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WO2022162377A1 - Stratégies de réduction d'actionnement pour mouvement de gouttelettes sur des réseaux d'électrodes de haute densité pour la microfluidique numérique - Google Patents

Stratégies de réduction d'actionnement pour mouvement de gouttelettes sur des réseaux d'électrodes de haute densité pour la microfluidique numérique Download PDF

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Publication number
WO2022162377A1
WO2022162377A1 PCT/GB2022/050228 GB2022050228W WO2022162377A1 WO 2022162377 A1 WO2022162377 A1 WO 2022162377A1 GB 2022050228 W GB2022050228 W GB 2022050228W WO 2022162377 A1 WO2022162377 A1 WO 2022162377A1
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Prior art keywords
electrode
droplet
location
electrodes
aqueous droplet
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English (en)
Inventor
David ZHITOMIRSKY
Cristina Visani
Richard J. PAOLINI JR.
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Nuclera Ltd
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Nuclera Nucleics Ltd
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    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
    • B01L3/00—Containers or dishes for laboratory use, e.g. laboratory glassware; Droppers
    • B01L3/50—Containers for the purpose of retaining a material to be analysed, e.g. test tubes
    • B01L3/502—Containers for the purpose of retaining a material to be analysed, e.g. test tubes with fluid transport, e.g. in multi-compartment structures
    • B01L3/5027—Containers for the purpose of retaining a material to be analysed, e.g. test tubes with fluid transport, e.g. in multi-compartment structures by integrated microfluidic structures, i.e. dimensions of channels and chambers are such that surface tension forces are important, e.g. lab-on-a-chip
    • B01L3/502769—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
    • B01L2300/00—Additional constructional details
    • B01L2300/16—Surface properties and coatings
    • B01L2300/161—Control and use of surface tension forces, e.g. hydrophobic, hydrophilic
    • 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

Definitions

  • DMF Digital microfluidic
  • EWoD electrowetting on dielectric
  • a continuous or pulsed electrical signal is applied to a droplet (typically aqueous), leading to a change in the contact angle between the droplet surface and the hydrophobic surface.
  • Liquids capable of electro wetting a hydrophobic surface typically include a polar solvent, such as water or an ionic liquid, and often feature ionic species, as is the case for aqueous solutions of electrolytes.
  • a polar solvent such as water or an ionic liquid
  • ionic species as is the case for aqueous solutions of electrolytes.
  • EWoD digital microfluidic devices There are two main architectures of EWoD digital microfluidic devices, i.e., open and closed systems.
  • EWoD configurations include a bottom plate featuring a stack of propulsion electrodes, an insulator dielectric layer, and a hydrophobic layer providing a working surface.
  • closed systems also feature a top plate parallel to the bottom plate and including a top electrode serving as common counter electrode to all the propulsion electrodes.
  • the top and bottom plates are provided in a spaced relationship defining a microfluidic region to permit droplet motion within the microfluidic region under application of propulsion voltages between the bottom electrode array and the top electrode.
  • each electrode of the DMF receives a voltage pulse (i.e., a voltage differential between the two electrodes associated with that electrode) or temporal series of voltage pulses (i.e., a “waveform” or “drive sequence” or “driving sequence”) in order to effect a transition from one electrowetting state of the electrode to another.
  • a voltage pulse i.e., a voltage differential between the two electrodes associated with that electrode
  • temporal series of voltage pulses i.e., a “waveform” or “drive sequence” or “driving sequence”
  • TFTs thin-film transistors
  • electro-mechanical switches may also be used.
  • TFT-based thin film electronics may be used to control the addressing of voltage pulses to an EWoD array by using circuit arrangements very similar to those employed in AM display technologies.
  • TFT arrays are highly desirable for this application, due to having thousands of addressable electrodes, thereby allowing mass parallelization of droplet procedures.
  • Driver circuits can be integrated onto the AM-EWoD array substrate, and TFT-based electronics are well suited to the AM-EWoD application.
  • the electrowetting microfluidic device includes a plurality of electrodes coated with a hydrophobic layer, wherein each electrode is roughly equivalent in area to each other electrode, and each electrode is coupled to circuitry configured to selectively apply driving voltages to the electrode.
