EP1778976B1 - Elektrodenadressierungsverfahren - Google Patents

Elektrodenadressierungsverfahren Download PDF

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Publication number
EP1778976B1
EP1778976B1 EP05789844A EP05789844A EP1778976B1 EP 1778976 B1 EP1778976 B1 EP 1778976B1 EP 05789844 A EP05789844 A EP 05789844A EP 05789844 A EP05789844 A EP 05789844A EP 1778976 B1 EP1778976 B1 EP 1778976B1
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EP
European Patent Office
Prior art keywords
line
electrodes
line selection
lines
selection
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EP05789844A
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English (en)
French (fr)
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EP1778976A2 (de
Inventor
Yves Fouillet
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Commissariat a lEnergie Atomique et aux Energies Alternatives CEA
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Commissariat a lEnergie Atomique CEA
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    • 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
    • B01F—MIXING, e.g. DISSOLVING, EMULSIFYING OR DISPERSING
    • B01F33/00—Other mixers; Mixing plants; Combinations of mixers
    • B01F33/30—Micromixers
    • B01F33/302—Micromixers the materials to be mixed flowing in the form of droplets
    • B01F33/3021—Micromixers the materials to be mixed flowing in the form of droplets the components to be mixed being combined in a single independent droplet, e.g. these droplets being divided by a non-miscible fluid or consisting of independent droplets
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01F—MIXING, e.g. DISSOLVING, EMULSIFYING OR DISPERSING
    • B01F33/00—Other mixers; Mixing plants; Combinations of mixers
    • B01F33/30—Micromixers
    • B01F33/3031—Micromixers using electro-hydrodynamic [EHD] or electro-kinetic [EKI] phenomena to mix or 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
    • B01L2300/089—Virtual walls for guiding liquids

Definitions

  • the invention relates to electro-fluidic multiplexing for the manipulation of several drops in a microsystem.
  • the invention is particularly well suited to the lab-on-a-chip requiring the control of a large number of different liquids, for example, for high-throughput analysis or combinatorial chemistry applications.
  • reaction volumes are drops manipulated by electrowetting on sets of electrodes.
  • the forces used for displacement are electrostatic forces.
  • the document FR-2 841 063 describes a device implementing a catenary facing electrodes activated for displacement.
  • a drop 2 rests on a network 4 of electrodes, from which it is isolated by a dielectric layer 6 and a hydrophobic layer 8 ( Figure 1A ).
  • Each electrode is connected to a common electrode via a switch, or rather an individual electrical relay control system 11.
  • the counter-electrode 10 can be either a catenary as described in FR - 2 841 063 ( Figure 2A ) a buried wire, or a planar electrode on a hood in the case of a confined system.
  • the hydrophobic layer thus becomes locally more hydrophilic.
  • the drop can thus be moved step by step ( figure 1C ), on the hydrophobic surface 8, by successive activation of the electrodes 4 - 1, 4 - 2, ... etc. and along the catenary 10.
  • the drops rest on the surface of a substrate comprising the matrix of electrodes, as illustrated in FIG. Figure 1A and as described in the document FR 2 841 063 .
  • a second family of embodiments consists in confining the droplet between two substrates, as explained, for example, in the document by M.G. POLLAK et al, already mentioned above.
  • the system generally consists of a chip and a control system.
  • the chips have electrodes as described above.
  • the electrical control system comprises a set 11 of relays and a PLC or a PC for programming relay switching.
  • the chip is electrically connected to the control system, so each relay can control one or more electrodes.
  • all the electrodes can be placed at a potential V0 or V1.
  • the number of electrical connections between the control system and the chip is equal to that of the number of relays.
  • the figure 2 illustrates the case of a matrix of N electrode lines.
  • the electrodes are connected in columns, each column of electrodes being connected to a relay, said parallel relay 20.
  • the operation of the lines is dissociated in order, for example, to bring a single drop given to one end, and to leave the other drops at the beginning of the line.
  • At least one column of electrodes is defined, each of the electrodes of this column being connected, via a conductor 21 - i, to a relay 22 - i which is independent of the relays to which connected the other electrodes of this same column.
  • These various relays are designated by the references 22 - 1, 22 - 6, 22 - 7, 22 - 8 on the figure 2 and are called line selection relays.
  • the drops thus selected can then continue their movement by controlling the relays 20.
  • the invention makes it possible to reduce the number of line selection conductors, and therefore of simplifying the line selection means in an electro-fluidic addressing matrix.
  • the invention thus makes it possible to drive line selection electrodes with only 2 n relays.
  • the invention makes it possible to drive 8, 16, 32, 64, 128, 256, 512, 1024 line selection electrodes with respectively 6, 8, 10, 12, 14, 16, 18, 20 conductors. line selection and the same number of line selection relays.
  • the invention is particularly well suited when the number of lines is large (> 16 or 32 for example).
  • the ESL-k electrodes for selecting the different lines can be connected to two line selection conductors for a given value of "k", the ESL-k electrodes being connected in packets of 2 k-1 alternatively to the conductor Ck. and the driver Ck '.
  • the selection means for selecting one or more line selection conductors may comprise selective electrical relays.
  • the line selection lead selection means comprise 2n electrical selection relay, each relay being connected to a single line selection conductor.
  • the line selection lead selection means comprising n electrical selection relays, each relay being connected to two line selection conductors.
  • Each line selection relay can then be combined with means for generating, in addition to an input signal, a complementary signal.
  • the line selection electrodes are arranged successively along each line, or non-sequentially along at least one line.
  • the line selection electrodes of at least one line may be rectangular in shape, the long side of each rectangle being arranged perpendicular to the line.
  • the line selection electrodes of at least one line may alternatively be square.
  • At least one electrode line of the matrix has a cut-off electrode (Ec).
  • Digital line selection means may be provided for controlling a device according to the invention.
