WO2019169060A1 - Dispositifs et techniques microfluidiques en couches - Google Patents

Dispositifs et techniques microfluidiques en couches Download PDF

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Publication number
WO2019169060A1
WO2019169060A1 PCT/US2019/019929 US2019019929W WO2019169060A1 WO 2019169060 A1 WO2019169060 A1 WO 2019169060A1 US 2019019929 W US2019019929 W US 2019019929W WO 2019169060 A1 WO2019169060 A1 WO 2019169060A1
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Prior art keywords
layer
microfluidic
channel
lateral
fluid
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PCT/US2019/019929
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English (en)
Inventor
David A. Weitz
Aaron Brace DELAHANTY
Jonathan E. Didier
Richard Novak
Feng XIN
Saraf NAWAR
Miles INGRAM
Carlos Ng PITTI
Elizabeth CALAMARI
Bret Andrew NESTOR
Benedikt GROEVER
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President And Fellows Of Harvard College
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Publication of WO2019169060A1 publication Critical patent/WO2019169060A1/fr

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Classifications

    • 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
    • B01F25/00—Flow mixers; Mixers for falling materials, e.g. solid particles
    • B01F25/30—Injector mixers
    • B01F25/31—Injector mixers in conduits or tubes through which the main component flows
    • B01F25/314—Injector mixers in conduits or tubes through which the main component flows wherein additional components are introduced at the circumference of the conduit
    • 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
    • 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
    • B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
    • B01L3/00—Containers or dishes for laboratory use, e.g. laboratory glassware; Droppers
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
    • B01L3/00—Containers or dishes for laboratory use, e.g. laboratory glassware; Droppers
    • B01L3/02—Burettes; Pipettes
    • B01L3/0241—Drop counters; Drop formers

Definitions

  • the present invention generally relates to microfluidic devices, and techniques for making and using such devices.
  • microfluidic devices have been developed to discretize fluids (including liquids, gases, colloids, and suspensions) in controlled, low- dispersity dimension volumes.
  • Droplet generators have been used to partition liquid into droplets inside an immiscible carrier fluid such as oil.
  • Higher-order emulsions, such as double emulsions have been made using a similar approach, but often include additional fluidic connections and microfluidic junctions. While these devices have been demonstrated to work, scalability of such devices may be an issue.
  • manufacturable or robust devices having easily integrated surface modification would be desirable.
  • the present invention generally relates to microfluidic devices, and techniques for making and using such devices.
  • 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 a microfluidic apparatus.
  • the microfluidic apparatus comprises a first lateral microfluidic channel defined by a first layer; a second lateral microfluidic channel, positioned substantially parallel to the first channel, defined by a second layer; a third lateral microfluidic channel, positioned substantially parallel to the first channel and the second channel, defined by a third layer; a first transverse microfluidic channel, defined by at least the first layer and the second layer, in fluid communication with the first lateral microfluidic channel and the second lateral microfluidic channel; and a second transverse microfluidic channel, defined by at least the second layer and the third layer, in fluid communication with the second lateral microfluidic channel and the third lateral microfluidic channel.
  • the microfluidic apparatus in accordance with another set of embodiments, comprises a first substantially planar layer, defining a first lateral microfluidic channel; and a second substantially planar layer, defining a second lateral microfluidic channel.
  • the second layer has a substantially identical composition to the first layer and is positioned substantially parallel to the first layer.
  • the first lateral microfluidic channel has a first surface characteristic and the second lateral microfluidic channel has a second surface characteristic different from the first hydrophobicity.
  • the apparatus may also comprise a transverse microfluidic channel, defined by and fluidly communicating between the first layer and the second layer, in fluid communication with the first lateral microfluidic channel and the second lateral microfluidic channel.
  • the microfluidic apparatus comprises a plurality of at least three substantially planar layers, positioned in liquid-tight contact with each other.
  • the plurality of layers defines a junction of first, second, third, and fourth microfluidic channels.
  • the first microfluidic channel and the second microfluidic channels are defined by a first layer
  • the third microfluidic channel and the fourth microfluidic channel are each defined by and fluidly communicate between the first layer and at least one additional layer.
  • the microfluidic apparatus in another set of embodiments, comprises a plurality of at least four substantially planar layers, positioned in liquid-tight contact with each other. In certain instances, at least one microfluidic channel passes substantially orthogonally through at least three of the planar layers.
  • the microfluidic apparatus comprises a first substantially planar layer, defining a first lateral microfluidic channel; a second substantially planar layer, positioned substantially parallel to the first layer, defining a second lateral microfluidic channel; a third substantially planar layer, positioned substantially parallel to the first layer and the second layer, defining a third lateral microfluidic channel; a first transverse microfluidic channel, defined by and fluidly communicating between the first layer and the second layer, in fluid communication with the first lateral microfluidic channel and the second lateral microfluidic channel; and a second transverse microfluidic channel, defined by and fluidly communicating between the second layer and the third layer, in fluid
  • the present invention is generally directed to a method.
  • the method includes flowing a first fluid through a first lateral microfluidic channel defined by a first substantially planar layer; flowing the first fluid into a transverse microfluidic channel, defined by and fluidly communicating between the first layer and a second substantially planar layer, wherein the second layer is positioned substantially parallel to the first layer; flowing a second fluid, through a second lateral microfluidic channel defined by the second layer, to contact the first fluid in the transverse microfluidic channel; and forming droplets of the first fluid, contained within the second fluid.
