EP1781409B1 - Vorrichtung zur handhabung von tropfen zur biochemischen analyse, verfahren zur herstellung einer derartigen vorrichtung und system zur mikrofluidischen analyse - Google Patents

Vorrichtung zur handhabung von tropfen zur biochemischen analyse, verfahren zur herstellung einer derartigen vorrichtung und system zur mikrofluidischen analyse Download PDF

Info

Publication number
EP1781409B1
EP1781409B1 EP05775767A EP05775767A EP1781409B1 EP 1781409 B1 EP1781409 B1 EP 1781409B1 EP 05775767 A EP05775767 A EP 05775767A EP 05775767 A EP05775767 A EP 05775767A EP 1781409 B1 EP1781409 B1 EP 1781409B1
Authority
EP
European Patent Office
Prior art keywords
wetting
layer
track
top surface
electrodes
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Not-in-force
Application number
EP05775767A
Other languages
English (en)
French (fr)
Other versions
EP1781409A2 (de
Inventor
Jean-Christophe Fourrier
François Caron
Pierre Tabourier
Christian Druon
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Centre National de la Recherche Scientifique CNRS
Universite de Lille 1 Sciences et Technologies
Original Assignee
Centre National de la Recherche Scientifique CNRS
Universite de Lille 1 Sciences et Technologies
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Centre National de la Recherche Scientifique CNRS, Universite de Lille 1 Sciences et Technologies filed Critical Centre National de la Recherche Scientifique CNRS
Publication of EP1781409A2 publication Critical patent/EP1781409A2/de
Application granted granted Critical
Publication of EP1781409B1 publication Critical patent/EP1781409B1/de
Not-in-force legal-status Critical Current
Anticipated expiration legal-status Critical

Links

Images

Classifications

    • 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
    • B01L3/502784—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 droplet or plug flow, e.g. digital microfluidics
    • B01L3/502792—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 droplet or plug flow, e.g. digital microfluidics for moving individual droplets on a plate, e.g. by locally altering surface tension
    • 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
    • B01L3/502707—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 manufacture of the container or its components
    • 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
    • F—MECHANICAL ENGINEERING; LIGHTING; HEATING; WEAPONS; BLASTING
    • F04—POSITIVE - DISPLACEMENT MACHINES FOR LIQUIDS; PUMPS FOR LIQUIDS OR ELASTIC FLUIDS
    • F04B—POSITIVE-DISPLACEMENT MACHINES FOR LIQUIDS; PUMPS
    • F04B19/00—Machines or pumps having pertinent characteristics not provided for in, or of interest apart from, groups F04B1/00 - F04B17/00
    • F04B19/006—Micropumps
    • 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
    • B01L2300/0887—Laminated structure
    • 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
    • B01L2300/16—Surface properties and coatings
    • B01L2300/161—Control and use of surface tension forces, e.g. hydrophobic, hydrophilic
    • B01L2300/165—Specific details about hydrophobic, oleophobic surfaces
    • 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
    • B01L2400/08—Regulating or influencing the flow resistance
    • B01L2400/084—Passive control of flow resistance
    • B01L2400/088—Passive control of flow resistance by specific surface properties
    • F—MECHANICAL ENGINEERING; LIGHTING; HEATING; WEAPONS; BLASTING
    • F05—INDEXING SCHEMES RELATING TO ENGINES OR PUMPS IN VARIOUS SUBCLASSES OF CLASSES F01-F04
    • F05C—INDEXING SCHEME RELATING TO MATERIALS, MATERIAL PROPERTIES OR MATERIAL CHARACTERISTICS FOR MACHINES, ENGINES OR PUMPS OTHER THAN NON-POSITIVE-DISPLACEMENT MACHINES OR ENGINES
    • F05C2225/00—Synthetic polymers, e.g. plastics; Rubber
    • F05C2225/04—PTFE [PolyTetraFluorEthylene]

