[go: up one dir, main page]
More Web Proxy on the site http://driver.im/

WO2015160919A1 - Systèmes et procédés de production d'émulsions de gouttelettes ayant des coques relativement minces - Google Patents

Systèmes et procédés de production d'émulsions de gouttelettes ayant des coques relativement minces Download PDF

Info

Publication number
WO2015160919A1
WO2015160919A1 PCT/US2015/025921 US2015025921W WO2015160919A1 WO 2015160919 A1 WO2015160919 A1 WO 2015160919A1 US 2015025921 W US2015025921 W US 2015025921W WO 2015160919 A1 WO2015160919 A1 WO 2015160919A1
Authority
WO
WIPO (PCT)
Prior art keywords
microfluidic channel
fluid
cross
sectional area
droplet
Prior art date
Application number
PCT/US2015/025921
Other languages
English (en)
Inventor
David A. Weitz
Esther Amstad
Laura R. ARRIAGA
Original Assignee
President And Fellows Of Harvard College
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by President And Fellows Of Harvard College filed Critical President And Fellows Of Harvard College
Publication of WO2015160919A1 publication Critical patent/WO2015160919A1/fr

Links

Classifications

    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J19/00—Chemical, physical or physico-chemical processes in general; Their relevant apparatus
    • B01J19/0093—Microreactors, e.g. miniaturised or microfabricated reactors
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61J—CONTAINERS SPECIALLY ADAPTED FOR MEDICAL OR PHARMACEUTICAL PURPOSES; DEVICES OR METHODS SPECIALLY ADAPTED FOR BRINGING PHARMACEUTICAL PRODUCTS INTO PARTICULAR PHYSICAL OR ADMINISTERING FORMS; DEVICES FOR ADMINISTERING FOOD OR MEDICINES ORALLY; BABY COMFORTERS; DEVICES FOR RECEIVING SPITTLE
    • A61J3/00—Devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61J—CONTAINERS SPECIALLY ADAPTED FOR MEDICAL OR PHARMACEUTICAL PURPOSES; DEVICES OR METHODS SPECIALLY ADAPTED FOR BRINGING PHARMACEUTICAL PRODUCTS INTO PARTICULAR PHYSICAL OR ADMINISTERING FORMS; DEVICES FOR ADMINISTERING FOOD OR MEDICINES ORALLY; BABY COMFORTERS; DEVICES FOR RECEIVING SPITTLE
    • A61J3/00—Devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms
    • A61J3/07—Devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms into the form of capsules or similar small containers for oral use
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A61K9/5094—Microcapsules containing magnetic carrier material, e.g. ferrite for drug targeting
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01F—MIXING, e.g. DISSOLVING, EMULSIFYING OR DISPERSING
    • B01F23/00—Mixing according to the phases to be mixed, e.g. dispersing or emulsifying
    • B01F23/40—Mixing liquids with liquids; Emulsifying
    • B01F23/41—Emulsifying
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01F—MIXING, e.g. DISSOLVING, EMULSIFYING OR DISPERSING
    • B01F23/00—Mixing according to the phases to be mixed, e.g. dispersing or emulsifying
    • B01F23/40—Mixing liquids with liquids; Emulsifying
    • B01F23/41—Emulsifying
    • B01F23/414—Emulsifying characterised by the internal structure of the emulsion
    • B01F23/4144—Multiple emulsions, in particular double emulsions, e.g. water in oil in water; Three-phase emulsions
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01F—MIXING, e.g. DISSOLVING, EMULSIFYING OR DISPERSING
    • B01F25/00—Flow mixers; Mixers for falling materials, e.g. solid particles
    • B01F25/40—Static mixers
    • B01F25/42—Static mixers in which the mixing is affected by moving the components jointly in changing directions, e.g. in tubes provided with baffles or obstructions
    • B01F25/43—Mixing tubes, e.g. wherein the material is moved in a radial or partly reversed direction
    • B01F25/433—Mixing tubes wherein the shape of the tube influences the mixing, e.g. mixing tubes with varying cross-section or provided with inwardly extending profiles
    • B01F25/4335—Mixers with a converging-diverging cross-section
    • 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
    • B01F33/301—Micromixers using specific means for arranging the streams to be mixed, e.g. channel geometries or dispositions
    • B01F33/3011—Micromixers using specific means for arranging the streams to be mixed, e.g. channel geometries or dispositions using a sheathing stream of a fluid surrounding a central stream of a different fluid, e.g. for reducing the cross-section of the central stream or to produce droplets from the central stream
    • 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
    • B01F33/3035—Micromixers using surface tension to mix, move or hold the fluids
    • B01F33/30351—Micromixers using surface tension to mix, move or hold the fluids using hydrophilic/hydrophobic surfaces
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J13/00—Colloid chemistry, e.g. the production of colloidal materials or their solutions, not otherwise provided for; Making microcapsules or microballoons
    • B01J13/02—Making microcapsules or microballoons
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J13/00—Colloid chemistry, e.g. the production of colloidal materials or their solutions, not otherwise provided for; Making microcapsules or microballoons
    • B01J13/02—Making microcapsules or microballoons
    • B01J13/06—Making microcapsules or microballoons by phase separation
    • B01J13/14—Polymerisation; cross-linking
    • C—CHEMISTRY; METALLURGY
    • C11—ANIMAL OR VEGETABLE OILS, FATS, FATTY SUBSTANCES OR WAXES; FATTY ACIDS THEREFROM; DETERGENTS; CANDLES
    • C11D—DETERGENT COMPOSITIONS; USE OF SINGLE SUBSTANCES AS DETERGENTS; SOAP OR SOAP-MAKING; RESIN SOAPS; RECOVERY OF GLYCEROL
    • C11D3/00—Other compounding ingredients of detergent compositions covered in group C11D1/00
    • C11D3/50—Perfumes
    • C11D3/502—Protected perfumes
    • C11D3/505—Protected perfumes encapsulated or adsorbed on a carrier, e.g. zeolite or clay
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J2219/00—Chemical, physical or physico-chemical processes in general; Their relevant apparatus
    • B01J2219/00781—Aspects relating to microreactors
    • B01J2219/00788—Three-dimensional assemblies, i.e. the reactor comprising a form other than a stack of plates
    • B01J2219/00792—One or more tube-shaped elements
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J2219/00—Chemical, physical or physico-chemical processes in general; Their relevant apparatus
    • B01J2219/00781—Aspects relating to microreactors
    • B01J2219/00819—Materials of construction
    • B01J2219/00837—Materials of construction comprising coatings other than catalytically active coatings
    • B01J2219/0084—For changing surface tension
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J2219/00—Chemical, physical or physico-chemical processes in general; Their relevant apparatus
    • B01J2219/00781—Aspects relating to microreactors
    • B01J2219/00851—Additional features
    • B01J2219/00858—Aspects relating to the size of the reactor
    • B01J2219/0086—Dimensions of the flow channels
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J2219/00—Chemical, physical or physico-chemical processes in general; Their relevant apparatus
    • B01J2219/00781—Aspects relating to microreactors
    • B01J2219/00889—Mixing
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J2219/00—Chemical, physical or physico-chemical processes in general; Their relevant apparatus
    • B01J2219/00781—Aspects relating to microreactors
    • B01J2219/00891—Feeding or evacuation
    • B01J2219/00894—More than two inlets
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J2219/00—Chemical, physical or physico-chemical processes in general; Their relevant apparatus
    • B01J2219/00781—Aspects relating to microreactors
    • B01J2219/00891—Feeding or evacuation
    • B01J2219/00903—Segmented flow