  • the method comprises flowing a first fluid through a first lateral microfluidic channel defined by a first substantially planar layer; flowing the first fluid into a first transverse microfluidic channel, defined by and fluidly communicating between the first layer and a second substantially planar layer, wherein the second layer is positioned substantially parallel to the first layer; flowing a second fluid, through a second lateral microfluidic channel defined by the second layer, to contact the first fluid in the first transverse microfluidic channel; forming droplets of the first fluid, contained within the second fluid; flowing the droplets and the second fluid into a second transverse microfluidic channel, defined by and fluidly communicating between the second layer and a third substantially planar layer, wherein the third layer is positioned substantially parallel to the first layer and the second layer; flowing a third fluid, through a third lateral microfluidic channel defined by the third layer, to contact the second fluid in the second transverse microfluidic channel; and forming double emulsion droplets, comprising droplets of the first
  • the method in yet another set of embodiments, includes flowing a first fluid through a first microfluidic channel defined by a first substantially planar layer; flowing the first fluid through a transverse face of the first layer into the transverse face of a second substantially planar layer, wherein the second layer is positioned substantially parallel to the first layer; flowing a second fluid, through a second microfluidic channel defined by the second layer, to contact the first fluid; and forming droplets of the first fluid, contained within the second fluid.
  • the present invention encompasses methods of making one or more of the embodiments described herein, for example, a microfluidic device, such as a layered microfluidic device.
  • the present invention encompasses methods of using one or more of the embodiments described herein, for example, a microfluidic device, such as a layered microfluidic device.
  • FIGs. 1 and 2 illustrate a device in accordance with one embodiment of the invention
  • Figs. 3 and 4 are schematic diagrams of certain devices according to various embodiments of the invention, which can be used to produce double emulsion droplets comprising a core fluid and a shell fluid;
  • Figs. 5A-5C illustrate various double emulsion droplets produced using certain embodiments of the invention
  • Figs. 6A-6B illustrate different channels produced in layers in accordance with some embodiments of the invention.
  • Figs. 7A-7G illustrate other devices according to various embodiments of the invention.
  • Fig. 8 illustrates one embodiment of the invention in which an array of droplet generators are contained within a single device
  • Fig. 9 are schematic diagrams of a device according to another embodiment, which can be used to produce double emulsion droplets.
  • Figs. 10A-10C a device for forming double emulsion droplets, in still another embodiment of the invention.
  • the present invention generally relates to microfluidic devices, and techniques for making and using such devices.
  • the microfluidic device may be formed from two or more layers, which can be assembled together.
  • the layers may include various channels that pass between different layers.
  • the layers may be treated (e.g., with different coatings), for example, prior to assembly. This may allow for relatively precise control of different surface characteristics (e.g., hydrophilicity) within different portions of the microfluidic device.
  • Such devices can be used in some embodiments to control or manipulate fluids, for example, to form droplets, or for other applications. Still other embodiments are generally directed to systems and methods for making and using such devices, kits including such devices, or the like.
  • microfluidic device 10 is composed of various layers. Although five layers are shown in this figure, it should be understood that this is by way of example only, and that in other embodiments, more or fewer layers may be used.
  • a second layer 21 is shown having a first lateral channel 22, while a fourth layer 41 has a second lateral channel 42.
  • a first transverse channel or pore 32 is partially defined within the second layer, the third layer, and the fourth layer.
  • second transverse channel 52 partially defined in the second layer, the third layer, the fourth layer, and the fifth layer.
  • channels defined within a layer need not necessarily be defined completely internally within the layer.
  • a channel may be defined partially within a layer, such that, when a first layer 11 is positioned next to a second layer 21, a channel 12 is defined.
  • channel 12 in first layer 11 may be defined in an outer surface of the layer.
  • the second layer may also have a complementary channel in it, but in some cases, no complementary channel is present as is shown in this figure, e.g., the second layer may be substantially flat, such that upon assembly, a substantially closed channel can be formed.
  • first lateral channel 52 in layer 21, the first transverse channel 32 in layer 31, and the second lateral channel 53 in layer 41 in Fig. 7 A may be substantially aligned to allow fluid flow to occur.
  • first lateral channel 52 and second lateral channel 53 are shown to be substantially aligned in this figure, e.g., forming a continuous channel that spans all five layers 11, 21, 31, 41, and 51 this is by way of example only, and that different channels may span some or all of the layers, without necessarily being all aligned with each other. Any combination of lateral, transverse, and/or other channels may be present within the device.
  • the various layers within the device may be bonded together, e.g., in liquid-tight contact so as to prevent dripping of fluid from the channels, for instance, through the seams between the layers.
  • Techniques for creating such liquid-tight contacts include applying pressure, bonding the layers together with an adhesive, or other techniques such as those described herein.
  • the layers may be formed from polymers such as cyclic olefin copolymers, polyethylene terephthalate, polymethyl methacrylate or the like, e.g., as discussed below.
  • the layers may be substantially transparent.
  • the layers may also be substantially flat or planar, e.g., as shown in this figure, although in some cases, the layers are non-planar, but can have complementary surfaces that can be assembled in liquid-tight contact with each other.
  • first lateral channel 52 may have a first surface characteristic within first layer 11 (for example, a hydrophobic surface), but a second surface characteristic within layer 31 (for example, a hydrophilic surface).
  • first surface characteristic within first layer 11 (for example, a hydrophobic surface)
  • second surface characteristic within layer 31 (for example, a hydrophilic surface).
  • Other surface characteristics include applied coatings, surface roughness, or the like, e.g., as discussed in more detail below.
  • one of the possible surface characteristics in the discussions herein may simply be the normal surface characteristics of the material forming the layer, i.e., without any treatment to change those surface characteristics.
  • transverse channel 18 may be defined in and pass between layers 11, 21, and 31, where layer 21 has been treated in some fashion to alter its surface characteristics, relative to layers 11 and 31.
  • layer 21 may have a coating 17 that allows it to have different surface characteristics.
  • coating 17 may include a species comprising a protein, an antibody, a nucleic acid, or another binding species that can bind to a species contained within fluid flowing through transverse channel 18. Due to the use of different layers in this example, the region where the binding species is present within the channel can be precisely controlled (for example, by applying the species to the channel before fabrication of the channel), e.g., to a small or relatively well- defined portion of the channel. In some embodiments, this may allow the control of a coating within a channel to a degree that is much more precise than can be achieved by simply flowing a species throughout the entire channel.
