openings 7 and 9 are indicated, which are provided in the plastic film 2, which, however, in Fig. 1 not shown.
  • an acoustic chip 15 which may be, for example, a piezoelectric solid-state chip on which an interdigital transducer for generating surface acoustic waves is applied in a conventional manner.
  • the interdigital transducer is designed such that the surface acoustic waves generated with it allow a Schallwellenabstrahlung in the reaction chamber 1.
  • the emission of sound waves into a volume of liquid separated by a solid from the surface acoustic wave generating interdigital transducer is shown in FIG DE 103 25 307 B3 described.
  • the acoustic chip 15 can also be provided on the film 2 or in a side region.
  • the acoustic chip 15 is connected via electrical connections, not shown, to an AC voltage source with which an AC voltage of a frequency of a few 10 MHz can be generated in order to generate surface acoustic waves with the interdigital transducer, which lead to the emission of sound waves into the reaction chamber 1.
  • acoustic chip 15 The location of the acoustic chip 15 is in Fig. 1 indicated, although the chip in this view would not be visible per se, since it is mounted in the embodiment shown on the underside of the device.
  • the acoustic chip is drawn in the form of parallel lines, which are intended only schematically to indicate the orientation of the individual finger electrodes of the interdigital transducer on the piezoelectric chip 15.
  • the emission direction of the surface acoustic waves of such an aligned interdigital transducer is perpendicular to the alignment of the finger electrodes.
  • the necessary size of the serving as a reaction reservoir chamber 1 depends on the frequency of the sound waves used. The smallest extent should be much larger than the wavelength of the sound used. Finally, the expansion of the reaction chamber 1 in the direction of propagation of the sound waves should be approximately one order of magnitude greater than the extent of the bottlenecks 11.
  • the smallest extent of the reservoirs is, for example, 1 mm to 10 mm at one Sound wave length of for example 100 microns. The total length of the channel system is a few centimeters.
  • the filling openings 7, 9 are at least an order of magnitude smaller than the reaction chamber 1.
  • the device according to the invention of this embodiment is used as follows.
  • the reaction reservoir comprises, for example, 100 .mu.l or 150 .mu.l while the metering reservoir holds 5 .mu.l.
  • Such fluid volumes are particularly characteristic of many diagnostic applications.
  • the metering reservoir 3 is filled by the filling hole 7 with a first liquid, which can be done for example by capillary force.
  • the liquid will remain at the bottlenecks 11, since here the capillary force is abruptly lower because of the larger diameter of the reservoir 1.
  • the reservoir 1 is filled through the filling holes 9 with a second liquid.
  • a possible supernatant of liquid on the respective filling holes 7, 9 is not critical.
  • the liquid of this supernatant does not participate in the following mixing process for geometrical reasons, in particular when the following mixing process is effected by a laminar flow pattern.
  • the volumes of the two liquids have now been defined geometrically, without great precision of the filling devices used, for example, pipettes, would be necessary.
  • the liquids are in contact. Diffusion takes place due to the narrow cross-section of the bottlenecks 11 only to a negligible extent.
  • Homogeneous mixing of the entire quantities of liquid is achieved with the aid of the acoustic chip 15.
  • By applying an AC voltage to the acoustic chip acoustic energy is radiated into the defined volumes of the liquids and a laminar flow pattern is generated.
  • the liquids or their ingredients are mixed and, if necessary, reacted.
  • the result of this reaction can be read, for example, optically or electrically. It is advantageous that the filling holes 7, 9 do not have to be closed.
  • the metering and mixing of the liquids thus takes place in a cost-effective optionally configured as a disposable cartridge device 5.
  • the dosing is also very simple. Even if it comes to a supernatant on the filling holes, this will not participate in the mixing reaction for geometric reasons and / or due to the laminar flow pattern used.