Definitions

  • the present invention relates to a drop handling device for biochemical analysis, a method of manufacturing such a device and a microfluidic analysis system using such a device.
  • proteomics an activity related to the identification and study of proteins, tries to use new technologies to reduce sampled volumes that are handled, and to reduce contamination.
  • the objective is, in a general way, to control the micromanipulation of the material, before spectrometric analysis for example.
  • the problematic of the control of fluid flows is strategically important insofar as the material, for example proteins, can not be handled outside a liquid medium.
  • the invention thus relates to the field of microfluidics, which more generally concerns flows in systems of micrometric or nanometric size, in which the sample handled can be subjected to electric fields or wall effects of a physical or chemical nature. complex, and in which the high ratio surface / volume is of great importance.
  • the displacement of calibrated microvolumes has a number of advantages. Indeed, it allows very small volumes of liquids and allows a suitable control of microvolume flow while the continuous flow pumping is characterized by a constant flow. Moreover, this type of movement allows various synchronizations that allow the mixing of liquids for example.
  • different modes of action are known: by pneumatic action, by surface acoustic waves, with dielectrophoretic effect, by electrowetting, and by electrowetting on dielectric (EWOD). This last mode of action makes use of a relatively simple technological achievement and allows the control of the flow and the circulation of a calibrated volume of conductive liquid on a network of electrodes.
  • the nonwettability and the wettability with respect to water are respectively the properties of hydrophobicity and hydrophilicity.
  • a hydrophobic material is a non-wetting material with respect to water
  • a hydrophilic material is a wetting material with respect to water.
  • the wettability is generally characterized by the angle ⁇ of contact between the drop 1 and the surface 2 (see Figures 1a to 1d ).
  • the wettability coefficient defined as the cosine of the above-mentioned angle is sometimes used.
  • the Figures 1c and 1d illustrate intermediate cases of wettability ( ⁇ ⁇ 90 °) or non-wettability ( ⁇ > 90 °) respectively.
  • the problem posed by the non-wetting materials with respect to a liquid, in particular the hydrophobic materials, which are otherwise essential for the displacement, is that the surface properties of these materials prevent the creation of chemical surface treatment zones by the These materials are characterized by low surface energy. If we try to functionalize locally the surface of such materials, which would chemically treat the liquids handled, the result is unreliable, difficult to control and too imperfect.
  • the alternative of making the non-wetting material more rough with respect to the liquid is not conceivable because it makes the ability of the material to favor the transport of the liquid lose. It is therefore necessary to use a layer of material that is partially wetting, that is to say that it must maintain the non-wetting character for movement, while creating wetting or high wettability for functionalization.
  • the layer of hydrophobic material is first subjected to a surface modification using a plasma, to modify its hydrophobic properties, that is to say to make it less hydrophobic.
  • This technique also poses the problem of permanently modifying the surface properties of the hydrophobic material.
  • the invention relates, in a first aspect, to a device for handling drops on an electrowetting displacement plane which comprises at least one electrowetting displacement track and which makes it possible to chemically treat or interact with the droplet. simultaneously with its transport.
  • the displacement track comprises at least two interdigitated electrodes which rest on an electrically insulating substrate and which are covered by an insulating dielectric layer.
  • This set insulating substrate, electrodes, insulating dielectric layer, is covered with a partially wetting layer vis-à-vis the manipulated drops.
  • the partially wetting layer is therefore a partially hydrophilic layer.
  • non-wetting, partially wetting or wetting layer or material will be used for a respectively non-wetting, partially wetting or wetting layer or material. manipulated drops.
  • the device of the invention comprises, in another variant embodiment, at least one counter electrode distinct from the first electrodes.
  • This counter-electrode may be a ground line which will then be located on, under or in the partially wetting layer.
  • the device comprises a second track positioned opposite to and separated from the first track so that a space, intended to be filled by an immiscible electrically insulating fluid opposite the transported drop, is formed between the first and second tracks, the second track comprising a non-wetting layer directly in contact with the space thus formed.
  • This non-wetting layer of the second track is possibly partially wetting.
  • This non-wetting layer is also possibly covered with an upper layer which is either electrically insulating, semiconductive, or conductive.
  • the second track comprises one or more counter-electrodes located between the non-wetting layer and the upper layer. It optionally comprises an insulating dielectric layer which will be located between said non-wetting layer and said one or more counter electrodes.
  • the partially wetting layer of the first track and / or the second track comprises non-wetting areas and wetting areas, the wetting areas being reactive functionalized areas.
  • the device for handling drops in a plane of the invention comprises two tracks separated by a space intended to be filled by an immiscible electrically insulating fluid with respect to the drop carried.
  • the first track comprises an electrically insulating layer or substrate on which at least two interdigitated electrodes are based. On this set rests a non-wetting layer.
  • the second track includes a partially wetting layer. The partially wetting layer of the first track and / or the second track includes non-wetting areas and wetting areas, the wetting areas being reactive functionalized areas.
  • the first track also comprises an insulating dielectric layer between the electrodes and the non-wetting layer.
  • the device in this embodiment variant comprises a ground line located on, under or inserted into the non-wetting layer.
  • the second track comprises an electrically insulating, semiconductive, or conductive upper layer.
  • the electrically insulating substrate of the first track is preferably transparent, such as a glass substrate.
  • the wetting zones are biochemically functionalized and reactive.
  • these wetting zones are preferably openings in non-wetting areas.
  • the non-wetting material constituting the non-wetting layer and / or the non-wetting areas of the partially wetting layer is a tetrafluoroetylene polymer.
  • the device of the invention advantageously makes it possible to manipulate a drop of liquid, by transporting it on a plane by electrowetting, on a single track or between two tracks facing each other, with or without the use of a counter-electrode, while acting chemically on the drop as it passes over chemically functionalized zones.
  • the desired optimization is thus obtained: concentrate the preparatory treatments for a subsequent analysis in a microsystem, during transport, to avoid contamination and losses on very expensive samples and in small volumes, while taking into account the aforementioned constraints microfluidics.
  • the invention relates to a method of manufacturing the aforementioned device, in which the creation of the partially wetting layer of the first or second track is derived from the so-called “lift off” technique used in microelectronics for create metal patterns.
  • This technique of the "lift off” as it is known if it allows the deposition of the non-wetting layer in the last step, thus avoiding a detrimental surface treatment, is however not suitable for creating patterns in such a way.
  • non-wetting material in particular a hydrophobic material, such as a tetrafluoroetylene polymer, because it does not allow to obtain sharp and precise wetting zones in this non-wetting material.
  • the invention thus relates, according to this second aspect, to a manufacturing method of the aforementioned device, in which the creation of the partially wetting layer of the first or second track comprises the following steps: creation of a mask of photosensitive material by depositing the photosensitive material on a substrate, photolithography, then revealing the photosensitive material; depositing a non-wetting material on the mask; at least one annealing before dissolution; dissolution of the mask; at least one annealing after dissolution.
  • the annealing temperature before dissolution is lower than the annealing temperature after dissolution.
  • the first annealing before dissolution is followed by at least one other annealing at a temperature greater than that of the first annealing.
  • the first annealing after dissolution is followed by at least one other annealing at a temperature higher than that of the first annealing.
  • the dissolution of the mask is followed by rinsing.
  • the nonwetting material deposited is a tetrafluoroetylene polymer.
  • the method of the invention advantageously allows the creation of a partially wetting layer which contains sharp and precise wetting zones, adapted to a chemical functionalization, and which contains non-wetting areas which retain their high nonwetting properties necessary for transport of drops.
  • the layer of non-wetting material is deposited in the last step and does not undergo surface treatment, so does not undergo any change in its surface properties.
  • the invention finally relates, according to a third aspect, to a microfluidic analysis system of a liquid sample which comprises at least one means for preparing the sample, coupled to at least one device for handling of gout according to the invention and as mentioned above, itself coupled to at least one means of analysis.
  • the preparation means comprises one or more tanks or loading docks.
  • the analysis means is a mass spectrometer, a fluorescence detector, a UV emission detector, or IR.