  • Such devices can be used in a variety of applications, e.g., involving microfluidic channels, some of which are discussed in more detail below.
  • applications e.g., involving microfluidic channels, some of which are discussed in more detail below.
  • microfluidic channels some of which are discussed in more detail below.
  • droplets 16 may be created by introducing a first fluid 15 from a suitable source of fluid into first lateral channel 22, and a second fluid 25 from a suitable source of fluid into second lateral channel 42.
  • first fluid 15 may be substantially immiscible with second fluid 25, and may be used to form droplets 16 within the second fluid, e.g., at intersection 33.
  • First fluid 15 may flow into one or more first lateral channels 22 within second layer 21, eventually reaching intersection 23 with transverse pore or channel 32 and flowing into fourth layer 41. First fluid 15 encounters second fluid 25 flowing through second lateral channel 42, meeting at intersection 33. At that intersection, first fluid 15 may form droplets 16, contained within second fluid 25, e.g., due to the immiscibility between first fluid 15 and second fluid 25. Droplets 16, contained within the second fluid, may then exit through second lateral channel 42, entering into fifth layer 51, and exiting the device by transverse channel 53.
  • a similar system may also be used to create double-emulsion droplets, as is illustrated in the example shown in Fig. 7D.
  • a third fluid 35 is introduced from a suitable source of fluid into third lateral channel 62.
  • Third fluid 35 may be substantially immiscible with second fluid 25, and may be the same or different than first fluid 15.
  • double-emulsion droplets may be created as second fluid 25 (which may be in coaxial flow with the first fluid 16) enters intersection 63 from second lateral channel 42 and contact third fluid 35 entering from third lateral channel 62. Due to the immiscibility between second fluid 25 and third fluid 35, droplets 26 of second fluid 25 are formed within third fluid 35.
  • the droplets 26 may contain droplets of first fluid 15 as the co-axial flow 16 of the second fluid may break up simultaneously with fluid 25 at intersection 63, forming double-emulsion droplets (i.e., droplet- within-a-droplet), e.g., as is shown in this figure.
  • double-emulsion droplets i.e., droplet- within-a-droplet
  • initial droplets of fluid 15 may form within fluid 25 at junction 43, these droplets may then be present singularly or in a plurality within droplet 26, forming double-emulsion or multi-core emulsion droplets.
  • various aspects of the invention are directed to various systems and methods for microfluidic devices, especially layered microfluidic devices, including various techniques for making and using such devices.
  • one aspect of the present invention is generally directed to microfluidic devices that may be formed from one or more layers, some or all of which may contain therein one or more microfluidic channels.
  • the microfluidic channels may flow largely within a single layer (a lateral microfluidic channel), or may go between two or more layers (a transverse microfluidic channel).
  • a microfluidic device may be fabricated from a plurality of layers.
  • the device may include any number of layers, e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10, or more layers that are assembled together to produce the microfluidic device.
  • microfluidic channels are defined within one or only a few layers, and do not pass between multiple layers of the device.
  • a device such as is shown in Fig. 7B may comprise a first layer 11 containing a microfluidic channel 12, and a second layer 21 defining the top of those channels.
  • second layer 21 does not contain any microfluidic channels, and simply defines the top of microfluidic channel 12 when placed in contact with first layer 11.
  • microfluidic channel 12 is laterally defined within first layer 11, but does not pass into second layer 12.
  • one or more microfluidic channels within the device may pass through two, three, or more layers, for instance, as is shown in Figs. 3 or 4. It should be understood, however, that not all of the microfluidic channels within the device have to pass through two or more layers; for instance, one or more channels may be laterally positioned within a single layer within the device.
  • one or more of the layers may be planar, or at least substantially planar.
  • a substantially planar plate or layer may be generally box shaped or shaped like a rectangular solid.
  • at least one surface of the layer is substantially planar.
  • one of the dimensions of the layer may be smaller than the other orthogonal dimensions. For example, the smallest dimension may be less than 25%, less than 20%, less than 15%, less than 10%, less than 5%, or less than 3% of the smallest of the other two orthogonal dimensions.
  • the smallest dimension (e.g., the cross-sectional dimension or the thickness) may be less than 10 cm, less than 8 cm, less than 6 cm, less than 5 cm, less than 4 cm, less than 3 cm, less than 2 cm, less than 1 cm, less than 9 mm, less than 8 mm, less than 7 mm, less than 6 mm, less than 5 mm, less than 4 mm, less than 3 mm, less than 2 mm, less than 1 mm, less than 900 micrometers, less than 800 micrometers, less than 700 micrometers, less than 600 micrometers, less than 500 micrometers, less than 400
  • micrometers less than 300 micrometers, less than 200 micrometers, less than 100
  • the smallest dimension may be at least about 10 micrometers, at least about lOOmicrometers, at least about 200 micrometers, at least about 300 micrometers, at least about 400 micrometers, at least about 500 micrometers, at least about 600 micrometers, at least about 700 micrometers, at least about 800 micrometers, at least about 900 micrometers, at least about 1 mm, at least about 2 mm, at least about 3 mm, at least about 4 mm, at least about 5 mm, at least about 6 mm, at least about 7 mm, at least about 8 mm.
  • the dimension may fall within any combination of these, e.g., the layer may have a thickness of between 100 micrometers and 500 micrometers, between 1 mm and 2 mm, between 1 cm and 3 cm, etc.
  • the two other dimensions may independently be the same or different.
  • the two dimensions may be substantially equal (i.e., forming a square), or the aspect ratio between the dimensions may be 1:2, 2:3, 3:4, etc.
  • one or both of the larger orthogonal dimension of the layer e.g., its length or width
  • one or both of the larger orthogonal dimension of the layer may be less than 25 cm, less than 20 cm, less than 15 cm, less than 10 cm, less than 9 cm, less than 8 cm, less than 7 cm, less than 6 cm, less than 5 cm, less than 4 cm, less than 3 cm, less than 2 cm, etc. Additionally, combinations of any of these are also possible; for example, each of larger orthogonal dimensions may independently be between 5 cm and 15 cm, or between 20 cm and 25 cm, etc.