  • Fig. 3 shows another embodiment of a metering device according to the invention. Shown here is the section of a plastic body 105 which contains the metering device, which likewise comprises recesses in the plastic structure 105. Visible is the reaction reservoir 101 with filling holes 109. 103 shows a capillary structure with a plurality of openings, wherein the opening 107 serves as a filling opening. The capillary structure 103 represents a metering capillary structure, which communicates with the reaction reservoir 101 via connection capillary structures 111. The entire structure is also finished with a plastic film. In this embodiment too, the openings 107, 109, 121 and 122, which are not visible in the opened representation, are indicated in order to represent their relative position. Also indicated in its position is arranged below the device and therefore not actually visible in the representation acoustic chip 115 with an interdigital transducer. The acoustic chip 115 corresponds to that with reference to FIGS Fig. 1 and 2 described chip 15.
  • the filling takes place via the filling hole 107, which is open. All other holes 109, 121, 122 are initially closed. The volume of the first liquid that is filled can now be adjusted by selectively opening the holes 121, 122. If, for example, only one hole 121 is opened in the direct vicinity of the filling opening 107 and the hole 121 arranged symmetrically on the other side, a liquid volume of a length corresponding to the distance between the two opened openings 121 can be defined.
  • the capillary structure 103 thereby causes the front of the liquid to fill the entire cross section of the capillary structure 103. If no other vent holes are opened, builds up a back pressure, which leads to the stopping of the liquid. Moving beyond the opened holes 121 is therefore not possible. This effect is exacerbated by the fact that through the open opening 121, the capillary force causing the movement becomes smaller.
  • the residual volume in channel 103 and the connection capillary structures 111 can be filled by filling via the reaction reservoir 101 through the then openable openings 109. The residual volume of the channel 103 then counts to the reaction reservoir.
  • the characteristic dimensions of an embodiment according to the Fig. 3 correspond to the characteristic dimensions of the embodiment of the Fig. 1 and 2 ,
  • Fig. 4 shows another embodiment.
  • a plurality of metering reservoirs 203, 223 are provided, which communicate with the reaction reservoir 201 via connection capillary structures 211, 212.
  • the metering reservoirs 203, 223 have volumes of different sizes and communicate via a connecting channel structure 216.
  • In the connecting channel structure 216 is the filling opening 207.
  • the metering reservoirs 203, 223 have ventilation openings 221.
  • the connection channel 216 is likewise connected to the reaction reservoir 201 via a connection capillary structure 210.
  • the structure 210 also includes a vent hole 221.
  • filling openings 209 are provided.
  • barrier structures 217, 218, 219, 220 and 224 schematically illustrate barrier structures.
  • the entire metering device of the Fig. 4 is provided in a plastic part, which is closed by a film with openings 207, 209, 221. It may be in the metering of the Fig. 4 also a disposable part, which is prefabricated ex works.
  • the barrier structures 217, 218, 219, 220, 224 are initially designed to be closed.
  • Fig. 4 Also in the presentation of Fig. 4 the filling openings 207, 209 or the ventilation openings 221, which are not visible per se in the opened representation, are indicated in their position.
  • the acoustic chip 215 is in Fig. 4 indicated, although it is not visible in this representation, since it is located below the arrangement.
  • the characteristic dimensions correspond to the characteristic dimensions of the embodiment of FIG Fig. 1 and 2 .
  • the metering reservoir 223 is selected. After the selection is made, the respective barriers 217, 219 adjoining the metering reservoir 223 are melted, for example, by a heater or laser energy. This can be done, for example, with the aid of a machine that processes the dosing device.
  • the appropriately selected metering reservoir 223 can then be filled via the filling opening 207 and used for metering.
  • the dosage is similar to, for example, in the embodiment of Fig. 1 and 2 described carried out.
  • the dimensions of the structures are selected so that filling of the metering reservoir can be effected by the action of the capillary force. Alternatively, a filling can be done with pressure.
  • the vent opening 221 is arranged so that a complete filling of the reservoir is possible.