  • the system according to the invention is optionally integrated into a microsystem that integrates itself one or more laboratory operations usually performed manually, and that will be called micro-laboratory.
  • the system according to the invention advantageously makes it possible to analyze liquid samples after preparation of the samples and then transport by displacement of calibrated microvolumes to an analyzer, by automating the preparation and transport tasks integrated into a microlaboratory. It thus advantageously makes it possible to reduce the risks of contamination and loss of material of the sample, and to reduce the reaction times.
  • FIGS 2a to 2r schematically represent different embodiments of the device of the invention (sectional views perpendicular to the direction of movement of the drop).
  • the device comprises at least one track with a substrate 1, preferably but not necessarily transparent, for example Pyrex ⁇ .
  • a substrate 1 preferably but not necessarily transparent, for example Pyrex ⁇ .
  • interdigital electrodes 2 Above this substrate 1 are the interdigital electrodes 2. The notion of interdigital electrodes will be specified later with reference to the figures 3 and 4 .
  • insulating dielectric layer 3 consisting for example of oxides or polymers.
  • non-wetting layer 4 which is rendered partially wetting by the method of creating wetting apertures 5 in the non-wetting material 4, a process which will be described in more detail a little later with reference to the figure 7 .
  • the device comprises a single track consisting of layers 1, 2, 3 and 4.
  • the device of the figure 2a makes it possible to implement a displacement by electrowetting that does not require counter-electrodes, a displacement which will be explained later with reference to the figure 3 .
  • the devices of figures 2b each have a counter-electrode in the form of a line of mass 6 placed on the partially wetting layer 4 ( figure 2b ), inserted in and not covered by the partially wetting layer 4 ( Figure 2c ), or inserted into and covered by the partially wetting layer 4 ( figure 2d ).
  • the devices of Figures 2b to 2d enable them to implement the electrowetting displacement with a ground line for counter-electrode, a displacement which will be described later with reference to the figure 4 .
  • FIGS. 2e and following show alternative embodiments in which is added a second track formed of a non-wetting layer 7 itself covered with an upper layer 8 which can be either electrically insulating or electrically semiconductive or electrically conductive.
  • This second track is placed opposite the first, with use of shims 9 to maintain a displacement space 10 to be filled with an immiscible electrically insulating fluid with respect to the drop carried.
  • the fluid filling the space 10 must effectively be electrically insulating.
  • the fluid in order not to interact with the drop carried, the fluid must actually be immiscible with respect to the liquid. It may be for example air or oil, in the case of a drop of aqueous solution.
  • Figures 2f to 2h show alternative embodiments which are respectively based on the devices of the Figures 2b to 2d to which we add a second track as described above.
  • the second track further comprises one or more counter-electrodes 11 inserted between the non-wetting layer 7 and the upper layer 8. Therefore, no ground line is used, unlike the devices of FIGS. Figures 2f to 2h since the counter-electrode is present in the second track.
  • the mode of travel is, however, identical to that of Figures 2f to 2h .
  • the figure 2m describes an alternative embodiment based on that previously described in the figure 2e with the following difference: the non-wetting layer 7 of the second track is rendered partially wetting by the method of creating wetting openings 5 in the non-wetting material 7 which will be described later with reference to the figure 7 .
  • the variant embodiment of the figure 2n is derived from the variant embodiment of the figure 2i with the following two differences: the non-wetting layer 7 of the second track is rendered partially wetting by creating wetting openings 5 in the non-wetting layer 7 according to the method which will be described later with reference to the figure 7 ; and, to allow the biochemical functionalization of these wetting apertures without interactions with the counter-electrode (s) 11, an insulating dielectric layer 12 similar to that present in the first track is inserted between the partially wetting layer 7 and the counter-seal (s). electrodes 11.
  • the variant embodiment described in the figure 2o relates to a device with two tracks.
  • the first track differs from the first track of the preceding embodiments in that the non-wetting layer 4 which constitutes it is not partially wetting: no wetting opening is created in this non-wetting layer 4.
  • this variant embodiment does not require an insulating dielectric layer between the interdigital electrodes 2 and the non-wetting layer 4 in the case where this non-wetting layer 4 is itself electrically insulating. This is particularly the case for a hydrophobic layer made of a material such as a tetrafluoroethylene polymer. However, in practice, such a material is effectively electrically insulating only if the thickness of the layer is important (thickness of about one micrometer).
  • the second track is identical to that of the variants of embodiment of Figures 2j to 2m .
  • the non-wetting layer 4 is not partially wetting since it does not comprise the openings 5.
  • These variant embodiments are therefore derived respectively from the variants of the Figures 2k and 2l , with the aforementioned difference (layer 4 totally non-wetting, whereas in the variants of Figures 2k and 2l it is partially wetting).
  • the variant embodiment of the figure 2r resumes the mode of movement of Figures 2a, 2e and 2m , that is to say without the use of a counter-electrode, and, as in the variants of the Figures 2o to 2p , has a non-wetting layer 7 in the second track which is partially wetting with the presence of wetting openings 5, and a non-wetting layer 4 in the first track which is completely non-wetting since it has no wetting opening.
  • this variant embodiment does not require an insulating dielectric layer between the interdigital electrodes 2 and the non-wetting layer 4 in the case where this non-wetting layer 4 is itself electrically insulating, which is particularly the case for a hydrophobic layer, material such as a tetrafluoroethylene polymer.
  • a material such as a tetrafluoroethylene polymer.
  • such a material is effectively electrically insulating only if the thickness of the layer is important (thickness of about one micrometer).
  • the figure 3 schematically represents the displacement of a drop on a track of the device according to an alternative embodiment.
  • This figure is broken down into two parts.
  • the representation of the device is a representation in top view and partial in that it does not show the non-wetting layer or partially wetting or the insulating dielectric layer, located between the drop 15 and the electrodes 2a, 2b, 2c and 2d.
  • the representation of the device is a representation in section from the side, in the direction of movement of the drop.
  • the device is of the type of that of figure 2a , that is to say with only one track.
  • the following explanations concerning the displacement of gout are applicable more generally to the cases of Figures 2a, 2e , 2m and 2r , that is to say a displacement on a track with interdigital electrodes, without counter-electrodes, possibly with a second upper plane.
  • the figure 4 schematically represents the displacement of a drop on a track of the device according to another embodiment variant.
  • the figure is divided into two parts.
  • the representation of the device is a representation in top view and partial in that it does not show either the non-wetting layer or partially wetting or insulating dielectric layer, located between the drop 15 and the electrodes 2a, 2b, 2c and 2d.
  • the representation of the device is a representation in section from the side, in the direction of movement of the drop.
  • the device presented corresponds to a device with a single track and a ground line 6 as a counter-electrode 6, as previously described in FIG. figure 2b .
  • the following explanations concerning the displacement of a droplet on this device are also applicable to the cases of FIGS. 2c, 2d, 2f, 2g, 2h, 2d, 2k, 2d, 2d, 2d, 2d .
  • the device comprises a layer of interdigital electrodes (2a, 2b, 2c, 2d) which rest on an electrically insulating and optionally transparent substrate 1. Above this layer of electrodes is an insulating dielectric layer 3. Above this insulating dielectric layer 11 is a non-wetting layer 4. This layer is optionally partially wetting, depending on the configuration in which it is located ( see figures 2 ). Above this non-wetting layer 4 (possibly partially wetting), there is an electrode of mass 6 or ground line 6.
  • the drop 15 is initially on the electrode 2a (step A). By creating a potential difference between the electrode 2c and the electrodes 2a, 2b, 2d and the ground electrode 6, the drop moves on the electrode 2c (step B). To move the drop on the electrode 2d, a potential difference is created between the electrode 2d and the electrodes 2a, 2b, 2c and the ground electrode 6, and so on.
  • the figure 5 schematically represents the steps of the creation process opening in a non-wetting material, which renders it partially wetting, according to the conventional photolithographic technique with surfactant.
  • step (a) a layer of non-wetting material 4 is deposited on a substrate 1.
  • step (b) a layer of resin 20 containing a surfactant is deposited on the non-wetting layer 4.
  • the surfactant allows to increase the wettability of the non-wetting layer with respect to the resin, so the attachment of the resin on this layer.
  • step (c) photolithographic step itself, the layer 20 is subjected to UV radiation.
  • the ultraviolet radiation causes a rupture of the macromolecules of the exposed zones, which gives these zones an increased solubility to the developing solvent which will be used in step (d), while the non insolated on the opposite will have polymerized.