  • a plurality of layers may be present.
  • the layers may all independently have the same, or different sizes.
  • various embodiments are generally directed to a microfluidic device comprising a plurality of substantially planar layers, e.g., assembled together as discussed herein. It should be understood, however, that the layers within the device need not be substantially planar or box-shaped.
  • the layers may be substantially curved, and/or have various protrusions or indentations, etc., although the layers may be able to be conformably assembled together, e.g., in liquid-tight fashion, at least proximate the region surrounding the channel.
  • the layers may be formed from any suitable material, and different layers within a device may independently be formed from the same or different materials. Non-limiting examples of suitable materials include metals (e.g., stainless steel), glass, or polymers or plastics, such as polydimethylsiloxane, cyclic olefin copolymers, or polyethylene
  • one or more of layers may each independently be transparent, translucent, or opaque.
  • some or all of the layers may each independently be coated, for example, with a reflective coating, metallic coating, an opaque coating, or the like.
  • one or more of the layers may have defined therein a channel, such as a microfluidic channel.
  • the microfluidic channel may be completely defined within the channel, or only partially defined within the channel.
  • channel 12 runs through the interior of layer 11, while in Fig. 7B, channel 12 is an open channel that is defined on an outer surface of layer 11.
  • channel 12 may also be defined by adding layer 21 to layer 11, as a portion of layer 21 will also define channel 12.
  • layer 21 does not contain a channel complementary to channel 12; the planar surface of layer 21 is sufficient to define the channel. In other embodiments, however, layer 21 may also contain a complementary channel to channel 12.
  • the systems and methods described herein may include one or more microfluidic components, for example, one or more microfluidic channels.
  • a microfluidic channel may have a cross-sectional dimension of less than 2 mm or 1 mm, and a ratio of length to largest cross-sectional dimension of at least 3: 1.
  • The“cross-sectional dimension” of the channel is measured perpendicular to the direction of fluid flow within the channel.
  • some or all of the fluid channels in microfluidic embodiments of the invention may have maximum cross-sectional dimensions less than 2 mm, and in certain cases, less than 1 mm.
  • all fluid channeis containing embodiments of the invention are microfluidic or have a largest cross sectional dimension of no more than 2 mm or 1 mm.
  • the fluid channels may be formed in part by a single component (e.g. an etched substrate or molded unit), as noted above.
  • larger channels, tubes, chambers, reservoirs, etc. can be used to store fluids and/or deliver fluids to various components or systems of the invention ln one set of embodiments, the maximum cross-sectional dimension of the channel, the largest dimension perpendicular to fluid flow is less than 5 mm, less than 3 mm, less than 2 mm.
  • the dimensions of the channel may be chosen such that fluid is able to freely flow through the channel.
  • the dimensions of the channel may also be chosen, for example, to allow a certain volumetric or linear flowrate of fluid in the channel.
  • microfluidic channels may independently stay within a single layer (a lateral microfluidic channel), or may go between two or more layers (a transverse microfluidic channel).
  • lateral microfluidic channel a lateral microfluidic channel
  • transverse microfluidic channel a transverse microfluidic channel
  • the transverse channels may be arranged to allow increased fluid flow.
  • the transverse channels may be positioned such that transverse channels downstream are larger (e.g., have a greater average cross-sectional area) than those that are upstream.
  • fluid may flow from a first transverse channel, to a second transverse channel, to a third transverse channel, etc.
  • the first transverse channel may have an average cross-sectional area that is the same size or smaller than the average cross-sectional area of the second transverse channel, which in turn may be the same size or smaller than the average cross-sectional area of the third transverse channel, etc.
  • the succeeding cross-sectional area of a transverse channel may be at least 1, at least 1.1, at least 1.2, at least 1.3, at least 1.4, at least 1.5, at least 1.6, at least 1.8, at least 2, at least 2.5, at least 3, at least 3.5, at least 4 times, at least 5 times, at least 6 times, etc. of the previous transverse channel, and/or no more than 7, no more than 6, no more than 5, no more than 4, no more than 3.5, no more than 3, no more than 2.5, no more than 2, no more than 1.8, no more than 1.6, no more than 1.5, no more than 1.4, no more than 1.3, no more than 1.2, or no more than 1.1 times the area of the previous transverse channel.
  • a transverse channel may be between 1.1 and 3 times the area of a succeeding transverse channel.
  • the channel may include features on or in an article (e.g., a layer) that at least partially directs flow of a fluid.
  • the channel can have any cross-sectional shape (circular, oval, triangular, irregular, square or rectangular, or the like) and can be covered or uncovered.
  • the channel may have a cross-sectional shape that varies with the length dimension as is the example of transverse channel 51 and channel 52 in Fig. 7D (e.g. a conical nozzle or diffuser).
  • at least one portion of the channel can have a cross-section that is completely enclosed, or the entire channel may be completely enclosed along its entire length with the exception of its inlet(s) and/or outlet(s).
  • a channel may also have an aspect ratio (length to average cross sectional dimension) of at least 2:1, more typically at least 3:1, 5:1, 10:1, 15: 1, 20: 1, or more.
  • An open channel generally will include characteristics that facilitate control over fluid transport, e.g., structural
  • hydrophilicity hydrophilicity or other characteristics that can exert a force (e.g., a containing force) on a fluid.
  • the fluid within the channel may partially or completely fill the channel.
  • the fluid may be held within the channel, for example, using surface tension (i.e., a concave or convex meniscus).
  • the channels within the device may have various surface characteristics, which may be defined by the materials forming the channels (e.g., the characteristics of the materials forming the layer containing channels), and/or the channels may be modified in some fashion to control or alter their surface characteristics.
  • the channels may be treated chemically, mechanically, etc.
  • Non-limiting examples of surface characteristics include hydrophilicity or hydrophobicity, surface roughness, color, concentrations of chemical agents or chemical groups, or the like.
