EP1345696B1 - Procede et dispositif de manipulation de petites quantites de liquides - Google Patents

Procede et dispositif de manipulation de petites quantites de liquides Download PDF

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Publication number
EP1345696B1
EP1345696B1 EP01986864A EP01986864A EP1345696B1 EP 1345696 B1 EP1345696 B1 EP 1345696B1 EP 01986864 A EP01986864 A EP 01986864A EP 01986864 A EP01986864 A EP 01986864A EP 1345696 B1 EP1345696 B1 EP 1345696B1
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EP
European Patent Office
Prior art keywords
liquid
area
external force
holding area
generating
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EP01986864A
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German (de)
English (en)
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EP1345696A1 (fr
Inventor
Achim Wixforth
Christoph Gauer
Jürgen SCRIBA
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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
    • B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
    • B01L2300/00—Additional constructional details
    • B01L2300/08—Geometry, shape and general structure
    • B01L2300/0809—Geometry, shape and general structure rectangular shaped
    • B01L2300/0816—Cards, e.g. flat sample carriers usually with flow in two horizontal directions
    • 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
    • B01L2300/0809—Geometry, shape and general structure rectangular shaped
    • B01L2300/0819—Microarrays; Biochips
    • 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
    • B01L2400/0415—Moving fluids with specific forces or mechanical means specific forces electrical forces, e.g. electrokinetic
    • 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
    • B01L2400/0415—Moving fluids with specific forces or mechanical means specific forces electrical forces, e.g. electrokinetic
    • B01L2400/0427—Electrowetting
    • 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
    • B01L2400/04—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
    • B01L2400/0439—Moving fluids with specific forces or mechanical means specific forces vibrational forces ultrasonic vibrations, vibrating piezo elements
    • 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
    • B01L2400/0442—Moving fluids with specific forces or mechanical means specific forces thermal energy, e.g. vaporisation, bubble jet
    • 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
    • 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 an apparatus and a method for manipulating small amounts of liquid on a solid surface and a method for generating at least a defined amount of liquid on a solid surface.
  • liquid in the present text includes u. a. pure liquids, mixtures, dispersions and suspensions, as well as liquids in which solid particles, eg. B. biological material, are.
  • Such methods are used inter alia for inorganic reagents or organic material, such as cells, molecules, macromolecules or genetic materials, as z. B. by O. Müller, Labor World 1/2000, pages 36 to 38 is described.
  • the transport of small amounts of liquid in the analysis and synthesis is carried out in known processes in microstructured channels (Anne Y. Fu et al, Nature Biotechnology 17, page 1109 et seq. (1999)). There, the movement of small amounts of liquid in microchannels of a few microns depth or width is described by electroosmotic methods.
  • Another already known technology is the transport of small quantities of liquid with micromechanical or electrostatic pumps in microstructured channels, as described in "Microsystem Technology in Chemistry and Life Sciences", edited by A. Manz and H. Becker (Springer Verlag, 1999) Pages 29 to 34 are described. Electrokinetic methods are described by M. Köhler et al. (Physical Leaves 56 , No. 11, pp. 57-61).
  • the object of the present invention is to specify an improved apparatus and an improved method by means of which a targeted manipulation of small quantities of liquid is possible.
  • the device according to the invention has at least one defined residence area on a solid body surface, on which the at least one liquid to be manipulated preferably remains.
  • the at least one defined residence area has different wetting properties than the solid body surface surrounding it.
  • the defined residence area for the liquid can, for. B. be given in the form of "traces" on the solid surface, the z. B. can be realized by an appropriate coating either the defined residence area or its surroundings. It is particularly advantageous that, despite the limited residence area of the liquid, achieved by the modulation of the wetting properties, no trenches, corners or edges are necessary, at which the liquid could be affected in their movement.
  • the modulation of the wetting properties may e.g. be achieved by the definition of hydrophilic or hydrophobic areas.
  • the preferred residence area z. B. chosen so that it is more hydrophilic than the surrounding solid surface. This can be achieved either by a hydrophilic coating of the preferred residence area or by a hydrophobic environment.
  • a hydrophobic environment may, for. B. in a preferred embodiment of the invention can be realized by a silanized surface.
  • the solid surface surrounding the residence area can also be chosen to be hydrophilic, lipophobic or lipophilic compared to the surface of the occupied area.
  • the preferred residence area is lipophilic compared to the environment.
  • the definition of the preferred location region can also be carried out or supported by an etching of the surface, wherein the etch depth is small compared to the width of the "conductor track", for. B. one hundredth of the width.