  • the revelation of the resin is accompanied by an attack of the exposed non-wetting material and thus the appearance of the zones or openings 5 in the non-wetting layer 4 (step (e)).
  • This technique is accompanied by the risk of permanently modifying the surface properties of the non-wetting material due to the use of the surfactant in the resin.
  • the figure 6 schematically represents the steps of the method of creating openings in a non-wetting material according to the conventional photolithographic technique with plasma.
  • This technique differs from the previous one in that it comprises an additional step of subjecting the non-wetting layer 4 to plasma-argon radiation (step (b)) before the deposition of the resin layer 20. which will modify the surface properties of the non-wetting layer 4, whereas in the previous technique ( figure 5 ), it is the presence of surfactant in the resin that plays this role.
  • the following steps ((c), (d), (e), (f)) are respectively the same as steps (b), (c), (d) and (e) of the figure 5 .
  • the conclusion is the same as for the conventional photolithographic technique with surfactant, namely that there is a risk of definitive modification of the surface properties of the non-wetting layer 4.
  • the process of the invention is therefore a method of manufacturing one or more tracks of the device described above, wherein the creation of the partially wetting layer first comprises a step of creating a mask of photosensitive material by depositing a layer of this material On a substrate 1 (step (a)), photolithography (step (b)), and revealing the photosensitive material (step (c)).
  • a negative resin is used as the photosensitive material, that is to say for which the UV radiation causes a polymerization of the insolated zones resulting in increased solubility of the unexposed areas in the developer.
  • step (b) It is therefore the areas not exposed to step (b) that disappear in step (c), while the areas exposed to step (b) remain present in step (c) and are marked by the number 20.
  • a negative resin is of course not limited to the invention. The considerations of the process of the invention are exactly the same in the case of the use of a positive resin.
  • Step (c) is followed by a step (d) of depositing a layer of non-wetting material 4.
  • the step (d) of deposition of the non-wetting material 4 is followed by a first annealing step.
  • a first annealing step Depending on the material chosen (tetrafluoroethylene polymer for example), it is possible to anneal at 50 ° C. for 5 minutes.
  • this annealing is followed by another complementary annealing. This other annealing can then be carried out at a temperature of 110 ° C. for 5 minutes also.
  • traces may be difficult or impossible to remove during the next dissolution step, which may change the surface properties of the partially wetting layer (partially hydrophilic in the case of wettability with respect to water ): the openings 5 may not be perfectly non-wetting (or hydrophobic for non-wettability with respect to water) and unopened areas may not be perfectly non-wetting (hydrophobic). Therefore, before proceeding to this second annealing step, we will first dissolve the resin for example in acetone, for example for 30 to 40 seconds. Preferably, but not necessarily, this dissolution step is followed by a rinsing step for example with alcohol.
  • the second annealing step is carried out, for example (depending on the material chosen) at 170 ° C. for 5 minutes, which has the effect of completely removing the solvent that may be present in the hydrophobic material.
  • another complementary annealing is carried out, for example at 330 ° C. for 15 min.
  • the method of the invention advantageously makes it possible to create a partially wetting layer in a non-wetting material.
  • This result is achieved by creating openings 5 in the non-wetting material, which become wetting areas, adapted to chemical or biochemical functionalization.
  • the unopened areas remain perfectly non-wetting and thus retain their high nonwetting properties necessary for the transport of drops.
  • the fact that the layer of non-wetting material is deposited in the last stage of the process unlike the state of the art, makes it possible not to subject this surface treatment material (technique using a surfactant, or using a plasma-argon).
  • the device of the invention therefore comprises at least one layer made partially wetting by creating wetting openings in a non-wetting layer, as explained above. These wetting zones will be able to be activated and chemically functionalized ( figure 8 ) then react with the manipulated gout ( figure 9 ). We will therefore use the principle of displacement of the drop as explained above to activate the areas not yet functionalized with a drop 15 containing an agent for functionalization.
  • the figure 10 schematically represents an alternative embodiment of the system according to the invention.
  • the system comprises one or more means 100 for preparing the liquid sample to be analyzed, one or more drop-handling devices 200 according to the invention and as explained above, and one or more means 300 for analyzing the output.
  • the means 100 of preparation may comprise for example one or more tanks or loading docks.
  • the analysis means 300 may for example be a mass spectrometer, a fluorescence detector or a UV emission detector.
  • the device 200 according to the invention at the heart of this system, is coupled upstream with the means or means 100 of preparation, and downstream with the means 300 of analysis.
  • the system according to the invention can thus be optionally integrated in a microsystem that itself integrates one or more laboratory operations usually performed manually. Such a system is called microlaboratory.
  • the device of the invention comprising a substrate of Pyrex ⁇ , nickel conductive electrodes interdigitated with a thickness of one hundred nanometers, a layer about one micrometer of resin SU8 deposited by centrifugation, insulating dielectric layer. Finally, the device comprises a hydrophobic layer of tetrafluoroethylene polymer, also deposited by centrifugation, on the previously mentioned resin layer.
  • the areas not covered by the hydrophobic layer will undergo a surface treatment to transform them into a reactive surface, for example a grafted-NH 2 support Streptavidin.
  • a drop of liquid containing proteins for example, and moving in the path of electrodes on a functionalized zone will see its molecules of interest (certain proteins such as biotin for example). ) having an affinity for previously grafted surfaces during functionalization, attach to these surfaces.
  • the drop continues its way in the device. Thereafter, the passage of a specific mixture (for example a denaturing buffer mixture) on these zones makes it possible to release the molecules of interest (by destroying the non-covalent interactions for example) and carries them with him.
  • a specific mixture for example a denaturing buffer mixture
  • the areas not covered by the hydrophobic layer will undergo a surface treatment in order to transform them into reactive surfaces, for example trypsin-grafted support-NH2.
  • a drop of liquid moving in the electrode path is immobilized on a functionalized zone, and certain molecules of interest (proteins for example). will react with the grafted surfaces. The result of such a reaction will be to cut the molecules (for example peptides obtained by tryptic digestion). Subsequently, the drop continues its path in the device.
  • Such a device therefore makes it possible, for example, to analyze long chains of molecules by preliminary cutting by means of specific enzymes, for mass spectrometry analysis.
  • the device; the method, and the system of the invention therefore make it possible to produce the basic elements of a microsystem intended to move microdrops from one functionalized zone to another, in an architecture which lends itself perfectly to integration. upstream or downstream with other complementary functions.
  • tetrafluoroethylene polymer material for the non-wetting or partially wetting layer is not limiting of the invention.
  • a tetrafluoroethylene polymer is a suitable choice in that it is effectively non-wetting, especially, but not only, with respect to water, therefore hydrophobic. More generally, we will always focus on a non-wetting material, which is biocompatible (does not adsorb material transported, does not mix with the transported material, does not cause chemical reactions, does not release material). It must therefore be neutral with regard to the preceding explanations, and also present a homogeneity of its properties on the surface.
  • the choice of silicon or Pyrex ⁇ for the substrate is of course not limit the invention. This is also the case of the choice of a positive or negative resin in the context of the manufacturing process of the device of the invention. It will also be noted, again in the context of the manufacturing process of the device of the invention, that the temperatures and times of the annealing steps of the process are not limiting of the invention, and are essentially a function of the nonwetting material chosen. Also, the use of acetone for dissolution and an alcohol for rinsing, is not limiting of the invention. Any other product suitable for dissolution and rinsing may be used.
  • the examples of displacement in a given direction are not limiting of the invention.
  • the displacement possibilities depend essentially on the geometrical arrangement of the electrodes.
  • An array of electrodes makes it possible to obtain a displacement of matrix type.
  • the shape of the electrodes in the examples of this description is of course not limiting of the invention. Any other form allowing the interdigitation of the electrodes is suitable.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Health & Medical Sciences (AREA)
  • Dispersion Chemistry (AREA)
  • Clinical Laboratory Science (AREA)
  • General Health & Medical Sciences (AREA)
  • Hematology (AREA)
  • Analytical Chemistry (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Engineering & Computer Science (AREA)
  • Mechanical Engineering (AREA)
  • General Engineering & Computer Science (AREA)
  • Physical Or Chemical Processes And Apparatus (AREA)
  • Investigating Or Analyzing Materials By The Use Of Electric Means (AREA)
  • Automatic Analysis And Handling Materials Therefor (AREA)
  • Micromachines (AREA)