  • These digital line selection means may be programmed to select the rows of the electrode array in a binary code.
  • a combinatorial logic obtained using an appropriate method is then used. interconnections between several electrodes at the chip or the device.
  • These digital line selection means may comprise means for selecting one or more lines of the matrix, and means for forming instructions for controlling the line selection conductors according to the selected line or lines.
  • These digital line selection means may furthermore comprise means for consecutively activating the line selection electrodes of a selected line and / or for simultaneously activating the line selection electrodes of a selected line.
  • the invention also relates to a device for forming drops of liquids, comprising a device as described above, and means forming reservoirs for liquids, each line of the matrix being connected to a reservoir.
  • Such a device according to the invention may also comprise means forming 2 n reservoirs for liquids, each line of the matrix being connected to a single reservoir.
  • Each line can be connected to a common line of electrodes, to mix drops of liquids formed on the different lines.
  • the invention also relates to a device for addressing an array of electrodes of p lines, with 2 n ⁇ p ⁇ 2 n + 1 lines, of an electrofluidic device, comprising a device with 2 n lines as described herein. -above.
  • the line selection electrodes of said line can be activated consecutively, or successively.
  • the invention also relates to a method of forming a drop of liquid comprising the displacement of a volume of liquid as described above, the spreading of this volume on several electrodes of said line by simultaneous selection of these electrodes, and breaking the spread volume using a cutoff electrode (Ec).
  • the implementation of the invention makes it possible to control a very large number of drops with a simple technology for manufacturing the chip, a minimization of the number of electrical connections between the chip and the control system, a simplification of the electrical control system and thus minimization of the manufacturing costs of the chip, the electrical connections, and the control system.
  • the device comprises 8 lines (No. 0 to No. 7) of electrodes, or 2 3 lines.
  • Each line has at least 3 electrodes, 6 in the example of the figure 3 .
  • the line selection electrodes Esl-i are connected to line selection relays, as explained in more detail below, or to line selection conductors C1, C1 ', C2, C2', C3, C3 'which are themselves connected to line selection relays.
  • N 2 n lines
  • 2n line selection conductors are available.
  • each electrode column is connected to a parallel relay.
  • the electrodes Es1 - i are not necessarily consecutive: there may be, for at least one line, a "normal" electrode (which is not a selection electrode) between two selection electrodes Es1 - i.
  • a "normal" electrode which is not a selection electrode
  • the rightmost selection electrode on the line is Esl - 1, Esl - 2 being the left selection electrode of Esl - 1 (even if it is not juxtaposed to it) and, more generally, Esl - k being the left selection electrode of Esl - (k - 1 ), even if it is not juxtaposed with it.
  • the electrodes Esl - 1 of the different lines are connected to C1 and C1 '(then to Rs1 - 1 and to Rs1 - 1') alternately: in other words, the electrodes Esl - 1 are alternately connected to C1 and C1 '(so there is change every 2 (1-1) lines, that is to say at every line).
  • the ESL-k electrodes of the different lines can be connected to two line selection conductors Ck or Ck '(and corresponding RSL-k or RSL-k' relays), the ESL-k electrodes being connected in a 2 k-1 packet, alternately on the conductor Ck and on the conductor Ck '.
  • the line selection electrodes of this line are assigned to different pairs Ck, Ck 'and therefore, in the configuration of the figure 3 , to different relay pairs Rs1-k, Rs1-k '.
  • the line selection electrodes are paired, two line selection electrodes of the same line are not assigned to the same pair Ck (Rs1 - k), Ck '(Rs1 - k').
  • each line selection conductor Ck is assigned or connected 2 n-1 line selection electrodes of 2 n-1 lines.
  • each line selection conductor and relay may have two different states.
  • a first state is said state "0".
  • the conductor Ck and the electrodes that this relay controls are then connected to the potential V0 (or to a floating potential): the electrowetting does not act on these electrodes, there is no displacement or spreading of the drops on these electrodes.
  • a second state is said state "1".
  • the conductors Ck and the electrodes that this relay controls are then connected to the potential V1: the electrowetting can act on these electrodes to move or spread the drops on these electrodes.
  • This embodiment of the invention makes it possible to work only with 2n line selection conductors, and as many control relays, 2 n xn line selection electrodes. the set of lines, these row selection electrodes being in number n on each line.
  • the known devices implement, at best, 2 n row selection electrodes, but with 2 n conductors and as many relays (see FIG. figure 2 ).
  • the gain provided by the invention in terms of the number of conductors and relays, is therefore significant, especially if the number of lines is of the order of 2 n. With n ⁇ 4, or 8, or 16 ... etc.
  • Means 40 for controlling the relays may be provided, for example programmable digital means (PC or other) to which the relays are connected and which can drive these relays.
  • PC programmable digital means
  • These means may be provided with a screen 42 allowing the user to select a line on which a drop must be able to be transferred.
  • the matrix is represented on this screen and the user selects one or more drop transfer lines, using a cursor or a stylus to designate the line or lines retained directly on the screen .
  • an automatic program can select the lines and send the corresponding control signals to the electrodes.
  • Means for memorizing the means 40 make it possible to memorize the information making it possible to select this or that line.
  • This information is for example that of Table I for the case of an addressing matrix of 8 lines, they are stored or stored in the form of Table I or in another form.
  • the digital means select, in the storage means, the data for opening or closing the relays Rs1 -k, Rsl-k 'necessary, and thus activate the electrodes Ck, Ck' necessary.
  • the line selection conductors Ck, Ck ' are connected to as many line selection relays Rs1-k, Rs1-k'.
  • the 2n relays can be further reduced to a number n if each pair of relays Rs1 - k, Rs1 - k 'is replaced by a single relay and logic gate type means for forming, for each relay Rs1 - k an output to a first state (state "1") and an output to a complementary state (the state "0").