  • the method comprises providing an aqueous droplet larger in area than at least four electrodes, retaining the aqueous droplet at a first location including a first electrode and a second electrode for a first period of time, (wherein the aqueous droplet covers both the first electrode and the second electrode, and wherein retaining includes applying a driving voltage to the first electrode with the driving circuitry but not to the second electrode), retaining the aqueous droplet at a second location including a third electrode and a fourth electrode for a second period of time, (wherein the aqueous droplet covers both the third electrode and the fourth electrode, and wherein retaining includes applying a driving voltage to the third electrode with the driving circuitry but not to the fourth electrode).
  • the method further comprises moving the aqueous droplet from the first location to the second location.
  • the aqueous droplet has a center, and the center moves less than 1 cm between the first location and the second location. In some embodiments, the center moves less than 2 mm between the first location and the second location.
  • the aqueous droplet is retained at the first location for a third period of time, wherein during the third period of time a driving voltage is applied to the second electrode but not to the first electrode. In some embodiments, the aqueous droplet is retained at the second location for a fourth period of time, wherein during the fourth period of time a driving voltage is applied to the fourth electrode but not to the third electrode.
  • the aqueous droplet covers a fifth electrode in addition to the first electrode and the second electrode during the first period of time, wherein no voltage is applied to the fifth electrode during the first period of time. In some embodiments, the aqueous droplet covers a fifth electrode in addition to the first electrode and the second electrode during the first period of time, wherein the same voltage is applied to the fifth electrode as to the first electrode during the first period of time. In some embodiments, the aqueous droplet covers a fifth electrode in addition to the first electrode and the second electrode during the first period of time, wherein a different voltage is applied to the fifth electrode as to the first electrode and the second electrode during the first period of time.
  • the first electrode and the second electrode each independently comprise from about 1% to about 25% of the area of the aqueous droplet.
  • each electrode is operatively coupled to a thin film transistor (TFT), and the TFT is additionally coupled to a gate line and a source line.
  • TFT thin film transistor
  • a method for moving an aqueous droplet from a first location to a second location within an electrowetting microfluidic device comprises a plurality of electrodes coated with a hydrophobic layer, wherein each electrode is roughly equivalent in area to each other electrode, and each electrode is coupled to circuitry configured to selectively apply driving voltages to the electrode.
  • the method comprises providing an aqueous droplet larger in area than at least nine electrodes at a first location, providing a droplet driving voltage to between 1% and 50% of the electrodes covered by the aqueous droplet, wherein the electrodes receiving the driving voltage are located on a side of the aqueous droplet closer to the second location compared to the undriven electrodes covered by the aqueous droplet, and propelling the aqueous droplet from the first location to the second location.
  • a secant can be drawn across the aqueous droplet such that the electrodes receiving the driving voltage are on a first side of the secant and the electrodes that are undriven are on a second side of the secant.
  • the secant is substantially perpendicular to a line drawn from the first location to the second location.
  • each electrode is operatively coupled to a thin film transistor (TFT), and the TFT is additionally coupled to a gate line and a source line.
  • TFT thin film transistor
  • a method for moving an aqueous droplet from a first location to a second location within an electrowetting microfluidic device comprises a plurality of electrodes coated with a hydrophobic layer, wherein each electrode is roughly equivalent in area to each other electrode, and each electrode is coupled to circuitry configured to selectively apply driving voltages to the electrode.
  • the method comprises providing an aqueous droplet having a first aspect ratio Li : Hi, wherein Li is the size of the droplet in a direction parallel to the direction of motion, and Hi is the size of the droplet in a direction perpendicular to the direction of motion, reshaping the aqueous droplet to have a second aspect ratio value L2 : H2, wherein the reshaped droplet covers a first set of electrode, and wherein, after the reshaping, L2 is the new size of the droplet in a direction parallel to the direction of motion, and H2 is the new size of the droplet in a direction perpendicular to the direction of motion, and L2 : H2 is greater than Li : Hi; and providing a driving voltage to a second set of electrodes under the aqueous droplet, wherein there are fewer electrodes in the second set of electrodes than in the first set of electrodes, thereby moving the aqueous droplet from the first location to the second location.
  • Li is the size of
  • FIG. 1 A is a diagrammatic cross-section of the cell of an example EWoD device.
  • FIG. IB illustrates EWoD operation with a constant voltage Top Plane.
  • FIG. 1C illustrates EWoD operation with top plane switching (TPS).
  • FIG. ID is a schematic diagram of a TFT connected to a gate line, a source line, and a propulsion electrode.