Claims (25)

  1. Vorrichtung zur Manipulation von Tropfen auf einer Ebene zur Bewegung mittels Elektrobenetzung, umfassend wenigstens eine Bahn, dadurch gekennzeichnet, daß die Bahn umfaßt:
    - ein elektrisch isolierendes Substrat (1), das eine obere Fläche aufweist,
    - wenigstens zwei erste leitende Elektroden (2, 2a bis 2d) mit einer oberen Fläche und einer unteren Fläche, die mit ihrer unteren Fläche auf der oberen Fläche des elektrisch isolierenden Substrats (1) aufliegen, wobei eine jede der ersten Elektroden (2, 2a bis 2d) mit wenigstens einer weiteren dieser ersten Elektroden (2, 2a bis 2d) interdigitiert ist,
    - eine dielektrische Isolationsschicht (3) mit einer unteren Fläche und einer oberen Fläche, die mit ihrer unteren Fläche auf der oberen Fläche der ersten Elektroden (2, 2a bis 2d) aufliegt,
    - eine teilbenetzende Schicht (4) mit einer unteren Fläche und einer oberen Fläche, die mit ihrer unteren Fläche auf der oberen Fläche der dielektrischen Isolationsschicht (3) aufliegt,
    wobei die teilbenetzende Schicht (4) aus einer Schicht aus nicht benetzendem Material mit benetzenden Öffnungen (5) besteht.
  2. Vorrichtung nach Anspruch 1, dadurch gekennzeichnet, daß sie wenigstens eine Gegenelektrode (6), die von den ersten Elektroden (2, 2a bis 2d) getrennt ist, umfaßt.
  3. Vorrichtung nach Anspruch 2, dadurch gekennzeichnet, daß die separate Gegenelektrode (6) eine Masseleitung (6) ist, die auf oder unter der oberen Fläche der teilbenetzenden Schicht (4) gelegen oder in letztere eingefügt ist.
  4. Vorrichtung nach einem der Ansprüche 1 bis 3, dadurch gekennzeichnet, daß sie eine zweite Bahn umfaßt, die der ersten Bahn gegenüber und von dieser getrennt angeordnet ist, derart, daß zwischen der ersten und der zweiten Bahn ein Raum (10) ausgebildet wird, wobei die zweite Bahn eine nicht benetzende Schicht (7) umfaßt, die eine untere Fläche auf der Seite des Raums (10) und eine obere Fläche auf der anderen Seite aufweist.
  5. Vorrichtung nach Anspruch 4, dadurch gekennzeichnet, daß die nicht benetzende Schicht (7) der zweiten Bahn eine teilbenetzende Schicht ist, die aus einer Schicht aus nicht benetzendem Material mit benetzenden Öffnungen (5) besteht.
  6. Vorrichtung nach einem der Ansprüche 4 und 5, dadurch gekennzeichnet, daß die zweite Bahn eine elektrisch isolierende, halbleitende oder leitende obere Schicht (8) umfaßt, die auf der Seite der oberen Fläche der nicht benetzenden Schicht (7) gelegen ist.
  7. Vorrichtung nach einem der Ansprüche 4 bis 6, dadurch gekennzeichnet, daß die zweite Spur eine oder mehrere Gegenelektroden (11) umfaßt, die zwischen der nicht benetzenden Schicht (7) und der oberen Schicht (8) gelegen sind.
  8. Vorrichtung nach Anspruch 7, dadurch gekennzeichnet, daß die zweite Bahn eine dielektrische Isolationsschicht (12) umfaßt, die zwischen der nicht benetzenden Schicht (7) und der oder den Gegenelektroden (11) gelegen ist.
  9. Vorrichtung zur Manipulation von Tropfen zwischen zwei Ebenen zur Bewegung mittels Elektrobenetzung, umfassend zwei durch einen Raum (10) getrennte Bahnen, dadurch gekennzeichnet, daß:
    - die erste Bahn umfaßt:
    i. ein elektrisch isolierendes Substrat (1), das eine obere Fläche aufweist,
    ii. wenigstens zwei erste Elektroden (2, 2a bis 2d) mit einer oberen Fläche und einer unteren Fläche, die mit ihrer unteren Fläche auf der oberen Fläche des elektrisch isolierenden Substrats (1) aufliegen, wobei eine jede der ersten Elektroden (2, 2a bis 2d) mit wenigstens einer weiteren dieser ersten Elektroden (2, 2a bis 2d) interdigitiert ist,
    iii. eine nicht benetzende Schicht (4) mit einer unteren Fläche und einer oberen Fläche, die auf der Seite der oberen Fläche der ersten Elektroden (2, 2a bis 2d) gelegen ist,
    - die zweite Bahn eine teilbenetzende Schicht (7) mit einer oberen Fläche und einer unteren Fläche umfaßt,
    wobei die teilbenetzende Schicht (7) der zweiten Bahn aus einer Schicht aus nicht benetzendem Material mit benetzenden Öffnungen (5) besteht.
  10. Vorrichtung nach Anspruch 9, dadurch gekennzeichnet, daß die erste Bahn eine dielektrische Isolationsschicht (3) umfaßt, die zwischen der oberen Fläche der ersten Elektroden (2, 2a bis 2d) und der unteren Fläche der nicht benetzenden Schicht (4) gelegen ist.
  11. Vorrichtung nach einem der Ansprüche 9 und 10, dadurch gekennzeichnet, daß sie eine Masseleitung (6) umfaßt, die auf oder unter der oberen Fläche der nicht benetzenden Schicht (4) gelegen oder in letztere eingefügt ist
  12. Vorrichtung nach einem der Ansprüche 9 bis 11, dadurch gekennzeichnet, daß die zweite Bahn eine elektrisch isolierende, leitende oder halbleitende Schicht (12) umfaßt, die auf der Seite der oberen Fläche der teilbenetzenden Schicht (7) gelegen ist.
  13. Vorrichtung nach einem der Ansprüche 1 bis 12, dadurch gekennzeichnet, daß das elektrisch isolierende Substrat (1) der ersten Bahn transparent ist.
  14. Vorrichtung nach Anspruch 13, dadurch gekennzeichnet, daß das elektrisch isolierende Substrat (1) der ersten Bahn ein Substrat aus Glas ist.
  15. Vorrichtung nach einem der Ansprüche 1 bis 14, dadurch gekennzeichnet, daß die benetzenden Bereiche, die von den benetzenden Öffnungen (5) in dem nicht benetzenden Material der teilbenetzenden Schicht (4, 7) der ersten und/oder zweiten Bahn gebildet sind, funktionalisierte reaktive Bereiche sind.
  16. Vorrichtung nach Anspruch 15, dadurch gekennzeichnet, daß die benetzenden Bereiche biochemisch funktionalisiert und reaktiv sind.
  17. Vorrichtung nach einem der Ansprüche 1 bis 16, dadurch gekennzeichnet, daß die nicht benetzende Schicht (4, 7) und/oder die nicht benetzenden Bereiche der teilbenetzenden Schicht (4, 7) nicht benetzend gegenüber Wasser, also hydrophob sind und daß die benetzenden Bereiche benetzend gegenüber Wasser, also hydrophil sind.
  18. Vorrichtung nach einem der Ansprüche 1 bis 17, dadurch gekennzeichnet, daß die nicht benetzende Schicht (4, 7) und/oder die nicht benetzenden Bereiche der teilbenetzenden Schicht (4, 7) aus Tetrafluorethylen-Polymer bestehen.
  19. Verfahren zur Herstellung der Vorrichtung nach einem der Ansprüche 1 bis 18, wobei die Erzeugung der teilbenetzenden Schicht (4, 7), bestehend aus einer Schicht aus nicht benetzendem Material mit benetzenden Öffnungen (5), der ersten Bahn oder der zweiten Bahn umfaßt:
    - einen Schritt zur Erzeugung einer Maske aus lichtempfindlichem Material, durch Abscheiden des lichtempfindlichen Materials auf einem Substrat, Photolithographie, anschließend Entwickeln des lichtempfindlichen Materials,
    - einen Schritt zum Abscheiden eines nicht benetzenden Materials auf der Maske,
    - wenigstens einen Temperschritt vor Auflösung,
    - einen Schritt zur Auflösung der Maske,
    - wenigstens einen Temperschritt nach Auflösung.
  20. Verfahren nach Anspruch 19, dadurch gekennzeichnet, daß die Tempertemperatur des Temperschrittes vor Auflösung niedriger als die Tempertemperatur des Temperschrittes nach Auflösung ist.
  21. Verfahren nach einem der Ansprüche 19 und 20, dadurch gekennzeichnet, daß der Schritt des Abscheidens eines nicht benetzenden Materials auf der Maske ein Schritt zum Abscheiden eines Tetrafluorethylen-Polymers ist.
  22. System zur mikrofluidischen Analyse einer Flüssigkeitsprobe, dadurch gekennzeichnet, daß es umfaßt:
    - wenigstens ein Mittel (100) zur Zubereitung der Flüssigkeitsprobe, das wenigstens einen Ausgang aufweist,
    - wenigstens eine Vorrichtung (200) zur Tropfenmanipulation nach einem der Ansprüche 1 bis 18, die über einen ihrer Eingänge mit einem der Ausgänge des Zubereitungsmittels (100) gekoppelt ist und wenigstens einen Ausgang aufweist,
    - wenigstens ein Analysemittel (300), das über einen seiner Eingänge mit einem der Ausgänge der Vorrichtung (200) zur Tropfenmanipulation gekoppelt ist.
  23. System nach Anspruch 22, dadurch gekennzeichnet, daß das Zubereitungsmittel (100) eine(n) oder mehrere Behälter oder Laderampen umfaßt.
  24. System nach einem der Ansprüche 22 und 23, dadurch gekennzeichnet, daß das Analysemittel (300) ein Massenspektrometer oder ein Fluoreszenzdetektor oder ein UV-Emissionsdetektor ist.
  25. System nach einem der Ansprüche 22 bis 24, dadurch gekennzeichnet, daß es in ein Mikrolabor integriert ist.
EP05775767A 2004-06-04 2005-06-06 Vorrichtung zur handhabung von tropfen zur biochemischen analyse, verfahren zur herstellung einer derartigen vorrichtung und system zur mikrofluidischen analyse Not-in-force EP1781409B1 (de)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
FR0406080A FR2871150B1 (fr) 2004-06-04 2004-06-04 Dispositif de manipulation de gouttes destine a l'analyse biochimique, procede de fabrication du dispositif, et systeme d'analyse microfluidique
PCT/FR2005/001385 WO2006003293A2 (fr) 2004-06-04 2005-06-06 Dispositif de manipulation de gouttes destine a l'analyse biochimique, procede de fabrication du dispositif, et systeme d'analyse microfluidique