  • the two RSL-i and RSL-i 'relays are replaced by a single RSL-i' relay using a complementary logic function ( figure 4 ). This allows the number of relays to be divided by 2.
  • Table II Line Binary number State of the RSL3 relay State of the RSL-2 relay State of the RSL1 relay 0 000 0 0 0 1 001 0 0 1 2 010 0 1 0 3 011 0 1 1 4 100 1 0 0 5 101 1 0 1 6 110 1 1 0 7 111 1 1 1
  • a single line will have the 3 line selection electrodes at potential V1, and only one line will be selected.
  • the number 101 makes it possible to define the state of the 3 relays allowing the 3 electrodes ESL-1, ESL-2, ESL-3 of line 5 to be at potential V1.
  • the other drops will not be able to cross the ESL electrodes because at least one of them is at potential V0.
  • means 40 for controlling the relays can be provided, for example programmable digital means (PC or other) to which the n relays are connected and which can drive these relays.
  • PC programmable digital means
  • These means may be provided with a screen 42 allowing the user to select a line on which a drop must be able to be transferred.
  • the matrix is represented on this screen and the user selects a drop transfer line, using a cursor or a stylus to designate the line or lines retained directly on the screen.
  • an automatic program can select the lines and send the corresponding control signals to the electrodes.
  • Means for storing the means 40 make it possible to store the information making it possible to select one or another line, for example the information in Table II as above, in the form of this table or in an equivalent form.
  • the digital means select, in the storage means, the data for opening or closing the relays Rs1 -k necessary, and thus activate the necessary Ck electrodes.
  • a drop spreads simultaneously on all line selection electrodes of this line, in a second case the drop moves successively on the line selection electrodes of this line.
  • the different row selection electrodes of the same line are activated simultaneously.
  • the control means 40 are specifically programmed to simultaneously activate these line selection electrodes.
  • an operator can choose, on a case-by-case basis, between simultaneous activation and subsequent activation.
  • liquids and technologies used allow the drops to spread over the entire series of these line selection electrodes.
  • a confined system includes, in addition to the substrate as illustrated on the figure 1 , a second substrate 11, which faces the first, as illustrated on the figure 9 or as described in the MG Pollack document cited in the introduction to this application.
  • references 13 and 15 respectively denote a hydrophobic layer and an underlying electrode.
  • the reference 17 designates an orifice made in the upper substrate 11 (or cover) and serves as a well for introducing a liquid.
  • liquids with a low surface tension for example water with surfactants are preferably used.
  • n 3 or 4
  • the row selection electrodes are driven consecutively.
  • a reset which is to replace at the beginning of line all drops stopped on one of the line selection electrodes.
  • the electrodes preceding the one on which the drop is located are reactivated in order to raise the drop along the line.
  • a series of electrodes E1 - E4 of a line of a matrix is activated, this line being connected to a reservoir R as shown in FIG. Figure 6A , which leads to the spreading of a drop, and therefore to a liquid segment 50 as shown in FIG. Figure 6B .
  • the method according to the invention can be applied by inserting the selection electrodes between the reservoir R and one or more electrodes Ec ( Figure 6C ) said breaking electrode.
  • the selection electrodes make it possible to select the lines where the drops are to be formed, to stretch the liquid up to the cutoff electrodes to form a drop.
  • Each reservoir is associated with a line of electrodes for the manufacture of a drop.
  • the set of lines thus forms a matrix as already described above.
  • n line selection electrodes as previously described, are located on each line.
  • the Figure 7B represents the first line, with its line selection electrodes Esl and the reservoir R1.
  • the other lines have a similar structure.
  • All electrode lines from the reservoirs result in a common electrode line 60, which may also include line selection electrodes.
  • the various reagents are brought onto this line 60, in the form of drops, to be mixed.
  • the structure of the Figure 7A is symmetrical with respect to this line 60, and for this reason has 2 x 2 n lines. But a structure according to the invention can also be asymmetrical and comprise only 2 n lines, all located on one side, or at 90 °, with respect to the common line 60.
  • the line selection conductors are not represented on the Figures 7A and 7B but are underlying a hydrophobic insulating layer, as illustrated on the Figure 1A .
  • line selection conductors are connected to control means such as the means 40, 42 of the figure 4 .
  • the lines each provided with line selection electrodes and connected to a tank R1,... Rk, R '1, ... R' k ', in a perpendicular architecture, according to a scheme such as that of the Figure 7C .
  • the lines are perpendicular to common lines 160, 162.
  • the lines each provided with line selection electrodes and connected to a tank R1,... Rk, R'1,... R 'k', R1, .. .Rj, R '1, ... R' j 'in a square architecture, according to a diagram such as that of the Figure 7D .
  • the lines are perpendicular to common lines 260, 262, which form a square.
  • the line selection conductors are not represented on the Figures 7C and 7D but are underlying a hydrophobic insulating layer, as illustrated on the Figure 1A .
  • line selection conductors are connected to control means such as the means 40, 42 of the figure 4 .
  • the chip may comprise a detection zone (not shown in the figure) in which detection can be carried out, for example by colorimetry, or by fluorescence, or electrochemistry.
  • the chip may optionally include other inputs / outputs or reservoirs 62 for injecting a sample to be mixed with, successively, a combination of the different reagents, each one coming from a reservoir connected to a line of electrodes, or to a zone 64, called the trash zone, to evacuate the liquids after analysis.
  • the invention applies not only to matrices with 2 n lines (n> 0 or 1), but also to any matrix of p lines (p integer), with 2 n ⁇ p ⁇ 2 n + 1 , n integer .
  • a matrix of 2 n + 1 lines is processed according to one of the embodiments described above, and the excess lines are then eliminated in this scheme.
  • the device then furthermore comprises two additional line selection conductors C4 and C4 'which, for the lines 0 to 7 are respectively completely occupied or empty, and therefore do not intervene in the marking of the lines.