  • FIG. 2 is a schematic illustration of an exemplary TFT backplane controlling droplet operations in an AM-EWoD propulsion electrode array.
  • FIG. 3 A is a schematic illustration of a traditional DMF electrode driving pattern, where the same image, approximately equivalent in size to the droplet, is scanned at every frame.
  • FIG. 3B illustrates an example area sampling partition where the actuation image oscillates between a first location and a second location.
  • FIG. 4A is approximately identical to FIG. 3A.
  • FIG. 4B illustrates a traditional DMF driving pattern on a triangular droplet.
  • FIG. 4C schematically illustrates a reduced representation driving pattern where the electrodes along a secant of the droplet are not actuated.
  • FIG. 4D illustrates a reduced representation driving pattern where the electrodes located along a plurality of droplet secants are not actuated.
  • FIGS. 4E and 4F illustrate a reduced representation driving pattern where the electrodes located along a leading edge in the shape of a “C” are used to propel a droplet.
  • FIGS. 4G-4I illustrate that the type of reduced representation driving may change as a droplet is moved around the array.
  • FIG. 5 A is approximately identical to FIG. 3 A.
  • FIG. 5B illustrates a droplet having an aspect ratio of 2 : 1.
  • FIG. 5C illustrates a droplet having an aspect ratio of 4 : 1.
  • FIG. 6A illustrates the movement (left to right) of a fluid droplet having a 1 : 1 aspect ratio.
  • FIG. 6B illustrates movement of a droplet where the aspect ratio is 2 : 1.
  • “Actuate” or “activate” with reference to one or more electrodes means effecting a change in the electrical state of the one or more electrodes which, in the presence of a droplet, results in a manipulation of the droplet. Activation of an electrode can be accomplished using alternating current (AC) or direct current (DC). Where an AC signal is used, any suitable frequency may be employed.
  • “Droplet” means a volume of liquid that electrowets a hydrophobic surface and is at least partially bounded by carrier fluid and/or, in some instances, a gas or gaseous mixture such as ambient air.
  • a droplet may be completely surrounded by carrier fluid or may be bounded by carrier fluid and one or more surfaces of an EWoD device.
  • Droplets may take a wide variety of shapes; non-limiting examples include generally disc shaped, slug shaped, truncated sphere, ellipsoid, spherical, partially compressed sphere, hemispherical, ovoid, cylindrical, and various shapes formed during droplet operations, such as merging or splitting or formed as a result of contact of such shapes with one or more working surface of an EWoD device.
  • Droplets may include typical polar fluids such as water, as is the case for aqueous or non-aqueous compositions, or may be mixtures or emulsions including aqueous and non-aqueous components. Droplets may also include dispersions and suspensions, for example magnetic beads in an aqueous solvent.
  • a droplet may include a biological sample, such as whole blood, lymphatic fluid, serum, plasma, sweat, tear, saliva, sputum, cerebrospinal fluid, amniotic fluid, seminal fluid, vaginal excretion, serous fluid, synovial fluid, pericardial fluid, peritoneal fluid, pleural fluid, transudates, exudates, cystic fluid, bile, urine, gastric fluid, intestinal fluid, fecal samples, liquids containing single or multiple cells, liquids containing organelles, fluidized tissues, fluidized organisms, liquids containing multi-celled organisms, biological swabs and biological washes.
  • a biological sample such as whole blood, lymphatic fluid, serum, plasma, sweat, tear, saliva, sputum, cerebrospinal fluid, amniotic fluid, seminal fluid, vaginal excretion, serous fluid, synovial fluid, pericardial fluid, peritoneal fluid, pleural fluid, transudates, ex
  • a droplet may include one or more reagent, such as water, deionized water, saline solutions, acidic solutions, basic solutions, detergent solutions and/or buffers.
  • reagents such as a reagent for a biochemical protocol, a nucleic acid amplification protocol, an affinity-based assay protocol, an enzymatic assay protocol, a gene sequencing protocol, a protein sequencing protocol, and/or a protocol for analyses of biological fluids.
  • reagents include those used in biochemical synthetic methods, such as a reagent for synthesizing oligonucleotides finding applications in molecular biology and medicine, and nucleic acid molecules.
  • the oligonucleotides may contain natural or chemically modified bases and are most commonly used as antisense oligonucleotides, small interfering therapeutic RNAs (siRNA) and their bioactive conjugates, primers for DNA sequencing and amplification, probes for detecting complementary DNA or RNAvia molecular hybridization, tools for the targeted introduction of mutations and restriction sites in the context of technologies for gene editing such as CRISPR-Cas9, and for the synthesis of artificial genes.