Publications (2)

Publication Number Publication Date
EP1781409A2 EP1781409A2 (de) 2007-05-09
EP1781409B1 true EP1781409B1 (de) 2012-01-11

Family

ID=34946857

Family Applications (1)

Application Number Title Priority Date Filing Date
EP05775767A Not-in-force EP1781409B1 (de) 2004-06-04 2005-06-06 Vorrichtung zur handhabung von tropfen zur biochemischen analyse, verfahren zur herstellung einer derartigen vorrichtung und system zur mikrofluidischen analyse

Country Status (9)

Country Link
US (1) US20080110753A1 (de)
EP (1) EP1781409B1 (de)
JP (1) JP4763690B2 (de)
KR (1) KR101179411B1 (de)
CN (1) CN101031362B (de)
AT (1) ATE540756T1 (de)
CA (1) CA2568805C (de)
FR (1) FR2871150B1 (de)
WO (1) WO2006003293A2 (de)

Families Citing this family (45)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
FR2871076A1 (fr) * 2004-06-04 2005-12-09 Univ Lille Sciences Tech Dispositif pour desorption par rayonnement laser incorporant une manipulation de l'echantillon liquide sous forme de gouttes individuelles permettant leur traitement chimique et biochimique
JP4632300B2 (ja) * 2005-02-14 2011-02-16 国立大学法人 筑波大学 送液装置
JP4893197B2 (ja) * 2006-09-28 2012-03-07 ブラザー工業株式会社 液体移送装置
US8702938B2 (en) * 2007-09-04 2014-04-22 Advanced Liquid Logic, Inc. Droplet actuator with improved top substrate
CN104297506B (zh) 2007-10-02 2017-05-03 赛拉诺斯股份有限公司 模块化现场护理装置及其应用
JP5383138B2 (ja) * 2008-10-01 2014-01-08 シャープ株式会社 エレクトロウエッティングバルブ付き送液構造体、これを用いたマイクロ分析チップ及び分析装置
US8877512B2 (en) * 2009-01-23 2014-11-04 Advanced Liquid Logic, Inc. Bubble formation techniques using physical or chemical features to retain a gas bubble within a droplet actuator
US8926065B2 (en) 2009-08-14 2015-01-06 Advanced Liquid Logic, Inc. Droplet actuator devices and methods
US8734628B2 (en) * 2010-03-10 2014-05-27 Empire Technology Development, Llc Microfluidic channel device with array of drive electrodes
EP2567213B1 (de) 2010-05-05 2018-01-24 The Governing Council of the Universtiy of Toronto Verfahren zur verarbeitung getrockneter proben mithilfe einer digitalen mikrofluidischen vorrichtung
CN101865928B (zh) * 2010-05-06 2012-07-18 大连理工大学 一种基于电场作用的超疏水表面微液滴操控方法
JP4949506B2 (ja) * 2010-07-16 2012-06-13 シャープ株式会社 流路構造体及びその製造方法、並びに、分析チップ及び分析装置
CA2813090C (en) * 2010-10-01 2019-11-12 The Governing Council Of The University Of Toronto Digital microfluidic devices and methods incorporating a solid phase
JP2012150098A (ja) * 2010-12-28 2012-08-09 Sharp Corp 検体検出用チップ、それを用いたセンサ、及び検体検出方法
SG192069A1 (en) 2011-01-21 2013-08-30 Theranos Inc Systems and methods for sample use maximization
US9268915B2 (en) 2011-09-25 2016-02-23 Theranos, Inc. Systems and methods for diagnosis or treatment
US8475739B2 (en) 2011-09-25 2013-07-02 Theranos, Inc. Systems and methods for fluid handling
US20140170735A1 (en) 2011-09-25 2014-06-19 Elizabeth A. Holmes Systems and methods for multi-analysis
US9664702B2 (en) 2011-09-25 2017-05-30 Theranos, Inc. Fluid handling apparatus and configurations
US8840838B2 (en) 2011-09-25 2014-09-23 Theranos, Inc. Centrifuge configurations
US9619627B2 (en) 2011-09-25 2017-04-11 Theranos, Inc. Systems and methods for collecting and transmitting assay results
US9632102B2 (en) 2011-09-25 2017-04-25 Theranos, Inc. Systems and methods for multi-purpose analysis
US9810704B2 (en) 2013-02-18 2017-11-07 Theranos, Inc. Systems and methods for multi-analysis
US9250229B2 (en) 2011-09-25 2016-02-02 Theranos, Inc. Systems and methods for multi-analysis
US10012664B2 (en) 2011-09-25 2018-07-03 Theranos Ip Company, Llc Systems and methods for fluid and component handling
CN108490204A (zh) * 2011-09-25 2018-09-04 赛拉诺斯知识产权有限责任公司 用于多重分析的系统和方法
CN102824933B (zh) * 2012-09-20 2014-09-03 复旦大学 一种单向液滴输运的数字微流芯片电极配置方法
US9366647B2 (en) * 2013-03-14 2016-06-14 Taiwan Semiconductor Manufacturing Company, Ltd. Optical detection for bio-entities
US10422806B1 (en) 2013-07-25 2019-09-24 Theranos Ip Company, Llc Methods for improving assays of biological samples
TWI507690B (zh) * 2014-09-02 2015-11-11 Silicon Optronics Inc 生物晶片構裝
US20200390811A1 (en) * 2015-04-23 2020-12-17 The Trustees Of The University Of Pennsylvania Compositions to disrupt protein kinase a anchoring and uses thereof
CN108026494A (zh) 2015-06-05 2018-05-11 米罗库鲁斯公司 限制蒸发和表面结垢的空气基质数字微流控装置和方法
CN208562324U (zh) 2015-06-05 2019-03-01 米罗库鲁斯公司 空气基质数字微流控(dmf)装置
US11148138B2 (en) * 2015-09-02 2021-10-19 Tecan Trading Ag Magnetic conduits in microfluidics
EP3500660A4 (de) 2016-08-22 2020-03-04 Miroculus Inc. Rückkopplungssystem für parallele tröpfchensteuerung in einer digitalen mikrofluidischen vorrichtung
EP3563151A4 (de) 2016-12-28 2020-08-19 Miroculus Inc. Digitale mikrofluidische vorrichtung und verfahren
WO2018187476A1 (en) 2017-04-04 2018-10-11 Miroculus Inc. Digital microfluidic apparatuses and methods for manipulating and processing encapsulated droplets
WO2019023133A1 (en) 2017-07-24 2019-01-31 Miroculus Inc. DIGITAL MICROFLUIDIC SYSTEMS AND METHODS WITH INTEGRATED PLASMA COLLECTION DEVICE
CA3073058A1 (en) 2017-09-01 2019-03-07 Miroculus Inc. Digital microfluidics devices and methods of using them
EP3796999A4 (de) 2018-05-23 2022-03-09 Miroculus Inc. Steuerung der verdampfung in digitaler mikrofluidik
EP3932537A4 (de) * 2019-02-25 2023-01-04 National Institute Of Advanced Industrial Science And Technology Open-space-artige vorrichtung zum manipulieren von flüssigkeiten
EP3953041A4 (de) 2019-04-08 2023-01-25 Miroculus Inc. Digitale mikrofluidikvorrichtungen mit mehreren patronen und verfahren zur verwendung
US11524298B2 (en) 2019-07-25 2022-12-13 Miroculus Inc. Digital microfluidics devices and methods of use thereof
CN111804354B (zh) 2020-04-07 2021-09-21 苏州大学 液滴无损转移装置及方法、液滴微反应方法
US11772093B2 (en) 2022-01-12 2023-10-03 Miroculus Inc. Methods of mechanical microfluidic manipulation