  • the preferred residence area can be defined by hydrophobically coating the surface surrounding the preferred residence area and etching a few nanometers to a few micrometers into the surface in the area of the residence area itself. In this way, the contrast with respect to the wetting angle is increased. Nevertheless, the surface is macroscopically substantially planar. Such a flat etching is very easy to manufacture and defined producible without the known problems of deep etching of a narrow channel occur.
  • the wetting properties can be further modulated by microstructuring, as is the case with the so-called lotus effect, which is based on the different roughness of the surface.
  • This can, for. B. be obtained by microstructuring the corresponding surface areas, z. B. by chemical treatment or ion irradiation.
  • the thus defined at least one preferred residence area for the at least one amount of liquid to be manipulated on the solid surface according to the invention further comprises at least one constriction whose width is less than the width of the adjacent parts of the preferred location area.
  • the width is chosen so that the amount of liquid can not overcome the bottleneck due to their surface tension without the action of an external force.
  • the amount of liquid to be manipulated is on the preferred residence area of the solid surface, e.g. in the form of a droplet.
  • the surface of the liquid droplet in equilibrium has the same curvature everywhere, since a different curvature in different parts of the liquid droplet surface would cause a different internal pressure for a given surface tension.
  • Locally different internal pressure in a droplet results in a flow of liquid from areas of high pressure into areas of low pressure. This, in turn, occurs until pressure equalization prevails, ie. H. everywhere the same curvature of the surface is present.
  • the wetting angle which depends in equilibrium and in an isotropic environment only of the two materials of the solid surface and the liquid.
  • the width of the "traces" defined by the preferred dwell regions is of the order of a few microns for transporting liquid volumes in the range of picoliters. For liquid quantities of the order of nanoliters, widths of 10 to several 100 micrometers are possible.
  • an external force acts on a small amount of fluid with a component in the direction of the constriction, it is unbalanced and can overcome the constriction.
  • the strength of the force is chosen so that the small amount of liquid can indeed overcome the bottleneck, but still does not move outside the preferred location area.
  • a disturbance of the balance e.g. serve a local temperature change or in a particularly preferred embodiment of the momentum transfer through a surface wave.
  • the width of the bottleneck essentially determines the strength of the external force necessary to overcome the bottleneck.
  • the preferred residence area defined on the solid surface may be composed in any form of bottlenecks and areas of greater width, that is, "tracks" for the fluid. It can be z.
  • a network or chessboard from defined areas and adjacent bottlenecks are formed. With such a network small defined amounts of liquid can be driven under the influence of an external force of a portion of defined area on the intermediate bottleneck in a second portion of defined area.
  • z For example, a network of subareas of defined areas can be filled selectively via intervening bottlenecks. Small amounts of liquid can thus be selectively positioned within a network in this way.
  • the subregions of the network between bottlenecks can take various forms. However, a round shape is particularly advantageous. In this way, the surface wetting properties at the edge of the area of the preferred residence area are defined very precisely and the amount of liquid, with a corresponding "degree of filling", touches the edge of the defined area area along its entire circumference.
  • the individual sub-areas of defined area can continue z. B. have a functionalized surface, so that certain reactions can take place.
  • Other areas of defined area can be used to perform chemical or physical analyzes, eg. B. by applying a local electric or magnetic field, heating or z. B. a local mechanical force.
  • a fluorescence analysis an amount of liquid on a certain portion of defined area are made.
  • a synthesis of various materials can be made, which were brought in or as liquid quantities on a residence area of defined area.
  • the surface tension is of thermodynamic parameters such. B. pressure and / or temperature dependent.
  • the volume of liquid e.g. can be stored on a geometrically defined "standard volume", also determined by the thermodynamic parameters.
  • the thermodynamic parameters thus provide a way to vary the volume of liquid on at least a portion of the preferred location area in addition to the geometric dimensions within a certain range.
  • a particularly simple method is to increase the temperature, eg. B. with a heater on the solid surface.
  • This heater can either act locally on a residence area defined surface or heat the entire solid surface.
  • a resistance heating is provided on the solid surface.
  • a micromechanical or a piezoelectrically driven pump is used.
  • an electrode can be used on the solid surface to move charged particle liquids through electrostatic forces.
  • the device according to the invention has at least one surface wave generation device.
  • This surface wave generating device generates surface waves which impart an impulse to the quantities of liquid to be manipulated in the preferred location area.
  • the momentum transfer is achieved either by the mechanical deformation of the solid surface or by the force of the accompanying electric fields on charged or polarizable matter.