  • the droplet contents may include reagents for peptide and protein production, for example by chemical synthesis, expression in living organisms such as bacteria or yeast cells or by the use of biological machinery in in vitro systems.
  • Droplet area means the area enclosed within the perimeter of a droplet.
  • the electrodes located within the droplet area are referred to as “droplet electrodes” or “pixel electrodes” or “pixels of the droplet”.
  • portion electrodes or “electrodes of the portion”.
  • DMF device EWoD device
  • Droplet actuator mean a device for manipulating droplets.
  • Droplet operation means any manipulation of one or more droplets on a microfluidic device.
  • a droplet operation may, for example, include: loading a droplet into the DMF device; dispensing one or more droplets from a source reservoir; splitting, separating or dividing a droplet into two or more droplets; moving a droplet from one location to another in any direction; merging or combining two or more droplets into a single droplet; diluting a droplet; mixing a droplet; agitating a droplet; deforming a droplet; holding a droplet in position; incubating a droplet; heating a droplet; vaporizing a droplet; cooling a droplet; disposing of a droplet; transporting a droplet out of a microfluidic device; other droplet operations described herein; and/or any combination of the foregoing.
  • merge “merge,” “merging,” “combine,” “combining” and the like are used to describe the creation of one droplet from two or more droplets. It should be understood that when such a term is used in reference to two or more droplets, any combination of droplet operations that are sufficient to result in the combination of the two or more droplets into one droplet may be used. For example, “merging droplet A with droplet B,” can be achieved by transporting droplet A into contact with a stationary droplet B, transporting droplet B into contact with a stationary droplet A, or transporting droplets A and B into contact with each other.
  • splitting is not intended to imply any particular outcome with respect to volume of the resulting droplets (i.e., the volume of the resulting droplets can be the same or different) or number of resulting droplets (the number of resulting droplets may be 2, 3, 4, 5 or more).
  • mixing refers to droplet operations which result in more homogenous distribution of one or more components within a droplet. Examples of “loading” droplet operations includes but is not limited to microdialysis loading, pressure assisted loading, robotic loading, passive loading, and pipette loading. Droplet operations may be electrode-mediated. In some cases, droplet operations are further facilitated by the use of hydrophilic and/or hydrophobic regions on surfaces and/or by physical obstacles.
  • Gate driver is a device directing a drive input for the gate of a transistor such as a TFT coupled to an EWoD electrode electrode.
  • Source driver is a device directing a drive input for the source of a transistor.
  • Topic plane common electrode driver is a power amplifier producing a drive input for the top plane electrode of an EWoD device.
  • Drive sequence denotes the entire voltage against time curve used to actuate an electrode in a microfluidic device.
  • a sequence will comprise a plurality of elements; where these elements are essentially rectangular (i.e., where a given element comprises application of a constant voltage for a period of time), the elements may be called “voltage pulses” or “drive pulses”.
  • drive scheme denotes a set of one or more drive sequences sufficient to effect one or more manipulations on one or more droplets in the course of a given droplet operation.
  • frame denotes a single update of all the electrode rows in a microfluidic device.
  • Nucleic acid molecule is the overall name for DNA or RNA, either single- or double-stranded, sense or antisense. Such molecules are composed of nucleotides, which are the monomers made of three moieties: a 5-carbon sugar, a phosphate group and a nitrogenous base. If the sugar is a ribosyl, the polymer is RNA (ribonucleic acid); if the sugar is derived from ribose as deoxyribose, the polymer is DNA (deoxyribonucleic acid).
  • Nucleic acid molecules vary in length, ranging from oligonucleotides of about 10 to 25 nucleotides which are commonly used in genetic testing, research, and forensics, to relatively long or very long prokaryotic and eukaryotic genes having sequences in the order of 1,000, 10,000 nucleotides or more.
  • Their nucleotide residues may either be all naturally occurring or at least in part chemically modified, for example to slow down in vivo degradation. Modifications may be made to the molecule backbone, e.g. by introducing nucleoside organothiophosphate (PS) nucleotide residues.
  • PS nucleoside organothiophosphate
  • Another modification that is useful for medical applications of nucleic acid molecules is 2’ sugar modifications.