Definitions

  • the present invention generally relates to microfluidics and, in particular, to systems and methods of producing droplets, including double and other multiple emulsion droplets.
  • Double emulsions are drops containing at least one smaller drop that is composed of a second, substantially immiscible fluid.
  • These core-shell structured fluids can be used, for instance, as templates to produce capsules; the outer drop contains the material that ultimately forms the shell of the capsule, whereas the inner drop constitutes the capsule interior core.
  • These capsules can be used as vehicles for delivery of active ingredients in many fields, such as food, pharmaceuticals, or cosmetics.
  • successful application of these capsules may require good control over their permeability and mechanical stability, parameters that can be tuned with the composition and thickness of the capsule shell. This may involve control over the dimensions and composition of the double emulsions. This control is often difficult to achieve if double emulsions are produced by mechanical stirring or membrane emulsification, since these conventional approaches typically yield double emulsion drops of different sizes that often contain multiple inner droplets.
  • the present invention generally relates to microfluidics and, in particular, to systems and methods of producing droplets, including double and other multiple emulsion droplets.
  • the subject matter of the present invention involves, in some cases, interrelated products, alternative solutions to a particular problem, and/or a plurality of different uses of one or more systems and/or articles.
  • the present invention is generally directed to an apparatus.
  • the apparatus comprises a first microfluidic channel intersecting at a junction with a second microfluidic channel and a third microfluidic channel.
  • the first microfluidic channel comprises a first portion having a first cross- sectional area and a second portion having a second cross- sectional area.
  • the second cross-sectional area is no more than about 40% of the first cross- sectional area.
  • the second portion may intersect the junction.
  • the second portion of the first microfluidic channel is hydrophobic, and the second and third microfluidic channels are hydrophilic, relative to each other, at the junction.
  • the apparatus in another set of embodiments, includes a first microfluidic channel intersecting at a junction with a second microfluidic channel and a third microfluidic channel.
  • the first microfluidic channel comprises a first portion having a first cross-sectional area and a second portion having a second cross- sectional area.
  • the second cross- sectional area is no more than about 40% of the first cross- sectional area.
  • the second portion may intersect the junction.
  • the second portion of the first microfluidic channel is hydrophilic, and the second and third microfluidic channels are hydrophobic, relative to each other, at the junction.
  • the apparatus comprises a double emulsion droplet contained within a microfluidic channel.
  • the double emulsion droplet comprises an inner interface between a first fluid and a second fluid, and an outer interface between the second fluid and a carrying fluid. In some cases, the outer interface is in contact with itself.
  • the present invention is generally directed to a method.
  • the method includes an act of providing a double emulsion droplet within a microfluidic channel, where the double emulsion droplet comprises an inner interface between a first fluid and a second fluid, and an outer interface between the second fluid and a carrying fluid.
  • the method also includes an act of distorting the double emulsion droplet such that the outer interface contacts itself, thereby forming a separate droplet of the second fluid within the carrying fluid.
  • the present invention in another set of embodiments, is generally directed to a method including an act of providing a double emulsion droplet within a microfluidic channel, where the double emulsion droplet comprises an inner interface between a first fluid and a second fluid, and an outer interface between the second fluid and a carrying fluid.
  • the method also includes an act of distorting the double emulsion droplet such that a portion of the second fluid exits the droplet to from a separate droplet of the second fluid within the carrying fluid.
  • the present invention encompasses methods of making one or more of the embodiments described herein, for example, emulsions, including double and other multiple emulsions, with relatively thin shells. In still another aspect, the present invention encompasses methods of using one or more of the embodiments described herein, for example, emulsions, including double and other multiple emulsions, with relatively thin shells.
  • Figs. 1A-1F illustrate a device for producing droplets, in one embodiment of the invention
  • Figs. 2A-2B illustrate various parameters for producing droplets, in another embodiment of the invention.
  • Figs. 3A-3D illustrate certain constrictions of a channel, in still another embodiment of the invention.
  • Figs. 4A-4E illustrate production of droplets, in yet another embodiment of the invention.
  • Figs. 5A-5D illustrate certain microfluidic devices, in certain embodiments of the invention.
  • Fig. 6 illustrates a microfluidic channel, in accordance with another embodiment of the invention.
  • Fig. 7 illustrates an asymmetric polymersome, in one embodiment of the invention.
  • the present invention generally relates to microfluidics and, in particular, to systems and methods of producing droplets, including double and other multiple emulsion droplets.
  • the present invention is generally directed to systems and methods for producing multiple emulsion droplets.
  • the multiple emulsion droplets may have relatively thin shells. These may be produced, for example, in a one- step process where multiple fluids are brought together at a junction, or by passing the multiple emulsion droplets through constrictions in microfluidic channels.
  • Other aspects of the invention are generally directed to systems and methods for using such double and other multiple emulsion droplets, kits involving such double and other multiple emulsion droplets, or the like.
  • a double emulsion is a droplet of a fluid that contains one or more inner droplets of a different fluid therein.
  • the droplet of fluid is, in turn, contained within a carrying fluid, typically substantially immiscible with the droplet of fluid.
  • the fluid within the inner droplets is typically substantially immiscible with the droplet of fluid.
  • the first fluid may be an aqueous fluid (a "water” phase)
  • the second fluid may be a lipophilic or “oil” phase that is substantially immiscible with the aqueous fluid
  • the third fluid may be an aqueous fluid (a "water” fluid) that is substantially immiscible with the second fluid.
  • This is sometimes generally referred to as a W/O/W double emulsion droplet (for water/oil/water), although it should be understand that this is mainly for the sake of convenience; for instance, the first fluid can be any suitable aqueous fluid as discussed herein, and it need not be pure water.
  • the third fluid may or may not be the same as the first fluid, and the third fluid may be substantially miscible or substantially immiscible with the first fluid, depending on the application.
  • an 0/W/O double emulsion droplet may be similarly defined.
  • these principles may be extended to higher-order multiple emulsions droplets.
  • a triple emulsion droplet may comprise a first fluid, surrounded by a second fluid, surrounded by a third fluid, contained in a fourth fluid (e.g., in an O/W/O/W configuration or a
  • a quadruple emulsion droplet may comprise a first fluid, surrounded by a second fluid, surrounded by a third fluid, surrounded by a fourth fluid, contained in a fifth fluid, etc.
  • device 10 includes a first fluid 15 flowing through channel 11 towards junction 18.
  • Channel 11 may be a microfluidic channel, or channel 11 may have a cross-sectional dimension (i.e., in a direction orthogonal to the direction of average fluid flow within the channel) of no more than about 2 mm or about 1 mm.
  • channel 11 is intersected by channels 21 and 22.
  • Channels 21 and 22 can intersect at a non-right angle as is shown in Fig. 5 A, or at a right angle in other embodiments.
  • Channels 21 and 22 may carry a second fluid 25, which may be substantially immiscible with first fluid 15. Thus, little or no mixing of these fluids may occur at junction 18; instead, a flow profile of first fluid 15 substantially surrounded by second fluid 25 may develop in channel 30 exiting junction 18.
  • channel 30 may have relatively hydrophobic walls, for instance, to facilitate having second fluid 25 closer to the walls and first fluid 15 farther away from the walls (and towards the center of the channel), e.g., if first fluid 15 is relatively hydrophilic and second fluid 25 is relatively hydrophobic (or if first fluid 15 is relatively hydrophobic and second fluid 25 is relatively hydrophilic, then channel 30 may have relatively hydrophilic walls).
  • a hydrophobic wall is fluorophilic.
  • Channel 30 may have portions having different cross- sectional areas (i.e., as determined orthogonally to the direction of average fluid flow within the channel).
  • channel 30 may have a first portion 31 having a first cross- sectional area and a second portion 32 having a second cross- sectional area, where the first cross- sectional area is substantially larger than the second cross- sectional area.
  • the cross-sectional area of the second portion may be less than about 40%, less than about 20% or less than about 10% of the cross- sectional area of the first portion.
  • channel 30 comprises a first portion 31 and a second portion 32, where first portion 31 has a larger cross-sectional area than second portion 32.
  • first portion and/or the second portion of the channel may each have a substantially uniform cross- sectional area, although the transition between first portion 31 and second portion 32 may be relatively abrupt in some cases. See, e.g., a side view of an example channel in Fig. 5C.
  • the change in cross-sectional area may cause fluids 15 and 25 to flow faster through second portion 32, e.g., without forming separate, discrete droplets. In some cases, for instance, the flow of fluids within the channel may exhibit jetting behavior.
  • junction 48 fluids 15 and 25 flowing through second portion 32 of channel 30 enter junction 48.
  • Junction 48 may be formed at the intersection of channel 30, channel 41, and channel 42.
  • channels 41 and 42 intersect channel 30 at a non-right angle (although they may intersect at a right angle in other embodiments).
  • Third fluid 45 may be the same or different from first fluid 15; in addition, third fluid 45 may be immiscible (or at least partially immiscible) with second fluid 25.
  • first fluid 15 and third fluid 45 do not come into contact with each other; thus, first fluid 15 and third fluid 45 can be the same fluid, or different fluids, depending on the application.
  • one or more of channels 41, 42, and 50 may have relatively hydrophilic walls, for instance, to facilitate having third fluid 45 closer to the walls and second fluid 25 farther away from the walls (e.g., towards the center of a channel), for example, in cases where second fluid 25 is relatively hydrophobic and third fluid 45 is relatively hydrophilic (or if second fluid 25 is relatively hydrophilic and third fluid 45 is relatively hydrophobic, then channels 41, 42, and/or 50 may have relatively hydrophobic walls).
  • third fluid 45 into junction 48 can cause second fluid 25 and first fluid 15 to from individual or discrete droplets 55 within third fluid 45.
  • Droplets 55 may be double emulsion droplets, e.g., comprising a droplet of first fluid 15, contained or surrounded by a droplet of second fluid 25, which in turn is contained or surrounded by third fluid 45.
  • the droplets may also be monodisperse in some instances.
  • additional "nestings" of fluids may similarly occur, e.g., to produce triple or higher multiple emulsion droplets. See, e.g., Fig. 5B for a non- limiting example of such an embodiment.
  • the change in cross- sectional area from first portion 31 to second portion 32 of channel 30 may prevent backflow of fluid 45 into second portion 32, e.g., due to the average velocity of fluid flow flowing in the other direction (i.e., the "forward' direction) through second portion 32 into junction 48.
  • This may be important, for instance, to facilitate relatively uniform or monodisperse production of double or other multiple emulsion droplets.
  • the volumes and/or thicknesses of the components of the double emulsion droplets may be controlled.
  • the droplets are formed such that the droplets contain a relatively large amount of first fluid but a lesser amount of second fluid, i.e., droplets may be formed that have relatively thin "shells" of second fluid surrounding the first fluid.
  • the thickness of the second fluid surrounding the first fluid may be less than about 10 micrometers or less than about 5 micrometers, e.g., as estimated volumetrically.
  • various aspects of the invention are directed to various systems and methods for producing double emulsion droplets and other multiple emulsion droplets.
  • the double or other multiple emulsion droplets may be produced in a single step, e.g., as was discussed with respect to Fig. 5A.
  • a droplet may be formed at a junction of a first channel with one, two or more adjacent channels.
  • the junction may be sized such that the flow of a fluid from the first channel entering the junction is slowed. If the adjacent channels contain a substantially immiscible fluid, then the fluid entering the junction from the first channel may be slowed such that the fluid forms a droplet.
  • the channels meeting at the junction may form any suitable angles with respect to each other. For example, in Fig. 5 A, channels 41 and 42 may form the same or different angles with respect to channel 30, and channels 41 and 42 may independently be orthogonal or non- orthogonal with respect to channel 30. The angles that are formed may also be acute or obtuse, depending on the embodiment.
  • the fluid entering the junction from the first channel may itself contain two fluids, e.g., that are substantially immiscible.
  • a double emulsion droplet may be formed with a first fluid being surrounded by a third fluid, which in turn may be surrounded by a third fluid.
  • Higher emulsion droplets may similarly be formed.
  • three nested fluids entering the junction from the first junction may be caused to from a triple emulsion droplet of a first fluid, surrounded by a second fluid, surrounded by a third fluid, contained in a fourth fluid.
  • first fluid 15, second fluid 25, and third fluid 75 entering through channels 71 and 72
  • channel 30 having first portion 31 and second portion 32, as previously discussed.
  • channels 41 and 42 of Fig. 5B may be relatively hydrophilic while channel 30 is relatively hydrophobic, or vice versa.
  • Even higher multiple emulsion droplets e.g., quadruple multiple emulsion droplets, quintuple multiple emulsion droplets, etc. can be similarly produced in still other embodiments of the invention, e.g., by control of the fluids entering a junction.
  • the channels entering the junction may be sized as discussed herein.
  • the channels may be of the same, or different sizes, and may intersect the junction at any suitable angle.
  • the channel is a microfluidic channel.
  • the channel may have a cross-sectional dimension of less than about 1 mm, or other dimensions as discussed below.
  • the first channel is substantially smaller than the other channels at the junction where the droplets are formed.
  • the first channel may have a cross-sectional area that is no more than about 75%, no more than about 50%, no more than about 45%, no more than about 40%, no more than about 35%, no more than about 30%, no more than about 25%, no more than about 20%, no more than about 15%, no more than about 10%, or no more than about 5% of the cross- sectional area of the smallest of the other channels meeting at the junction.
  • the first channel may exhibit a narrowing in cross- sectional dimension prior to the junction.
  • the first channel has a first portion and a second portion (which enters the junction), where the second portion has a cross- sectional area that is smaller than a cross-sectional area of the first portion. For instance, in some cases, no more than about 50%, no more than about 45%, no more than about 40%, no more than about 35%, no more than about 30%, no more than about 25%, no more than about 20%, no more than about 15%, no more than about 10%, or no more than about 5% of the cross-sectional area of the first portion.
  • the first portion and the second portion may have the same width, but a different height, and or vice versa. In other cases, however, both the width and the height may be different between the first portion and the second portion.
  • the cross- sectional area of the first portion is substantially constant, and/or the cross- sectional area of the second portion is substantially constant (e.g., one or both of these channels may be substantially rectangular or cylindrical). However, in some cases, one or both of these may not necessarily be substantially constant. For example, one or both may be tapered.