  • Surface waves can be on piezoelectric substrates or substrates with piezoelectric regions, eg. As piezoelectric coatings produce. It is sufficient if the substrate or the corresponding coating is present only in the region in which the surface wave generating device is located. The surface acoustic wave also propagates outside the piezoelectric region.
  • a per se known interdigital transducer is advantageously used.
  • Such an interdigital transducer has two electrodes which engage in one another like a finger.
  • a high-frequency alternating field, z. B. on the order of several 100 MHz, a surface wave is excited in a piezoelectric substrate or in a piezoelectric region of the substrate, the wavelength of which results as a quotient of the surface acoustic velocity and the frequency.
  • the propagation direction is perpendicular to the interdigitated finger electrode structures.
  • a very defined surface wave can be generated in a very simple manner.
  • the preparation of the interdigital transducer is inexpensive and simple with known lithographic and coating technologies.
  • Interdigital transducers can also, for. B. by irradiation of an electromagnetic alternating field in an antenna device connected to the interdigital transducer, are wirelessly controlled.
  • a surface wave generating device is provided at the respective constriction whose surface wave propagation direction is along the constriction.
  • a surface wave generating device is provided at the respective constriction whose surface wave propagation direction is along the constriction.
  • momentum transfer at least a portion of a small amount of liquid may be driven from a portion of the preferred location area via the throat to a second portion of the preferred location area having a defined area.
  • This area defines a "standard volume" of a small amount of liquid that can be selectively filled or emptied. This happens at a defined point in time when the surface wave generating device becomes active.
  • a liquid droplet can be further defined in this arrangement by driving through a series of bottlenecks and thus deliberately occupying the network with small quantities of liquid.
  • a drop of liquid which is sonicated according to the invention with a surface wave, this attenuates.
  • a second surface wave With the same or a second surface wave generating device whose propagation direction z. B. is parallel to the propagation direction of the first surface acoustic wave generating device, a second surface wave, optionally with weaker intensity, in the direction of a liquid volume in a part of the preferred location area are sent. By measuring the attenuation of this second surface wave, the amount and volume of the liquid can be determined.
  • Particularly simple and safe to operate is an arrangement of the network in which the bottlenecks are perpendicular to each other and the emission directions of at least two surface wave generating means for filling or for emptying the common areas of defined surface are parallel to the bottlenecks.
  • This arrangement is particularly safe because there are substantially no pulse components common to the surface waves generated by the first and second surface wave generating means, respectively.
  • the surface wave generating device is designed as a so-called "tapered" interdigital transducer.
  • the finger spacing along the axis of the transducer is not constant.
  • the finger distance determines the wavelength of the surface wave.
  • the resonant condition that the frequency of the surface wave results as the quotient of the surface acoustic wave velocity and the wavelength at a certain applied frequency is thus satisfied only for a certain finger distance.
  • a surface wave can be generated, which has only a very small lateral extent perpendicular to the propagation direction.
  • individual bottlenecks can be selected from a number of bottlenecks arranged in parallel.
  • a defined volume of liquid can be generated.
  • the inventive method can also be used to manipulate the liquid quantities z. B. to supply a region on the solid substrate, where an analysis or synthesis takes place.
  • Such an analysis or synthesis may, for. B. chemical, physical and / or biological nature.
  • an amount of liquid can be brought into a range where it reacts with a different amount of liquid.
  • the device according to the invention and the method according to the invention are suitable both for the analysis and for the synthesis of the amount of liquid or the quantities of liquid.
  • the means for generating an external force may be connected to software programmable by appropriate software.
  • portions 1 and 3 of a preferred residence area having a width indicated at 2 are provided for the liquid to be manipulated.
  • the exact shape of areas 1 and 3 and their width may be different.
  • At the areas 1 and 3 close bottlenecks 7 and 9, which on the same Be generated manner as the areas 1 and 3, as described below.
  • the bottlenecks connect to a circular area 5.
  • the width 8 of the bottlenecks 7 and 9 is less than half the width 2 of the regions 1 and 3 and does not necessarily have to be the same for different bottlenecks.
  • the entire assembly is located on the surface of a solid, z. B. a chip. This can be made of piezoelectric material, for. As quartz or LiNbO 3 , or an at least partially piezoelectric surface, for. B. from ZnO, have.
  • the preferred residence areas 1, 3, 5, 7 and 9 have different wetting properties than the surrounding surface of the solid, which are chosen so that the liquid to be manipulated preferably in the areas 1, 3, 5, 7 and 9.