  • Modifying the 2’ position sugar is believed to increase the effectiveness of therapeutic oligonucleotides by enhancing their target binding capabilities, specifically in antisense oligonucleotides therapies.
  • Two of the most commonly used modifications are 2’-O-methyl and the 2’-Fluoro.
  • a liquid in any form e.g., a droplet or a continuous body, whether moving or stationary
  • a liquid in any form e.g., a droplet or a continuous body, whether moving or stationary
  • such liquid could be either in direct contact with the electrode/array/matrix/surface, or could be in contact with one or more layers or films that are interposed between the liquid and the electrode/ array/matrix/ surface.
  • a droplet When a droplet is described as being “in”, “on”, or “loaded on” a microfluidic device, it should be understood that the droplet is arranged on the device in a manner which facilitates using the device to conduct one or more droplet operations on the droplet, the droplet is arranged on the device in a manner which facilitates sensing of a property of or a signal from the droplet, and/or the droplet has been subjected to a droplet operation on the droplet actuator.
  • the present invention provides novel methods of mitigating dielectric layer degradation and/or hydrophobic layer degradation and/or electrode degradation, and thereby extend the lifetime of DMF devices.
  • the methods provided herein reduce the extent of electrode actuation that is required for inducing motion in a fluid object, e.g., a droplet or a reservoir. This reduction results in extending the lifetime of the device while minimizing any negative impact on actuation efficacy.
  • a fluid object e.g., a droplet or a reservoir.
  • FIG. 1 A shows a diagrammatic cross-section of the “cell” in an example traditional closed EWoD device 100 where droplet 104 is surrounded on the sides by carrier fluid 102 and sandwiched between top hydrophobic layer 107 and bottom hydrophobic layer 110.
  • Propulsion electrodes 105 beneath dielectric layer 108 can be directly driven or switched by transistor arrays arranged to be driven with data (source) and gate (select) lines, much like an active matrix in liquid crystal displays (LCDs), resulting in what is known as active matrix (AM) EWoD.
  • Typical electrode spacing (and accordingly cell spacing) is usually in the range of about 20 pm to about 500 pm.
  • FIG. IB illustrates EWoD operation in DC Top Plane mode, where the top plane electrode 106 is set to a constant potential, e.g., a potential of zero volts, for example, by grounding.
  • a constant potential e.g., a potential of zero volts, for example, by grounding.
  • the potential applied across the cell is the voltage on the active pixel electrodes, that is, electrode 101 having a different voltage to the top plane so that conductive droplets are attracted to the electrode.
  • An alternate driving method includes driving the cell with top-plane switching (TPS), in which case the driving voltage can be substantially increased, e.g., doubled to ⁇ 30 V, by powering the top electrode out of phase with active pixel electrodes, such that the top plane voltage is additional to the voltage supplied by the TFT.
  • TPS top-plane switching
  • Amorphous silicon TFT plates usually have only one transistor per electrode, although configurations having two or more transistors are also contemplated. As illustrated in in FIG. ID, the transistor is connected to a gate line, a source line (also known as “data line”), and a propulsion electrode. When there is large enough positive voltage on the TFT gate then there is low impedance between the source line and electrode (Vg “ON”), so the voltage on the source line is transferred to the electrode of the electrode. When there is a negative voltage on the TFT gate then the TFT is high impedance and voltage is stored on the electrode storage capacitor and not affected by the voltage on the source line as the other electrodes are addressed (Vg “OFF”).
  • the TFT should act as a digital switch. In practice, there is still a certain amount of resistance when the TFT is in the “ON” setting, so the electrode takes time to charge. Additionally, voltage can leak from Vs to Vp when the TFT is in the “OFF” setting, causing cross-talk. Increasing the capacitance of the storage capacitor C s reduces cross-talk, but at the cost of rendering the electrodes harder to charge.
  • the drivers of a TFT array receive instructions relating to droplet operations from a processing unit.
  • the processing unit may be, for example, a general purpose computer, special purpose computer, personal computer, or other programmable data processing apparatus providing processing capabilities, such as storing, interpreting, and/or executing software instructions, as well as controlling the overall operation of the device.
  • the processing unit is coupled to a memory which includes programmable instructions to direct the processing unit to perform various operations, such as, but not limited to, providing the TFT drivers with input instructions directing them to generate electrode drive signals in accordance with embodiments herein.
  • the memory may be physically located in the DMF device or in a computer or computer system which is interfaced to the device and hold programs and data that are part of a working set of one or more tasks being performed by the device.