  • only a portion of a channel may have a specific surface characteristic, e.g., as is shown in Fig. 1C.
  • one or more of the channels within a layer may be treated, for example, with an agent, to alter their hydrophilicity, hydrophobicity, organophilicity, etc.
  • a microfluidic channel may be treated such that it exhibits a contact angle of less than 90° (e.g., to render it hydrophilic) or greater than 90° (e.g., to render it hydrophobic).
  • agents that can be applied to a channel to render it more hydrophobic include silanes, Aquapel®, metal oxides, silicone, or the like.
  • agents that can be applied to a channel to render it more hydrophilic include polyethylene glycol, polypropylene glycol, silica nanoparticles, or the like.
  • silanes include, but are not limited to, a fluorosilane (i.e., a silane containing at least one fluorine atom) such as heptadecafluorosilane or
  • heptadecafluorooctylsilane or other silanes such as methyltriethoxy silane (MTES) or a silane containing one or more lipid chains, such as octadecylsilane or other CH 3 (CH2) 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, octadecyltrimethoxysilane.
  • silanes include alkoxysilanes such as ethoxysilane or methoxysilane, halosilanes such as chlorosilanes, or other silicon-containing compounds containing hydrolyzable moieties on the silicon atom, such as hydroxide moieties.
  • the silanes may contain other groups, for example, groups such as amines, which would make the coating more
  • Non-limiting examples include diamine silane, triamine silane, or N-[ 3- (trimethoxysilyl)propyl]ethylenediamine silane. In some cases, more than one silane may be present. In addition, in some cases, one or more of the silanes may be hydrolyzed to form the corresponding silanol. Additional examples of slianes include perfluorosilanes,
  • alkyl silanes e.g., octadecyltrichlorosilanes
  • WO 2009/120254 incorporated herein by reference.
  • metal oxides include, but are not limited to, aluminum, antimony, barium, bismuth, cadmium, calcium, cerium, cesium, chromium, cobalt, copper, dysprosium, erbium, gadolinium, germanium, hafnium, holmium, indium, iridium, iron, lanthanum, lead, lithium, lutetium, magnesium, manganese, molybdenum, neodymium, nickel, niobium, palladium, potassium, praseodymium, rhodium, rubidium, ruthenium, samarium, scandium, silicon, silver, sodium, strontium, tantalum, terbium, thallium, tin, titanium, tungsten, vanadium, ytterbium, yttrium, or zirconium oxide.
  • Additional examples include S1O2, vanadia (V2O5), titania (T1O2), and/or alumina (AI2O3). See, e.g., Int. Pat. Apl. Pub. No. WO 2009/020633, incorporated herein by reference.
  • other coatings may be applied to a channel in a layer.
  • materials such as a polymer, a metal, chemical species, or a biological species may be coated onto a surface of a channel.
  • biological species include proteins, peptides, antibodies, enzymes, nucleic acids (e.g., DNA, RNA, etc.), carbohydrates, or the like may be coated onto a channel.
  • the coating may be applied to a channel to expose a certain type of chemical group to the interior of the channel, for example, carboxylic acid groups, or hydroxide groups.
  • the surface characteristics of a channel may be altered without necessarily coating an agent to the surface.
  • the channel can be plasma-treated, corona-treated, ozone-treated, etc. to alter its hydrophilicity or other surface characteristics.
  • the channel may be mechanically altered, e.g., by applying abrasive to the channels to increase or decrease their surface roughness.
  • the layers may be assembled together to form a device, in accordance with certain aspects of the invention.
  • the layers may be bonded together in liquid-tight contact with each other, e.g., such that fluid does not leak through the seams between each layer during normal operation of the device.
  • An entire layer, or only a portion thereof, may be bonded in liquid- tight contact with another layer.
  • Each layer within the device may be bonded in liquid-tight contact to another layer, although in some cases, one or more of the layers may not necessarily be in liquid-tight contact with another layer.
  • a variety of techniques may be used to bond the layers together, including thermal- bonding, hot embossing, solvent-bonding, microwave welding, plasma bonding (e.g., with oxygen plasma), anodic bonding, use of an adhesive, or the like.
  • adhesives include, but are not limited to, cyanoacrylates, or APTES (3-aminopropyl-triethoxysilanes).
  • the layers may include one or more holes that can be aligned together, e.g., through the use of alignment pins or screws that pass through the holes when the layers are properly aligned, for instance, as is shown in Figs. 1 and 2. These may pass through one or more, or all, of the layers to be aligned.
  • one or more layers may be aligned and bonded prior to formation of holes or other features.
  • the device illustrated in Fig. 7D may be partially or fully assembled prior to formation of the concentrically aligned channels 51 , 52, and 53.
  • a force may be applied to the device, e.g., to keep the layers together.
  • a force may be applied using screws (e.g., driven through holes in one or more of the layers, clamps, or the like.
  • Fluids may be delivered into channels within a device via one or more fluid sources.
  • Any suitable source of fluid can be used, and in some cases, more than one source of fluid is used.
  • a pump, gravity, capillary action, surface tension, electroosmosis, centrifugal forces, etc. may be used to deliver a fluid from a fluid source into one or more channels in the device.
  • a vacuum e.g., from a vacuum pump or other suitable vacuum source
  • Non-limiting examples of pumps include syringe pumps, peristaltic pumps, pressurized fluid sources, or the like.
  • the device can have any number of fluid sources associated with it, for example, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, etc., or more fluid sources.
  • the fluid sources need not be used to deliver fluid into the same channel, e.g., a first fluid source can deliver a first fluid to a first channel while a second fluid source can deliver a second fluid to a second channel, etc.
  • the same fluid source may be used to deliver fluid to more than one layer, e.g., a first layer and a third layer.
  • two or more channels are arranged to intersect at one or more intersections. There may be any number of fluidic channel intersections within the device, for example, 2,
  • certain aspects of the invention are generally directed to systems and methods for making droplets, including single droplets, double emulsion droplets (e.g., water-in-oil-in-water or oil-in- water- in-oil), or higher order droplets.