  • the transition between the first and second portion of the channel is relatively short.
  • the transition may be abrupt, e.g., a step change, as is shown in Fig. 5C between first portion 31 and second portion 32.
  • the step may be vertically or horizontally oriented (or both), depending on the embodiment.
  • the transition may be more gradual.
  • Fig. 5D there is a tapered region 33 between first portion 31 and second portion 32.
  • the length of the tapered region may be any suitable length as determined in the direction of average fluid flow within the channel; for example, the length can be less than about 1 mm, less than about 500 micrometers, less than about 300 micrometers, less than about 100 micrometers, less than about 50 micrometers, less than about 30 micrometers, less than about 10 micrometers, less than about 5 micrometers, less than about 3
  • micrometers less than about 1 micrometer, etc.
  • one or more of the channels within the device may be relatively hydrophobic or relatively hydrophilic, e.g. inherently, and/or by treating one or more of the surfaces or walls of the channel to render them more hydrophobic or hydrophilic.
  • the fluids that are formed droplets in the device are substantially immiscible, at least on the time scale of forming the droplets, and the fluids will often have different degrees of hydrophobicity or hydrophilicity.
  • a first fluid may be more hydrophilic (or more hydrophobic) relative to a second fluid, and the first and the second fluids may be substantially immiscible.
  • the first fluid can from a discrete droplet within the second fluid, e.g., without substantial mixing of the first fluid and the second fluid (although some degree of mixing may nevertheless occur under some conditions).
  • the second fluid may be more hydrophilic (or more hydrophobic) relative to a third fluid (which may be the same or different than the first fluid), and the second and third fluids may be substantially immiscible. Immiscibility is further discussed in additional detail below.
  • a surface of a channel may be relatively hydrophobic or hydrophilic, depending on the fluid contained within the channel.
  • a surface of the channel is hydrophobic or hydrophilic relative to other surfaces within the device.
  • a relatively hydrophobic surface may exhibit a water contact angle of greater than about 90°, and/or a relatively hydrophilic surface may exhibit a water contact angle of less than about 90°.
  • relatively hydrophobic and/or hydrophilic surfaces may be used to facilitate the flow of fluids within the channel, e.g., to maintain the nesting of multiple fluids within the channel in a particular order.
  • first fluid 15 is surrounded by second fluid 25 as it flows within channel 30. If the second fluid is more hydrophobic than the first fluid, then the walls of channel 30 may be relatively hydrophobic (or treated to render them more hydrophobic), such that the second fluid can be maintained near the walls, relative to the first fluid.
  • the walls of channel 30 may be relatively hydrophilic (or treated to render them more hydrophilic), so that the second fluid can be maintained near the walls, relative to the first fluid.
  • fluid flow can be maintained within channel 30, e.g., without disrupting the flow of the fluids contained therein, and/or without causing droplet formation prior to junction 48.
  • channels 41 and 42 containing a third fluid may also be rendered hydrophobic or hydrophilic.
  • these channels may have a different hydrophilicity than the first channel. For instance, if the first channel is relatively hydrophobic, then these channels may be relatively hydrophilic, or vice versa. This may be useful, for instance, to cause droplet formation at junction 48 to occur.
  • the volumes and/or thicknesses of the components of the double emulsion droplets may be controlled.
  • double emulsion droplets are formed such that the droplets contain a relatively large amount of first fluid but a lesser amount of second fluid, i.e., droplets may be formed that have relatively thin "shells" of second fluid surrounding the first fluid.
  • the outermost shell of fluid may be formed with a relatively thin shell.
  • the thickness of the outermost fluid shell of a double or other multiple emulsion droplet may be less than about 15 micrometers, less than about 12 micrometers, less than about 10 micrometers, less than about 9 micrometers, less than about 8 micrometers, less than about 7 micrometers, less than about 6 micrometers, less than about 5 micrometers, less than about 4 micrometers, less than about 3 micrometers, less than about 2 micrometers, less than about 1 micrometers, etc.
  • the volume of the second fluid, relative to the first fluid (or of an outermost layer of fluid, relative to the adjacent layer of fluid) may be less than about 25%, less than about 20%, less than about 15%, less than about 12%, less than about 10%, less than about 9%, less than about 8%, less than about 7%, less than about 6%, less than about 5%, less than about 4%, less than about 3%, less than about 2%, or less than about 1% of the total volume of the droplet. Additional suitable dimensions for the outermost shell of fluid for a double or other multiple emulsion droplet are also discussed in more detail below.
  • certain aspects of the present invention are generally directed to systems and methods of reducing the thicknesses of the outermost layer of fluid of such double emulsion and other multiple emulsion droplets.
  • the double emulsion droplet may be produced as discussed above (e.g., with respect to Fig. 5), or through other techniques such as those discussed in any of Int. Pat. Apl. Pub. Nos. WO 2006/096571, WO 2008/121342, WO 2011/028760, WO 2011/028764, or WO 2013/006661, each incorporated herein by reference in its entirety.
  • the double or other multiple emulsion droplet may have a relatively thin outermost shell, e.g., with dimensions as discussed herein, although in some embodiments, double or other multiple emulsion droplets may also be formed with relatively thicker outermost layers.
  • double or other multiple emulsion droplets produced using any of these techniques, can be treated to reducing the thicknesses of the outermost layer of fluid of such double emulsion and other multiple emulsion droplets.
  • device 60 contains one or more double emulsion droplets 62 flowing within a channel 65 (a double emulsion droplet is discussed here for purposes of clarity, although in other embodiments, triple or other multiple emulsion droplets may be used).
  • Double emulsion droplets 62 may include a first fluid 71 surrounded by a second fluid 72, which is in turn carried by a third fluid 73.
  • Double emulsion droplets 62 may be produced using any suitable technique, including any of those discussed herein, or in any of those discussed in any of the patent applications described above or incorporated herein by reference.
  • Droplets 62 may then be distorted in some fashion, e.g., by passing droplets 62 through a narrowing of channel 65 able to cause a distortion of droplet 62 to occur.
  • droplet 62 upon reaching constriction 70, droplet 62 may become distorted as it passes through the channel.
  • constriction 70 comprises a first portion 75, a second portion 76, and a third portion 77, although other configurations are also possible in other embodiments.
  • first portion 75 and third portion 77 are generally tapered, while second portion 76 has a generally constant cross- sectional area.
  • first portion 75 and third portion 77 may be the same or different, and the slopes may be linear or non-linear (e.g., curved).
  • constriction 70 may be symmetric, e.g., about the center line of channel 65.
  • the distortion may be such that one or more portions of the interface between second fluid 71 and third fluid 72 contact each other, thereby resulting in a pinching off of a portion of the droplet as a separate droplet, e.g., once droplet 62 passes through constriction 70.
  • a portion of droplet 62 has become separated as droplet 66.
  • Droplet 66 may contain only second fluid 72. Accordingly, droplet 62 now contains a less amount of second fluid 72, and thus, the shell formed by second fluid 72 around first fluid 71 is correspondingly thinner after droplet 62 has exited constriction 70. Droplets 66 and 62 may then continue to flow through channel 65.
  • this process may be repeated one or more times, e.g., by passing droplet 62 through additional constrictions, in order to reduce the amount of second fluid within the droplet, or to produce droplets with thinner shells of second fluid.
  • droplets 62 and 66 may be separated from each other after formation, e.g., by using size or density differences between the droplets.
  • a double or other multiple emulsion droplet may be distorted such that a portion of the outermost layer of the droplet is separated from the remainder of the droplet.
  • the double or other multiple emulsion droplet may be distorted such that a portion of the outermost layer of the droplet is caused to exit the droplet to from a separate droplet within the carrying fluid. This may be useful, for example, for decreasing the volume or average thickness of the outermost layer of the droplet.
  • the outermost layer of a droplet may decrease in volume by at least about 5%, at least about 10%, at least about 15%, at least about 20%, at least about 25%, etc., relative to the volume of the outermost layer of a droplet prior to distortion.
  • the outermost layer of a droplet may decrease in volume by no more than about 30%, no more than about 25%, no more than about 20%, no more than about 15%, no more than about 10%, or no more than about 5%, etc. Combinations of any of these are also possible.
  • the volume of the outermost layer of a double or other multiple emulsion droplet may decrease between about 5% and about 10%.
  • the thickness of the outermost layer of the droplet may be decreased.
  • this decrease may be a decrease in thickness of at least about 1%, at least about 2%, at least about 3%, at least about 4%, at least about 5%, at least about 6%, at least about 7%, at least about 8%, at least about 9%, at least about 10%, at least about 12%, at least about 15%, at least about 18%, at least about 20%, etc., and/or no more than about 25%, no more than about 20%, no more than about 18%, no more than about 15%, no more than about 12%, no more than about 10%, no more than about 9%, no more than about 8%, no more than about 7%, no more than about 6%, no more than about 5%, no more than about 4%, no more than about 3%, no more than about 2%, or the like.
  • the decrease may be determined relative to the droplet prior to distortion.
  • the volumes or thicknesses of a layer of fluid in a droplet may be determined or estimated (e.g., before and/or after distortion) using any suitable technique, e.g., visually or optically.
  • the volumes or thickness of a layer of fluid may be estimated statistically, e.g., by determining the amount of fluid present in a plurality of double or other multiple emulsion droplets, and assuming that the droplets are spherical, calculating the volume and/or thicknesses of the fluid around each droplet.
  • the fluid flows through a constriction in a channel that is able to cause distortion of the droplet.
  • the constriction may be sized such that a droplet cannot pass through the constriction without coming into contact with at least one wall of the constriction, and in some cases, without coming into contact with each wall of the constriction.
  • the constriction may be, for example, a narrowing of the cross-sectional area of the channel, e.g., in one or two dimensions.
  • the constriction may comprise a first tapered portion, a portion having substantially constant cross-sectional area, and a second tapered portion, e.g., as is shown in Fig. 6 with portions 75, 76, and 77.
  • the constriction may contain a first tapered portion and a second tapered portion, but without a portion having a substantially constant cross- sectional area.
  • the first tapered portion has an inlet portion dimensioned such that an entering droplet does not come into contact with the walls of the inlet portion, although the tapered portion may substantially narrow such that the droplet comes into contact with one or more walls, e.g., to cause distortion of the droplet.
  • the second tapered portion may have an outlet dimensioned such that an exiting droplet is able to assume a generally spherical shape, e.g., without contact any of the walls upon exiting the tapered portion.
  • the construction may also take the form of an annular orifice, a valve, or the like. In some cases, the constriction is non-valved. That is, it is an orifice that cannot be switched between an open state and a closed state, and typically is of fixed size.
  • the constriction may comprise a first generally tapered portion, a second generally constant portion, and a third generally tapered portion.
  • the channel to either side of the constriction may have substantially the same cross-sectional area or the same dimensions, although in other cases, these may be different.
  • the constant portion has substantially a substantially constant cross- sectional area or constant dimensions.
  • the taperings of the tapered portions may be the same or different, and the slopes may be linear or non-linear (e.g., curved). The transitions between these portions may be the same or different.
  • the lengths of these portions may each independently be the same or different. For example, their lengths may be less than about 1 mm, less than about 500
  • micrometers less than about 300 micrometers, less than about 100 micrometers, less than about 50 micrometers, less than about 30 micrometers, less than about 10 micrometers, less than about 5 micrometers, less than about 3 micrometers, less than about 1 micrometer, etc.
  • the distortion may be caused by other techniques, for example, by exposure to different fluids or fluid flows that are able to deform the droplet, or by introducing obstacles into the flow path of the fluid that causes the droplets to distort as they flow past the obstacle.
  • this distortion may be such that a portion of an interface between the droplet and the carrying fluid comes into contact with itself, which can cause a portion of the outermost layer of fluid within the droplet to detach and form a separate droplet. This can cause the outermost layer of fluid to thin or decrease in volume in some cases.
  • multiple emulsion droplets can include more than two nestings (e.g., triple emulsions, quadruple emulsions, etc.).
  • the multiple emulsion droplets can have any of the properties described elsewhere herein with respect to double emulsions.
  • the flow rates of the fluids can be controlled such that each nesting includes a single droplet.
  • the multiple emulsion comprises a core fluid surrounded by multiple layers of multiple outer fluids.
  • Each droplet within such multiple emulsions may have any of the properties (e.g., thicknesses, variations in thickness (or lack thereof), cross-sectional diameter, etc.) described elsewhere herein.
  • the inner fluid forms a plurality of droplets within a middle fluid
  • the middle fluid is surrounded by a thin layer of an outer fluid which is, in turn, surrounded by a carrying fluid.
  • the outer fluid surrounds a middle fluid which surrounds a plurality of outer fluids, each of which forms a thin layer of fluid around a plurality of innermost fluids within a carrying fluid.
  • vesicles can be formed that can include lipids (e.g., as in a liposome) and/or polymers (e.g., as in a polymersome). See, e.g., Int. Pat. Apl. Pub. No. WO 2009/148598 or WO 2006/096571, each incorporated herein by reference. Vesicles such as polymersomes or liposomes may be formed, for example, using multiple emulsion techniques such as those described below.
  • Non-limiting examples of polymers that can be used include normal butyl acrylate and acrylic acid, which can be
  • the copolymer may comprise more than two types of monomers, for example, as in a copolymer of poly(ethylene glycol)-poly(lactic acid)-poly(glycolic acid).
  • the copolymer may include amphiphilic molecules.
  • the amphiphilic molecules can be lipids.
  • the monomers may be distributed in any suitable order within the copolymer, for example, as separate blocks (e.g., a multiblock copolymer), randomly, alternating, etc.
  • a polymer may include polymeric compounds, as well as compounds and species that can form polymeric compounds, such as prepolymers. Prepolymers include, for example, monomers and oligomers. In some cases, however, only polymeric compounds are used and
  • prepolymers may not be appropriate.
  • the present invention can be used to produce polymersomes.
  • the polymersome is an asymmetric polymersome.
  • the polymersome comprises a multiblock copolymer.
  • at least one of the blocks of the copolymer is a biodegradable polymer.
  • a polymer within the polymersome comprises a copolymer, e.g., a block copolymer.
  • the polymer may be, for instance, diblock or a triblock copolymer, which can be
  • block copolymers may also be used (e.g., having the same composition as one of the blocks of the copolymer), e.g., to stabilize the vesicle.