  • the memory may store programmable instructions to carry out the drive schemes described in connection with a set of droplet operations.
  • the processing unit executes the programmable instructions to generate control inputs that are delivered to the drivers to implement one or more drive schemes associated with a given droplet operation.
  • FIG. 2 is a diagrammatic view of an exemplary TFT backplane controlling droplet operations in an AM-EWoD propulsion electrode array.
  • the elements of the EWoD device are arranged in the form of a matrix as defined by the source lines and the gate lines of the TFT array.
  • the source line drivers provide the source levels corresponding to a droplet operation.
  • the gate line drivers provide the signals for opening the transistor gates of electrodes which are to be actuated in the course of the operation.
  • the gate line drivers may be integrated in a single integrated circuit.
  • the data line drivers may be integrated in a single integrated circuit.
  • the integrated circuit may include the complete gate and source driver assemblies together with a controller. Commercially available controller/driver chips include those commercialized by Ultrachip Inc.
  • electrode matrix is made of 1024 source lines and a total of 768 gate lines, although either number may change to suit the size and spatial resolution of the DMF device.
  • each element of the matrix could contain a TFT of the type illustrated in FIG. ID for controlling the potential of a corresponding pixel electrode, and each TFT could be connected to one of the gate lines and one of the source lines.
  • MMT Maximum Line Time
  • FR Frame Rate
  • n Number of Lines
  • gate and source lines are characterized by RC time constants of values depending on the TFT array design and size, and switch slower than the ideal pulse. As such, 2 to 3 ps are typically needed between one gate line being switched “OFF” and the next one "ON", resulting in real times for electrode charging typically 2 to 3 ps shorter than the MLT.
  • the present application provides methods based on droplet envelope representation whereby alternating subsets of the electrodes enclosed within the perimeter of a droplet are driven to move the droplet, thereby minimizing the total area actuated in the course of a droplet operation.
  • This reduced representation strategy is schematically illustrated in FIGS. 3A-3B.
  • the droplet is shown in blue and actuated electrodes under its surface are colored in yellow.
  • the white electrodes are not actuated.
  • each actuation of a TFT matrix is comprised of several driving frames. In traditional systems, all the driving frames of an actuation drive the same set of electrodes.
  • each actuation cycle also known in this context as “image”
  • image is 1 second in duration
  • the frame rate is 100 Hz
  • a TFT that is scanned will have its area driven with the same image for 100 frames.
  • FIG. 3 A Such is the pattern shown in FIG. 3 A, where the same image is scanned at every frame so that all the electrodes under the surface of the droplet are driven throughout the entire duration of the actuation cycle.
  • FIG. 3B illustrates an example of this approach: in first frame 300 at a first location, only a first subset of the pixel electrodes are driven. The actuated electrodes are marked in yellow, and cover about 50% of the original area of the droplet. Then, in second frame 302 at a second location, a different set of electrodes, also marked in yellow and covering about 50% of the droplet area, are driven instead.
  • a center of the droplet 305 can be defined and the center may move locations between frames, or as part of a series of steps that move the droplet from a first location to a second location. This pattern is repeated throughout the actuation cycle so that the actuated image oscillates between the two frames until the end of the cycle. As a result the droplet area is maintained under constant actuation, which is especially advantageous in droplet operations involving motion of one or more droplets.
  • the droplet only moves slightly between a first location and a second location as the droplet is maintained in approximately the same area as it is incubated, measured, etc.
  • the first location and the second location are less than 1 cm apart, e.g., less than 5 mm apart, e.g., less than 2 mm apart, e.g., less than 1 mm apart.
  • the first electrode subset and the second electrode subset differ in at least one electrode, i.e., at least one electrode belonging to the first subset is not a part of the second subset.
  • the second electrode subset includes no electrodes belonging to the first electrode subset.
  • the actuation cycle of FIG. 3B is composed of two types of frames, e.g., arrangements of active and inactive electrodes, namely 300 and 302, but the actuation may include three, four, five or more differing types of frames, depending on the nature and requirements of the droplet operation being carried out on the DMF device.
  • Frames 300 and 302 are based on a checkerboard design, but other patterns may be applied, for example concentric rings that span large droplets and reservoirs at higher electrode resolutions.