  • the procedure is analogous using the corresponding barrier structures 218, 220 and the connection capillary structure 212.
  • Another embodiment of this embodiment includes no barrier structures 217, 219 ex factory. Before the application, it is first decided again which of the metering reservoirs 203, 223 is to be used. If z. For example, if the metering reservoir 223 is selected, the other metering reservoir 203 is decoupled with the aid of a machine which, at the locations of the barriers 218, 220 which are adjacent to the metering reservoir 203 not to be used, melts the corresponding connection channel structures by application of heating energy or laser energy.
  • the individual metering reservoirs 203, 223 can each be connected to the reaction reservoir 201 via a plurality of connecting capillary structures 211, 212, which are open when the corresponding metering reservoir is selected.
  • connection capillary structure 210 may be provided, which connects the connection channel 216 to the reaction reservoir 201.
  • This connection capillary structure 210 also includes a vent opening 221 and optionally a barrier structure 224.
  • the additional channel 210 can serve to form a circuit which promotes effective mixing.
  • this in turn is the metering reservoir 223.
  • the barrier structures 217, 218, 219, 220, 224 are initially closed.
  • the barrier structure 217 is melted as described.
  • Liquid is introduced through the filling opening 207, which fills the metering reservoir 223 and the connecting capillary structure 211.
  • connection capillary structure 210 is filled with this liquid. The filling takes place for example by capillary force.
  • the barrier structures 219, 224 can be melted.
  • the liquid does not enter the reservoir 201 due to the capillary action which abruptly decreases at the entry points of the connection capillary structures 211, 210 into the reservoir 201.
  • Filling the reservoir 201 through the apertures 209 with a second liquid effects contact of the liquids at the entry sites of the interconnecting capillaries 210, 211.
  • Generating, for example, laminar flow with the acoustic chip 215 then effects effective mixing of the liquids. This can lead to a circulatory movement of the liquids.
  • connection capillary structure 210 taking advantage of capillary forces in the connection capillary structures 210, 211, 212, the barrier structure 224 can also be completely dispensed with. Especially in one embodiment with only two Dosierreservoirs, as in Fig. 4 In any case, the connection capillary structure 210 participates in the cycle process, so that decoupling is not necessary.
  • the barrier structures 219, 224 only after the introduction of the second liquid in the reservoir 201 melted. Otherwise the procedure is the same.
  • the connection structures 210, 211, 212 need not necessarily be able to exert capillary action on the liquids.
  • FIG. 4 Another process using an apparatus according to Fig. 4 uses barrier structures 217, 218, 219, 220, 224, which are originally open.
  • first liquid is introduced. Due to the capillary action, the latter flows into the metering reservoirs 203, 223 and into the connection capillary structures 210, 211, 212. They do not enter the reaction reservoir 201, since the capillary action at the points of entry of the connection structures 210, 211, 212 into the reaction reservoir 201 breaks off. It is only now decided which dosing reservoir, and therefore which dosing volume of the first liquid, should be used. For the purpose of the present description, this in turn is the metering reservoir 223.
  • the barrier structures 218, 220 are then sealed as described and thus uncoupling the unused metering reservoir 203 with the liquid therein. Second liquid is then filled into the reaction reservoir 201.
  • the subsequent procedure corresponds to the already described cycle procedure.
  • Fig. 5 shows the schematic plan view of a further embodiment of a metering device according to the invention.
  • the entire assembly 50 is disposed on the surface of a plastic carrier 305.
  • the reaction reservoir 1 is formed, for example, by a milled recess of 1 mm depth and has a volume of, for example, 20 ⁇ l.
  • This is followed in the example shown by two metering reservoirs 303, which are formed, for example, by 1 mm deep milled depressions each having a volume of 10 ⁇ l.
  • the dosing reservoirs close over two bottlenecks 311 to the reaction reservoir 301 at.
  • Via feeders 308 and 310, filling structures 307 and 309 are connected to the metering reservoir 303 and to the reaction reservoir 301, respectively.
