EP1843833B1 - Procede et dispostif de dosage et de melange des petites quantites de liquide, appareil et utilisation - Google Patents

Procede et dispostif de dosage et de melange des petites quantites de liquide, appareil et utilisation Download PDF

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Publication number
EP1843833B1
EP1843833B1 EP05820542A EP05820542A EP1843833B1 EP 1843833 B1 EP1843833 B1 EP 1843833B1 EP 05820542 A EP05820542 A EP 05820542A EP 05820542 A EP05820542 A EP 05820542A EP 1843833 B1 EP1843833 B1 EP 1843833B1
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European Patent Office
Prior art keywords
liquid
reservoir
accordance
reservoirs
passage structure
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EP05820542A
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German (de)
English (en)
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EP1843833A1 (fr
Inventor
Christoph Gauer
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Advalytix AG
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Advalytix AG
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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
    • B01L3/50273—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 or forces applied to move the fluids
    • 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
    • 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
    • B01F31/87—Mixing by means of high-frequency vibrations above one kHz, e.g. ultrasonic vibrations transmitting the vibratory energy by means of a fluid, e.g. by means of air shock waves
    • 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
    • B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
    • B01L2300/00—Additional constructional details
    • B01L2300/08—Geometry, shape and general structure
    • B01L2300/089—Virtual walls for guiding liquids
    • 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
    • B01L2400/0436—Moving fluids with specific forces or mechanical means specific forces vibrational forces acoustic forces, e.g. surface acoustic waves [SAW]
    • 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
    • B01L2400/0493—Specific techniques used
    • B01L2400/0496—Travelling waves, e.g. in combination with electrical or acoustic 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
    • B01L2400/0688—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
    • 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
    • B01L3/502769—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 multiphase flow arrangements
    • B01L3/502776—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 multiphase flow arrangements specially adapted for focusing or laminating flows

Definitions

  • the invention relates to a method for integrated metering and mixing of small amounts of liquid, a device and an apparatus for carrying out this 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 recently introduced "lab-on-a-chip" technology could be used, in which the Processing of liquids can be performed on or integrated into a chip. 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 method for mixing liquids 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 creates high costs due to the necessary wetting structuring the surface (hydrophilic for filling the channel itself and hydrophobic for the barrier and the branch).
  • US 5,674,742 describes a device for manipulating, reacting and detecting small amounts of liquid with a first reservoir for a first quantity of liquid, a reaction reservoir and a connection channel structure connecting the reservoir, which has a cross-section in a region in the direction of the connecting line of the reservoir, which is smaller than the cross-sections of the reservoirs is.
  • the apparatus includes means for generating flow along the connection channel structure and mixing the amounts of liquid in the second reservoir.
  • liquid in the present text includes i.a. pure liquids, mixtures, dispersions and suspensions; and liquids containing solid particles, for example, biological material.
  • dosing and mixing liquids may also be two or more similar solutions that differ in ingredients dissolved therein that are to be reacted.
  • the object of the present invention is to provide a method and a device by means of which a precise metering of liquid quantities on or in an integrated chip is possible and which enable precise mixing of the liquids.
  • a first liquid is produced placed in or on a first reservoir.
  • a second liquid is brought into or onto a second reservoir in such a way that it is completely filled.
  • the first and second liquids are brought into contact via at least one first connection channel structure which comprises at least one region which has a smaller cross section than the reservoirs themselves in the direction of the connection line of the two reservoirs.
  • Liquid exchange is effected by laminar flow in the connection channel structure and the liquids are mixed in and on the second reservoir.
  • the liquids come into contact via the connecting channel structure. At the interface between the two liquids, only negligible diffusion occurs because the cross-section of the connection channel structure is comparatively small.
  • a laminar flow is generated along the connection channel structure in the direction of the second reservoir, the first liquid is moved through the connection channel structure in the direction of the second reservoir. For example, by accurately selecting the period of time over which the laminar flow is generated in the connection channel structure, or the flow rate, a precise definition of the volume of the first liquid to be metered to the second liquid is made.
  • the amount of the second liquid is precisely determined by the size of the reservoir. In or on the second reservoir then optionally takes place the reaction between the liquids.
  • the second reservoir thus constitutes a reaction chamber.