Family Cites Families (23)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1998000705A1 (en) * 1996-06-28 1998-01-08 Caliper Technologies Corporation Electropipettor and compensation means for electrophoretic bias
JP3791999B2 (ja) * 1997-03-24 2006-06-28 株式会社アドバンス 液体微粒子ハンドリング装置
JP3829491B2 (ja) * 1998-08-27 2006-10-04 株式会社日立製作所 プローブチップ、プローブチップ作成方法、試料検出方法、及び試料検出装置
US6565727B1 (en) * 1999-01-25 2003-05-20 Nanolytics, Inc. Actuators for microfluidics without moving parts
JP2002031638A (ja) * 2000-07-17 2002-01-31 Mitsubishi Chemicals Corp 生体試料検出用チップ及び生体試料検出方法
JP2002027984A (ja) * 2000-07-17 2002-01-29 Mitsubishi Chemicals Corp マイクロリアクタチップ，化学反応試験方法及びマイクロリアクタチップ用薄膜部材
US6773566B2 (en) * 2000-08-31 2004-08-10 Nanolytics, Inc. Electrostatic actuators for microfluidics and methods for using same
JP2003222611A (ja) * 2001-11-20 2003-08-08 Nec Corp 分離装置、分離方法および分離装置の製造方法
US7163612B2 (en) * 2001-11-26 2007-01-16 Keck Graduate Institute Method, apparatus and article for microfluidic control via electrowetting, for chemical, biochemical and biological assays and the like
JP2003230829A (ja) * 2001-12-06 2003-08-19 Hitachi Ltd 平面マイクロファクトリー
US7459127B2 (en) * 2002-02-26 2008-12-02 Siemens Healthcare Diagnostics Inc. Method and apparatus for precise transfer and manipulation of fluids by centrifugal and/or capillary forces
JP2003294733A (ja) * 2002-03-29 2003-10-15 Sumitomo Bakelite Co Ltd 細胞内蛋白量の同定方法及び基板
JP3914806B2 (ja) * 2002-04-09 2007-05-16 三菱化学株式会社 分析用チップ
KR100455293B1 (ko) * 2002-05-15 2004-11-06 삼성전자주식회사 친수성 영역과 소수성 영역으로 구성되는 생물분자용어레이 판의 제조방법
JPWO2004008132A1 (ja) * 2002-07-11 2005-11-10 三菱電機株式会社 生体分子分離セル及びその製造方法並びにｄｎａ分取装置
JP2004061229A (ja) * 2002-07-26 2004-02-26 Hitachi Ltd 感染症検査装置、検査方法、及び感染検査用マイクロファブリケーション
US7329545B2 (en) * 2002-09-24 2008-02-12 Duke University Methods for sampling a liquid flow
US6911132B2 (en) * 2002-09-24 2005-06-28 Duke University Apparatus for manipulating droplets by electrowetting-based techniques
US6989234B2 (en) * 2002-09-24 2006-01-24 Duke University Method and apparatus for non-contact electrostatic actuation of droplets
JP4590542B2 (ja) * 2003-06-10 2010-12-01 国立大学法人九州工業大学 マイクロ液滴輸送デバイス
JP4385124B2 (ja) * 2004-03-12 2009-12-16 国立大学法人九州工業大学 電気的制御可能な微量液滴輸送デバイス
FR2871076A1 (fr) * 2004-06-04 2005-12-09 Univ Lille Sciences Tech Dispositif pour desorption par rayonnement laser incorporant une manipulation de l'echantillon liquide sous forme de gouttes individuelles permettant leur traitement chimique et biochimique
US20060266700A1 (en) * 2005-05-31 2006-11-30 General Electric Company Porous structures with engineered wettability properties and methods of making them

Also Published As

Publication number Publication date
KR20070053165A (ko) 2007-05-23
CA2568805C (fr) 2012-08-28
WO2006003293A2 (fr) 2006-01-12
JP2008502882A (ja) 2008-01-31
CN101031362B (zh) 2012-01-11
EP1781409A2 (de) 2007-05-09
US20080110753A1 (en) 2008-05-15
FR2871150B1 (fr) 2006-09-22
JP4763690B2 (ja) 2011-08-31
CA2568805A1 (fr) 2006-01-12
FR2871150A1 (fr) 2005-12-09
ATE540756T1 (de) 2012-01-15
CN101031362A (zh) 2007-09-05
KR101179411B1 (ko) 2012-09-07
WO2006003293A3 (fr) 2006-09-21