  • a percentage of the droplet electrodes to be actuated in each frame may be specified, then frames meeting this specification are generated and set in a sequence which is repeated for the duration of the actuation cycle. In some embodiments, this sequence results in the droplet center 305 moving between a first location and a second location. Taking as example an actuation cycle where the percentage of droplet electrodes per frame is capped at 30%, a sequence of three frames may be generated. Each frame of the sequence actuates a number of electrodes equal to about 30% of the electrode droplets, and the sequence may be repeated for the entire duration of the actuation cycle. However, the frames need not necessarily actuate equal shares of the droplet electrodes.
  • the first frame and second frame may each actuate 25% of the electrodes associated with a droplet and the third frame 50% of the electrodes associated with a droplet.
  • the percentage of droplet electrodes actuated in a single frame may range from about 1% to about 100% of the droplet electrodes, although practical values may be more limited in range from about 1% to about 50%, e.g., between about 1% of the electrodes and 25% of the electrodes associated with the droplet.
  • the present invention provides a “surface tension pull” method which takes advantage of surface tension to a greater degree than traditional electrowetting driving patterns.
  • uniform actuation of the droplet is sacrificed in favor of driving patterns having reduced complexity which result in shorter electrode driving times.
  • this strategy is implemented by defining a first portion and a second portion of a droplet located on a pixelated electrode surface.
  • the second portion includes the electrodes located along a secant of the droplet.
  • secant means a straight line or ray that intersects the perimeter of a droplet at two or more points.
  • a “width” of a droplet typically means the number of electrodes spanned by a secant in a horizontal direction as defined by the grid pattern while a “height” is defined as the number of electrodes spanned by a secant in a vertical direction.
  • the droplet of FIG. 4A being approximately square-like in shape, spans a length of 4 electrodes along any secant in the horizontal direction, e.g. secants 402, 404, 406, and 408.
  • the droplet of FIG. 4B has an approximately triangular perimeter: as such, the number of electrodes that it spans in a horizontal direction varies according to whether the electrodes are counted along secant 410, 412, or 414.
  • the traditional approach as illustrated in FIG. 4A actuates the entire area of the droplet.
  • the first portion of the droplet includes all the electrode droplets except for those located along secant 416 which forms a second portion on the trailing edge and is perpendicular to the intended direction of motion 418.
  • the reduced representation of FIG. 4D is smaller than either the height or width of the droplet as the second portion spans two dimensions, one of which lies in the direction of perpendicular secants 420 and 422 while the other spans the electrodes along secants 424 and 426.
  • the electrodes of the first portion are actuated, as indicated by their yellow coloring, while those of the second portion are left unactuated.
  • the droplet of FIG. 4C begins moving along the direction of motion 418, the back of the droplet, where the second portion is located, is not actuated.
  • both the edges and the back of the droplet will not be actuated and a dragging edge will form.
  • the actuated area will be located along the leading edge of the droplet in a manner similar to how the actuated area is depicted in FIGS. 4C and 4D.
  • the actuated area is smaller than the overall footprint of the droplet.
  • the droplet electrode fill rate may range from about 0% to about 100%, with practical values typically falling between about 1% to about 25%, i.e., between about 2% to about 20%.
  • the electrodes of the actuated area may be further subsampled as disclosed in the first aspect of the application, thereby leading to a double reduction in the extent of electrode actuation needed to move the droplet.
  • a leading edge drive scheme will require fewer drive pixels than a “C” driving edge scheme, which will require fewer drive pixels than a perimeter drive scheme.
  • a “C” driving edge scheme may use between 2% and 15% of the covered pixels.
  • a drive method may involve switching between, e.g., a leading edge drive scheme and a “C” driving edge scheme as the droplet is driven to reduce the number of consecutive times that a pixel is driven during a protocol.
  • a droplet may be propelled with a leading edge drive scheme while continuing in a single direction 418 and then transition to a “C” driving edge in anticipation of changing the direction of movement 430. See FIG. 4G-4I.
  • the present application provides an additional reduced representation method for moving a droplet in a microfluidic space.
  • a droplet Prior to or in the course of motion along a desired direction, a droplet is reshaped to a new aspect ratio which renders moving the droplet more effective in terms of a reduced total actuated area.
  • FIG. 5A Schematically illustrated in FIG. 5A is a droplet in the same configuration as in FIG. 3 A. It can be seen that its aspect ratio Li : Hi is equal to 1 : 1, where Li is the size of the droplet in the direction of motion 418, and Hi is the size of the droplet in a direction perpendicular to the direction of motion.