  • the method according to the invention enables the metering and mixing of liquids in a large dynamic range. Thus, the mixing ratio of reagents to sample liquid z. B. from 1: 100 to 100: 1 can be set.
  • pipettes and / or corresponding filling structures can be used.
  • the precision requirements of these elements are low, since the definition of the volumes of liquid participating in the reaction are determined by the method according to the invention or the device itself, in particular by the duration or the velocity of the laminar flow in the connection channel structure and the Volume of the second reservoir.
  • the laminar flow is preferably caused by the irradiation of sound waves towards at least a part of the connection channel structure.
  • the reservoirs and the connection channel structure may be configured three-dimensionally or two-dimensionally.
  • the reservoirs and interconnect channel structures may be correspondingly shaped depressions in a surface.
  • Other configurations are correspondingly shaped cavities.
  • the reservoirs and connection channel 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. The liquids are held by their surface tension on the preferably wetted areas.
  • the amount of the second liquid participating in the reaction is determined by the dimensions of the second reservoir. If the second reservoir, for example via corresponding filling structures, for. As filling channels and / or filling, filled, any existing supernatants of liquid in these filling structures outside of the reservoir for geometric reasons do not participate in the mixing, especially when the mixing is effected by laminar flow pattern.
  • the laminar flow is generated in or on the connecting channel structure with the aid of sound waves.
  • surface acoustic waves are used, which can be generated for example with one or more interdigital transducers.
  • Surface sound waves transmit their impulse to the liquid or substances contained in it in order to put it in motion.
  • the latter has a radiation direction in the direction of the extension of at least one part of the connection channel structure.
  • the first and second liquids may be contacted via the connection channel structure using, for example, capillary forces.
  • the connecting channel structure is chosen so small in its lateral dimensions, that at least one of the liquids is pulled by the capillary forces along the channel. So z.
  • a first liquid can be brought onto or into the first reservoir, which propagates through the capillary forces in or on the connection channel structure.
  • the liquid stops its movement, since only small capillary forces act through the larger cross-section of the reservoir compared to the connecting channel structure.
  • the second liquid is applied, which comes into contact with the first liquid at the entry point of the connecting channel structure in the second reservoir.
  • connection between the two liquids is made via a small "bridge drop" which is placed between the two liquids and creates a liquid bridge.
  • the bridge drop has a much smaller volume than either of the two liquid quantities.
  • pipettes and / or corresponding filling structures can be used.
  • the requirements for the precision of these elements are low, since the definition of the participating in the reaction volumes of liquid by the inventive method or the inventive Device itself, in particular by the duration or the speed of the laminar flow in the connection channel structure and the volume of the second reservoir.
  • the filling structures may also comprise filling channel structures with small cross-sections compared to the reservoirs.
  • the production of a corresponding structure is very simple, since the same process steps are used, which are also used in the production of the reservoir or in the connecting channel structure.
  • the comparatively small cross-sections effectively prevent any supernatants present after filling in the filling channel structures from taking part in the mixing. In this way it is prevented that possibly existing liquid supernatants in the filling channel structures make the specification of the liquid volumes participating in the mixing inaccurate.
  • Such filling channel structures can have a small cross-section, which ensures that the liquid moves through the filling channel structures or on the filling channel structures due to capillary action in the direction of the reservoirs. For a precise filling is easy to carry out.
  • the inventive method can be carried out with a single connection channel structure between the two reservoirs.
  • This is the first reservoir at least partially emptied by the laminar outflow of the first liquid.
  • Another embodiment according to the invention comprises at least two connecting channel structures between the two reservoirs.
  • a laminar flow is generated by means of surface acoustic waves, which serves for moving the first liquid from the first reservoir in the direction of the second reservoir.
  • the first fluid in the first reservoir is thus becoming less and less due to the laminar outflow.
  • second liquid flows into the first reservoir from the second reservoir via the second connection channel structure.
  • the liquids are mixed. It is particularly favorable if this mixing process is effected by generating substantially laminar flow patterns. This ensures that any supernatants at the filling structures take part in the mixing as little as possible or not at all.
  • sound waves which are radiated into the second reservoir, are suitable for generating such flow patterns.
  • the surface acoustic waves can be used to radiate sound waves through a solid, such as a reservoir bottom, into the liquid.