Similar Documents

Publication Publication Date Title
EP1781409B1 (de) Vorrichtung zur handhabung von tropfen zur biochemischen analyse, verfahren zur herstellung einer derartigen vorrichtung und system zur mikrofluidischen analyse
EP1750840B1 (de) Laserstrahlungsdesorptionsgerät zur manipulation einer flüssigprobe in form von einzeltropfen zur ermöglichung ihrer chemischen und biologischen behandlung
EP2609993B1 (de) Nano- und mikro-fluidische Vorrichtung für die Trennung und Konzentration von in einem Fluid vorhandenen Partikeln
EP3347128B1 (de) Anordnung mit trägersubstrat für flüssigkeitsprobe und verwendung davon
FR2884437A1 (fr) Dispositif et procede microfluidique de transfert de matiere entre deux phases immiscibles.
WO2006131679A2 (fr) Dispositif planaire avec adressage de puits automatise par electromouillage dynamique
WO2010086378A1 (fr) Procede de formation de nano-fils et procede de fabrication de composant optique associe
FR2863626A1 (fr) Procede et dispositif de division d'un echantillon biologique par effet magnetique
FR2861610A1 (fr) Dispositif de travail comprenant une zone localisee de capture d'une goutte d'un liquide d'interet
FR3035009A1 (fr) Dispositif microfluidique de controle d'ecoulement d'un fluide
Kim et al. High‐Density Microfluidic Particle‐Cluster‐Array Device for Parallel and Dynamic Study of Interaction between Engineered Particles
EP3162441A1 (de) Mikrofluidische vorrichtung zur fluidischen verbindung
EP1677914B1 (de) Verfahren zur verteilung von tropfen einer betreffenden flüssigkeit auf einer fläche
EP1682273A1 (de) Begrenzte bearbeitungszonen umfassende bearbeitungsvorrichtung, on-chip-labor und mikrosystem
FR2890975A1 (fr) Plaque de tests a puits.
FR2865806A1 (fr) Laboratoire sur puce comprenant un reseau micro-fluidique et un nez d'electronebulisation coplanaires
EP1261426B1 (de) Testkarte und verfahren ihrer verwendung
WO2018065741A2 (fr) Procédé de concentration d'analytes
EP3807001B1 (de) Verfahren zur materialübertragung in einer millifluidischen vorrichtung
WO2007014775A1 (fr) Procede de fonctionnalisation successive d’un substrat et microstructure obtenue par ce procede
WO2006027532A1 (fr) Dispositif de transfert d'elements contenus dans un liquide
EP2875345A1 (de) Verfahren zur herstellung einer chromatografischen analysesäule
Arayanarakool Toward single enzyme analysis in a droplet-based micro and nanofluidic system
EP1429866A1 (de) Verfahren und vorrichtung zur isolierung und/oder bestimmung eines analyten
EP1652579A1 (de) Fluidische Systeme mit Kapilaren und Verfahren zu ihrer Herstellung

Legal Events

Date Code Title Description
PUAI Public reference made under article 153(3) epc to a published international application that has entered the european phase

Free format text: ORIGINAL CODE: 0009012

17P Request for examination filed

Effective date: 20061205

AK Designated contracting states

Kind code of ref document: A2

Designated state(s): AT BE BG CH CY CZ DE DK EE ES FI FR GB GR HU IE IS IT LI LT LU MC NL PL PT RO SE SI SK TR

DAX Request for extension of the european patent (deleted)
17Q First examination report despatched

Effective date: 20090318

GRAP Despatch of communication of intention to grant a patent

Free format text: ORIGINAL CODE: EPIDOSNIGR1

GRAS Grant fee paid

Free format text: ORIGINAL CODE: EPIDOSNIGR3

GRAA (expected) grant

Free format text: ORIGINAL CODE: 0009210

AK Designated contracting states

Kind code of ref document: B1

Designated state(s): AT BE BG CH CY CZ DE DK EE ES FI FR GB GR HU IE IS IT LI LT LU MC NL PL PT RO SE SI SK TR

REG Reference to a national code

Ref country code: GB

Ref legal event code: FG4D

Free format text: NOT ENGLISH

REG Reference to a national code

Ref country code: CH

Ref legal event code: EP

REG Reference to a national code

Ref country code: AT

Ref legal event code: REF

Ref document number: 540756

Country of ref document: AT

Kind code of ref document: T

Effective date: 20120115

REG Reference to a national code

Ref country code: IE

Ref legal event code: FG4D

REG Reference to a national code

Ref country code: DE

Ref legal event code: R096

Ref document number: 602005032145

Country of ref document: DE

Effective date: 20120315

REG Reference to a national code

Ref country code: NL

Ref legal event code: VDEP

Effective date: 20120111

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: SI

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20120111

LTIE Lt: invalidation of european patent or patent extension

Effective date: 20120111

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: LT

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20120111

Ref country code: BG

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20120411

Ref country code: NL

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20120111

Ref country code: IS

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20120511

REG Reference to a national code

Ref country code: IE

Ref legal event code: FD4D

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: GR

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20120412

Ref country code: PL

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20120111

Ref country code: PT

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20120511

Ref country code: FI

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20120111

REG Reference to a national code

Ref country code: AT

Ref legal event code: MK05

Ref document number: 540756

Country of ref document: AT

Kind code of ref document: T

Effective date: 20120111

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: CY

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20120111

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: RO

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20120111

Ref country code: CZ

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20120111

Ref country code: DK

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20120111

Ref country code: IE

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20120111

Ref country code: SE

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20120111

Ref country code: EE

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20120111

PLBE No opposition filed within time limit

Free format text: ORIGINAL CODE: 0009261

STAA Information on the status of an ep patent application or granted ep patent

Free format text: STATUS: NO OPPOSITION FILED WITHIN TIME LIMIT

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: SK

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20120111

Ref country code: IT

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20120111

26N No opposition filed

Effective date: 20121012

BERE Be: lapsed

Owner name: UNIVERSITE DES SCIENCES ET TECHNOLOGIES DE LILLE

Effective date: 20120630

Owner name: CENTRE NATIONAL DE LA RECHERCHE SCIENTIFIQUE (CNR

Effective date: 20120630

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: MC

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20120630

Ref country code: AT

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20120111

REG Reference to a national code

Ref country code: CH

Ref legal event code: PL

REG Reference to a national code

Ref country code: DE

Ref legal event code: R097

Ref document number: 602005032145

Country of ref document: DE

Effective date: 20121012

REG Reference to a national code

Ref country code: CH

Ref legal event code: PL

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: LI

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20120630

Ref country code: BE

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20120630

Ref country code: CH

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20120630

Ref country code: ES

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20120422

PGFP Annual fee paid to national office [announced via postgrant information from national office to epo]

Ref country code: GB

Payment date: 20130620

Year of fee payment: 9

Ref country code: DE

Payment date: 20130611

Year of fee payment: 9

PGFP Annual fee paid to national office [announced via postgrant information from national office to epo]

Ref country code: FR

Payment date: 20130724

Year of fee payment: 9

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: TR

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20120111

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: LU

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20120606

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: HU

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20050606

REG Reference to a national code

Ref country code: DE

Ref legal event code: R119

Ref document number: 602005032145

Country of ref document: DE

GBPC Gb: european patent ceased through non-payment of renewal fee

Effective date: 20140606

REG Reference to a national code

Ref country code: DE

Ref legal event code: R119

Ref document number: 602005032145

Country of ref document: DE

Effective date: 20150101

REG Reference to a national code

Ref country code: FR

Ref legal event code: ST

Effective date: 20150227

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: DE

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20150101

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: FR

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20140630

Ref country code: GB

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20140606