  • the filling structures 307, 309 are likewise formed by depressions, for example 1 mm deep, in the plastic carrier 305.
  • the feeders 308, 310 are in the example shown wells with 300 microns depth. Over the entire arrangement is a non-visible plastic film, similar to the plastic film 2, as in Fig. 2 is recognizable. In the area of the filling structures 307, 309 to be used, this plastic film is pierced as required, for example, in order to be able to introduce liquid with the aid of a pipette.
  • 315 is a schematic diagram of an interdigital transducer formed of a large number of interdigitated finger electrodes. The operation has already been explained above with reference to the other embodiment.
  • a pulse in the direction of the arrow shown can be transmitted to the liquid in the leg 304 of the metering reservoir 303 shown in the upper half of the figure.
  • Fig. 6a to 6f show a sequence in the implementation of a method according to the invention with the embodiment of the Fig. 5 , Lines 320 and 322 have been plotted to indicate the arrangement of the reaction reservoir 301 with the feeders 310 and filling structures 309 shown in the illustrations of FIGS Fig. 6a to 6f otherwise would not be recognizable due to the low contrast.
  • Fig. 6a shows a state in which a dark colored liquid has already been filled into the metering reservoir 303 through the filling structure 307 and the feed 308.
  • the covering plastic film was pierced in the region of the filling structure 307 and the liquid was introduced into the filling structure 307 with a pipette. It can be clearly seen that the dark colored liquid does not enter the still empty reaction reservoir 301 due to its surface tension at the bottlenecks 311.
  • the volume is precisely defined in the dosing reservoir 303 between the bottlenecks 311 and the feeder 308 (10 ⁇ l in the example shown).
  • FIG. 6a shows the beginning of this filling process.
  • the covering plastic film was pierced in the region of the right filling structure 309 and started to fill in liquid with the aid of a pipette.
  • This liquid flows through the feed 310 into the reaction reservoir.
  • the fluid limit at this snapshot is approximately at the dotted auxiliary line 324.
  • Fig. 6b shows a state in which the entire reaction reservoir 301 is filled with the light liquid. A liquid exchange with the dark liquid in the metering reservoir 303 has taken place at this time only to a very limited extent.
  • Fig. 6c shows how the laminar flow generated thereby in the metering reservoir 303 causes the dark liquid enters the reaction reservoir 301.
  • Fig. 6d and 6e show the progress of this process. It can be clearly seen how the dark liquid, which was originally located in the dosing reservoir 303, and the light liquid which was in the reaction reservoir 301, mix.
  • Fig. 6f shows the state at the end of the process.
  • the liquids in the metering reservoir 303 and the reaction reservoir 301 are mixed homogeneously, which can be recognized by the homogeneous shading.
  • a further exchange with the liquid in the feeders 310 from the filling structures 309 to the reaction reservoir 301 has not taken place. Due to the dimensions of the reaction reservoir 301, therefore, the amount of the supplied light liquid is exactly determined. Since the dimensions of the metering reservoir 301 precisely determine the amount of dark liquid added, a very precise metering process has thus been carried out, so that the amounts of the various liquids in the in Fig. 6f present mixture are precisely determined.
  • Fig. 5 and 6 embodiment shown has two Dosierreservoirs 303. Other embodiments have only one dosing or even more Dosierreservoirs to dose different amounts.
  • the illustrated two metering reservoirs 303 are the same size in this embodiment. In order to be able to dose different amounts, differently sized metering reservoirs can also be used.
  • barrier structures may be provided as they relate to Fig. 4 were described. In this way, the number of connected Dosierreservoirs control, as well as for the embodiment of Fig. 4 is described.
  • a plurality of interdigital transducers can also be provided on the plastic carrier 305 in order to be able to address different dosing reservoirs at different times and to be able to produce laminar flow in the individual dosing reservoirs in order to effect a mixing with a liquid in the reaction reservoir.