  • known per se interdigital transducers can be used, which can be easily produced by lithographic techniques.
  • the invention also includes embodiments in which the laminar flow and the mixing are produced with the same device.
  • the method according to the invention is not limited to the metering and mixing of only two quantities of liquid.
  • additional reservoirs may be connected to the second reservoir in addition via further connecting channel structures, from which further fluids are metered into the second reservoir.
  • the addition can be done simultaneously or sequentially.
  • a device for metering small quantities of liquid has a first reservoir for a first liquid, a second reservoir for a quantity of a second liquid and at least one connecting channel structure which connects the two reservoirs and has at least in one region a cross section in the direction of the line of connection of the reservoirs which is smaller than the cross sections of the reservoirs.
  • the reservoirs and the at least one connecting channel structure may be formed as depressions or cavities in a solid body.
  • the reservoirs and the at least one connecting channel structure are formed by surface areas which are more preferably wetted by the liquids.
  • the device according to the invention furthermore has at least one device for generating laminar flow along the at least one connecting channel structure.
  • a preferred embodiment comprises a device for generating sound waves, preferably surface acoustic waves.
  • the use is at least particularly simple an interdigital transducer for generating surface acoustic waves, which can be easily produced by lithographic techniques.
  • the device according to the invention has at least one device for mixing the quantities of liquid in or on the second reservoir.
  • a second sound wave generating device is provided for generating sound waves entering the second reservoir.
  • the device according to the invention can be designed as a cost-effective and practical disposable part.
  • a device according to the invention which is to be used for metering and mixing of more than two quantities of liquid, has a corresponding number of reservoirs with a corresponding number of connection channel structures for integrated metering and mixing of more than two quantities of liquid.
  • the method according to the invention and the device 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 fluid is necessary.
  • the devices according to the invention can be operated automatically with a correspondingly designed automatic machine.
  • FIGS Fig. 1 to 4 includes a disposable part made of plastic, for example. While Fig. 1 shows the horizontal cross-section to illustrate the arrangement of the individual elements, shows Fig. 2 a section along the line AB and Fig. 3 a section along the line CD.
  • the individual elements are, as it is in the Fig. 2 to 4 clearly recognizable cavities in the plastic part. In the lateral sectional figures, only the cavities are shown.
  • the structures can be formed for example by pressing metallic counterparts of the molds and subsequently with a film - here from below - be completed.
  • the plastic part can be produced as an injection molded part.
  • the reservoir 1 is connected via two further channels 7 with upwardly open filling nozzle 17.
  • the channels 7 also have such a small cross-section that capillary forces act on a liquid therein.
  • the reservoir 3 is connected via a capillary channel 11 with the filling nozzle 19.
  • the dimensions and the process control are chosen so that the Reynolds number of the considered liquids is in the range of the laminar flow.
  • the necessary parameters can be determined in preliminary tests. Typical viscosities of liquids used are in the range of 1 mPa.s to several 100 mPa.s at speeds of 1 mm per second to 1 cm per second. Suitable system cross sections are then in the range of a few 100 microns with a total length of a few cm.
  • acoustic chip 13 denotes an acoustic chip. This is, for example, a piezoelectric solid-state chip on which an interdigital transducer for generating surface acoustic waves is applied in a manner known per se.
  • the interdigital transducer on the acoustic chip 13 is a unidirectional radiating transducer which generates surface acoustic waves only in the direction of the reservoir 1.
  • acoustic chip 15 designates a further acoustic chip, which likewise carries an interdigital transducer in a manner known per se.
  • This interdigital transducer is configured in such a way that the surface sound waves generated with it enable sound wave radiation into the reservoir 1.
  • the emission of sound waves into a liquid volume, the is removed by a solid from the surface acoustic wave generating interdigital transducer is in DE 103 25 307 B3 described.
  • the acoustic chip 15 may, for. B. also be provided on the other side of the reservoir 1.
  • the acoustic chips 13, 15 are connected via electrical connections, not shown, to an AC voltage source, with which an AC voltage of a frequency of a few tens of MHz can be generated in order to produce surface acoustic waves with the interdigital transducers.
  • Such a device is used as follows for carrying out the method according to the invention.