  • double emulsion droplets e.g., water-in-oil-in-water or oil-in- water- in-oil
  • higher order droplets e.g., water-in-oil-in-water or oil-in- water- in-oil
  • the device may comprise a second layer defining a first lateral microfluidic channel, in which a first fluid flows, which ultimately will form droplets within a second fluid.
  • a first fluid flows, which ultimately will form droplets within a second fluid.
  • One or more than one such lateral channel may be present within the layer.
  • the first fluid need not originate from the second layer.
  • the first fluid may pass through one or more other layers before entering the first lateral channel.
  • the first fluid may then pass through one or more layer, e.g., through a transverse channel between the first layer and the third layer.
  • the transverse channel may be straight or it may have any number of turns, bends, chambers, or other features between the first channel and the second channel, e.g., as is shown in Fig. 7E.
  • additional channels may be present, e.g., which may add or remove additional material to or from the first fluid.
  • the layer which the first fluid enters through an intersection may be a layer which contains a second fluid.
  • the second fluid may pass through a second lateral channel.
  • One, two, three, four, or more such channels may be present. It should be understood, however, that the second fluid need not originate from the second lateral channel; for example, the second fluid may pass through one or more other channels before entering the second layer.
  • An intersection between any two or more channels may allow a first fluid from a transverse channel and the second fluid from one or more second lateral channels to come into contact with each other.
  • the channels defining the intersection may meet orthogonally, or at any other suitable angles.
  • the first fluid may form co-axially flow with the second fluid (as shown in Fig. 7D), or may form droplets contained within the second fluid (as shown in Fig. 7A).
  • the droplets may exit the channel through an exiting channel.
  • the exiting channel may also be present within the layer containing the lateral channel, or the exiting channel may be a second transverse channel that exits the layer into one or more other layers. Accordingly, exiting the intersection may be a plurality of droplets of first fluid contained within the second fluid.
  • the second transverse channel may extend into another layer, e.g., containing an intersection with a third fluid, e.g., in a third lateral channel.
  • the channels defining the intersection may be meet orthogonally, or at any other suitable angles.
  • the second and third lateral channels may be adjacent or there may be any number of layers between the second and third lateral channels, and this number may be the same or different than the number of layers between the first and second lateral channels.
  • the second fluid may be caused to form droplets, some or all of which may contain droplets of first fluid therein to form a double-emulsion droplet.
  • the droplets exiting the intersection may then pass into an exiting channel, which may be laterally contained within the layer, or extend transversally into yet another layer within the device.
  • this pattern may also be repeated any number of additional times (e.g., with additional layers and fluids, etc. to create higher-order triple, quadruple, etc. droplets).
  • FIG. 9 A non-limiting example of such a device for producing double emulsion droplets can be seen in Fig. 9, in accordance with another embodiment of the invention.
  • a plurality of substantially planar layers forms the device.
  • Layer 0 is the bottommost layer, while the double emulsion droplets are collected from layer 7.
  • Layer 1 is a first layer defining a first lateral microfluidic channel containing a first fluid (which becomes the core fluid of the double emulsion droplet)
  • layer 3 is a second layer defining a second lateral microfluidic channel containing a second fluid (which becomes the shell fluid)
  • layer 5 is a third layer defining a third lateral microfluidic channel containing a third fluid (which contains the double emulsion of the first and second fluids).
  • the first fluid flows through the first layer to the first transverse channel in layer 2, where it flows up and intersects with the second fluid in layer 3 (shaded for ease of identification in this figure).
  • the first fluid can form droplets in other embodiments, the first fluid need not form droplets as shown here, and instead, the first and second fluids may flow alongside each other.
  • the fluids travel through a second transverse channel in layer 4, intersecting the third fluid in layer 5.
  • the second transverse channel may, in some cases, have an average cross-sectional area greater than the first transverse channel, e.g., to allow more fluid flow to occur.
  • the third fluid and the first fluid may be the same or different fluids.
  • the fluids may then pass through an exit transverse channel in layer 6 into layer 7.
  • the exit transverse channel may have an average cross-sectional arear greater than the second transverse channel.
  • the fluids may then form a double emulsion droplet within layer 7 (with a droplet of the first fluid contained within a droplet of the second fluid, which in turn is contained within the third fluid).
  • the double emulsion droplet may be collected for subsequent use.
  • the droplets and the fluid containing the droplets are substantially immiscible. In some cases, however, they may be miscible.
  • a hydrophilic liquid may be suspended in a hydrophobic liquid
  • a hydrophobic liquid may be suspended in a hydrophilic liquid
  • a gas bubble may be suspended in a liquid
  • a hydrophobic liquid and a hydrophilic liquid are substantially immiscible with respect to each other, where the hydrophilic liquid has a greater affinity to water than does the hydrophobic liquid.
  • hydrophilic liquids include, but are not limited to, water and other aqueous solutions comprising water, such as cell or biological media, ethanol, salt solutions, etc.
  • hydrophobic liquids include, but are not limited to, oils such as hydrocarbons, silicon oils, fluorocarbon oils, organic solvents etc.
  • two fluids can be selected to be substantially immiscible within the time frame of formation of a stream of fluids.
  • suitable substantially immiscible fluids using contact angle measurements or the like.
  • one or more of the fluids may be one that is high- viscosity, or at least has a viscosity greater than water.
  • the viscosity of a fluid may be at least 1 cP, at least 2 cP, at least 3 cP, at least 5 cP, at least 10 cP, at least 20 cP, at least 30 cP, at least 50 cP, at least 100 cP, at least 200 cP, at least 300 cP, at least 500 cP, at least 1,000 cP, at least 2,000 cP, at least 3,000 cP, at least 5,000 cP, at least 10,000 cP, etc.
  • 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 or more fluids may be selected to be immiscible within the time frame of the formation of the fluidic droplets.
  • a fluid is substantially immiscible with an adjacent fluid, although fluids that are not adjacent need not be immiscible, and may be miscible (or even identical) in some cases.
