WO2009136300A2 - Production microfluidique de paires de gouttelettes - Google Patents

Production microfluidique de paires de gouttelettes Download PDF

Info

Publication number
WO2009136300A2
WO2009136300A2 PCT/IB2009/006478 IB2009006478W WO2009136300A2 WO 2009136300 A2 WO2009136300 A2 WO 2009136300A2 IB 2009006478 W IB2009006478 W IB 2009006478W WO 2009136300 A2 WO2009136300 A2 WO 2009136300A2
Authority
WO
WIPO (PCT)
Prior art keywords
droplet
fusion
module
flow channel
droplets
Prior art date
Application number
PCT/IB2009/006478
Other languages
English (en)
Other versions
WO2009136300A3 (fr
Inventor
Lucas Frenz
Sylvie Begin-Colin
Jean-Christophe Baret
Andrew Griffiths
Abdeslam El Harrak
Original Assignee
Universite De Strasbourg
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 Universite De Strasbourg filed Critical Universite De Strasbourg
Publication of WO2009136300A2 publication Critical patent/WO2009136300A2/fr
Publication of WO2009136300A3 publication Critical patent/WO2009136300A3/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
    • 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
    • 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
    • B01F25/4337—Mixers with a diverging-converging 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
    • B01F33/302—Micromixers the materials to be mixed flowing in the form of droplets
    • B01F33/3021—Micromixers the materials to be mixed flowing in the form of droplets the components to be mixed being combined in a single independent droplet, e.g. these droplets being divided by a non-miscible fluid or consisting of independent droplets
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01F—MIXING, e.g. DISSOLVING, EMULSIFYING OR DISPERSING
    • B01F33/00—Other mixers; Mixing plants; Combinations of mixers
    • B01F33/30—Micromixers
    • B01F33/3031—Micromixers using electro-hydrodynamic [EHD] or electro-kinetic [EKI] phenomena to mix or move the fluids
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
    • B01L3/00—Containers or dishes for laboratory use, e.g. laboratory glassware; Droppers
    • B01L3/50—Containers for the purpose of retaining a material to be analysed, e.g. test tubes
    • B01L3/502—Containers for the purpose of retaining a material to be analysed, e.g. test tubes with fluid transport, e.g. in multi-compartment structures
    • B01L3/5027—Containers for the purpose of retaining a material to be analysed, e.g. test tubes with fluid transport, e.g. in multi-compartment structures by integrated microfluidic structures, i.e. dimensions of channels and chambers are such that surface tension forces are important, e.g. lab-on-a-chip
    • B01L3/502769—Containers for the purpose of retaining a material to be analysed, e.g. test tubes with fluid transport, e.g. in multi-compartment structures by integrated microfluidic structures, i.e. dimensions of channels and chambers are such that surface tension forces are important, e.g. lab-on-a-chip characterised by multiphase flow arrangements
    • B01L3/502784—Containers for the purpose of retaining a material to be analysed, e.g. test tubes with fluid transport, e.g. in multi-compartment structures by integrated microfluidic structures, i.e. dimensions of channels and chambers are such that surface tension forces are important, e.g. lab-on-a-chip characterised by multiphase flow arrangements specially adapted for droplet or plug flow, e.g. digital microfluidics
    • 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
    • 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
    • B01J2219/00873—Heat exchange
    • 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
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
    • B01L2300/00—Additional constructional details
    • B01L2300/08—Geometry, shape and general structure
    • B01L2300/0861—Configuration of multiple channels and/or chambers in a single devices
    • B01L2300/0867—Multiple inlets and one sample wells, e.g. mixing, dilution
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
    • B01L2400/00—Moving or stopping fluids
    • B01L2400/04—Moving fluids with specific forces or mechanical means
    • B01L2400/0403—Moving fluids with specific forces or mechanical means specific forces
    • B01L2400/0415—Moving fluids with specific forces or mechanical means specific forces electrical forces, e.g. electrokinetic
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
    • B01L2400/00—Moving or stopping fluids
    • B01L2400/04—Moving fluids with specific forces or mechanical means
    • B01L2400/0475—Moving fluids with specific forces or mechanical means specific mechanical means and fluid pressure
    • B01L2400/0487—Moving fluids with specific forces or mechanical means specific mechanical means and fluid pressure fluid pressure, pneumatics
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
    • B01L2400/00—Moving or stopping fluids
    • B01L2400/08—Regulating or influencing the flow resistance
    • B01L2400/084—Passive control of flow resistance
    • B01L2400/086—Passive control of flow resistance using baffles or other fixed flow obstructions
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
    • B01L3/00—Containers or dishes for laboratory use, e.g. laboratory glassware; Droppers
    • B01L3/50—Containers for the purpose of retaining a material to be analysed, e.g. test tubes
    • B01L3/502—Containers for the purpose of retaining a material to be analysed, e.g. test tubes with fluid transport, e.g. in multi-compartment structures
    • B01L3/5027—Containers for the purpose of retaining a material to be analysed, e.g. test tubes with fluid transport, e.g. in multi-compartment structures by integrated microfluidic structures, i.e. dimensions of channels and chambers are such that surface tension forces are important, e.g. lab-on-a-chip
    • B01L3/502746—Containers for the purpose of retaining a material to be analysed, e.g. test tubes with fluid transport, e.g. in multi-compartment structures by integrated microfluidic structures, i.e. dimensions of channels and chambers are such that surface tension forces are important, e.g. lab-on-a-chip characterised by the means for controlling flow resistance, e.g. flow controllers, baffles