  • the surface in the preferred location areas z. B. hydrophilic compared to the more hydrophobic surface of the remaining solid. This can be z. B. be achieved by silanizing or microstructuring the solid surface in the surrounding areas and thereby becomes hydrophobic.
  • the width 2 is z. B. a few microns and is therefore suitable for the manipulation of liquid quantities in Pikoliter- or nanoliter range.
  • 11 and 17, respectively denote surface wave generating means having a radiation direction 23 and 25, respectively.
  • the embodiment shown is an interdigital transducer having electrodes 13 and 19, respectively, having finger-like interlocking extensions 15 and 21, respectively. Upon application of an alternating field to the electrodes of the individual transducer, a surface wave having a wavelength corresponding to the finger spacing of the electrodes is generated. The direction of propagation is perpendicular to the interlocking fingers.
  • the transducers comprise a large number of fingers, only a few of which are shown schematically and not to scale.
  • the interdigital transducers are z. Example, using lithographic processes and coating processes on the chip surface have been generated and are contacted via the electrodes 13 and 19, respectively.
  • the area of the area 5 is round and has a defined size.
  • FIG. 1b shows a schematic sectional view through the area of the solid-state surface in which the preferred residence area 5 is located. A liquid drop 27 is indicated on the solid surface 29.
  • the device according to the invention of FIG. 1 is used as follows.
  • the "conductor” 1 is externally filled with the liquid to be manipulated, which forms a "liquid column". This wets the conductor 1 to just before the constriction 7.
  • the curvature of the liquid surface is determined by the width of the "conductor” 1 and the volume of the liquid.
  • the amount of liquid can be "pumped" through the throat 7.
  • the required surface wave strength may be determined by prior calibration or adjusted during the experiment until the amount of liquid moves across the throat 7 to the surface 5. In this way, a defined amount of liquid passes from the conductor 1 to the defined surface. 5
  • the necessary amount of liquid on the surface 5 is present, it can be analyzed, for. By physical or chemical processes, or is available for reaction with another substance.
  • a surface wave in direction 25 can be sent to the quantity of liquid to the defined surface 5.
  • the quantity of liquid is driven across the constriction 9 in a manner analogous to that described above for the constriction 7. It reaches the conductor 3 by its movement in the direction 26. In this way, can create a defined volume of liquid. Just when the desired amount of liquid is on the area 5, with the help of the second surface wave, which is generated by the interdigital transducer 17, exactly this amount of liquid is driven out of area 5.
  • FIG. 1 thus permits the exact definition of very small amounts of liquid while at the same time having a planar surface of the solid.
  • a resistance heater which is not shown in the figures, or with the aid of an infrared heater, the surface tension of the liquid can be lowered so that a lower strength of the surface wave necessary is to overcome the bottleneck.
  • the "standard volume" of the defined area 5 can be set within certain limits.
  • a bottleneck may be a reservoir formed by a larger area having the same wetting characteristics as the residence areas shown. Then a larger amount of the liquid can be stored. By external impulse action e.g. a surface wave can be driven from this reservoir, an amount of liquid over the bottleneck described in the parts of the occupied area shown.
  • the shown residence areas may also be e.g. be filled with a pipette.
  • drops of liquid can be purposefully transported to specific locations on the surface and deposited there.
  • a checkered arrangement Provided is a number of defined subregions corresponding to region 5 of FIG. 1a, some of which are exemplarily labeled 105. These are connected via bottlenecks 107 and 109 with each other.
  • For feeding serves a "conductor" 100 with a greater width than the width of the bottlenecks.
  • the regions 100, 105, 107, 109 in turn have different wetting properties than the surrounding solid surface, analogously to the embodiment of FIG. 1.
  • groups 115, 117 and 119 of interdigital transducers are provided which can be individually driven.
  • the individual transducers are aligned in such a way that the propagation direction is in each case along a series of bottlenecks 107 and 109, respectively.
  • this is shown on the interdigital transducer 120 with the propagation direction 118.
  • the groups of interdigital transducers 119 and 117 are opposite each other.
  • another group of interdigital transducers can also be provided on the other side of the checkerboard pattern in relation to the group of interdigital transducers 115.
  • a certain amount of liquid is introduced via the "conductor track" 100 on the defined residence area in Figure 2 top left.
  • corresponding tracks can lead to other defined areas 105.
  • the described surface tension effect prevents the amount of liquid from entering further surface areas 105 through the adjacent bottlenecks. Only by generating a surface wave by applying an alternating field z.