  • the reservoir 3 is filled with a small amount of liquid. Due to capillary forces, this liquid enters the channel 5. However, the liquid does not enter the reservoir 1, because there the cross-section is considerably larger and so the capillary force is abruptly weaker.
  • the reservoir 1 is pressurized, for. B. completely filled by a pipette with a larger amount of another liquid. It is harmless if 17 supernatants remain in liquid in the filling channels 7 for the reservoir 1 or the filling nozzle. These do not participate in the mixing process to be carried out later by generating laminar flow patterns in the reservoir 1 for geometrical reasons and are therefore not relevant for the determination of the liquid volume participating in the mixing process.
  • a laminar flow is generated by the momentum transfer of the surface acoustic waves to the liquid in the channel 5.
  • the time duration over which the interdigital transducer is operated, or the pumping power the amount of liquid which flows laminarly via the capillary channel 5 into the reservoir 1 can be precisely determined.
  • the determination of the necessary time duration or the pumping power can be determined for example on the basis of preliminary tests.
  • the laminar flow thus ensures a defined supply of liquid.
  • the reservoir 1 then serves as a reaction chamber in which a reaction of the two defined amounts of liquid or their ingredients can take place.
  • Fig. 5 shows a modification of the embodiment of the Fig. 1 to 4 ,
  • the capillary channel 6 between the reservoir 3 and the reservoir 1 is not rectilinear.
  • An acoustic chip 14 with an interdigital transducer is used, which does not have to radiate unidirectionally here. It is sufficient if the acoustic chip 14 is arranged such that one of its emission directions points in the direction of the capillary channel 6.
  • a surface acoustic wave is radiated in the indicated direction, the momentum transfer of which leads to the liquid in the capillary channel 6 to a laminar flow.
  • the 6 and 7 show an embodiment that can be realized on the surface of a solid state chip.
  • the reservoirs 101 and 103 include surface regions whose wetting properties are selected such that they are preferably wetted by a liquid.
  • the reservoirs 101, 103 are hydrophilic compared to the surrounding solid surface. This is z. B. achieved by silanization of the surrounding surface, which leads to a hydrophobic surface.
  • the reservoirs 101 and 103 are connected by a laminar connection channel structure 105 whose wetting properties are also selected.
  • a laminar connection channel structure 105 On the surface is located in a manner not shown, an interdigital transducer whose emission direction along the channel 105 goes to produce laminar flow in the channel 105.
  • the channel 105 is selected so narrow that capillary forces act on liquid thereon.
  • Such a device is used as follows.
  • a liquid drop 123 of a first liquid is applied to the reservoir 103 and, due to the described wetting properties of the surface, does not move outward from the reservoir 103 and is held together by its surface tension. Due to capillary forces, this liquid moves along the channel structure 105. The abruptly decreasing capillary forces at the junction between the channel structure 105 and the larger reservoir surface 101 stops the movement of the liquid at the juncture between the channel structure 105 and the reservoir surface 101.
  • a second liquid drop 121 is applied to the reservoir surface 101. Also, this liquid drop 121 is held together by the selected wetting properties of the surface and its surface tension. Its size is selected so that the reservoir surface 101 is completely filled. By selecting the size of the surface 101 so that the volume is determined.
  • interdigital transducer In the area of the reservoir surface 101 is an interdigital transducer, with the aid of which a laminar flow pattern for mixing the liquids is produced.
  • the interdigital transducer is in the 6 and 7 also not shown for the sake of clarity.
  • the liquid drop 121 on the reservoir surface 101, the liquid drop 123 on the reservoir surface 103, and the liquid bridge 125 along the channel structure 105 can be seen.
  • FIG. 8 and 9 show a modification of the embodiment of the 6 and 7 ,
  • the reservoir surfaces 101 and 103 are not interconnected by a channel structure 105 here.
  • a connection of the amounts of liquid 121 and 123 is done here by deliberately introducing a "bridge drop" 127 small volume, which provides a liquid bridge between the two liquid quantities, via which by means of the as in the embodiment of 6 and 7 generated laminar flow in the manner described a liquid transport can take place.
  • Fig. 10 serves the schematic representation of another procedure.
  • Reservoirs 201 and 203 are interconnected via two capillary structures 223, 227.