  • a "block copolymers" may also be used (e.g., having the same composition as one of the blocks of the copolymer), e.g., to stabilize the vesicle.
  • copolymer is given its usual definition in the field of polymer chemistry.
  • a block is typically a portion of a polymer comprising a series of repeat units that are
  • a diblock copolymer comprises a first repeat unit and a second repeat unit; a triblock copolymer includes a first repeat unit, a second repeat unit, and a third repeat unit; a multiblock copolymer includes a plurality of such repeat units, etc.
  • a diblock copolymer may comprise a first portion defined by a first repeat unit and a second portion defined by a second repeat unit; in some cases, the diblock copolymer may further comprise a third portion defined by the first repeat unit (e.g,. arranged such that the first and third portions are separated by the second portion), and/or additional portions defined by the first and second repeat units.
  • biodegradable or biocompatible polymers include, but are not limited to, poly(lactic acid), poly(glycolic acid), polyanhydride, poly(capro lactone), poly(ethylene oxide), polybutylene terephthalate, starch, cellulose, chitosan, and/or combinations of these.
  • a "biodegradable material,” as used herein, is a material that will degrade in the presence of physiological solutions (which can be mimicked using phosphate-buffered saline) on the time scale of days, weeks, or months (i.e., its half-life of degradation can be measured on such time scales).
  • biocompatible is given its ordinary meaning in the art.
  • a biocompatible material may be one that is suitable for implantation into a subject without adverse consequences, for example, without substantial acute or chronic inflammatory response and/or acute rejection of the material by the immune system, for instance, via a T-cell response.
  • biocompatibility is a relative term, and some degree of inflammatory and/or immune response is to be expected even for materials that are highly biocompatible.
  • non-biocompatible materials are typically those materials that are highly inflammatory and/or are acutely rejected by the immune system, i.e., a non-biocompatible material implanted into a subject may provoke an immune response in the subject that is severe enough such that the rejection of the material by the immune system cannot be adequately controlled, in some cases even with the use of immunosuppressant drugs, and often can be of a degree such that the material must be removed from the subject.
  • the immune response by the subject is of such a degree that the material ceases to function; for example, the inflammatory and/or the immune response of the subject may create a fibrous "capsule" surrounding the material that effectively isolates it from the rest of the subject's body; materials eliciting such a reaction would also not be considered as "biocompatible.”
  • a droplet such as a double or other multiple emulsion droplet, may include amphiphilic species such as amphiphilic polymers or lipids.
  • amphiphilic species typically includes a relatively hydrophilic portion, and a relatively hydrophobic portion.
  • the hydrophilic portion may be a portion of the molecule that is charged
  • the hydrophobic portion of the molecule may be a portion of the molecule that comprises hydrocarbon chains.
  • Other amphiphilic species may also be used, besides diblock copolymers.
  • other polymers, or other species such as lipids or phospholipids may be used with the present invention.
  • an amphiphilic species that is contained, dissolved, or suspended in the emulsion can spontaneously associate along a hydrophilic/hydrophobic interface in some cases.
  • the hydrophilic portion of an amphiphilic species may extend into the aqueous phase and the hydrophobic portion may extend into the non-aqueous phase.
  • the amphiphilic species can spontaneously organize under certain conditions so that the amphiphilic species molecules orient substantially parallel to each other and are oriented substantially perpendicular to the interface between two adjoining fluids, such as an inner droplet and outer droplet, or an outer droplet and an outer fluid.
  • amphiphilic species may form a sheet or a membrane, e.g., a substantially spherical sheet, with a hydrophobic surface and an opposed hydrophilic surface.
  • the hydrophobic side may face inwardly or outwardly and the hydrophilic side may face inwardly or outwardly.
  • the resulting structure may be a bilayer or a multi-lamellar structure.
  • an asymmetric liposome or polymersome i.e., a liposome or polymersome comprising a lipid bilayer having a first, inner surface comprising a first lipid or polymer composition and a second outer surface comprising a second lipid or polymer composition distinguishable from the first composition, where the first, inner surface and the second, outer surface together form a lipid bilayer membrane defining the liposome or polymersome, or at least one shell of the liposome or polymersome, e.g., in a double or multiple emulsion droplet.
  • Such asymmetric liposomes or polymersomes may be formed, for example, by incorporating a first lipid or polymer in a first fluid and a second lipid or polymer in a second fluid surrounding the first fluid in a multiple emulsion droplet.
  • the lipids or polymers on one interface of a fluid within the liposome or polymersome are not necessarily the same as the lipids or polymers on a different interface of the fluid.
  • there may be a first lipid or polymer within the interface between the core of the droplet and oil 1 there may be a second lipid or polymer within the interface between oil 1 and oil 2.
  • the first polymer is block-co-polymer 1
  • the second polymer is block-co-polymer 2, although other polymers and/or lipids may be used in other embodiments.
  • a first shell of a liposome or polymersome may comprise a first, inner surface comprising a first lipid or polymer composition and a second outer surface comprising a second lipid or polymer composition distinguishable from the first lipid or polymer composition, and a second shell comprising a first, inner surface comprising a third lipid or polymer composition and a second outer surface comprising a fourth lipid or polymer composition distinguishable from the third lipid or polymer composition.
  • a liposome or a polymersome may be formed by removing a portion of the middle fluid of a multiple emulsion.
  • a component of the middle fluid such as a solvent or carrier
  • the middle fluid comprises a solvent system used as a carrier, and dissolved or suspended polymers or lipids.
  • the solvent can be removed from the middle fluid using techniques such as evaporation or diffusion, leaving the polymers or lipids behind.
  • a liposome or a polymersome may be formed by creating a double or other multiple emulsion droplet having a relatively thin layer or shell or fluid, e.g., using techniques such as those described herein.
  • the droplet may initially be created with a relatively thin layer or shell or fluid, and/or a portion of the fluid may be removed, e.g., through distortion of the droplet or passage of the droplet through a construction.
  • an asymmetric liposome or polymersome may be formed.
  • a portion of a double or other multiple emulsion droplet may be solidified to form a particle or a capsule, for example, containing an inner fluid and/or a species as discussed herein.
  • a fluid e.g., within an outermost layer of a multiple emulsion droplet, can be solidified using any suitable method.
  • the fluid may be dried, gelled, and/or polymerized, and/or otherwise solidified, e.g., to form a solid, or at least a semisolid.
  • the solid that is formed may be rigid in some embodiments, although in other cases, the solid may be elastic, rubbery, deformable, etc.
  • an outermost layer of fluid may be solidified to form a solid shell at least partially containing an interior containing a fluid and/or a species. Any technique able to solidify at least a portion of a fluidic droplet can be used.
  • a fluid within a fluidic droplet may be removed to leave behind a material (e.g., a polymer) capable of forming a solid shell.
  • a fluidic droplet may be cooled to a temperature below the melting point or glass transition temperature of a fluid within the fluidic droplet, a chemical reaction may be induced that causes at least a portion of the fluidic droplet to solidify (for example, a polymerization reaction, a reaction between two fluids that produces a solid product, etc.), or the like.
  • a chemical reaction may be induced that causes at least a portion of the fluidic droplet to solidify (for example, a polymerization reaction, a reaction between two fluids that produces a solid product, etc.), or the like.
  • Other examples include pH- responsive or molecular-recognizable polymers, e.g., materials that gel upon exposure to a certain pH, or to a certain species.
  • a fluidic droplet is solidified by increasing the temperature of the fluidic droplet.
  • a rise in temperature may drive out a material from the fluidic droplet (e.g., within the outermost layer of a multiple emulsion droplet) and leave behind another material that forms a solid.
  • a material from the fluidic droplet e.g., within the outermost layer of a multiple emulsion droplet
  • another material that forms a solid.
  • an outermost layer of a multiple emulsion droplet may be solidified to form a solid shell that encapsulates one or more fluids and/or species.
  • the systems and methods described herein can be used in a plurality of applications.
  • fields in which the particles and multiple emulsions described herein may be useful include, but are not limited to, food, beverage, health and beauty aids, paints and coatings, chemical separations, agricultural applications, and drugs and drug delivery.
  • a precise quantity of a fluid, drug, pharmaceutical, or other species can be contained in a droplet or particle designed to release its contents under particular conditions.
  • cells can be contained within a droplet or particle, and the cells can be stored and/or delivered, e.g., to a target medium, for example, within a subject.
  • species that can be contained within a droplet or particle and delivered to a target medium include, for example, biochemical species such as nucleic acids such as siRNA, RNAi and DNA, proteins, peptides, or enzymes. Additional species that can be contained within a droplet or particle include, but are not limited to, colloidal particles, magnetic particles,
  • the target medium may be any suitable medium, for example, water, saline, an aqueous medium, a hydrophobic medium, or the like.
  • particles comprising relatively thin shells can be formed using the multiple emulsion techniques described herein.
  • at least some of the particles may comprise a solid portion or shell at least partially containing an interior containing a fluid and/or a species.
  • the shells of the particles can comprise a polymer in some embodiments.
  • Examples include, but are not limited to, polystyrene, polycaprolactone, polyisoprene, poly(lactic acid), polystyrene (PS), polycaprolactone (PCL), polyisoprene (PIP), poly(lactic acid), polyethylene, polypropylene, polyacrylonitrile, polyimide, polyamide, and/or mixtures and/or co- polymers of these and/or other polymers.
  • the carrying fluid may be used in some embodiments as a vehicle used to contact the particles with a target medium, and/or the carrying fluid may be substituted by a suitable vehicle, as discussed elsewhere herein.
  • the particles When the particles contact the target medium, at least a portion of the shells of the particles can be disrupted in some cases, for instance, such that at least some of the fluid and/or species within the particles is expelled or otherwise transported from the particles and into the target medium.
  • the particles may be used in other applications as well, e.g., as discussed herein.
  • the particles or droplets described herein may have any suitable average cross- sectional diameter.
  • Those of ordinary skill in the art will be able to determine the average cross- sectional diameter of a single and/or a plurality of particles or droplets, for example, using laser light scattering, microscopic examination, or other known techniques.
  • the average cross-sectional diameter of a single particle or droplet, in a non- spherical particle or droplet is the diameter of a perfect sphere having the same volume as the non-spherical particle or droplet.
  • the average cross- sectional diameter of a particle or droplet (and/or of a plurality or series of particles or droplets) may be, for example, less than about 1 mm, less than about 500 micrometers, less than about 200 micrometers, less than about 100 micrometers, less than about 75 micrometers, less than about 50 micrometers, less than about 25 micrometers, less than about 10 micrometers, or less than about 5 micrometers, or between about 50 micrometers and about 1 mm, between about 10 micrometers and about 500 micrometers, or between about
  • the average cross- sectional diameter may also be at least about 1 micrometer, at least about 2 micrometers, at least about 3 micrometers, at least about 5 micrometers, at least about 10 micrometers, at least about 15 micrometers, or at least about 20 micrometers in certain cases. In some embodiments, at least about 50%, at least about 75%, at least about 90%, at least about 95%, or at least about 99% of the particles or droplets within a plurality of particles or droplets has an average cross-sectional diameter within any of the ranges outlined in this paragraph.
  • the outermost layer of the particles or droplets is relatively thin.
  • the outermost layer of a particle or droplet has an average thickness (averaged over the entire particle) of less than about 0.05, less than about 0.01, less than about 0.005, or less than about 0.001 times the average cross- sectional diameter of the particle or droplet, or between about 0.0005 and about 0.05, between about 0.0005 and about 0.01, between about 0.0005 and about 0.005, or between about 0.0005 and about 0.001 times the average cross- sectional diameter of the particle or droplet.
  • the outermost layer of a particle or droplet has an average thickness of less than about 1 micron, less than about 500 nm, or less than about 100 nm, or between about 50 nm and about 1 micron, between about 50 nm and about 500 nm, or between about 50 nm and about 100 nm. In some embodiments, at least about 50%, at least about 75%, at least about 90%, at least about 95%, or at least about 99% of the particles within a plurality of particles or droplets.
  • SEM scanning electron microscope
  • a plurality of particles or droplets at least some of which contain a fluid and/or a species such as those described herein, to a target.
  • some embodiments advantageously employ particles or droplets with relatively consistent properties.
  • a plurality of particles or droplets is provided wherein the distribution of thicknesses of the outermost layer among the plurality of particles or droplets is relatively uniform.
  • a plurality of particles or droplets is provided having an overall thickness, measured as the average of the average thicknesses of each of the plurality of particles or droplets.
  • the distribution of the average thicknesses can be such that no more than about 5%, no more than about 2%, or no more than about 1% of the particles or droplets have an outermost layer with an average thickness thinner than 90% (or thinner than 95%, or thinner than 99%) of the overall average thickness and/or thicker than 110% (or thicker than 105%, or thicker than about 101%) of the overall average thickness of the outermost layer.
  • the plurality of particles or droplets may have relatively uniform cross-sectional diameters in certain embodiments. The use of particles or droplets with relatively uniform cross-sectional diameters can allow one to control viscosity, the amount of species delivered to a target, and/or other parameters of the delivery of fluid and/or species from the particles or droplets.
  • the particles or droplets of particles is monodisperse, or the plurality of particles or droplets has an overall average diameter and a distribution of diameters such that no more than about 5%, no more than about 2%, or no more than about 1% of the particles or droplets have a diameter less than about 90% (or less than about 95%, or less than about 99%) and/or greater than about 110% (or greater than about 105%, or greater than about 101%) of the overall average diameter of the plurality of particles or droplets.
  • the plurality of particles or droplets has an overall average diameter and a distribution of diameters such that the coefficient of variation of the cross- sectional diameters of the particles or droplets is less than about 10%, less than about 5%, less than about 2%, between about 1% and about 10%, between about 1% and about 5%, or between about 1% and about 2%.
  • the coefficient of variation can be determined by those of ordinary skill in the art, and may be defined as:
  • ⁇ is the standard deviation and ⁇ is the mean.
  • two fluids are immiscible, or not miscible, with each other when one is not soluble in the other to a level of at least 10% by weight at the temperature and under the conditions at which the emulsion is produced.
  • two fluids may be selected to be immiscible within the time frame of the formation of the fluidic droplets.