  • Fig. 6a to 6f show that the inventive method leads in particular without pressure build-up to a liquid mixing, laminar flow.
  • a device according to the invention may also comprise more than two metering reservoirs with corresponding connection structures. It is then possible to connect a plurality of metering reservoirs in the circuit "in series" in order to increase the metering volume of the first fluid.
  • the individual Dosierreservoirs may have different or the same size.
  • reaction reservoir in a process using a loop of liquids, a reaction between the liquids does not take place only in the part of the device called the reaction reservoir.
  • the term "dosing reservoir”, with which the dosage of the first liquid is made the term "reaction reservoir” was nevertheless used in the present text, since in particular in the embodiments shown, the reaction reservoir is the main structure due to its size the reaction takes place.
  • the Dosierreservoirs and the reaction reservoir z. B. are the same size and in a circulation process also takes place in both reservoirs a reaction.
  • the dosing or mixing devices according to the invention can be processed in an automatic machine which fills the liquids into the devices, controls the devices, controls the acoustic chips and also opens or closes or opens or opens barriers.
  • an automatic machine which fills the liquids into the devices, controls the devices, controls the acoustic chips and also opens or closes or opens or opens barriers.
  • the z. B. electrical or optical evaluation are made.
  • Such machines can be usefully used in diagnostics or in laboratory automation in general.
  • the filling of the reservoir is carried out only by one or at most two filling structures, since this simplifies the addition of the liquid through the machine.
  • Corresponding pipetting heads or dispensers for filling can then be made stationary.
  • the method according to the invention a metering and mixing of liquids in a large dynamic range, ie with very different mixing ratios can be performed precisely.
  • the requirements on the accuracy of the filling devices used are not high, since the dosage by the process control according to the invention or use of the device according to the invention happens.
  • the mixing ratio between reagents and sample liquid can be set between 1: 100 to 100: 1 1.

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Claims (46)

  1. Procédé de dosage et de mélange intégré de petites quantités de liquide, dans lequel
    au moins un réservoir de dosage (3, 103, 203, 223, 303) est complètement rempli avec un premier liquide et est en communication via au moins une structure de liaison (11, 111, 211, 212, 311) avec un réservoir de réaction (1, 101, 201, 301), la structure de liaison ayant de préférence des dimensions telles que la tension superficielle du premier liquide empêche une entrée dans le réservoir de réaction (1, 101, 201, 301),
    un réservoir de réaction (1, 101, 201, 301) est rempli avec un deuxième liquide, et dans le liquide est engendré au moins dans ou respectivement sur le réservoir de réaction (1, 101, 201, 301) un modèle d'écoulement qui mène au mélange des liquides, caractérisé en ce que le réservoir de réaction est rempli complètement avec le deuxième liquide, de telle sorte que le deuxième liquide vient, au niveau de la structure de liaison (11, 111, 211, 212, 311), en communication avec le premier liquide.
  2. Procédé selon la revendication 1, dans lequel pour le mélange, on engendre un modèle d'écoulement sensiblement laminaire
  3. Procédé selon la revendication 2, dans lequel le modèle d'écoulement laminaire est engendré au moins dans une structure de liaison (311) entre le réservoir de dosage (303) et le réservoir de réaction (301), de préférence aussi dans le réservoir de dosage (303).
  4. Procédé selon la revendication 3, dans lequel pour générer le modèle d'écoulement laminaire, on utilise des ondes acoustiques.
  5. Procédé selon l'une des revendications 1 à 4, dans lequel pour le mélange, on injecte des ondes acoustiques dans le liquide dans ou sur le deuxième réservoir (1, 101, 201, 301).
  6. Procédé selon l'une des revendications 4 ou 5, dans lequel les ondes acoustiques sont engendrées avec des ondes acoustiques de surface, de préférence à l'aide d'au moins un transducteur interdigité.
  7. Procédé selon l'une des revendications 1 à 6, dans lequel au moins ladite au moins une structure de liaison comprend une structure capillaire de liaison.