  • two adjacent fluids are not immiscible, but may retain separation in other ways, e.g., kinetically or through short exposure times.
  • two fluids e.g., the third fluid and the first fluid of a double emulsion droplet system
  • the intervening fluid e.g., the second fluid of a double emulsion droplet
  • 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.
  • each nesting layer of fluidic droplets may each be independently controlled, e.g., by control over the composition of each nesting level, for example, by controlling the fluids entering each layer of the device.
  • the first fluid in a double emulsion droplet, the first fluid
  • the first fluid may be any suitable aqueous fluid, and it need not be pure water.
  • the aqueous fluid may be water, saline, an aqueous solution, ethanol, or the like, or any other fluid miscible in water.
  • the oil in contrast, may be immiscible in water, at least when left undisturbed under ambient conditions.
  • an O/W/O double emulsion droplet may be similarly defined.
  • these principles may be extended to higher-order multiple emulsions droplets, e.g., as discussed herein.
  • a triple emulsion droplet may comprise a first fluid, surrounded by a second fluid, surrounded by a third fluid, contained in a fourth fluid, etc.
  • a double emulsion droplet may contain two, three, or more droplets of first fluid, contained within a droplet of a second fluid, that in turn is contained within a third fluid.
  • Figs. 7F and 7G show an example in which at least some of the channels are not completely defined as completely passing through a layer.
  • Fig. 7G illustrates another embodiment for producing double emulsion droplets. These embodiments comprise a variety of layers 11, 21, 31, 41 and channels passing through one or more of these layers to produce various intersections, where various fluids can interact, for example, to mix, react, form droplets as shown in these examples, or the like.
  • Double emulsions are used widely in both industry and academia, but devices used to produce such double emulsions tend to be made of either expensive or hard to manufacture- at-volume materials.
  • the device described in this example offers an inexpensive, easily manufactured, reconfigurable, and scalable method of producing microfluidic droplets.
  • the device described in this example is manufactured from low-cost thin polymer films or layers, and can be assembled easily, for example, by non-expert users, or through automated manufacturing.
  • various surface properties can be precisely controlled.
  • localized surface treatments e.g., hydrophilic, hydrophobic, organophilic, etc.
  • pores or holes within a layer can readily be made concentric by various alignment methods, and/or by fabricating multiple pores or holes at once after partially or fully assembling multiple layers.
  • the concentric design may allow well-defined sheath flows, and/or prevent certain fluids from contacting side walls within the device.
  • the hole and channel dimensions can be easily controlled, e.g., to produce a variety of droplet sizes.
  • the device in some cases may be well suited to scale-up of droplet throughput, e.g., via multiple devices, multiple droplet-making junctions in a single device, or the like.
  • the device in this example is composed of seven 150- micrometer thick polymer layers.
  • Materials such as polycarbonate (PC), cyclic-olefin-copolymer (COC), polymethyl methacrylate (PMMA) and polyethylene terephthalate (PET) can be used (PET, for example, can be easily laser-cut).
  • the thin polymer layers were aligned by two 2-mm alignment pins fixed to a solid base comprised of a rigid substrate such as polymethyl methacrylate (PMMA) or aluminum.
  • Polymer layers may be, for example, solvent, thermal or adhesive bonded. Functional devices have been developed using a polypropylene-silicone adhesive to bond layers.
  • a PDMS block was attached to the top layer with 1 -mm punched holes for use with 18 gauge pin connectors.
  • This device is shown in Fig. 1 as an exploded view of a complete layered double emulsion device
  • the device was attached to inlet and outlet reagents via gauge-pins and tubing. Flow was provided via peristaltic, diaphragm pumps, pressure-driven and volumetrically-driven commercially available pumps.
  • the port configuration is shown in Fig. 2. In this figure, 1 and 6 are inlets for the core fluid, 3 and 4 are inlets for the shell fluid, 5 is the carrier inlet, and 2 is the device outlet.
  • the central portion of the device features the pores and a T-junction, dimensions of which are used to control droplet breakup.
  • a cross-section view of this region and a functional schematic are shown in Fig. 3.
  • One feature of the device is the co-axial flow between the core and shell phase combined with the T-junction orthogonal flow of the carrier phase.
  • Droplet break-up may occur as the core enters the shell phase, and is believed to be driven by a balance between shear-elongation and interfacial tension.
  • core phase may enter a state of co-axial flow with the shell phase.
  • the formation of the final double emulsion may include“squeezing” or“plugging” due to obstruction or partial- obstruction of the top carrier channel. See, e.g., Fig. 4, showing a schematic of double emulsion droplet generation.
  • formation of the final double emulsion may again be a result of a balance between viscous shear elongation and interfacial tension depending on the surfactant chemistry and flowrates used.
  • double emulsions may be seen in Figs. 5A-5C, with double emulsion outer shell diameters ranging from about 50 micrometers to about 200 micrometers (although smaller or larger diameters are also possible).
  • Different thickness shells can be seen in Fig. 5. Due to the transparent nature of the device, droplet imaging can be done in situ, which may allow for real-time analysis of droplet quality, dimensions, etc. This may be useful, for example, in the context of high- volume manufacturing of microcapsules.
  • each individual layer may contain a plurality of droplet generators.
  • These droplet generators may have independent and isolated fluidic channels (e.g., as shown in Fig. 8) or may have common lateral supply channels.
  • the device in this example is assembled from individual layers and the flow path is orthogonal to the plane of each layer, it is possible to have distinct and opposing surface treatments in close physical proximity.
  • the layers associated with the core phase and the carrier phase could be plasma, corona, or otherwise treated to be hydrophilic, while the layers associated with the oil phase could be silane- treated or otherwise made hydrophobic, fluorophilic, or organophilic.
  • the same laser-cutting process used to cut the outline and channels of each layer can also be used to drill the holes.
  • hole diameters of various sizes e.g., ranging from 50 to 150 micrometers in diameter, can be produced (Figs.