  • a device comprising p lines, with 2 n ⁇ p ⁇ 2 n + 1 therefore comprises a device with 2 n lines according to the invention.
  • Each of these lines has no more n line selection electrodes, but n + 1, of which n are connected as already described above in connection with the figures 3 or 4 .
  • the invention therefore makes it possible to produce a method and a system for addressing an electro-fluidic matrix having any number of lines.
  • a device according to the invention can be realized in a structure such as that illustrated on the Figures 1A - 1C the electrodes, arranged in a matrix, being situated under an insulating layer 6 and a hydrophobic layer 8.
  • the substrate 1 is for example silicon or glass or plastic.
  • the distance between the conductor 10 ( Figures 1A - 1C ) on the one hand and the hydrophobic surface 8 on the other hand is for example between 1 micron and 100 microns or 500 microns.
  • the conductor 10 is for example in the form of a wire diameter between 10 microns and a few hundred microns, for example 200 microns.
  • This wire may be a gold or aluminum wire or tungsten or other conductive materials.
  • two substrates 1, 11 are used, in the case of a confined structure ( figure 9 ), they are separated by a distance of, for example, 10 ⁇ m and 100 ⁇ m or 500 ⁇ m.
  • the second substrate comprises a hydrophobic layer 13 on its surface intended to be in contact with the liquid of a drop.
  • a counter electrode 15 may be buried in the second substrate, or a planar electrode may cover a large part of the hood surface.
  • a catenary can also be used.
  • a drop of liquid 2 will have a volume between, for example, 1 nanolitre and a few microliters, for example between 1 nl and 5 .mu.l.
  • each of the electrodes of a row of the matrix will have for example a surface of the order of a few tens of ⁇ m2 (for example 10 ⁇ m2) up to 1 mm 2, depending on the size of the drops to be transported, the spacing between neighboring electrodes being for example between 1 .mu.m and 10 .mu.m.
  • the structuring of the electrodes of the matrix can be obtained by conventional methods of micro-technologies, for example by photolithography, the electrodes being for example made by depositing a metal layer (AU, or AL, or ITO, or Pt, or Cr, or Cu) and then photolithography.
  • AU or AL, or ITO, or Pt, or Cr, or Cu
  • a dielectric layer of Si3N4 or SiO2 is then covered with a dielectric layer of Si3N4 or SiO2.
  • a hydrophobic layer may be deposited, for example a teflon deposit made by spinning.
  • Methods for producing chips incorporating a device according to the invention can also be directly derived from the methods described in the document FR - 2 841 063 .
  • the electrodes of at least one line preferably have a sawtooth profile like that illustrated in FIG. figure 10 .
  • the saw teeth of the consecutive electrodes fit into each other. This makes it easier to move the menisci from one electrode to another.
  • the number of 3 line selection electrodes is given as an example and could be any.
  • each electrode column is connected to a parallel relay.
  • the conductors Ci, Ci ' can be arranged as illustrated on the Figure 11B : there are then as many of these drivers as on the figure 3 or 4 , and as many relays (not shown on the Figure 11B ) than on the figures 3 or 4 .
  • Each line selection electrode Esl-1, Esl-2, Esl-3 is connected to these conductors as on the figure 3 or 4 . The same is true for the electrodes Esl-1 ', Esl-2', Esl-3 ', - Esl-1 ", Esl-2", Esl-3 ".
  • the electrodes Esl-1, Esl-1 ', and Esl-1 "of one and the same line are activated at the same time, a drop, placed on one of the lines, will advance step by step, of a system electrodes to another arranged in series therewith.
  • This type of serialization can also be applied to an addressing device of a matrix of electrodes of p lines, with 2 n ⁇ p ⁇ 2 n + 1 lines, of an electro-fluidic device, comprising a 2 n line device according to the invention.
  • FIG. 12 Another example of a chip according to the invention, for carrying out storage operations, and / or mixing, and / or dilution will be described in connection with the figure 12 .
  • the n tanks communicate with each other (that is to say that liquid volumes can be moved between these tanks) by a bus 301 consisting of a line of electrodes.
  • the drops are placed or dispensed on this bus 301 by means of lines of line selection electrodes Esl-i, Esl-i 'according to the invention.
  • the steering of these lines is for example one of the driving modes described above in the context of the present invention.
  • the conductors C k , C k ' and the relays Rs1 are not shown in this figure for the sake of clarity.
  • Various modes of operation of a reservoir with one or more electrode lines have also been described above in connection with the Figures 6A - 7D and are applicable to the present embodiment.
  • a drop of a liquid from the tank R 1 or R 16 can be selected, as well as at least one drop of one of the secondary tanks R 2 - R 15 and these drops can be mixed by electrowetting on the path of electrodes 301.
  • FIG. 13A An example of mask design used for photolithography of the electrical level of electrodes is reported on the figure 13A .
  • This figure clearly shows the structure of the electrodes, in particular those leading from each tank to the bus line 301.
  • the chip here comprises 16 tanks, which requires 8 electrical connections (as in figure 8 ) not shown on the figure 13A .
  • the bus 301 consists of an activated electrode line 3 to 3. Three relays make it possible to move a drop across the entire bus.
  • the bus and its connection to the relay-controlled conductors 330, 331, 332 is illustrated in more detail on the Figure 13B the electrodes 301-1, 301-4, 301-7 will be activated simultaneously; then the electrodes 301-2, 301-5, ... etc will be activated simultaneously, ... etc.
  • References 320, 321 of the figure 13A represent the passages of the connection line of an electrode of the bus 301 to the conductor 330.
  • the line passes under the conductors 331, 332, which explains that it passes into the substrate at 320, then leaves at 321 to come to driver contact 330.
  • a second electrical level (not shown on the figure 13A ) is thus realized in order to electrically interconnect certain connection lines. Only the connections to the nearest conductor (for example the connection of the electrodes of the bus 301 to the conductor 332) do not require this passage under the other conductors.