  • the amount of liquid is "pumped” in the manner described above the adjacent bottleneck into the next surface area 105.
  • the direction 118 of the surface wave predetermines the direction. In this way, by appropriate switching of the interdigital transducer, the liquid droplets can be transported from one area 105 to the next until it has arrived at the desired location.
  • the individual bottlenecks are in each case emptied due to the higher internal pressure prevailing there at the expense of the surfaces 105.
  • the liquid comes here z. B. from a reservoir, which consists of a surface which has wetting properties, such as the "tracks", so that the liquid is preferably there.
  • This area may have a larger area to store a corresponding amount of liquid on it. It is z. B. connected via the conductor 100 and / or a corresponding bottleneck to the system, which in turn can only be overcome by sonication with a surface wave from the liquid.
  • a partial area with a defined area 105 can be filled after the other in the direction of the surface wave 118.
  • the attenuation of the surface wave by liquid droplets in front of it prevents that drops further away from the surface wave generation device are excessively influenced.
  • the liquid droplets in the figure 2 vertical direction can be moved in an analogous manner.
  • the drops of liquid can be moved back again.
  • the transducers 120 and 116 by measuring the surface wave from an interdigital transducer to an opposite interdigital transducer, exemplified by the transducers 120 and 116, at smaller amplitude, it is also possible to measure whether the individual surfaces 105 are filled with liquid or not, since the surface wave is damped by the presence of the liquid becomes. The smaller amplitude is chosen so that the droplets do not leave their respective location area 105 through the adjacent bottleneck.
  • a "microtiter plate" for subsequent fluorescence analyzes feasible This will be liquid drops on different surfaces 105, for example, subjected to a fluorescence analysis.
  • individual surfaces 105 are functionalized with a surface coating, which lead to a reaction. This reaction then takes place locally only on this single area and can be studied precisely.
  • each group of interdigital transducers 115, 117, 119 there is provided in each case a tapered interdigital transducer whose finger spacing is not constant along its axis.
  • the location of the radiation can be adjusted with the frequency, since the frequency results as a quotient of the constant surface wave velocity and the wavelength corresponding to the finger distance.
  • the individual embodiments of the invention can also be combined to form an overall system.
  • the individual elements may be part of a larger overall system, if necessary on a single chip, which, in addition to the embodiments according to the invention, also has other measuring and analysis or synthesis stations in the sense of a "lab-on-the-chip".
  • the devices and methods according to the invention can be used particularly advantageously.
  • the entire structure can be very easily produced with known lithographic methods and integrated with other elements on a chip, the z. B. are provided for transport or analysis of small quantities of matter.

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  • Chemical & Material Sciences (AREA)
  • Health & Medical Sciences (AREA)
  • Dispersion Chemistry (AREA)
  • Analytical Chemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Hematology (AREA)
  • Clinical Laboratory Science (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Physical Or Chemical Processes And Apparatus (AREA)
  • Separation Of Particles Using Liquids (AREA)
  • Automatic Analysis And Handling Materials Therefor (AREA)

Claims (32)

  1. Dispositif pour manipuler de petites quantités de liquide sur une surface de solide, avec
    - un substrat de solide avec une surface (29)
    - au moins une zone de séjour (1,3, 5, 7, 9, 100, 105, 107, 109) sur la surface du solide (29), qui présente des propriétés de mouillage autres que celles de la surface du solide environnante et dont la matière est choisie de sorte à ce que le liquide (27) à manipuler séjourne de préférence sur la zone de séjour, au moins l'une des zones de séjour comprenant au moins un emplacement étroit (7, 9, 107, 109), qui présente une largeur (8) minimale, qui est inférieure à la largeur (2) des parties voisines de la zone de séjour, et qui ne peut être franchi par le liquide (27) du fait de sa tension superficielle sans l'effet supplémentaire d'une force externe, sans quitter au moins partiellement la zone de séjour (1, 3, 5, 7, 9, 100, 105, 107, 109), et
    - au moins un dispositif (11, 17, 116, 120) pour produire une force externe avec une composante dans la direction dudit au moins un emplacement étroit, qui est tellement intense que la quantité de liquide peut franchir l'emplacement étroit.
  2. Dispositif selon la revendication 1, avec un dispositif pour commander le dispositif (11, 17, 116, 120) pour produire une force externe, qui peut être programmé au moyen d'un logiciel.
  3. Dispositif selon la revendication 1, dans lequel la modulation des propriétés de mouillage est réalisée par au moins une zone hydrophobe et au moins une zone comparativement hydrophile ou au moins une zone lipophobe et au moins une zone comparativement lipophile.