  8. Procédé selon l'une des revendications 1 à 7, dans lequel les réservoirs et ladite au moins une structure de liaison sont formés par des zones surfaciques sur une surface qui, en comparaison avec la surface environnante, sont de préférence mouillées par les liquides.
  9. Procédé selon l'une des revendications 1 à 7, dans lequel les réservoirs et ladite au moins structure de liaison sont formés par des renfoncements dans une surface.
  10. Procédé selon l'une des revendications 1 à 7, dans lequel les réservoirs (1, 3, 101, 103, 201, 203, 223) et ladite au moins une structure de liaison (11, 111,210, 211,212) sont formés par des cavités dans une structure de corps solide (5, 105).
  11. Procédé selon la revendication 10, dans lequel les réservoirs (1, 3, 101, 103, 201, 203, 223) sont remplis par des ouvertures de remplissage (7, 9, 107, 109, 207, 209) de préférence dans la bordure supérieure du réservoir.
  12. Procédé selon l'une des revendications 10 ou 11, dans lequel on utilise en tant que réservoir de dosage une structure capillaire de réservoir (103) qui présente le long de son extension longitudinale au moins deux ouvertures (107, 121, 122).
  13. Procédé selon la revendication 12, dans lequel le volume de la première quantité de liquide est choisi par le choix des ouvertures (121, 122) à ouvrir dans la structure capillaire de réservoir (103).
  14. Procédé selon l'une des revendications 1 à 11, dans lequel pour remplir ledit au moins un réservoir de dosage (303), on utilise au moins une structure de remplissage (307) ouverte qui est reliée via des amenées (308) audit au moins un réservoir de dosage (303).
  15. Procédé selon l'une des revendications 1 à 11 ou 14, dans lequel pour remplir le réservoir de réaction (301), on utilise au moins une structure de remplissage (309) ouverte qui est reliée via des amenées (310) au réservoir de réaction (301).
  16. Procédé selon l'une des revendications 14 ou 15, dans lequel au moins une structure capillaire est utilisée en tant qu'amenée (308, 310).
  17. Procédé selon l'une des revendications 1 à 16, dans lequel on utilise un dispositif avec plusieurs réservoirs de dosage (203, 223, 303) de préférence de différentes tailles, qui communiquent d'une part via des structures de liaison (211, 212, 311) avec le réservoir de réaction (201, 301) et d'autre part avec une ouverture de remplissage (207, 307).
  18. Procédé selon la revendication 17, dans la mesure où elle dépend directement ou indirectement de l'une des revendications 9 ou 10, dans lequel les structure de liaison (211, 212) sont tout d'abord fermées et sont ouvertes pour choisir le réservoir de dosage (203, 223) souhaité.
  19. Procédé selon la revendication 17, dans la mesure où elle dépend directement ou indirectement de l'une des revendications 9 ou 10, dans lequel le réservoir de dosage (203, 223) souhaité est choisi par fermeture des structures de liaison (211, 212) vers les autres réservoirs de dosage.
  20. Procédé selon l'une des revendications 18 ou 19, dans lequel l'ouverture ou la fermeture des structures de liaison (211), respectivement, est provoquée par un processus de fusion dans une partie en matière plastique.
  21. Dispositif de dosage et de mélange intégré de petites quantités de liquide, pour mettre en oeuvre le procédé selon la revendication 1, comportant
    au moins un réservoir de dosage (3, 103, 203, 223, 303) pour une première quantité de liquide,
    un réservoir de réaction (1, 101, 201, 301) pour une deuxième quantité de liquide,
    au moins une structure de liaison (11,111,211,212,311) entre ledit au moins un réservoir de dosage et le réservoir de réaction, la structure de liaison ayant de préférence des dimensions telles que le premier liquide, en raison de sa tension superficielle, n'entre pas dans le réservoir de réaction (1, 101, 201, 301) et
    un système (15, 115, 215, 315) pour générer un modèle d'écoulement pour le mélange de liquide au moins dans ou sur le réservoir de réaction, respectivement,
    caractérisé en ce que le système (15, 115, 215, 315) comprend au moins un système (15, 115, 215, 315) de génération d'ondes acoustiques pour injecter des ondes acoustiques dans le réservoir de réaction (1, 101, 201) ou en direction du réservoir de réaction (301) respectivement.