  • Reference 400 designates another connection, from a line selection electrode 411 to a conductor 410 via a conductor 401.
  • a comb 340 gathers all the contacts.
  • References 341, 342 designate electrodes for making contact at a lid.
  • conductive lines 343 come from the comb 340 to connect the line selection conductors (represented or not) but also conductors providing other functions on the chip. Again for the sake of clarity of the figure, the conductors 343 are not shown completely, but interrupted (they end in the dashed figure).
  • the electrodes are formed of a conductive layer (eg gold) with a thickness of 0.3 ⁇ m.
  • the patterns of the electrodes and connection lines are etched by conventional photolithography techniques.
  • a deposit of an insulating layer is made, for example silicon nitride 0.3 ⁇ m thick. This layer is locally etched to resume the electrical contacts.
  • the technology used is the same as for the electrode level, ie a metal deposit and a photolithography.
  • the interconnections (some of them only) are designated by the 400 marks on the figure 13A .
  • the chip is silicon and measures 4 to 5 cm 2 .
  • the area of each electrode of the bus 301 and the electrodes of the tanks R 2 to R 15 is 1.4 mm 2 square.
  • the area of each ESL selection electrode is 0.24mm 2 .
  • the liquid can be moved by electrowetting to the outlet of the tank, or to one of the electrodes of the electrode line connected to this tank.
  • the reservoir R1 (respectively R2) has two electrowetting electrodes 448, 448 '(respectively 449, 449').
  • the shape of the electrodes 448 and 449, respectively corresponding to the tanks R 1 and R 16 is star.
  • This form of the reservoir electrodes makes it possible to constantly plating or attracting the liquid towards the drop formation electrodes, the first of which at the outlet of the reservoirs are, respectively, the electrodes 450 and 451. This allows the initiation of the finger formation process to take place. liquid when dispensing drop, as explained above in connection with the Figures 6A - 6D .
  • an electrode 448 (and possibly an electrode 449 of the same shape) in the form of a comb, which guarantees, as in the case of the half-star, an electrode surface gradient.
  • electrowetting on insulation has the effect of spreading the liquid at the activated electrodes, which is reflected here by a liquid position to maximize the surface facing the electrode. This results in a "collecting" effect of the liquid near the first drop forming electrode 450.
  • This improvement also makes it possible to empty the tank completely.
  • the fingers of the comb ( figure 3C ) or the half-star ( figure 13A ) can be square or pointed.
  • FIG 13D which shows schematically the chip during operation, in section at the level of the tank R1, summarizes the technological stack.
  • References 460, 461, 462, 463 designate electrowetting electrodes.
  • Reference 470 designates an interconnection of the electrowetting electrodes between different lines.
  • Reference 471 designates an electrode of the comb 340 ( figure 13A ).
  • a thick resin (100 ⁇ m thick for example) is laminated and then structured by photolithography, and a hydrophobic treatment is performed (Teflon AF example from Dupont).
  • This resin film is used to define the spacing 350, 351 between the lower plate 1 and the upper plate 11 ( figures 9 and 13D ).
  • this resin film makes it possible to confine the reservoirs and to avoid the risks of contamination or coalescence between the drops placed in the different reservoirs.
  • the chip is glued and then electrically wired onto a printed circuit board.
  • the chip is covered with a polycarbonate lid (substrate 11) with an ITO electrode (indium-titanium oxide) and a thin hydrophobic layer 13.
  • the fluidic component thus formed is filled with silicone oil.
  • the liquid containing the solution to be diluted (liquid containing a reagent, and / or one or more biological samples, and / or beads, and / or cells, etc.) is dispensed into the reservoir R 16 .
  • the purpose of the protocol is to dilute the reagent, (respectively: sample, beads, cells).
  • the tank R 1 is filled with the dilution buffer (water, biological buffer, etc.).
  • the chip is driven by means such as the means 40, 42 of the figures 3 and 4 (typically: a PC programmed to implement a method according to the invention) and an instruction list, which corresponds to the dilution method to be implemented, is executed.
  • Each instruction corresponds to an elementary operation.
  • g1 and g2 are therefore placed on two adjacent electrodes, which naturally causes the coalescence of the two drops g1 and g2 in a drop g3 ( figure 14D ). Due to the geometry of the electrodes, g1 is larger than g2; for example, the volumes of g1 and g2 are respectively 141 nl and 24 nl. A dilution ratio of (144 + 24) / 24 is thus obtained, ie approximately 7.
  • the new drop G3 thus formed can be stored, for example in the tank R3.
  • the dilution operation is repeated by forming a droplet g4 from R2 and a new drop from R1, the result being stored in the tank R4. This operation is repeated until, in each tank R2 to Rn, concentrations C1, C1 / 7, C1 / 49, Ci / 7n .
  • FIG 15 This situation is represented in figure 15 , which schematically represents the device of the figures 12 and 13A , and at which various concentrations in the tanks R 2 - R 6 are indicated.
  • the process can be repeated on all 14 tanks R2 to R15. Several drops can also be formed with equivalent concentrations.
  • the drop can be moved on the bus 301 to homogenize and / or mix the liquids. Typically 12 to 20 displacements on the bus electrodes are sufficient for efficient mixing.
  • the line selection electrodes can also be used to make back-and-forth drops between the reservoirs and the bus 301 for stirring the liquids.
  • the figure 16 corresponds to a dilution carried out with fluorescent beads (Diameter 20 ⁇ m in water). With 4 dilutions one goes to a high concentration of balls (tank R2: 400 balls for 140nl) to a few balls (tank R3: 80 balls, tank R4: 27 balls, tank R5: 8 balls, each time for 140 nl).
  • the same protocol can be performed with cells. Thanks to the implementation of the invention it is possible to handle drops containing only a few cells, or even a single cell. One can then apply a biological protocol on this drop to study and / or analyze the behavior of the cell. This protocol can be performed in parallel on a very large number of droplets. One of the applications is the "screening" of drugs.