  • Fig. 6B shows an example of hole sizes prepared as a function of laser power and speed.
  • This example illustrates a layered device prepared in accordance with another embodiment of the invention.
  • the layered device was used to produce double emulsion droplets of an inner fluid, contained within a middle fluid, contained within an outer phase fluid.
  • the inner and outer phases each were water with 5 wt% PVA (polyvinyl alcohol) (Sigma Aldrich 363170, dissolved at 60 °C for 24 hours, then filtered).
  • the middle phase was substantially immiscible with the inner and outer phases.
  • the middle fluid contained 98 wt% mineral oil (Sigma Aldrich 330779), 2 wt% SPAN 80, and 0.01 mg/ml red nile (to make it easier to identify) (Sigma Aldrich 72485).
  • Fig. 9 shows a cross section of the device.
  • the device in this example is made of sequentially stacked layers which are individually cut prior assembly.
  • the double emulsions (capsules) are formed at a single junction out of three different phases: the inner, middle and outer phase flow inside the channel cut into layers 1, 3, and 5 respectively.
  • the pores inside layer 2 and 3 extrude the inner and middle phase.
  • the pore in layer 6 is used for droplet break-up.
  • This device was assembled as outlined below:
  • PET Grafix 0.005 inches (0.127 mm) Clear DuraLar
  • Adhesive Adhesive Research, AR90880
  • Layer 1 Adhesive + PET + Adhesive (375 micrometers)
  • Layer 2 PET (125 micrometers)
  • the device was prepared as follows. First, channels were laser cut in the
  • Fig. 10B is an image of four devices on the same chip with stainless steel dispensing needles for inlets and outlets (McMaster-Carr 75165A675, OD 1.27 mm). Each device has a total of 3 inlets (inner, middle, and outer phase) plus 1 outlet, each with a corresponding needle. For each incoming phase, the acrylic manifold divided the fluid flow into a left coming and a right-coming flow as shown in Fig. 9.
  • Fig. 10C shows an alignment station for stacking layers passively using pin alignment (alignment pins: low tolerance metric gauge pins, McMaster-Carr 2281A2). The holes for each pin are drilled with a high precision CNC machine.
  • the deice was able to produce double emulsion droplets having an average size (diameter) of about 600 micrometers. Images of the double emulsions in the outlet channel inside the manifold can be seen in Fig. 10A. It should be understood, however, that this is by way of example only, and other size emulsion droplets (including smaller droplets) can be produced in other embodiments of the invention.
  • Fig. 10A illustrates the formation of such droplets (looking in through the exit transverse channel).
  • This microscope image shows double emulsion droplets produced using the device described in Fig. 9. There can be seen a clear distinction between the inner (water + 5% PVA), middle (mineral oil), and outer phases (water + 5% PVA).
  • 3 syringe pumps were used for each of the three phases into their respective channels, with an acrylic manifold on the top layer (which could also be made of stainless steel or aluminum) that distributed the liquids into the device.
  • a reference to“A and/or B”, when used in conjunction with open-ended language such as“comprising” can refer, in one embodiment, to A only (optionally including elements other than B); in another embodiment, to B only (optionally including elements other than A); in yet another embodiment, to both A and B (optionally including other elements); etc.
  • “or” should be understood to have the same meaning as“and/or” as defined above.
  • “or” or“and/or” shall be interpreted as being inclusive, i.e., the inclusion of at least one, but also including more than one, of a number or list of elements, and, optionally, additional unlisted items. Only terms clearly indicated to the contrary, such as“only one of’ or“exactly one of,” or, when used in the claims,“consisting of,” will refer to the inclusion of exactly one element of a number or list of elements.
  • 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

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Abstract

De manière générale, cette invention concerne des dispositifs microfluidiques, et des techniques de fabrication et d'utilisation de tels dispositifs. Dans certains modes de réalisation, le dispositif microfluidique peut être formé à partir de deux ou plusieurs couches ou plaques, qui peuvent être assemblées l'une à l'autre. Par exemple, les couches peuvent comprendre divers canaux qui passent entre différentes couches ou plaques. Dans certains cas, les couches peuvent être traitées (par exemple, avec différents revêtements), par exemple, avant l'assemblage. Ceci peut permettre une commande relativement précise de différentes caractéristiques de surface (par exemple, l'hydrophilie) dans différentes parties du dispositif microfluidique. De tels dispositifs peuvent être utilisés dans certains modes de réalisation pour commander ou manipuler des fluides, par exemple, pour former des gouttelettes, ou pour d'autres applications. D'autres modes de réalisation de l'invention concernent généralement des systèmes et des procédés de fabrication ou d'utilisation de tels dispositifs, des kits comprenant de tels dispositifs, ou analogues.
PCT/US2019/019929 2018-03-02 2019-02-28 Dispositifs et techniques microfluidiques en couches WO2019169060A1 (fr)

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US11351514B2 (en) * 2020-07-02 2022-06-07 Lawrence Livermore National Security, Llc Parallelized multiple nozzle system and method to produce layered droplets and fibers for microencapsulation
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WO2023146870A1 (fr) * 2022-01-25 2023-08-03 President And Fellows Of Harvard College Systèmes microfluidiques contenant des couches de films
WO2023250283A1 (fr) * 2022-06-23 2023-12-28 The Trustees Of The University Of Pennsylvania Formation de motifs de mouillabilité dans des canaux microfluidiques complexes pour la génération à très grande échelle d'émulsions doubles

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US11123735B2 (en) 2019-10-10 2021-09-21 1859, Inc. Methods and systems for microfluidic screening
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WO2023146870A1 (fr) * 2022-01-25 2023-08-03 President And Fellows Of Harvard College Systèmes microfluidiques contenant des couches de films
WO2023250283A1 (fr) * 2022-06-23 2023-12-28 The Trustees Of The University Of Pennsylvania Formation de motifs de mouillabilité dans des canaux microfluidiques complexes pour la génération à très grande échelle d'émulsions doubles

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