  22. Dispositif selon la revendication 21, dans laquelle au moins un système de génération d'ondes acoustiques comprend un système de génération d'ondes acoustiques de surface (15, 115, 215, 315).
  23. Dispositif selon la revendication 22, comportant au moins un transducteur interdigité pour générer les ondes acoustiques de surface.
  24. Dispositif selon l'une des revendications 21 à 23, dans lequel ladite au moins une structure de liaison comprend une structure capillaire de liaison.
  25. Dispositif selon l'une des revendications 21 à 24, dans lequel les réservoirs et ladite au moins une structure de liaison comprennent des zones surfaciques sur une surface qui, en comparaison avec la surface environnante, est de préférence mouillée par les liquides.
  26. Dispositif selon l'une des revendications 21 à 24, dans lequel les réservoirs et ladite au moins une structure de liaison comprennent des renfoncements dans une surface.
  27. Dispositif selon l'une des revendications 21 à 24, dans lequel les réservoirs (1, 3, 101, 103, 201, 203, 223) et ladite au moins une structure de liaison (11, 111, 211, 212, 311) comprennent des cavités dans une structure de corps solide (5, 105).
  28. Dispositif selon la revendication 27, dans laquelle les cavités comprennent des renfoncements dans un corps solide (5, 105, 305) qui sont fermés par un couvercle (2).
  29. Dispositif selon la revendication 28, dans lequel le couvercle (2) est formé par une feuille (2), de préférence en matière plastique.
  30. Dispositif selon l'une des revendications 27 à 29, dans lequel ledit au moins un réservoir de dosage comprend une structure capillaire de dosage (103).
  31. Dispositif selon l'une des revendications 27 à 30, dans lequel les cavités comprennent des ouvertures (121, 122) prédéterminées qui sont tout d'abord fermées et qui peuvent être ouvertes en cas de besoin.
  32. Dispositif selon l'une des revendications 30 à 31, dans lequel la structure capillaire de dosage (103) comprend au moins deux ouvertures (121, 122) prédéterminées, le cas échéant à ouvrir, qui sont agencées le long de la structure capillaire de dosage.
  33. Dispositif selon l'une des revendications 21 à 32, comportant au moins une structure de remplissage (307) pour remplir ledit au moins un réservoir de dosage (303), laquelle est reliée via des amenées (308) avec ledit au moins un réservoir de dosage (303).
  34. Dispositif selon l'une des revendications 21 à 33, comportant au moins une structure de remplissage (309) ouverte pour remplir le réservoir de réaction (301), laquelle est reliée via une amenée (310) au réservoir de réaction (301).
  35. Dispositif selon l'une des revendications 33 ou 34, dans lequel les amenées (308, 310) comprennent des structures capillaires.
  36. Dispositif selon l'une des revendications 21 à 35, dans lequel il est prévu plusieurs réservoirs de dosage (203, 223, 303), de préférence de différentes tailles, qui communiquent via des structures de liaison (211, 212, 311) avec le réservoir de réaction (201, 301).
  37. Dispositif selon la revendication 36, dans lequel les structures de liaison (211, 212, 311) sont tout d'abord fermées et peuvent être ouvertes en cas de besoin.
  38. Dispositif selon la revendication 37, dans la mesure où elle dépend directement ou indirectement de l'une des revendications 26 ou 27, dans laquelle les structures de liaison (211, 212) comprennent des barrières (219, 220) fusibles en matière plastique.