  • the figure 17 represents a variant or an improvement of the device of the figure 4 in which only one relay device Rs1-k is required for two electrode lines Ck, Ck '.
  • the references are identical to those of the figure 4 .
  • a microfluidic switching device 501, 502, 503 is used in combination with each relay.
  • Such a microfluidic switching device operates on the following principles, which will first be explained in the context of an open configuration. So we consider the case, illustrated on the figure 18 , and close derivative of the case illustrated in Figures 1A - 1C , where the driver 10 is interrupted.
  • the end 33 of a second conductor 12, which may be at a floating potential, is situated at a short distance from the end 11 of the first conductor 10. This distance is such that, if, by simultaneous activation of the electrodes 4-1, 4-2, 4-3, the drop 2, after being brought to the end 11 of the conductor 10, is stretched, it puts, in its position 2 'shown in broken lines on the figure 18 both ends 11 and 33 in contact and carries the conductor 12 at the same potential as the conductor 10.
  • the reverse operation can then be performed, the drop then returns to its initial position 2 and the driver 12 is no longer at the potential of the driver 10.
  • the drop 2 is stretched, but not displaced.
  • the contact is made by stretching the drop on the flat surface 8. A switching or a change of state therefore results from a stretching of the drop in order to bring into contact two lines 10, 12.
  • the drop 2 may be formed on a reservoir electrode and stretched on another adjacent electrode 4-3.
  • FIG. 19C Another embodiment is illustrated on the figure 19C the switching of the drop towards a second conductor 12, 12 'varies according to the direction of deformation imposed on the drop by the activation of the electrowetting electrodes.
  • a device according to the invention may also be of closed configuration, of the type illustrated in FIG. figure 9 .
  • the drop 2 goes, by stretching or deformation as in the previous case, to be switched between a first state and a second state. It is preferable, in this case, to have a low or zero voltage difference between the conductors 15 and the conductors 10 and 12, to avoid any risk of reaction or heating of the drop 2.
  • the drop is, by stretching or deformation, brought into contact with two conductors located parallel to the substrate 1 or located between the substrate 1 and the cover 11.
  • the second substrate or the cover 11 comprises two electrodes or two conductors 11-2, 11-2 '.
  • the layer 13 of hydrophobic material has a zone 107, 107 'for which the layer of hydrophobic material is either zero (the corresponding conductor 11-2, 11-2' of the cover is then apparent from the cavity), or low enough to pass a current or loads .
  • a portion 107, respectively 107 ', of the layer 13 of the cover 11 is for example etched, so that a drop 2 of conductive liquid makes it possible to make contact with the conductor 11-2, respectively 11-2' (drop in stretched position 2 ') of the hood. It is also possible to leave in zone 107 and / or zone 107 'a very fine hydrophobic layer, for example of the order of a few tens of nm for teflon; it is then porous to electrical charges. In this case, it is not necessary to completely etch the hydrophobic layer 13 in this zone.
  • the hydrophobic layer thickness allowing a certain porosity to the charges, sufficient to ensure a flow of the current with the counter electrode 11-2, respectively 11-2 ', will depend on the material of the layer 13.
  • Teflon we find indications on this subject in the document of S.-K. Cho et al., "Spliting a liquid droplet for electrowetting - based microfluidics," Proceedings of 2001 ASME International Mechanical Engineering Congress and Exhibition, Nov. 11 - 16, New York.
  • a layer of 20 nm, or for example less than 30 nm is sufficient to pass charges.
  • a test may be performed according to the thickness deposited to determine if the desired potential is achieved with respect to the electrode 15.
  • the passage from one state to another can be controlled by the passage of a contact of the drop with a zone of the layer 13 where the latter is non-existent or weak, at a contact of the drop with two zones of this layer where the latter is non-existent or weak.
  • two electrodes 4-2 and 4-4 of the substrate 1 are non-passivated and not covered by the hydrophobic layer 8.
  • the non-passivated areas of the first substrate are designated by references 17 and 17 '.
  • the two electrodes 4-2 and 4-4 are therefore used as contact zones for two states, one in which the droplet 2 is in contact only with the electrode 4-2, and the other in which the drop 2 is in contact with the two electrodes 4-2 and 4-4.
  • the passage from one to the other is effected by electrowetting by activation of electrodes located between the elongated electrodes.
  • a device according to the invention combines a cover, with an electrode 13 whose area or portion 107 is without a hydrophobic layer, or has a hydrophobic layer of very thin thickness, and two conductors 10, 12 arranged in the cavity between the two. substrates, parallel to the surfaces of these two substrates which delimit said cavity.
  • the figure 24A represents a function "complement", so that the output 12 is never at a floating potential.
  • At least 4 electrodes 4-1, 4-2, 4-1 ', 4-2' are concerned.
  • the electrodes 4-1 and 4-1 ' are respectively at the state 1 and 0, while the electrodes 4-2 and 4-2' are at an initially potential potential Va.
  • This device can advantageously be used in a device according to the present invention.
  • At least one of the two contact conductors of a switching device may include an elongated electrowetting electrode 4-2, 4-4.
  • a switching device may further comprise a cover 11 with a hydrophobic surface 13 facing the hydrophobic layer of the substrate, at least one of the two contact conductors comprising an electrode 11-2, 11-2 'arranged in the cover, a portion 107, 107 'of the hydrophobic surface of this cover being either etched or having a sufficiently small thickness to pass electric charges.
  • the means for switching a drop may comprise means for switching a voltage applied to at least one electrowetting electrode, called the switching electrode, between a first value, for which the drop is not in contact with the second conductor, and a second value, for which the drop is in contact with the second conductor.