  • Li is the size of the droplet in the direction of motion 418
  • Hi is the size of the droplet in a direction perpendicular to the direction of motion.
  • the aspect ratio L2 : H2 is increased to 3 : 1.
  • the droplet of FIG. 5C has an aspect ratio L3 : H3 which is equal to 4 : 1. Further increases in the aspect ratio may be feasible depending on factors such as the content of the droplet and the waveforms which may be implemented on the DMF device, but a typical practical range includes ratios from about 1 : 1 to about 5 : 1.
  • FIGS. 6A and 6B compare the movement of a fluid droplet having a 1 : 1 aspect ratio (FIG. 6A) to that of a droplet where the aspect ratio has been increased to 2 : 1 (FIG. 6B).
  • the area of each droplet partially overlaps that covered by the droplet prior to the step, where the amount of overlap is dependent on the length of the step.
  • the degree of overlap is about 50% which typically ensures robust operation.
  • less or more overlap for example any value in the range about 10% to about 90%, may be chosen depending on the application at hand.
  • FIG. 6A is greater in FIG. 6A than in FIG. 6B, which is illustrative of how reshaping a droplet into a higher aspect ratio may improve track utilization, and therefore reduce the number of electrodes that have to be actuated to achieve the target motion.
  • a droplet is subjected to reshaping either before or while it is set into motion by applying a reduced representation actuation pattern as disclosed in the first aspect of the application.
  • a reduced representation actuation pattern as disclosed in the first aspect of the application.
  • the number of driving electrodes is reduced by the droplet reshaping while the driving time of each electrode is cut by the alternating drive pattern, thereby further reducing the amount of electrode actuation required to move the droplet.
  • a reshaped droplet may be moved by applying a “surface tension pull” electrode actuation pattern as disclosed in the second aspect of the application.
  • the number of electrodes driving the droplet is reduced both by the reshaping and by the actuation pattern which combine their respective contributions in limiting the extent of required electrode actuation.

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Abstract

L'invention concerne un procédé destiné à déplacer une gouttelette aqueuse d'un premier emplacement à un second emplacement à l'intérieur d'un dispositif microfluidique, le dispositif microfluidique comprenant une pluralité d'électrodes d'électromouillage couplées à des circuits configurés pour appliquer sélectivement des tensions d'entraînement aux électrodes. Le procédé comprend l'utilisation seulement d'une partie des électrodes qui sont recouvertes par la gouttelette aqueuse, réduisant ainsi le nombre d'électrodes qui peuvent être soumises à une dégradation en raison d'un entraînement excessif.
PCT/GB2022/050228 2021-01-28 2022-01-28 Stratégies de réduction d'actionnement pour mouvement de gouttelettes sur des réseaux d'électrodes de haute densité pour la microfluidique numérique Ceased WO2022162377A1 (fr)

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Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20110220505A1 (en) * 2010-03-09 2011-09-15 Sparkle Power Inc. Droplet manipulations on ewod microelectrode array architecture
EP3311919A1 (fr) * 2016-10-19 2018-04-25 Sharp Life Science (EU) Limited Extraction de fluide dans un dispositif microfluidique
EP3381557A1 (fr) * 2017-03-31 2018-10-03 Sharp Life Science (EU) Limited Dispositif am-ewod et procédés de commande à motifs d'actionnement intermittent
EP3384988A1 (fr) * 2017-04-04 2018-10-10 Sharp Life Science (EU) Limited Procédé d'actionnement de gouttelettes pour un dispositif microfluidique

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20110220505A1 (en) * 2010-03-09 2011-09-15 Sparkle Power Inc. Droplet manipulations on ewod microelectrode array architecture
EP3311919A1 (fr) * 2016-10-19 2018-04-25 Sharp Life Science (EU) Limited Extraction de fluide dans un dispositif microfluidique
EP3381557A1 (fr) * 2017-03-31 2018-10-03 Sharp Life Science (EU) Limited Dispositif am-ewod et procédés de commande à motifs d'actionnement intermittent
EP3384988A1 (fr) * 2017-04-04 2018-10-10 Sharp Life Science (EU) Limited Procédé d'actionnement de gouttelettes pour un dispositif microfluidique

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
WHEELER: "Digital Microfluidics", ANNU. REV. ANAL. CHEM., vol. 5, 2012, pages 413 - 40

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