  • An interdigital transducer 213, which is indicated only schematically, has at least one emission direction along the channel structure 227.
  • Beneath the reservoir 201 is a surface acoustic wave generation device 215, eg, a surface acoustic wave generator 215.
  • B. also an interdigital transducer, which can emit a sound wave in the liquid in the overlying reservoir similar to the surface acoustic wave generating device 15 already described.
  • a first liquid is introduced in the reservoir 203.
  • the liquid enters the capillaries 223, 227 due to the capillary force.
  • a second liquid is introduced into the reservoir 201 for its complete filling.
  • the operation of the interdigital transducer 213 generates a surface acoustic wave at least in the direction indicated. By the momentum transfer of the surface acoustic wave to the liquid in the channel 227, a laminar flow is generated there.
  • the liquid from the channel 227 enters the reservoir 201 and is replenished from the reservoir 203.
  • the liquid boundaries 229, 231 move accordingly. Since it is a laminar and not a turbulent flow, apart from the diffusion at the liquid boundaries 229, 231 no mixing takes place. It creates a state like him in Fig. 10b is shown.
  • the respective proportion of the liquids in the reservoir 201 can be determined.
  • a surface acoustic wave is generated, which leads to the radiation of a sound wave in the liquid in the reservoir 201 and there causes corresponding flow pattern for mixing the two liquids. It creates a mixture 233, as in Fig. 10c indicated.
  • connection channel structures between the reservoirs can be carried out both two-dimensionally with corresponding wetting structures as well as three-dimensionally with corresponding recesses or cavities.
  • the figures are not to scale. This is the ratio of the volumes the channel structures to the volume of the reservoirs z. Between 1/10 and 1/100.
  • the method according to the invention and the devices according to the invention make it possible to precisely meter in a quantity of liquid to a quantity of liquid defined by the volume of the second reservoir, for example by selecting the time during which a laminar flow is generated along the connection channel structure of the devices according to the invention.
  • the method is easy to carry out and the device can be made small, compact and possibly disposable.
  • the embodiments according to the invention can be operated in an automaton.
  • a machine has z.
  • a receptacle for a device according to the invention which makes electrical contact with the interdigital transducers.
  • Automatically operated pipetting heads and / or dispensers are provided, which are arranged in such a way that they are arranged above the reservoirs or the filling structures when the device is inserted in the receptacle.
  • a control preferably provided with a microprocessor unit, which serves for timing the pipetting heads / dispensers and the interdigital transducer in order to process a desired metering and mixing protocol.
  • the evaluation instruments such. B. optical measuring devices, etc., to detect the possibly triggered by the mixing process reaction.

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Claims (29)

  1. Procédé pour le dosage intégré et pour le mélange intime de petites quantités de liquide, dans lequel :
    un premier liquide est amené dans ou sur un premier réservoir (3, 103, 203),
    un second réservoir (1, 101, 201) est totalement rempli avec un second liquide,
    le premier et le second liquide sont amenés en contact via au moins une structure en canal de liaison (5, 6, 105, 227) qui comprend au moins une région qui, dans la direction d'observation de la ligne de liaison des deux réservoirs, présente une plus petite section que les réservoirs,
    on génère un écoulement laminaire dans la structure en canal de liaison (5, 6, 105, 227) pour l'échange des deux liquides, et
    les liquides sont mélangés de façon intime dans ou sur le second réservoir (1, 101, 201).
  2. Procédé selon la revendication 1, dans lequel l'échange de liquides est effectué par injection d'ondes sonores en direction d'au moins une partie de la structure en canal de liaison (5, 6, 105, 227).
  3. Procédé selon la revendication 2, dans lequel l'injection d'ondes sonores pour la génération de l'échange de liquide dans la zone d'écoulement laminaire est maintenue pendant une période temporelle définie.
  4. Procédé selon l'une des revendications 2 ou 3, dans lequel l'écoulement laminaire est généré à l'aide d'un transfert par impulsion d'ondes sonores de surface.
  5. Procédé selon la revendication 4, dans lequel les ondes sonores de surface sont générées avec au moins un transducteur interdigité (213) avec une direction de rayonnement en direction le long d'au moins une partie d'une structure en canal de liaison (5, 6, 105, 227).