  • the conductive liquid used for the drops 2 ', 2 1 used in a switching device can be a liquid conductive gel, or a low temperature fuse material (for example: lead, or tin, or indium or silver or alloy of at least two of these materials) which, by phase change, induces definitive or temporarily fixed contact (the phase change may indeed be reversible), or a conductive adhesive (hardening or solidifying by polymerization for example).
  • a definitive contact, or the blocking of a switch can indeed be useful, not to electrically power the contactor or logic functions while maintaining the spreading of the drop.
  • the switch or the logic function consumes energy only during the change of state.

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Claims (37)

  1. Adressierungsvorrichtung einer 2n-Zeilen Elektrodenmatrix einer elektrofluidischen Vorrichtung, wobei jede Zeile N Elektroden (n<N) besitzt und diese Vorrichtung umfasst:
    - in jeder Zeile n sogenannte Selektionselektroden (Esl - i), wobei die Gesamtheit dieser Zeilenselektionselektroden mit 2n Zeilenselektionsleitern (C1, C1', C2, C2', C3, C3') verbunden ist, 2n-1 Zeilenselektionselektroden von 2n-1 Zeilen mit jedem Zeilenselektionsleiter verbunden sind,
    - Selektionseinrichtungen (Rsl-k, Rsl-k'), um einen oder mehrere Zeilenselektionsleiter zu selektieren.
  2. Vorrichtung nach Anspruch 1, wobei die Selektionselektroden ESL-k der verschiedenen Zeilen für einen bestimmten Wert von "k" mit zwei Zeilenselektionsleitern (Ck, Ck') verbunden sind und die Elektroden ESL-k dabei alternativ durch Pakete von 2k-1 mit dem Leiter Ck und dem Leiter Ck' verbunden sind.
  3. Vorrichtung nach Anspruch 1 oder 2, wobei die Selektionseinrichtungen zur Selektion eines oder mehrerer Zeilenselektionsleiter elektrische Selektionsrelais umfassen.
  4. Vorrichtung nach einem der Ansprüche 1 bis 3, wobei die Selektionseinrichtungen zur Selektion von Zeilenselektionsleitern 2n elektrische Selektionsrelais (Rsl - 1, Rsl - 2, Rsl - 3) umfassen und jedes Relais dabei mit einem einzigen Zeilenselektionsleiter verbunden ist.
  5. Vorrichtung nach einem der Ansprüche 1 bis 3, wobei die Selektionseinrichtungen zur Selektion von Zeilenselektionsleitern n elektrische Selektionsrelais (Rsl - 1, Rsl - 2, Rsl - 3) umfassen und jedes Relais dabei mit zwei Zeilenselektionsleitern verbunden ist.
  6. Vorrichtung nach Anspruch 5, wobei jedes Zeilenselektionsrelais mit Einrichtungen (31, 33, 35, 501, 502, 503) kombiniert ist, um außer einem Eingangssignal ein komplementäres bzw. zusätzliches Signal zu erzeugen.
  7. Vorrichtung nach Anspruch 6, wobei die Einrichtungen (31, 33, 35) durch Elektrobenetzung außer einem Eingangssignal ein komplementäres bzw. zusätzliches Signal erzeugen.
  8. Vorrichtung nach einem der Ansprüche 1 bis 7, wobei die Zeilenselektionselektroden längs jeder Zeile sukzessiv angeordnet sind.
  9. Vorrichtung nach einem der Ansprüche 1 bis 8, wobei die Zeilenselektionselektroden längs wenigstens einer Zeile nicht-sukzessiv angeordnet sind.
  10. Vorrichtung nach einem der Ansprüche 1 bis 9, wobei die Zeilenselektionselektroden wenigstens einer Zeile rechteckförmig sind, wobei die große Seite jedes Rechtecks senkrecht zu der Zeile angeordnet ist.
  11. Vorrichtung nach einem der Ansprüche 1 bis 9, wobei die Zeilenselektionselektroden wenigstens einer Zeile quadratisch sind.
  12. Vorrichtung nach einem der Ansprüche 1 bis 11, wobei wenigstens eine Elektrodenzeile der Matrix eine Trennelektrode (Ec) besitzt.
  13. Adressiervorrichtung einer Elektrodenmatrix mit einer Vielzahl Adressiervorrichtungen nach einem der Ansprüche 1 bis 12, Elementarvorrichtungen genannt und in Serie angeordnet, wobei jede Zeile von einer dieser Vorrichtungen in Serie mit einer Zeile von wenigstens einer zweiten solchen Vorrichtung angeordnet ist.
  14. Vorrichtung nach Anspruch 13, wobei die Zeilenselektionsleiter von einer der Elementarvorrichtungen allen in Serie angeordneten Elementarvorrichtungen gemeinsam sind.
  15. Vorrichtung nach einem der Ansprüche 1 bis 14, die außerdem digitale Zeilenselektionseinrichtungen (40) umfasst.
  16. Vorrichtung nach dem vorangehenden Anspruch, wobei die digitalen Zeilenselektionseinrichtungen (40) so programmiert sind, dass sie die Zeilen der Elektrodenmatrix nach einem Binärcode selektieren.
  17. Vorrichtung nach Anspruch 15 oder 16, wobei die digitalen Zeilenselektionseinrichtungen (40) Einrichtungen zur Selektion einer oder mehrerer Matrixzeilen und Einrichtungen zur Erzeugung der Steuerbefehle der Zeilenselektionsleiter in Abhängigkeit von der/den selektierten Zeile/Zeilen umfasst.
  18. Vorrichtung nach einem der Ansprüche 15 bis 17, wobei die digitalen Zeilenselektionseinrichtungen (40) Einrichtungen zur sukzessiven Aktivierung der Zeilenselektionselektroden einer selektierten Zeile umfassen.
  19. Vorrichtung nach einem der Ansprüche 15 bis 17, wobei die digitalen Zeilenselektionseinrichtungen (40) Einrichtungen zur simultanen Aktivierung der Zeilenselektionselektroden einer selektierten Zeile umfassen.