  4. Dispositif selon la revendication 3, dans lequel ladite au moins une zone hydrophile et ladite au moins une zone hydrophobe, ou ladite au moins une zone lipophile et ladite au moins une zone lipophobe, sont définies par lithographie.
  5. Dispositif selon l'une quelconque des revendications 1 à 4, dans lequel les zones de propriétés de mouillage différentes sont définies par des zones latéralement microstructurées ou nanostructurées.
  6. Dispositif selon l'une quelconque des revendications 1 à 5, dans lequel les zones de propriétés de mouillage différentes sont définies par une fonctionnalisation et/ou un revêtement, appropriés.
  7. Dispositif selon l'une quelconque des revendications 1 à 6, dans lequel la largeur (2) dans une direction spatiale de ladite au moins une zone de séjour (1, 3, 5, 100, 105) en dehors d'un emplacement étroit (7, 9, 107, 109) est au maximum de quelques millimètres et la largeur (8) d'un emplacement étroit (7, 9, 107, 109) est inférieure à la moitié de la largeur (2) de ladite au moins une zone de séjour en dehors de l'emplacement étroit.
  8. Dispositif selon l'une quelconque des revendications 1 à 7, dans lequel la largeur (2) dans une direction spatiale de ladite au moins une zone de séjour (1, 3, 5, 100, 105) en dehors d'un emplacement étroit (7, 9, 107, 109) est au minimum de quelques nanomètres et la largeur (8) d'un emplacement étroit (7, 9, 107, 109) est inférieure à la moitié de la largeur (2) de ladite au moins une zone de séjour en dehors de l'emplacement étroit.
  9. Dispositif selon l'une quelconque des revendications 1 à 8, dans lequel au moins une surface partielle (5, 105) de ladite au moins une zone de séjour est reliée seulement par l'intermédiaire d'au moins un emplacement étroit (7, 9, 107, 109) à d'autres parties (1, 3) de la zone de séjour (1, 3) et présente une surface définie.
  10. Dispositif selon la revendication 9, ayant au moins deux emplacements étroits (7, 9, 107, 109), qui sont reliés à la surface partielle définie (5, 105) de la zone de séjour, dont l'orientation n'est pas parallèle.
  11. Dispositif selon la revendication 10, dans lequel au moins à chaque fois un dispositif (11, 17, 116, 120) pour produire une force externe essentiellement dans la direction de l'emplacement étroit respectivement associé (7, 9) est associé à au moins deux des emplacements étroits (7, 9, 107, 109).
  12. Dispositif selon l'une quelconque des revendications 10 ou 11, dans lequel l'orientation des emplacements étroits non parallèles (7, 9, 107, 109) est perpendiculaire l'une à l'autre.
  13. Dispositif selon l'une quelconque des revendications 9 à 12, dans lequel la surface partielle (5, 105) de surface définie de la zone de séjour, est essentiellement ronde.
  14. Dispositif selon l'une quelconque des revendications 1 à 13, ayant au moins une zone de séjour avec une pluralité de surfaces partielles (105), qui sont reliées les unes aux autres par l'intermédiaire d'une pluralité d'emplacements étroits (107, 109) à la façon d'un réseau.
  15. Dispositif selon la revendication 14, ayant au moins un premier dispositif (120) pour produire une force externe le long des emplacements étroits qui se trouvent le long d'une droite.
  16. Dispositif selon la revendication 15, ayant au moins un deuxième dispositif (116) pour produire une force externe contre la direction de la force externe qui peut être produite par le premier dispositif (120) pour produire une force externe.
  17. Dispositif selon l'une quelconque des revendications 1 à 16, dans lequel ledit au moins un dispositif (11, 17, 116, 120) pour produire une force externe comprend un dispositif de production d'ondes de surface.
  18. Dispositif selon la revendication 17, qui comprend au moins un transducteur interdigité (11, 17, 116, 120) en tant que dispositif de production d'ondes de surface.
  19. Dispositif selon la revendication 18, dans lequel au moins un transducteur interdigité ayant une distance non constante entre les doigts, est prévu pour la production d'ondes de surface.
  20. Dispositif selon l'une quelconque des revendications 1 à 19, qui comprend un substrat de solide piézoélectrique pour produire des ondes de surface, ou bien un substrat avec au moins une zone piézoélectrique.
  21. Dispositif selon l'une quelconque des revendications 1 à 20, dans lequel ladite au moins un dispositif pour produire une force externe, comprend un dispositif de chauffage, de préférence un chauffage à résistance.