  • two fluids e.g., the carrying fluid and the inner droplet fluid of a multiple emulsion
  • two fluids are compatible, or miscible, while the outer droplet fluid is incompatible or immiscible with one or both of the carrying and inner droplet fluids.
  • all three (or more) fluids may be mutually immiscible, and in certain cases, all of the fluids do not all necessarily have to be water soluble.
  • additional fourth, fifth, sixth, etc. fluids may be added to produce increasingly complex droplets within droplets, e.g., a carrying fluid may surround a first fluid, which may in turn surround a second fluid, which may in turn surround a third fluid, which in turn surround a fourth fluid, etc.
  • the physical properties of each nesting layer of fluidic droplets may each be independently controlled, e.g., by control over the composition of each nesting level.
  • fluid generally refers to a substance that tends to flow and to conform to the outline of its container, i.e., a liquid, a gas, a viscoelastic fluid, etc.
  • fluids are materials that are unable to withstand a static shear stress, and when a shear stress is applied, the fluid experiences a continuing and permanent distortion.
  • the fluid may have any suitable viscosity that permits flow. If two or more fluids are present, each fluid may be independently selected among essentially any fluids (liquids, gases, and the like) by those of ordinary skill in the art, by considering the relationship between the fluids.
  • multiple emulsions are formed by flowing fluids through one or more channels.
  • the system may be a microfluidic system.
  • Microfluidic refers to a device, apparatus, or system including at least one fluid channel having a cross- sectional dimension of less than about 1 millimeter (mm), and in some cases, a ratio of length to largest cross- sectional dimension of at least 3: 1.
  • One or more channels of the system may be a capillary tube. In some cases, multiple channels are provided, and in some
  • the channels may be in the microfluidic size range and may have, for example, average inner diameters, or portions having an inner diameter, of less than about 1 millimeter, less than about 300
  • One or more of the channels may (but not necessarily), in cross-section, have a height that is substantially the same as a width at the same point. In cross-section, the channels may be rectangular or substantially non-rectangular, such as circular or elliptical.
  • a variety of materials and methods, according to certain aspects of the invention, can be used to form articles or components such as those described herein, e.g., channels such as microfluidic channels, chambers, etc.
  • various articles or components can be formed from solid materials, in which the channels can be formed via micromachining, film deposition processes such as spin coating and chemical vapor deposition, laser fabrication, photolithographic techniques, etching methods including wet chemical or plasma processes, 3D printing, and the like. See, for example, Scientific American, 248:44-55, 1983 (Angell, et al).
  • various structures or components of the articles described herein can be formed of a polymer, for example, an elastomeric polymer such as polydimethylsiloxane (“PDMS”), polytetrafluoroethylene (“PTFE” or Teflon ® ), epoxy, norland optical adhesive, or the like.
  • a microfluidic channel may be implemented by fabricating the fluidic system separately using PDMS or other soft lithography techniques (details of soft lithography techniques suitable for this embodiment are discussed in the references entitled “Soft Lithography,” by Younan Xia and George M. Whitesides, published in the Annual Review of Material Science, 1998, Vol. 28, pages 153-184, and "Soft Lithography in Biology and
  • various structures or components of the articles described herein can be formed of a metal, for example, stainless steel.
  • polyethylene terephthalate PET
  • polyacrylate polymethacrylate
  • polycarbonate polystyrene
  • polyethylene polypropylene
  • polyvinylchloride polyvinylchloride
  • COC cyclic olefin copolymer
  • fluorinated polymer a silicone such as
  • the device may also be formed from composite materials, for example, a composite of a polymer and a semiconductor material.
  • various structures or components of the article are fabricated from polymeric and/or flexible and/or elastomeric materials, and can be conveniently formed of a hardenable fluid, facilitating fabrication via molding (e.g. replica molding, injection molding, cast molding, etc.).
  • the hardenable fluid can be essentially any fluid that can be induced to solidify, or that spontaneously solidifies, into a solid capable of containing and/or transporting fluids contemplated for use in and with the fhiidic network.
  • the hardenable fluid comprises a polymeric liquid or a liquid polymeric precursor (i.e. a "prepolymer").
  • Suitable polymeric liquids can include, for example, thermoplastic polymers, thermoset polymers, waxes, or mixtures or composites thereof heated above their melting point.
  • a suitable polymeric liquid may include a solution of one or more polymers in a suitable solvent, which solution forms a solid polymeric material upon removal of the solvent, for example, by evaporation.
  • Such polymeric materials which can be solidified from, for example, a melt state or by solvent evaporation, are well known to those of ordinary skill in the art.
  • a variety of polymeric materials, many of which are elastomeric, are suitable, and are also suitable for forming molds or mold masters, for embodiments where one or both of the mold masters is composed of an elastomeric material.
  • a non-limiting list of examples of such polymers includes polymers of the general classes of silicone polymers, epoxy polymers, and acrylate polymers.
  • Epoxy polymers are characterized by the presence of a three-membered cyclic ether group commonly referred to as an epoxy group, 1,2-epoxide, or oxirane.
  • diglycidyl ethers of bisphenol A can be used, in addition to compounds based on aromatic amine, triazine, and cycloaliphatic backbones.
  • Another example includes the well-known Novolac polymers.
  • Non-limiting examples of silicone elastomers suitable for use according to the invention include those formed from precursors including the chlorosilanes such as methylchlorosilanes, ethylchlorosilanes, phenylchlorosilanes, dodecyltrichlorosilanes, etc.
  • Silicone polymers are used in certain embodiments, for example, the silicone elastomer polydimethylsiloxane.
  • Non-limiting examples of PDMS polymers include those sold under the trademark Sylgard by Dow Chemical Co., Midland, MI, and particularly Sylgard 182, Sylgard 184, and Sylgard 186.
  • Silicone polymers including PDMS have several beneficial properties simplifying fabrication of various structures of the invention. For instance, such materials are inexpensive, readily available, and can be solidified from a prepolymeric liquid via curing with heat.
  • PDMSs are typically curable by exposure of the prepolymeric liquid to temperatures of about, for example, about 65 °C to about 75 °C for exposure times of, for example, about an hour, about 3 hours, about 12 hours, etc.
  • silicone polymers such as PDMS
  • PDMS can be elastomeric and thus may be useful for forming very small features with relatively high aspect ratios, necessary in certain embodiments of the invention.
  • Flexible (e.g., elastomeric) molds or masters can be advantageous in this regard.
  • One advantage of forming structures such as microfluidic structures or channels from silicone polymers, such as PDMS, is the ability of such polymers to be oxidized, for example by exposure to an oxygen-containing plasma such as an air plasma, so that the oxidized structures contain, at their surface, chemical groups capable of cross-linking to other oxidized silicone polymer surfaces or to the oxidized surfaces of a variety of other polymeric and non-polymeric materials.
  • structures can be fabricated and then oxidized and essentially irreversibly sealed to other silicone polymer surfaces, or to the surfaces of other substrates reactive with the oxidized silicone polymer surfaces, without the need for separate adhesives or other sealing means.
  • oxidized silicone such as oxidized PDMS can also be sealed irreversibly to a range of oxidized materials other than itself including, for example, glass, silicon, silicon oxide, quartz, silicon nitride, polyethylene, polystyrene, glassy carbon, and epoxy polymers, which have been oxidized in a similar fashion to the PDMS surface (for example, via exposure to an oxygen-containing plasma). Oxidation and sealing methods useful in the context of the present invention, as well as overall molding techniques, are described in the art, for example, in an article entitled "Rapid Prototyping of Microfluidic Systems and
  • a base portion including a bottom wall and side walls can be fabricated from an opaque material such as silicon or PDMS, and a top portion can be fabricated from a transparent or at least partially transparent material, such as glass or a transparent polymer, for observation and/or control of the fluidic process.
  • Components can be coated so as to expose a desired chemical functionality to fluids that contact interior channel walls, where the base supporting material does not have a precise, desired functionality.
  • components can be fabricated as illustrated, with interior channel walls coated with another material, e.g., as discussed herein.
  • Material used to fabricate various components of the systems and devices of the invention may desirably be selected from among those materials that will not adversely affect or be affected by fluid flowing through the fluidic system, e.g., material(s) that is chemically inert in the presence of fluids to be used within the device.
  • a non-limiting example of such a coating is disclosed below; additional examples are disclosed in Int. Pat. Apl. Ser. No. PCT/US2009/000850, filed February 11, 2009, entitled “Surfaces, Including Microfluidic Channels, With Controlled Wetting Properties," by Weitz, et al., published as WO 2009/120254 on October 1, 2009, incorporated herein by reference.
  • certain microfluidic structures of the invention may be formed from certain oxidized silicone polymers. Such surfaces may be more hydrophilic than the surface of an elastomeric polymer. Such hydrophilic surfaces can thus be more easily filled and wetted with aqueous solutions.
  • a bottom wall of a microfluidic device of the invention is formed of a material different from one or more side walls or a top wall, or other components.
  • the interior surface of a bottom wall comprises the surface of a silicon wafer or microchip, or other substrate.
  • Other components may, as described above, be sealed to such alternative substrates. Where it is desired to seal a component comprising a silicone polymer (e.g.
  • the substrate may be selected from the group of materials to which oxidized silicone polymer is able to irreversibly seal (e.g., glass, silicon, silicon oxide, quartz, silicon nitride, polyethylene, polystyrene, epoxy polymers, and glassy carbon surfaces which have been oxidized).
  • materials to which oxidized silicone polymer is able to irreversibly seal e.g., glass, silicon, silicon oxide, quartz, silicon nitride, polyethylene, polystyrene, epoxy polymers, and glassy carbon surfaces which have been oxidized.
  • other sealing techniques may be used, as would be apparent to those of ordinary skill in the art, including, but not limited to, the use of separate adhesives, bonding, solvent bonding, ultrasonic welding, etc.
  • the design and/or fabrication of the article may be relatively simple, e.g., by using relatively well-known soft lithography and other techniques such as those described herein.
  • rapid and/or customized design of the article is possible, for example, in terms of geometry.
  • the article may be produced to be disposable, for example, in embodiments where the article is used with substances that are radioactive, toxic, poisonous, reactive, biohazardous, etc., and/or where the profile of the substance (e.g., the toxicology profile, the radioactivity profile, etc.) is unknown.
  • channels or other structures can be much more hydrophilic than the surfaces of typical elastomeric polymers (where a hydrophilic interior surface is desired).
  • Such hydrophilic channel surfaces can thus be more easily filled and wetted with aqueous solutions than can structures comprised of typical, unoxidized elastomeric polymers or other hydrophobic materials.
  • emulsions such as those described herein may be prepared by controlling the hydrophilicity and/or hydrophobicity of the channels used to form the emulsion, according to various aspects.
  • the hydrophilicity and/or hydrophobicity of the channels may be controlled by coating a sol-gel onto at least a portion of a channel.
  • relatively hydrophilic and relatively hydrophobic portions may be created by applying a sol-gel to the channel surfaces, which renders them relatively hydrophobic.
  • the sol-gel may comprise an initiator, such as a photoinitiator.
  • Portions may be rendered relatively hydrophilic by filling the channels with a solution containing a hydrophilic moiety (for example, acrylic acid), and exposing the portions to a suitable trigger for the initiator (for example, light or ultraviolet light in the case of a photoinitiator).
  • a suitable trigger for the initiator for example, light or ultraviolet light in the case of a photoinitiator.
  • the portions may be exposed by using a mask to shield portions in which no reaction is desired, by directed a focused beam of light or heat onto the portions in which reaction is desired, or the like.
  • the initiator may cause the reaction (e.g., polymerization) of the hydrophilic moiety to the sol-gel, thereby rendering those portions relatively hydrophilic (for instance, by causing poly(acrylic acid) to become grafted onto the surface of the sol- gel coating in the above example).
  • the reaction e.g., polymerization
  • a sol-gel is a material that can be in a sol or a gel state, and typically includes polymers.
  • the gel state typically contains a polymeric network containing a liquid phase, and can be produced from the sol state by removing solvent from the sol, e.g., via drying or heating techniques.
  • the sol may be pretreated before being used, for instance, by causing some polymerization to occur within the sol.
  • the sol-gel coating may be chosen to have certain properties, for example, having a certain hydrophobicity.
  • the properties of the coating may be controlled by controlling the composition of the sol-gel (for example, by using certain materials or polymers within the sol-gel), and/or by modifying the coating, for instance, by exposing the coating to a polymerization reaction to react a polymer to the sol-gel coating, as discussed below.
  • sol-gel coating may be made more hydrophobic by
  • the sol-gel may contain one or more silanes, for example, a fluorosilane (i.e., a silane containing at least one fluorine atom) such as heptadecafluorosilane, or other silanes such as
  • methyltriethoxy silane or a silane containing one or more lipid chains, such as octadecylsilane or other CH 3 (CH 2 ) n - silanes, where n can be any suitable integer. For instance, n may be greater than 1, 5, or 10, and less than about 20, 25, or 30.
  • the silanes may also optionally include other groups, such as alkoxide groups, for instance, octadecyltrimethoxy silane. In general, most silanes can be used in the sol-gel, with the particular silane being chosen on the basis of desired properties such as hydrophobicity.
  • silanes may also be chosen in other embodiments of the invention, depending on factors such as the relative hydrophobicity or hydrophilicity desired.
  • the silanes may contain other groups, for example, groups such as amines, which would make the sol-gel more hydrophilic.
  • groups such as amines, which would make the sol-gel more hydrophilic.
  • Non- limiting examples include diamine silane, triamine silane, or N-[3- (trimethoxysilyl)propyl] ethylene diamine silane.
  • the silanes may be reacted to form oligomers or polymers within the sol-gel, and the degree of polymerization (e.g., the lengths of the oligomers or polymers) may be controlled by controlling the reaction conditions, for example by controlling the temperature, amount of acid present, or the like.
  • the degree of polymerization e.g., the lengths of the oligomers or polymers
  • more than one silane may be present in the sol-gel.
  • the sol-gel may include fluorosilanes to cause the resulting sol-gel to exhibit greater hydrophobicity, and other silanes (or other compounds) that facilitate the production of polymers.
  • materials able to produce Si0 2 compounds to facilitate polymerization may be present, for example, TEOS (tetraethyl orthosilicate).
  • the sol-gel is not limited to containing only silanes, and other materials may be present in addition to, or in place of, the silanes.
  • the coating may include one or more metal oxides, such as Si0 2 , vanadia (V 2 0 5 ), titania (Ti0 2 ), and/or alumina (A1 2 0 3 ).
  • the microfluidic channel is present in a material suitable to receive the sol-gel, for example, glass, metal oxides, or polymers such as