  20. Vorrichtung zur Bildung von Flüssigkeitströpfchen, eine Vorrichtung nach einem der Ansprüche 1 bis 19 und Einrichtungen (R1, Rk) umfassend, die Speicher für Flüssigkeiten bilden, wobei jede Zeile der Matrix mit einem Speicher verbunden ist.
  21. Vorrichtung nach Anspruch 20, wobei 2n Einrichtungen 2n Speicher für die Flüssigkeiten bilden und jede Zeile der Matrix mit einem einzigen Speicher verbunden ist.
  22. Vorrichtung nach Anspruch 20 oder 21, wobei jede Zeile mit einer gemeinsamen Elektrodenzeile (60, 301) verbunden ist, um Tropfen der in den verschiedenen Zeilen gebildeten Flüssigkeiten zu mischen.
  23. Vorrichtung nach Anspruch 21 oder 22, mit einer Vielzahl gemeinsamer Zeilen (160, 162, 260, 262, 301), die senkrecht zueinander oder quadratisch angeordnet sind.
  24. Vorrichtung nach einem der Ansprüche 20 bis 23, wobei wenigstens einer der Speicher Elektrobenetzungselektroden (448, 448', 449, 449') umfasst, um einen Flüssigkeitstropfen aus dem Speicher zur entsprechenden Elektrodenzeile zu bringen.
  25. Vorrichtung nach dem vorangehenden Anspruch, wobei eine der Elektroden (448, 449) des Speichers die Form eines Kamms oder eines Sterns aufweist.
  26. Vorrichtung nach dem vorangehenden Anspruch, wobei der Stern oder der Kamm Zacken bzw. Zähne aufweist, deren Enden eckig bzw. breit oder spitz sind.
  27. Vorrichtung nach einem der Ansprüche 1 bis 26, wobei wenigstens eine der Zeilen Elektroden umfasst, deren Profil sägezahnförmig ist.
  28. Adressiervorrichtung einer Elektrodenmatrix von p Zeilen, mit 2n<p<2n+1 Zeilen, einer elektrofluidischen Vorrichtung mit einer Vorrichtung mit 2n Zeilen nach einem der Ansprüche 1 bis 27.
  29. Verfahren zur Verschiebung wenigstens eines Flüssigkeitsvolumens mit Hilfe einer Vorrichtung nach einem der Ansprüche 1 bis 28, umfassend:
    - die Verschiebung eines Fluidvolumens längs wenigstens einer Zeile der Matrix durch Aktivierung der Elektroden der genannten Zeile.
  30. Verfahren nach Anspruch 29, wobei die Zeilenselektionselektroden der genannten Zeile konsekutiv aktiviert werden.
  31. Verfahren nach Anspruch 29, wobei die Zeilenselektionselektroden der genannten Zeile sukzessiv aktiviert werden.
  32. Verfahren zur Bildung eines Flüssigkeitstropfens, mit Verschiebung eines Flüssigkeitsvolumens nach einem der Ansprüche 29 bis 31, Ausbreitung dieses Volumens über mehrere Elektroden der genannten Zeile durch simultane Selektion dieser Elektroden und Durchtrennung des ausgebreiteten Volumens mit Hilfe einer Trennelektrode (Ec).
  33. Verfahren zur Modifizierung der Verdünnung einer ersten Flüssigkeit mit einer ersten Lösung mit einer ersten Konzentration mit Hilfe einer Vorrichtung nach einem der Ansprüche 1 bis 28, wenigstens einen ersten und einen zweiten Speicher bildenden Einrichtungen jeweils für die genannte Flüssigkeit und für wenigstens eine zweite Flüssigkeit oder einen Puffer, wobei jeder Speicher mit einer Zeile der Elektrodenmatrix verbunden ist und dieses Verfahren dabei umfasst:
    - das Bilden eines Tropfens der ersten Flüssigkeit aus dem ersten Speicher,
    - das Bilden eines Tropfens der zweiten Flüssigkeit aus dem zweiten Speicher,
    - das Mischen der beiden Tropfen, um einen Tropfen mit einer zweiten, anderen Konzentration als der ersten zu bilden.
  34. Verfahren nach dem vorangehenden Anspruch, wobei die Modifikation der Verdünnung einer ersten Flüssigkeit eine Verringerung dieser Verdünnung ist, die zweite Konzentration niedriger als die erste ist.
  35. Verfahren nach einem der Ansprüche 33 oder 34, wobei die erste Flüssigkeit ein Reagenz und/oder ein oder mehrere biologische Proben, und/oder Kugeln, und/oder Zellen enthält.
  36. Verfahren nach einem der Ansprüche 33 bis 35, wobei die zweite Flüssigkeit oder der Puffer Wasser oder einen biologischen Puffer enthält.
  37. Verfahren nach einem der Ansprüche 33 bis 36, wobei die Vorrichtung eine gemeinsame Elektrodenzeile (301) umfasst, welche die Zeilen der elektrofluidischen Vorrichtung verbindet und in der die Tropfen durch Elektrobenetzung verschieben werden.
EP05789844A 2004-07-09 2005-07-11 Elektrodenadressierungsverfahren Not-in-force EP1778976B1 (de)

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FR0451494A FR2872809B1 (fr) 2004-07-09 2004-07-09 Methode d'adressage d'electrodes
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FR2872809B1 (fr) 2006-09-15
DE602005005337T2 (de) 2009-03-26
ATE389113T1 (de) 2008-03-15
DE602005005337D1 (de) 2008-04-24
JP4814230B2 (ja) 2011-11-16
WO2006008424A2 (fr) 2006-01-26
JP2008505631A (ja) 2008-02-28
FR2872809A1 (fr) 2006-01-13
WO2006008424A3 (fr) 2006-04-13
EP1778976A2 (de) 2007-05-02
US8603413B2 (en) 2013-12-10

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