  22. Dispositif selon l'une quelconque des revendications 1 à 21, dans lequel ledit au moins un dispositif pour produire une force externe comprend au moins une pompe micromécanique.
  23. Dispositif selon l'une quelconque des revendications 1 à 22, dans lequel ledit au moins un dispositif pour produire une force externe comprend au moins une pompe piézoélectrique.
  24. Dispositif selon l'une quelconque des revendications 1 à 23, dans lequel ledit au moins dispositif pour produire une force externe comprend au moins une électrode.
  25. Dispositif selon l'une quelconque des revendications 1 à 24, ayant au moins un dispositif pour modifier la température.
  26. Procédé pour manipuler de petites quantités de liquide sur une surface de solide, en employant un dispositif selon l'une quelconque des revendications 1 à 25, dans lequel une quantité de liquide (27), qui se trouve sur une surface partielle (1, 3, 5, 105) d'une zone de séjour de la surface du solide, produite par modulation des propriétés de mouillage, est déplacée au moyen d'une transmission d'impulsion d'une force externe le long d'un emplacement étroit (7, 9, 107, 109) de la zone de séjour, qui se trouve en liaison avec la surface partielle et qui, sans l'effet d'impulsion d'une force externe, du fait de la tension superficielle du liquide (27), ne serait pas traversée par celui-ci.
  27. Procédé pour produire une quantité de liquide définie, dans lequel, en mettant en oeuvre un procédé selon la revendication 26, une quantité de liquide est déplacée dans une surface partielle (5) d'une zone de séjour (1, 3, 5, 7, 9) produite par modulation des propriétés de mouillage, qui présente une surface définie et qui est seulement reliée à la zone de séjour restante (1, 3) sur la surface du solide par l'intermédiaire d'emplacements étroits (7, 9).
  28. Procédé selon la revendication 27, dans lequel la quantité du liquide dans la surface partielle (5) de la zone de séjour ayant une surface définie, est détectée par l'amortissement d'une onde de surface, qui traverse la surface du solide dans la zone de la surface partielle (5) d'une surface définie.
  29. Procédé selon l'une quelconque des revendications 27 ou 28, dans lequel la surface partielle (5) de surface définie est vidée par transmission d'impulsion d'une force externe.
  30. Procédé selon l'une quelconque des revendications 27 à 29, dans lequel à l'aide d'un ajustement des paramètres thermodynamiques externes, de préférence la pression et/ou la température, il est possible de faire varier le volume de la quantité de liquide, déterminé par la tension superficielle et la pression interne de la quantité de liquide (27) sur la surface partielle (5) de la zone de séjour ayant une surface définie.
  31. Procédé selon la revendication 30, dans lequel la température est modifiée par un dispositif de chauffage sur la surface du solide.
  32. Procédé selon l'une quelconque des revendications 26 à 31, dans lequel des ondes de surface sont mises en oeuvre pour produire la force externe.
EP01986864A 2000-12-14 2001-12-12 Procede et dispositif de manipulation de petites quantites de liquides Expired - Lifetime EP1345696B1 (fr)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
DE10062246A DE10062246C1 (de) 2000-12-14 2000-12-14 Verfahren und Vorrichtung zur Manipulation kleiner Flüssigkeitsmengen
DE10062246 2000-12-14
PCT/EP2001/014598 WO2002057014A1 (fr) 2000-12-14 2001-12-12 Procede et dispositif de manipulation de petites quantites de liquides

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EP1345696B1 true EP1345696B1 (fr) 2006-03-08

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EP (1) EP1345696B1 (fr)
JP (1) JP4015021B2 (fr)
AT (1) ATE319518T1 (fr)
DE (2) DE10062246C1 (fr)
WO (1) WO2002057014A1 (fr)

Families Citing this family (22)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
AU2002306486A1 (en) * 2001-02-09 2002-08-28 Microchem Solutions Method and apparatus for sample injection in microfabricated devices