  6. Procédé selon l'une des revendications 1 à 5, dans lequel l'un au moins des liquides est amené dans ou sur ladite au moins une structure en canal de liaison (5, 6, 105, 227) en utilisant des forces capillaires.
  7. Procédé selon la revendication 6, dans lequel on amène tout d'abord un premier liquide (123) dans ou sur le premier réservoir (3, 103, 203) qui se propage par des forces capillaires à travers la structure en canal de liaison (5, 105, 227) jusqu'au second réservoir (1, 101, 201), et ensuite un second liquide (121) est amené dans ou sur le second réservoir (1, 101, 201) lequel vient en contact avec le premier liquide au niveau de l'emplacement d'entrée de la structure en canal de liaison (5, 6, 105, 201) dans le second réservoir (1, 101, 201).
  8. Procédé selon l'une des revendications 1 à 5, dans lequel le contact des deux quantités de liquide (121, 123) est établi via une troisième quantité de liquide (125) avec un volume inférieur aussi bien à celui de la première quantité de liquide qu'à celui de la seconde quantité de liquide et qui est amené entre la première et la seconde quantité de liquide.
  9. Procédé selon l'une des revendications 1 à 8, dans lequel on utilise des ondes sonores pour le mélange intime des liquides dans ou sur le second réservoir (1, 101, 201).
  10. Procédé selon la revendication 9, dans lequel on emploie des ondes sonores de surface pour générer les ondes sonores pour le mélange intime.
  11. Procédé selon la revendication 10, dans lequel on emploie au moins un transducteur interdigité (215) pour la génération des ondes sonores de surface.
  12. Procédé selon l'une des revendications 1 à 11, dans lequel le remplissage du réservoir (1, 101, 201, 3, 103, 203) a lieu via des structures en canal de remplissage (7, 11).
  13. Procédé selon l'une des revendications 1 à 12, dans lequel les deux réservoirs (201, 203) sont en communication via au moins deux structures en canal de liaison (223, 227).
  14. Procédé selon l'une des revendications 1 à 13, dans lequel on utilise comme réservoirs et/ou comme ladite au moins une structure en canal des renfoncements de formes correspondantes dans une surface.
  15. Procédé selon l'une des revendications 1 à 13, dans lequel on utilise comme réservoirs (1, 3) et comme ladite au moins une structure en canal (5, 6, 7, 11) des cavités de formes correspondantes.
  16. Procédé selon l'une des revendications 1 à 13, dans lequel on utilise comme réservoirs (101, 103) et comme ladite au moins une structure en canal (105) des zones de formes correspondantes d'une surface, qui sont mouillées par les liquides (121, 123, 125) de préférence aux zones environnantes de la surface.
  17. Procédé selon l'une des revendications 1 à 16, dans lequel on dose et on mélange de façon intime plus de deux liquides à l'aide d'un nombre correspondant de réservoirs et de structures en canal de liaison.
  18. Appareil pour le dosage intégré et le mélange intime de petites quantités de liquide, comprenant :
    un premier réservoir (3, 103, 203) pour une première quantité de liquide (123),
    un second réservoir (1, 101, 201) pour une seconde quantité de liquide (121),
    au moins une structure en canal de liaison (5, 6, 105, 227), qui relie les deux réservoirs et qui comprend, au moins dans une zone, dans la direction d'observation de la ligne de liaison des réservoirs, une section qui est plus petite que les sections des réservoirs,
    au moins un moyen pour générer un écoulement laminaire le long de ladite au moins une structure en canal de liaison (5, 6, 105, 227), et au moins un moyen (15, 215) pour le mélange intime des quantités de liquide dans ou sur le second réservoir (1, 101, 201),
    caractérisé en ce que l'appareil comporte des structures en canal de remplissage (7, 11) qui communiquent respectivement à une extrémité avec un réservoir et respectivement à l'autre extrémité avec un moyen de remplissage (17, 19).
  19. Appareil selon la revendication 18, dans lequel ledit au moins un moyen pour générer un écoulement laminaire comprend au moins un dispositif de génération d'ondes sonores (13, 213) avec au moins une direction de rayonnement le long d'au moins une partie de ladite au moins une structure en canal de liaison (5, 6, 105, 227).