  • the microfluidic channel may be one in which contains silicon atoms, and in certain instances, the microfluidic channel may be chosen such that it contains silanol (Si-OH) groups, or can be modified to have silanol groups.
  • Si-OH silanol
  • microfluidic channel may be exposed to an oxygen plasma, an oxidant, or a strong acid cause the formation of silanol groups on the microfluidic channel.
  • the sol-gel may be present as a coating on the microfluidic channel, and the coating may have any suitable thickness.
  • the coating may have a thickness of no more than about 100 micrometers, no more than about 30 micrometers, no more than about 10 micrometers, no more than about 3 micrometers, or no more than about 1 micrometer. Thicker coatings may be desirable in some cases, for instance, in applications in which higher chemical resistance is desired. However, thinner coatings may be desirable in other applications, for instance, within relatively small microfluidic channels.
  • the hydrophobicity of the sol-gel coating can be controlled, for instance, such that a first portion of the sol-gel coating is relatively hydrophobic, and a second portion of the sol-gel coating is relatively hydrophilic.
  • the hydrophobicity of the coating can be determined using techniques known to those of ordinary skill in the art, for example, using contact angle measurements such as those discussed herein. For instance, in some cases, a first portion of a microfluidic channel may have a hydrophobicity that favors an organic solvent to water, while a second portion may have a hydrophobicity that favors water to the organic solvent.
  • a hydrophilic surface is one that has a water contact angle of less than about 90° while a hydrophobic surface is one that has a water contact angle of greater than about 90°.
  • the hydrophobicity of the sol-gel coating can be modified, for instance, by exposing at least a portion of the sol-gel coating to a polymerization reaction to react a polymer to the sol-gel coating.
  • the polymer reacted to the sol-gel coating may be any suitable polymer, and may be chosen to have certain hydrophobicity properties.
  • the polymer may be chosen to be more hydrophobic or more hydrophilic than the microfluidic channel and/or the sol-gel coating.
  • a hydrophilic polymer that could be used is poly(acrylic acid).
  • the polymer may be added to the sol-gel coating by supplying the polymer in monomeric (or oligomeric) form to the sol-gel coating (e.g., in solution), and causing a polymerization reaction to occur between the polymer and the sol-gel.
  • free radical polymerization may be used to cause bonding of the polymer to the sol-gel coating.
  • a reaction such as free radical polymerization may be initiated by exposing the reactants to heat and/or light, such as ultraviolet (UV) light, optionally in the presence of a photoinitiator able to produce free radicals (e.g., via molecular cleavage) upon exposure to light.
  • UV ultraviolet
  • the photoinitiator may be included with the polymer added to the sol-gel coating, or in some cases, the photoinitiator may be present within the sol-gel coating.
  • a photoinitiator may be contained within the sol-gel coating, and activated upon exposure to light.
  • the photoinitiator may also be conjugated or bonded to a component of the sol-gel coating, for example, to a silane.
  • a photoinitiator such as Irgacur 2959 may be conjugated to a silane-isocyanate via a urethane bond, where a primary alcohol on the photoinitiator may participate in nucleophilic addition with the isocyanate group, which may produce a urethane bond.
  • the monomer and/or the photoinitiator may be exposed to only a portion of the microfluidic channel, or the polymerization reaction may be initiated in only a portion of the microfluidic channel.
  • a portion of the microfluidic channel may be exposed to light, while other portions are prevented from being exposed to light, for instance, by the use of masks or filters, or by using a focused beam of light. Accordingly, different portions of the microfluidic channel may exhibit different hydrophobicities, as polymerization does not occur everywhere on the microfluidic channel.
  • the microfluidic channel may be exposed to UV light by projecting a de-magnified image of an exposure pattern onto the microfluidic channel.
  • small resolutions e.g., 1 micrometer, or less
  • projection techniques may be achieved by projection techniques.
  • Certain aspects of the invention are generally directed to techniques for scaling up or "numbering up" devices such as those discussed herein.
  • relatively large numbers of devices may be used in parallel, for example at least about 10 devices, at least about 30 devices, at least about 50 devices, at least about 75 devices, at least about 100 devices, at least about 200 devices, at least about 300 devices, at least about 500 devices, at least about 750 devices, or at least about 1,000 devices or more may be operated in parallel.
  • an array of such devices may be formed by stacking the devices horizontally and/or vertically.
  • the devices may be commonly controlled, or separately controlled, and can be provided with common or separate sources of various fluids, depending on the application.
  • a fluid distributor can be used to distribute fluid from one or more inputs to a plurality of outputs, e.g., in one more devices.
  • a plurality of articles may be connected in three dimensions.
  • channel dimensions are chosen that allow pressure variations within parallel devices to be substantially reduced.
  • suitable techniques include, but are not limited to, those disclosed in International Patent Application No. PCT/US2010/000753, filed March 12, 2010, entitled “Scale-up of Microfluidic Devices," by Romanowsky, et al., published as WO 2010/104597 on November 16, 2010, incorporated herein by reference in its entirety.
  • these examples illustrate a PDMS-based microfluidic device that forms double emulsion drops with thin shells through a continuous one-step emulsification.
  • the double emulsions can be used as templates to produce capsules with thin shells.
  • microfluidic device made through soft lithography that allows the continuous production of double emulsions with shell thicknesses down to, e.g., 1 micrometer, through a one-step emulsification process.
  • the size and shell thickness of the double emulsions can be easily tuned by varying either the flow rate ratio of the fluids and/or the height of the injection channel.
  • the shell thickness of the double emulsion droplets can be further decreased after they are produced by squeezing them through constrictions.
  • the resultant double emulsions may be used as templates to produce polymeric capsules with thin shells. Importantly, scale-up of this process is also demonstrated by parallelizing three individual drop makers. These examples thus demonstrate a versatile and robust approach for the continuous fabrication of double emulsion drops with thin shells that enables parallelization.
  • a microfluidic device was made of poly(dimethyl siloxane)
  • PDMS fabricated using soft lithography. It contained three inlets and an outlet, as shown in Fig. 1 A.
  • the inner phase flows through the main channel, which was initially 30 micrometers tall and 50 micrometers wide.
  • a pair of inlets for the middle phase intersected the main channel at an angle of 45°.
  • the width of the main channel increased to 100 micrometers.
  • the main channel width tapered from 100 to 20 micrometers, whereas its height abruptly changed from 30 to 10 micrometers, yielding into a rectangular orifice that was 20 micrometers wide and 10 micrometers high.
  • the pair of inlets for the outer phase intersected the orifice at an angle of 45°.
  • This second junction was three dimensional (3D); the height of the channel abruptly increased from 10 micrometers in the orifice to 50 micrometers in the collection channel, as shown in Fig. IB.
  • Double emulsions with thin shells could be made in one step because the inner and middle fluids co-flowed in the main channel and were then simultaneously emulsified.
  • the surface chemistry of the main channel was adjusted to make the inner phase non- wetting and the middle phase wetting.
  • the main channel upstream of the 3D junction was treated with a perfluorinated oil-based solution that contained 1 wt of perfluorinated trichlorosilane to make the channel wall fluorophilic.
  • the main channel downstream of the 3D junction was treated with a cationic
  • the osmolarity of the outer phase matched that of the inner phase to reduce or avoid any mechanical stresses that may induce rupture or coalescence of double emulsion droplets within the microfluidic device.
  • the fluids were injected into the device at fixed flow rates using pumps.
  • the fluorophilic treatment applied to the walls of the main channel upstream the 3D junction made the inner phase flow through the center of the main channel, and the middle phase wet the channel walls.
  • the water thus formed a stable jet that was surrounded by a thin oil film. At the 3D junction, this stable jet broke up into double emulsion drops with very thin shells, as shown in Fig. 1C.
  • the resultant emulsion droplets were monodisperse in size and shell thickness as shown in Fig. ID.
  • a diameter, J of 91 +/- 2 micrometers and a shell thickness, t, of 4.7 +/- 1.5 micrometers.
  • the drop size decreased with increasing flow rate of the outer phase, as shown by the solid circles in Fig. IE.
  • the shell thickness decreased with increasing flow rate of the continuous phase, as shown by the solid circles in Fig. IF.
  • the shell thickness was determined by the volumetric flow rate ratio q q .
  • the shell thickness could thus be decreased by reducing q m .
  • q m becomes too low, instabilities in the flow of the middle phase along the walls develop and the oil film surrounding the stable water jet ruptures, which could result in the failure of the device.
  • the shell thickness could also be reduced by increasing the flow rate of the inner phase; however, if , is too high, the stable water jet does not break up at the 3D junction, but jets into the collection channel. This results in a less controlled break up and thus more polydisperse drops. Hence the device was generally operated at flow rates between these limits.
  • Fig. 1A shows a schematic overview over the thin- shell device which contains one inlet for the inner phase (1), one for the middle phase (2), and one for the outer phase (3).
  • Fig. IB shows a schematic illustration of the junctions of the device used in this example. The white areas were 10 micrometers tall, the grey areas 30 micrometers and region 3 was 50 micrometers.
  • Figs. 1C and ID are optical micrographs of the microfluidic device in operation and the resulting thin-shell double emulsions, respectively. The flow rates of the inner, middle, and outer phases were 800, 400, and 5000 microliters/h. Figs.
  • IE and IF show the influence of the flow rate of the outer phase, q a , on the diameter, d, and the shell thickness, t, of double emulsions containing oils with viscosities of 1 mPa s (circles) and 10 mPa s (triangles).
  • EXAMPLE 2 One way to control the shell thickness over a wide range is by varying the height, h, of the tapered region of the main channel, represented by the white region in Fig. IB.
  • Fig. 2 shows the influence of the height, h, of the orifice on (a) the diameter and (b) shell thickness of the double emulsion.
  • the viscosity of the oil was 1 mPa s.
  • Double emulsions were injected into a device consisting of a single channel that is 100 micrometers wide and 100 micrometers tall and contained a 20 micrometers wide and 200 micrometers long constriction. The deformation of the drops in this constriction forced the oil to flow towards the tailing end of the drop, where it was deformed into a column and broken up into single emulsion drops, as shown in Fig. 3A.
  • the same constrictions could also be incorporated close to the end of the main channel of the double-emulsion drop-maker to reduce the shell thickness directly on- chip.
  • drop-makers were successfully operated with two constrictions, resulting in a decrease in shell thickness of approximately 10%.
  • the incorporation of more constrictions could increase the resistance too much.
  • the double emulsions were re-injected into microfluidic channels comprising up to three constrictions to further reduce their shell thickness, as shown by the open symbols in Fig. 3D.
  • Figs. 3A-3C show optical micrographs of double emulsion drops that are pushed through (Fig. 3A) one, (Fig. 3B) two, and (Fig. 3C) three 20 micrometer wide constrictions at a flow rate of 5000 microliter s/h.
  • Fig. 3D shows the influence of the number of times double emulsions are pushed through these constrictions N on the shell thickness, t.
  • the viscosity of the oils were 1 mPas (circles) and 10 mPas (triangles).
  • Double emulsions were produced in devices without any constrictions, and subsequently re- injected into devices with constrictions (solid symbols). Double emulsions were also produced in devices whose outlet has two 20 micrometer wide constrictions. They were collected and subsequently re-injected into devices that have additional constrictions (open symbols).
  • ETPTA ethoxylated trimethylolpropane triacrylate
  • ETPTA dodecyltrichlorosilane.
  • the high viscosity of ETPTA made the device used in this example operate in the jetting mode, as shown in Fig. 4A, yet the resulting double emulsions were monodisperse, as shown in Fig. 4B. Since the device was operated in this example in a continuous mode, the shell thickness decreases with decreasing flow rate of the middle to the inner phase. Indeed, the shell was made as thin as 1 micrometer in some experiments, as shown in Fig. 4E.
  • Ethylene glycol acrylate was also used in some experiments, which has a viscosity only 10 fold higher than water and HFE7500, but a much lower surface tension as oil.
  • the device was operated in a discontinuous mode where the oil drops were formed at the first junction and re-emulsified at the second junction to form thin-shell double emulsions, as shown in Fig. 4C.
  • This operation mode resulted in a mixture of single emulsion drops and double emulsion drops, as shown in Fig. 4D.
  • the shells of the double emulsions were even thinner, as shown in Fig. 2C.
  • Figs 4A and 4B are optical micrographs of (Fig. 4A) the microfluidic device operated using ETPTA as an oil phase and (Fig. 4B) the resulting double emulsions.
  • Figs. 4C and 4D are optical micrographs of (Fig. 4C) the microfluidic device operated using EPA as an oil phase and (Fig. 4D) the resulting mixture of single and double emulsion drops.
  • 4E shows the influence of the flow rate ratio of the middle to the inner phase on the thickness of double emulsions containing ETPTA (tringales) and EGA (circles) as an oil.
  • ETPTA tringales
  • EGA circles
  • this method is not restricted to the parallelization of only three devices, but allows parallelizing many more and demonstrates the potential of this device to produce large quantities of double emulsions of a controlled size and shell thickness.
  • the PDMS-based thin shell double emulsion device used in these examples was able to form monodisperse double emulsions with thin shells in continuous production. Since the device was produced using soft lithography, it can easily be parallelized and thus opens up possibilities to form monodisperse thin-shell double emulsions in large quantities. For example, a single device can be used to produce 1.5 ml/h of capsules and occupied a volume of 10 microliter. If 100,000 of these devices were packed into one liter, they would produce 150 liters of drops per hour. The device used in this particular example thus has the potential to make monodisperse capsules of a well-defined size and shell thickness.
  • the phrase "at least one,” in reference to a list of one or more elements, should be understood to mean at least one element selected from any one or more of the elements in the list of elements, but not necessarily including at least one of each and every element specifically listed within the list of elements and not excluding any combinations of elements in the list of elements.
  • This definition also allows that elements may optionally be present other than the elements specifically identified within the list of elements to which the phrase "at least one" refers, whether related or unrelated to those elements specifically identified.
  • At least one of A and B can refer, in one embodiment, to at least one, optionally including more than one, A, with no B present (and optionally including elements other than B); in another embodiment, to at least one, optionally including more than one, B, with no A present (and optionally including elements other than A); in yet another embodiment, to at least one, optionally including more than one, A, and at least one, optionally including more than one, B (and optionally including other elements); etc.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Health & Medical Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Organic Chemistry (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Medicinal Chemistry (AREA)
  • Dispersion Chemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Epidemiology (AREA)
  • Oil, Petroleum & Natural Gas (AREA)
  • Wood Science & Technology (AREA)
  • Physical Or Chemical Processes And Apparatus (AREA)