DE10120035B4 (de) * 2001-04-24 2005-07-07 Advalytix Ag Verfahren und Vorrichtung zur Manipulation kleiner Flüssigkeitsmengen auf Oberflächen
DE10307801A1 (de) * 2003-02-24 2004-09-09 Advalytix Ag Analyseverfahren und -device zur Untersuchung von spezifischen Bindungsereignissen
US20070264161A1 (en) * 2003-02-27 2007-11-15 Advalytix Ag Method and Device for Generating Movement in a Thin Liquid Film
DE10325313B3 (de) * 2003-02-27 2004-07-29 Advalytix Ag Verfahren und Vorrichtung zur Erzeugung von Bewegung in einem dünnen Flüssigkeitsfilm
DE502004004027D1 (de) * 2003-02-27 2007-07-19 Advalytix Ag Verfahren und vorrichtung zur durchmischung kleiner flüssigkeitsmengen in mikrokavitäten
CN100404121C (zh) * 2003-07-11 2008-07-23 日本碍子株式会社 微型反应器
US7048889B2 (en) * 2004-03-23 2006-05-23 Lucent Technologies Inc. Dynamically controllable biological/chemical detectors having nanostructured surfaces
DE102004037348A1 (de) * 2004-08-02 2006-03-16 Infineon Technologies Ag Fluid-Transport-Vorrichtung, Sensor-Anordnung, Fluid-Misch-Vorrichtung und Verfahren zum Herstellen einer Fluid-Transport-Vorrichtung
JP4570945B2 (ja) * 2004-12-02 2010-10-27 一般社団法人オンチップ・セロミクス・コンソーシアム 液滴操作装置及び操作方法
DE102004051394B4 (de) * 2004-10-21 2006-08-17 Advalytix Ag Verfahren zur Bewegung von kleinen Flüssigkeitsmengen in Mikrokanälen und Mikrokanalsystem
DE102005000835B3 (de) * 2005-01-05 2006-09-07 Advalytix Ag Verfahren und Vorrichtung zur Dosierung kleiner Flüssigkeitsmengen
EP1833598B1 (fr) 2005-01-05 2008-10-08 Olympus Life Science Research Europa GmbH Procede et dispositif de dosage et de melange de petites quantites de liquide
JP4733404B2 (ja) * 2005-02-21 2011-07-27 日本無線株式会社 弾性波センサ
US20070047388A1 (en) * 2005-08-25 2007-03-01 Rockwell Scientific Licensing, Llc Fluidic mixing structure, method for fabricating same, and mixing method
DE102005043034A1 (de) * 2005-09-09 2007-03-15 Siemens Ag Vorrichtung und Verfahren zur Bewegung einer Flüssigkeit
US20070062594A1 (en) * 2005-09-16 2007-03-22 Extrand Charles W Microfluidic device with anisotropic wetting surfaces
US20070065637A1 (en) * 2005-09-16 2007-03-22 Extrand Charles W Carrier with anisotropic wetting surfaces
US20070065702A1 (en) * 2005-09-16 2007-03-22 Extrand Charles W Fuel cell with anisotropic wetting surfaces
WO2007066478A1 (fr) * 2005-12-08 2007-06-14 Olympus Corporation Reacteur et analyseur
DE102007021563A1 (de) 2007-05-08 2008-11-20 Universität Augsburg Vorrichtung für die Oberflächenplasmonen-Resonanzspektroskopie
JP5159197B2 (ja) * 2007-07-25 2013-03-06 キヤノン株式会社 液体制御装置

Family Cites Families (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4049982A (en) * 1976-08-18 1977-09-20 The United States Of America As Represented By The Secretary Of The Air Force Elliptical, interdigital transducer
US4751530A (en) * 1986-12-19 1988-06-14 Xerox Corporation Acoustic lens arrays for ink printing
US5474796A (en) * 1991-09-04 1995-12-12 Protogene Laboratories, Inc. Method and apparatus for conducting an array of chemical reactions on a support surface
US6130098A (en) * 1995-09-15 2000-10-10 The Regents Of The University Of Michigan Moving microdroplets
AU763497B2 (en) * 1998-10-13 2003-07-24 Biomicro Systems, Inc. Fluid circuit components based upon passive fluid dynamics
DE19935433A1 (de) * 1999-08-01 2001-03-01 Febit Ferrarius Biotech Gmbh Mikrofluidischer Reaktionsträger
US6362006B1 (en) * 2000-03-13 2002-03-26 General Electric Company Rapid parallel determination of non-volatile analytes in complex combinatorial samples
US20020031835A1 (en) * 2000-05-12 2002-03-14 University Of Delaware Laboratory-on-a-chip device using wetting forces and thermal marangoni pumping

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JP2004517335A (ja) 2004-06-10
EP1345696A1 (fr) 2003-09-24
ATE319518T1 (de) 2006-03-15
US20040072366A1 (en) 2004-04-15
JP4015021B2 (ja) 2007-11-28
WO2002057014A1 (fr) 2002-07-25
DE10062246C1 (de) 2002-05-29
DE50109179D1 (de) 2006-05-04

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