  20. Appareil selon la revendication 19, comprenant au moins un dispositif de génération d'ondes sonores de surface (13, 213), en particulier un transducteur interdigité (213) avec une direction de rayonnement en direction d'au moins une zone de la structure en canal de liaison (5, 227) pour la génération de l'écoulement laminaire dans ou sur la structure en canal de liaison.
  21. Appareil selon l'une des revendications 18 à 20, dans lequel le dispositif pour le mélange intime comprend au moins un second dispositif de génération d'ondes sonores (15, 215) pour générer des ondes sonores pénétrant dans le second réservoir (1, 101, 201).
  22. Appareil selon la revendication 21, comprenant au moins un dispositif de génération d'ondes sonores de surface (15, 215), en particulier un transducteur interdigité (215), dans la zone du second réservoir (1, 101, 201) pour générer des ondes sonores pénétrant dans le second réservoir (1, 101, 201).
  23. Appareil selon l'une des revendications 18 à 22, dans lequel ladite au moins une structure en canal de liaison (5, 6, 105, 227) comporte une section aussi étroite qu'en raison des délimitations latérales des forces capillaires sont exercées sur l'un au moins des liquides.
  24. Appareil selon l'une des revendications 18 à 23, dans lequel les réservoirs et ladite au moins une structure en canal sont formés par des renfoncements dans une surface.
  25. Appareil selon l'une des revendications 18 à 23, dans lequel les réservoirs (1, 3) et ladite au moins une structure en canal (5, 6, 7, 11) sont formés par des cavités.
  26. Appareil selon l'une des revendications 18 à 23, dans lequel les réservoirs (101, 103) et ladite au moins une structure en canal (105) sont définis par des régions sur une surface, qui sont mouillées par les liquides (121, 123, 125) de préférence à la surface environnante.
  27. Appareil selon l'une des revendications 18 à 26, comprenant plus de deux réservoirs et un nombre correspondant de structures en canaux de liaison pour le dosage intégré et le mélange intime de plus de deux quantités de liquide.
  28. Appareil pour la mise en oeuvre automatique d'un procédé selon l'une des revendications 1 à 17, comprenant :
    un logement de réception pour un appareil selon l'une des revendications 18 à 27,
    des contacts électriques qui, lorsqu'un appareil est mis en place dans le logement de réception, établissent un contact électrique pour ledit au moins un dispositif (5, 14, 213) pour la génération d'un écoulement laminaire le long de ladite au moins une structure en canal de liaison, et pour ledit au moins un dispositif (15, 215) pour le mélange intime des quantités de liquide dans ou sur le second réservoir,
    des moyens pour l'alimentation automatique de liquide vers les réservoirs (1, 3, 101, 103, 201, 203) de l'appareil mis en place dans le logement de réception, et
    une commande, qui comprend de préférence un microprocesseur, pour la commande dudit au moins un dispositif (5, 14, 213) pour la génération d'un écoulement laminaire, dudit au moins un dispositif (5, 215) pour le mélange intime, et des moyens pour l'alimentation automatique de liquide.
  29. Utilisation d'un procédé selon l'une des revendications 1 à 17, d'un appareil selon l'une des revendications 18 à 27, ou d'un appareil selon la revendication 28 pour le dosage et le mélange intime de liquides biologiques.
EP05820542A 2005-01-05 2005-12-16 Procede et dispostif de dosage et de melange des petites quantites de liquide, appareil et utilisation Not-in-force EP1843833B1 (fr)

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DE102005000835A DE102005000835B3 (de) 2005-01-05 2005-01-05 Verfahren und Vorrichtung zur Dosierung kleiner Flüssigkeitsmengen
PCT/EP2005/013598 WO2006072384A1 (fr) 2005-01-05 2005-12-16 Procede et dispositif de dosage et de melange de petites quantites de liquide

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DE502005007112D1 (de) 2009-05-28
WO2006072384A1 (fr) 2006-07-13
US8186869B2 (en) 2012-05-29
JP4956439B2 (ja) 2012-06-20
DE102005000835B3 (de) 2006-09-07
ATE428492T1 (de) 2009-05-15
JP2008527338A (ja) 2008-07-24
US20080186799A1 (en) 2008-08-07

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