Abstract

De manière générale, cette invention concerne la microfluidique et, en particulier, des systèmes et des procédés de production de gouttelettes (55), y compris des gouttelettes (55) en doubles émulsions et autres émulsions multiples. Dans certains modes de réalisation, l'invention concerne en général des systèmes et des procédés de production de gouttelettes (55) en émulsions multiples. Dans certains cas, les gouttelettes (55) en émulsions multiples peuvent avoir des coques relativement minces qui peuvent être produites, par exemple, dans un procédé en une seule étape où de multiples fluides (15,25,45) sont mis en contact à une jonction (18,48), ou par passage des gouttelettes (55) en multiples émulsions par les étranglements (76) ménagés dans des canaux microfluidiques. Selon d'autres aspects, l'invention concerne de manière générale des systèmes et des procédés d'utilisation desdites gouttelettes (55) en doubles émulsions et autres émulsions multiples, des kits les impliquant, ou analogues.
PCT/US2015/025921 2014-04-16 2015-04-15 Systèmes et procédés de production d'émulsions de gouttelettes ayant des coques relativement minces WO2015160919A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US201461980541P 2014-04-16 2014-04-16
US61/980,541 2014-04-16

Publications (1)

Publication Number Publication Date
WO2015160919A1 true WO2015160919A1 (fr) 2015-10-22

Family

ID=53039969

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US2015/025921 WO2015160919A1 (fr) 2014-04-16 2015-04-15 Systèmes et procédés de production d'émulsions de gouttelettes ayant des coques relativement minces

Country Status (1)

Country Link
WO (1) WO2015160919A1 (fr)

Cited By (32)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN105363503A (zh) * 2015-11-02 2016-03-02 华东理工大学 多组分微液滴微流控芯片及其加工方法
CN105771825A (zh) * 2016-05-11 2016-07-20 中国工程物理研究院激光聚变研究中心 一种可连续生产的乳粒发生器
CN105771826A (zh) * 2016-03-08 2016-07-20 清华大学 制备微乳化液滴的系统及方法
CN106492716A (zh) * 2016-12-20 2017-03-15 中国工程物理研究院激光聚变研究中心 一体式双重乳粒发生装置及其加工方法
WO2019110590A1 (fr) * 2017-12-06 2019-06-13 Samplix Aps Dispositif microfluidique et procédé de fourniture de gouttelettes d'émulsion double
WO2019110591A1 (fr) * 2017-12-06 2019-06-13 Samplix Aps Dispositif microfluidique et procédé de fourniture de gouttelettes d'émulsion
US10357771B2 (en) 2017-08-22 2019-07-23 10X Genomics, Inc. Method of producing emulsions
CN110290774A (zh) * 2016-09-30 2019-09-27 株式会社爱茉莉太平洋 含有利用微流体通道瞬时乳化的乳化物质的化妆品组合物制备装置
US10471016B2 (en) 2013-11-08 2019-11-12 President And Fellows Of Harvard College Microparticles, methods for their preparation and use
US10544413B2 (en) 2017-05-18 2020-01-28 10X Genomics, Inc. Methods and systems for sorting droplets and beads
US10596541B2 (en) 2014-04-21 2020-03-24 President And Fellows Of Harvard College Systems and methods for barcoding nucleic acids
WO2020086549A1 (fr) * 2018-10-22 2020-04-30 Klaris Corporation Puces microfluidiques à génération de gouttelettes et chargées sous vide et procédés associés
WO2020095927A1 (fr) * 2018-11-09 2020-05-14 国立大学法人北海道大学 Procédé de production d'une solution aqueuse contenant des particules
WO2020097073A1 (fr) 2018-11-06 2020-05-14 President And Fellows Of Harvard College Dispositif multicanal microfluidique anti-obstruction
CN111229070A (zh) * 2020-02-28 2020-06-05 广东工业大学 一种用于大批量生成多重乳液滴的装置
WO2020157262A1 (fr) * 2019-01-31 2020-08-06 Samplix Aps Dispositif microfluidique et procédé de fourniture de gouttelettes à double émulsion
US10876156B2 (en) 2015-03-13 2020-12-29 President And Fellows Of Harvard College Determination of cells using amplification
WO2021035044A1 (fr) * 2019-08-20 2021-02-25 Pattern Bioscience, Inc. Puces microfluidiques comprenant une gouttière pour faciliter leur chargement et procédés associés
US10953404B1 (en) 2020-04-24 2021-03-23 Pattern Bioscience, Inc. Apparatuses for contactless loading and imaging of microfluidic chips and related methods
CN112569878A (zh) * 2020-01-21 2021-03-30 苏州恒瑞宏远医疗科技有限公司 制备粒径均一的聚乙烯醇栓塞微球的设备及其生产工艺
US11001883B2 (en) 2012-03-05 2021-05-11 The General Hospital Corporation Systems and methods for epigenetic sequencing
US11123297B2 (en) 2015-10-13 2021-09-21 President And Fellows Of Harvard College Systems and methods for making and using gel microspheres
CN114534590A (zh) * 2022-02-26 2022-05-27 四川大学 一种可控制备单分散双重乳液的旋转式套管微流控装置及方法
US11401550B2 (en) 2008-09-19 2022-08-02 President And Fellows Of Harvard College Creation of libraries of droplets and related species
CN115228515A (zh) * 2021-04-23 2022-10-25 中国石油化工股份有限公司 调控多相体系中分散相尺寸分布的串联限域装置和方法
CN115228516A (zh) * 2021-04-23 2022-10-25 中国石油化工股份有限公司 用于调控多相体系中分散相尺寸分布的限域单元和方法
US11660601B2 (en) 2017-05-18 2023-05-30 10X Genomics, Inc. Methods for sorting particles
US11746367B2 (en) 2015-04-17 2023-09-05 President And Fellows Of Harvard College Barcoding systems and methods for gene sequencing and other applications
US11833515B2 (en) 2017-10-26 2023-12-05 10X Genomics, Inc. Microfluidic channel networks for partitioning
US12036556B2 (en) 2018-04-16 2024-07-16 Pattern Bioscience, Inc. Methods and apparatus for forming 2-dimensional drop arrays
US12059679B2 (en) 2019-11-19 2024-08-13 10X Genomics, Inc. Methods and devices for sorting droplets and particles
US12138629B2 (en) 2019-01-31 2024-11-12 Samplix Aps Microfluidic device and a method for provision of double emulsion droplets

Citations (20)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2004002627A2 (fr) 2002-06-28 2004-01-08 President And Fellows Of Harvard College Procede et appareil pour la dispersion de fluides
WO2004091763A2 (fr) 2003-04-10 2004-10-28 President And Fellows Of Harvard College Formation et regulation d'especes fluidiques
WO2005021151A1 (fr) 2003-08-27 2005-03-10 President And Fellows Of Harvard College Controle electronique d'especes fluidiques
WO2006096571A2 (fr) 2005-03-04 2006-09-14 President And Fellows Of Harvard College Procede et dispositif permettant de former des emulsions multiples
GB2433448A (en) * 2005-12-20 2007-06-27 Q Chip Ltd Device and method for the control of chemical processes
WO2008121342A2 (fr) 2007-03-28 2008-10-09 President And Fellows Of Harvard College Émulsions, et techniques de formation
WO2009120254A1 (fr) 2008-03-28 2009-10-01 President And Fellows Of Harvard College Surfaces comportant des canaux microfluidiques et présentant des propriétés de mouillage contrôlées
WO2009148598A1 (fr) 2008-06-05 2009-12-10 President And Fellows Of Harvard College Polymersomes, colloïdosomes, liposomes et autres espèces associées à des gouttelettes fluides
WO2010104597A2 (fr) 2009-03-13 2010-09-16 President And Fellows Of Harvard College Mise à l'échelle de dispositifs microfluidiques
WO2010104604A1 (fr) 2009-03-13 2010-09-16 President And Fellows Of Harvard College Procédé destiné à la création contrôlée d'émulsions, comprenant des émulsions multiples
WO2010146261A2 (fr) * 2009-06-19 2010-12-23 Commissariat A L'energie Atomique Et Aux Energies Alternatives Systeme microfluidique et procede correspondant pour le transfert d'elements entre phases liquides et utilisation de ce systeme pour extraire ces elements
CA2767056A1 (fr) * 2009-09-02 2011-03-10 Bio-Rad Laboratories, Inc. Systeme de melange de fluides par coalescence d'emulsions multiples
WO2011028760A2 (fr) 2009-09-02 2011-03-10 President And Fellows Of Harvard College Emulsions multiples créées à l'aide de jonctions
WO2011028764A2 (fr) 2009-09-02 2011-03-10 President And Fellows Of Harvard College Multiples émulsions créées par éjection et autres techniques
WO2011116154A2 (fr) 2010-03-17 2011-09-22 President And Fellows Of Harvard College Emulsification à l'état fondu
WO2012162296A2 (fr) 2011-05-23 2012-11-29 President And Fellows Of Harvard College Génération d'émulsions et, notamment, d'émulsions multiples
WO2013006661A2 (fr) 2011-07-06 2013-01-10 President And Fellows Of Harvard College Émulsions multiples et techniques de formation d'émulsions multiples
WO2013032709A2 (fr) 2011-08-30 2013-03-07 President And Fellows Of Harvard College Systèmes et procédés d'encapsulation dans des coques
US20130323764A1 (en) * 2008-07-15 2013-12-05 L3 Technology Limited Assay test card
US20140024023A1 (en) * 2012-07-23 2014-01-23 Bio- Rad Laboratories, Inc Droplet generation system with features for sample positioning