  39. Dispositif selon la revendication 38, dans lequel les structures de liaison (211, 212) sont tout d'abord ouvertes et peuvent être fermées en cas de besoin.
  40. Dispositif selon la revendication 39, dans la mesure où elle dépend directement ou indirectement de l'une des revendications 26 ou 27, dans laquelle les structures de liaison (211, 212) comprennent des structures de barrière qui, par un processus de fusion, peuvent être façonnées en des barrières (219, 220).
  41. Appareil pour la mise en oeuvre automatique d'un procédé selon la revendication 1, comportant
    un logement pour un dispositif (10, 20, 30) selon la revendication 21, des contacts électriques pour la mise en contact dudit au moins un système (15, 115, 215, 315) pour générer un modèle d'écoulement, qui, lorsque le dispositif (10, 20, 30, 50) est placé dans le logement, viennent en contact électrique avec au moins un système (15, 115,215, 315) destiné à générer un modèle d'écoulement,
    des systèmes pour l'amenée automatique de liquide dans les réservoirs (1, 3, 101, 103, 201, 203, 223, 301, 303) qui comprennent des pointes de pipetage et/ou des distributeurs pilotables qui, lorsque le dispositif (10, 20, 30, 50) est placé dans le logement, sont agencés au-dessus d'ouvertures de remplissage ou de structures de remplissage (7, 9, 107, 109, 207, 209, 307, 309) correspondantes, et
    une commande, comportant de préférence un microprocesseur, pour commander ledit au moins un système (15, 115, 215, 315) pour générer un modèle d'écoulement et les systèmes pour l'amenée automatique de liquide.
  42. Appareil selon la revendication 41, comportant des systèmes d'ouverture pilotables par la commande pour ouvrir les ouvertures (121, 122) d'un dispositif (20) selon l'une des revendications 32 ou 33, mis en place dans le logement.
  43. Appareil selon la revendication 42, dans lequel les systèmes d'ouverture comprennent des pointes de perforation pour perforer une feuille de matière plastique prévue en tant que couvercle du dispositif (20).
  44. Appareil selon la revendication 41, comportant des systèmes de génération de chaleur pilotables par la commande pour générer de la chaleur aux emplacements des structures de barrière (217, 218, 219, 220, 224) d'un dispositif (30) selon l'une des revendications 39 ou 41.
  45. Appareil selon la revendication 44, dans lequel les systèmes de génération de chaleur comprennent des fils chauffants ou un laser.
  46. Utilisation d'un procédé selon l'une des revendications 1 à 20, d'un dispositif (10, 20, 30, 50) selon l'une des revendications 21 à 40 ou d'un appareil selon l'une des revendications 41 à 45 pour doser et mélanger des liquides biologiques.
EP05818698A 2005-01-05 2005-12-16 Procede et dispositif de dosage et de melange de petites quantites de liquide Not-in-force EP1833598B1 (fr)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
DE102005000835A DE102005000835B3 (de) 2005-01-05 2005-01-05 Verfahren und Vorrichtung zur Dosierung kleiner Flüssigkeitsmengen
DE102005000834A DE102005000834B4 (de) 2005-01-05 2005-01-05 Verfahren und Vorrichtung zur Dosierung und Durchmischung kleiner Flüssigkeitsmengen
PCT/EP2005/013597 WO2006072383A1 (fr) 2005-01-05 2005-12-16 Procede et dispositif de dosage et de melange de petites quantites de liquide

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EP1833598A1 EP1833598A1 (fr) 2007-09-19
EP1833598B1 true EP1833598B1 (fr) 2008-10-08

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JP (1) JP5112880B2 (fr)
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WO2006072383A1 (fr) 2006-07-13
JP2008527337A (ja) 2008-07-24
JP5112880B2 (ja) 2013-01-09
DE502005005660D1 (de) 2008-11-20
ATE410220T1 (de) 2008-10-15
US8062904B2 (en) 2011-11-22
EP1833598A1 (fr) 2007-09-19

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