Patent Citations (20)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2004002627A2 (fr) 2002-06-28 2004-01-08 President And Fellows Of Harvard College Procede et appareil pour la dispersion de fluides
WO2004091763A2 (fr) 2003-04-10 2004-10-28 President And Fellows Of Harvard College Formation et regulation d'especes fluidiques
WO2005021151A1 (fr) 2003-08-27 2005-03-10 President And Fellows Of Harvard College Controle electronique d'especes fluidiques
WO2006096571A2 (fr) 2005-03-04 2006-09-14 President And Fellows Of Harvard College Procede et dispositif permettant de former des emulsions multiples
GB2433448A (en) * 2005-12-20 2007-06-27 Q Chip Ltd Device and method for the control of chemical processes
WO2008121342A2 (fr) 2007-03-28 2008-10-09 President And Fellows Of Harvard College Émulsions, et techniques de formation
WO2009120254A1 (fr) 2008-03-28 2009-10-01 President And Fellows Of Harvard College Surfaces comportant des canaux microfluidiques et présentant des propriétés de mouillage contrôlées
WO2009148598A1 (fr) 2008-06-05 2009-12-10 President And Fellows Of Harvard College Polymersomes, colloïdosomes, liposomes et autres espèces associées à des gouttelettes fluides
US20130323764A1 (en) * 2008-07-15 2013-12-05 L3 Technology Limited Assay test card
WO2010104597A2 (fr) 2009-03-13 2010-09-16 President And Fellows Of Harvard College Mise à l'échelle de dispositifs microfluidiques
WO2010104604A1 (fr) 2009-03-13 2010-09-16 President And Fellows Of Harvard College Procédé destiné à la création contrôlée d'émulsions, comprenant des émulsions multiples
WO2010146261A2 (fr) * 2009-06-19 2010-12-23 Commissariat A L'energie Atomique Et Aux Energies Alternatives Systeme microfluidique et procede correspondant pour le transfert d'elements entre phases liquides et utilisation de ce systeme pour extraire ces elements
WO2011028760A2 (fr) 2009-09-02 2011-03-10 President And Fellows Of Harvard College Emulsions multiples créées à l'aide de jonctions
WO2011028764A2 (fr) 2009-09-02 2011-03-10 President And Fellows Of Harvard College Multiples émulsions créées par éjection et autres techniques
CA2767056A1 (fr) * 2009-09-02 2011-03-10 Bio-Rad Laboratories, Inc. Systeme de melange de fluides par coalescence d'emulsions multiples
WO2011116154A2 (fr) 2010-03-17 2011-09-22 President And Fellows Of Harvard College Emulsification à l'état fondu
WO2012162296A2 (fr) 2011-05-23 2012-11-29 President And Fellows Of Harvard College Génération d'émulsions et, notamment, d'émulsions multiples
WO2013006661A2 (fr) 2011-07-06 2013-01-10 President And Fellows Of Harvard College Émulsions multiples et techniques de formation d'émulsions multiples
WO2013032709A2 (fr) 2011-08-30 2013-03-07 President And Fellows Of Harvard College Systèmes et procédés d'encapsulation dans des coques
US20140024023A1 (en) * 2012-07-23 2014-01-23 Bio- Rad Laboratories, Inc Droplet generation system with features for sample positioning

Non-Patent Citations (4)

* Cited by examiner, † Cited by third party
Title
ANGELL, SCIENTIFIC AMERICAN, vol. 248, 1983, pages 44 - 55
DUFFY: "Rapid Prototyping of Microfluidic Systems and Polydimethylsiloxane", ANAL. CHEM., vol. 70, 1998, pages 474 - 480
GEORGE M. WHITESIDES; EMANUELE OSTUNI; SHUICHI TAKAYAMA; XINGYU JIANG; DONALD E. INGBER: "Soft Lithography in Biology and Biochemistry", ANNUAL REVIEW OF BIOMEDICAL ENGINEERING, vol. 3, 2001, pages 335 - 373
YOUNAN XIA; GEORGE M.: "Soft Lithography", ANNUAL REVIEW OF MATERIAL SCIENCE, vol. 28, 1998, pages 153 - 184

Cited By (61)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US11401550B2 (en) 2008-09-19 2022-08-02 President And Fellows Of Harvard College Creation of libraries of droplets and related species
US12116631B2 (en) 2008-09-19 2024-10-15 President And Fellows Of Harvard College Creation of libraries of droplets and related species
US11047003B2 (en) 2012-03-05 2021-06-29 The General Hospital Corporation Systems and methods for epigenetic sequencing
US11001883B2 (en) 2012-03-05 2021-05-11 The General Hospital Corporation Systems and methods for epigenetic sequencing
US10471016B2 (en) 2013-11-08 2019-11-12 President And Fellows Of Harvard College Microparticles, methods for their preparation and use
US10596541B2 (en) 2014-04-21 2020-03-24 President And Fellows Of Harvard College Systems and methods for barcoding nucleic acids
US11052368B2 (en) 2014-04-21 2021-07-06 Vilnius University Systems and methods for barcoding nucleic acids
US10876156B2 (en) 2015-03-13 2020-12-29 President And Fellows Of Harvard College Determination of cells using amplification
US11746367B2 (en) 2015-04-17 2023-09-05 President And Fellows Of Harvard College Barcoding systems and methods for gene sequencing and other applications
US11123297B2 (en) 2015-10-13 2021-09-21 President And Fellows Of Harvard College Systems and methods for making and using gel microspheres
CN105363503B (zh) * 2015-11-02 2017-10-03 华东理工大学 多组分微液滴微流控芯片及其加工方法
CN105363503A (zh) * 2015-11-02 2016-03-02 华东理工大学 多组分微液滴微流控芯片及其加工方法
CN105771826A (zh) * 2016-03-08 2016-07-20 清华大学 制备微乳化液滴的系统及方法
CN105771825A (zh) * 2016-05-11 2016-07-20 中国工程物理研究院激光聚变研究中心 一种可连续生产的乳粒发生器
JP2019536745A (ja) * 2016-09-30 2019-12-19 アモーレパシフィック コーポレーションＡｍｏｒｅｐａｃｉｆｉｃ Ｃｏｒｐｏｒａｔｉｏｎ マイクロ流体チャネルに基づいて瞬時に乳化された乳化物を含有する化粧品組成物調製装置
US11534778B2 (en) 2016-09-30 2022-12-27 Amorepacific Corporation Device for preparing cosmetic composition containing emulsion material instantly emulsified based on microfluidic channel
CN110290774B (zh) * 2016-09-30 2022-10-14 株式会社爱茉莉太平洋 含有利用微流体通道瞬时乳化的乳化物质的化妆品组合物制备装置
CN110290774A (zh) * 2016-09-30 2019-09-27 株式会社爱茉莉太平洋 含有利用微流体通道瞬时乳化的乳化物质的化妆品组合物制备装置
JP7039575B2 (ja) 2016-09-30 2022-03-22 アモーレパシフィック コーポレーション マイクロ流体チャネルに基づいて瞬時に乳化された乳化物を含有する化粧品組成物調製装置
EP3520766A4 (fr) * 2016-09-30 2020-10-28 Amorepacific Corporation Dispositif de préparation de composition cosmétique contenant un matériau en émulsion instantanément émulsifié à base de canal microfluidique
CN106492716B (zh) * 2016-12-20 2024-01-30 中国工程物理研究院激光聚变研究中心 一体式双重乳粒发生装置及其加工方法
CN106492716A (zh) * 2016-12-20 2017-03-15 中国工程物理研究院激光聚变研究中心 一体式双重乳粒发生装置及其加工方法
US11660601B2 (en) 2017-05-18 2023-05-30 10X Genomics, Inc. Methods for sorting particles
US10544413B2 (en) 2017-05-18 2020-01-28 10X Genomics, Inc. Methods and systems for sorting droplets and beads
US11565263B2 (en) 2017-08-22 2023-01-31 10X Genomics, Inc. Droplet forming devices and system with differential surface properties
US10821442B2 (en) 2017-08-22 2020-11-03 10X Genomics, Inc. Devices, systems, and kits for forming droplets
US10583440B2 (en) 2017-08-22 2020-03-10 10X Genomics, Inc. Method of producing emulsions
US10898900B2 (en) 2017-08-22 2021-01-26 10X Genomics, Inc. Method of producing emulsions
US10610865B2 (en) 2017-08-22 2020-04-07 10X Genomics, Inc. Droplet forming devices and system with differential surface properties
US10357771B2 (en) 2017-08-22 2019-07-23 10X Genomics, Inc. Method of producing emulsions
US10766032B2 (en) 2017-08-22 2020-09-08 10X Genomics, Inc. Devices having a plurality of droplet formation regions
US10549279B2 (en) 2017-08-22 2020-02-04 10X Genomics, Inc. Devices having a plurality of droplet formation regions
US11833515B2 (en) 2017-10-26 2023-12-05 10X Genomics, Inc. Microfluidic channel networks for partitioning
US11618023B2 (en) 2017-12-06 2023-04-04 Samplix Aps Microfluidic device and a method for provision of emulsion droplets
WO2019110591A1 (fr) * 2017-12-06 2019-06-13 Samplix Aps Dispositif microfluidique et procédé de fourniture de gouttelettes d'émulsion
US11779923B2 (en) 2017-12-06 2023-10-10 Samplix Aps Microfluidic device and a method for provision of double emulsion droplets
WO2019110590A1 (fr) * 2017-12-06 2019-06-13 Samplix Aps Dispositif microfluidique et procédé de fourniture de gouttelettes d'émulsion double
US12036556B2 (en) 2018-04-16 2024-07-16 Pattern Bioscience, Inc. Methods and apparatus for forming 2-dimensional drop arrays
US11344890B2 (en) 2018-10-22 2022-05-31 Pattern Bioscience, Inc. Vacuum-loaded, droplet-generating microfluidic chips and related methods
WO2020086549A1 (fr) * 2018-10-22 2020-04-30 Klaris Corporation Puces microfluidiques à génération de gouttelettes et chargées sous vide et procédés associés
US10792659B2 (en) 2018-10-22 2020-10-06 Pattern Bioscience, Inc. Droplet-generating microfluidic chips and related methods
US10731012B2 (en) 2018-11-06 2020-08-04 President And Fellows Of Harvard College Anti-clogging microfluidic multichannel device
WO2020097073A1 (fr) 2018-11-06 2020-05-14 President And Fellows Of Harvard College Dispositif multicanal microfluidique anti-obstruction
WO2020095927A1 (fr) * 2018-11-09 2020-05-14 国立大学法人北海道大学 Procédé de production d'une solution aqueuse contenant des particules
WO2020157262A1 (fr) * 2019-01-31 2020-08-06 Samplix Aps Dispositif microfluidique et procédé de fourniture de gouttelettes à double émulsion
JP7231748B2 (ja) 2019-01-31 2023-03-01 サンプリックス エーピーエス マイクロ流体デバイスおよびダブルエマルション液滴の提供のための方法
JP2022519200A (ja) * 2019-01-31 2022-03-22 サンプリックス エーピーエス マイクロ流体デバイスおよびダブルエマルション液滴の提供のための方法
CN113710352A (zh) * 2019-01-31 2021-11-26 赛普公司 微流体装置和用于提供双乳液液滴的方法
CN113710352B (zh) * 2019-01-31 2024-03-26 赛普公司 微流体装置和用于提供双乳液液滴的方法
US12138629B2 (en) 2019-01-31 2024-11-12 Samplix Aps Microfluidic device and a method for provision of double emulsion droplets
WO2021035044A1 (fr) * 2019-08-20 2021-02-25 Pattern Bioscience, Inc. Puces microfluidiques comprenant une gouttière pour faciliter leur chargement et procédés associés
US12059679B2 (en) 2019-11-19 2024-08-13 10X Genomics, Inc. Methods and devices for sorting droplets and particles
CN112569878A (zh) * 2020-01-21 2021-03-30 苏州恒瑞宏远医疗科技有限公司 制备粒径均一的聚乙烯醇栓塞微球的设备及其生产工艺
CN111229070A (zh) * 2020-02-28 2020-06-05 广东工业大学 一种用于大批量生成多重乳液滴的装置
US12128415B2 (en) 2020-04-24 2024-10-29 Pattern Bioscience, Inc. Apparatuses for contactless loading and imaging of microfluidic chips and related methods
US10953404B1 (en) 2020-04-24 2021-03-23 Pattern Bioscience, Inc. Apparatuses for contactless loading and imaging of microfluidic chips and related methods
CN115228516A (zh) * 2021-04-23 2022-10-25 中国石油化工股份有限公司 用于调控多相体系中分散相尺寸分布的限域单元和方法
CN115228515B (zh) * 2021-04-23 2024-07-26 中国石油化工股份有限公司 调控多相体系中分散相尺寸分布的串联限域装置和方法
CN115228515A (zh) * 2021-04-23 2022-10-25 中国石油化工股份有限公司 调控多相体系中分散相尺寸分布的串联限域装置和方法
CN114534590B (zh) * 2022-02-26 2023-06-09 四川大学 一种可控制备单分散双重乳液的旋转式套管微流控装置及方法
CN114534590A (zh) * 2022-02-26 2022-05-27 四川大学 一种可控制备单分散双重乳液的旋转式套管微流控装置及方法

Similar Documents

Publication Publication Date Title
WO2015160919A1 (fr) Systèmes et procédés de production d'émulsions de gouttelettes ayant des coques relativement minces
US10874997B2 (en) Multiple emulsions created using jetting and other techniques
EP2714254B1 (fr) Génération d'émulsions et, notamment, d'émulsions multiples
EP2136786B1 (fr) Dispositif de formation de gouttelettes
EP2248578B1 (fr) Procédé pour former des émulsions multiples
US10876688B2 (en) Rapid production of droplets
US20170319443A1 (en) Multiple emulsions comprising rigidified portions
WO2016085743A1 (fr) Procédés et systèmes pour encapsuler des agents actifs dans des gouttelettes et autres compartiments
US20140026968A1 (en) Systems and methods for splitting droplets
US20120199226A1 (en) Multiple emulsions created using junctions
WO2010104604A1 (fr) Procédé destiné à la création contrôlée d'émulsions, comprenant des émulsions multiples
EP2547436A2 (fr) Emulsification à l'état fondu

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 15720151

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 15720151

Country of ref document: EP

Kind code of ref document: A1