Definitions

  • IVC in vitro compartmentalization
  • microfluidic systems in the synthesis of nanoparticles is attracting increasing attention. Compared to conventional bulk synthesis strategies, microfluidic systems allow more precise control of the reaction conditions which can lead to reductions in particle size and polydispersity [20].
  • a range of different nanoparticles have been synthesized in microfluidic systems: CdSe, CdS, TiO2, Boehmite, Au, Co, Ag, Pd, Cu, BaSO4, and CdSe-ZnS core-shell nanoparticles [20, 21]. So far, however, microfluidic synthesis of magnetic iron oxide nanoparticles has not been demonstrated. Spinel iron oxide nanocrystals have attracted attention for their use as high density data storage media, [22] or in biomedical applications, such as contrast enhancement agents for magnetic resonance imaging (MRI) and for drug delivery. [23, 24].
  • MRI magnetic resonance imaging
  • the present invention is directed to a novel microfluidic device for the production of droplet pairs based on hydrodynamic coupling of two spatially separated nozzles and uses thereof. Compared to prior systems, the present invention provides for reliable production of droplet pairs, with errors in pairing of only 10 ⁇ 5 or less.
  • Droplets are paired by the hydrodynamic coupling of two nozzles over a wide range of aqueous and non-aqueous flow rates. After formation, the droplet pairs, each containing separate reagents, are fused creating picoliter to nano liter reactors. Fast mixing of the contents of the droplets results in a homogenous distribution of reagents that do not require further mixing modules.
  • the pre- compartmentalization of reagents into droplet pairs allows for increased control over the initiation and quenching of reactions, as well as a means for capturing solid precipitates or other solid objects formed after the fusion of droplet pairs.
  • the device and methods of the present invention can be used to conduct and study chemical and biochemical reactions at the single molecule or single cell level, as well as formation of nanoparticles.
  • the present invention is directed to a novel microfluidic device comprising: a synchronization module and a coalescence module in fluid communication with the synchronization module.
  • the synchronization module comprises a central flow channel, a first and second lateral flow channel and a first and second nozzle.
  • the central flow channel is in fluid communication with the first and second nozzles.
  • the proximity of the two nozzles leads to a passive coupling of the two nozzles by this central flow channel allowing for the passive synchronization of droplet formation in the first and second nozzles.
  • the first and second lateral flow channels run adjacent to the central flow channel on opposite sides and are in fluid communication with the first and second nozzles, respectively.
  • the coalescence module is in fluid communication with the first and second nozzles.
  • the microfluidic device is placed in fluid communication with a flow control module.
  • the flow control module may be integrated onto the microfluidic device ("on-chip"), or separable from the microfluidic device ("off-chip”). Whether located on-chip or off-chip, the flow control module is placed in fluid communication with the first and second lateral flow channels and the central flow channel.
  • the flow control module may comprise any system suitable for the controlled injection of a liquid or gas phase into the lateral and central flow channels.
  • the flow control module comprises one or more syringe pumps.
  • the microfluidic device further comprises a collection module in fluid communication with the coalescence module.
  • the device of the present invention may further comprise a detection module in communication with the coalescence and/or collection modules for detection of the formation of fused droplet pairs.
  • the device of the present invention may be connected in line with other microfluidic devices or modules for further processing of products made after fusion of droplet pairs.
  • a newly formed encapsulated nanoparticle may then be injected into the same or a separate device for fusion with an additional set of droplets to quench or further modify the newly formed particles.
  • the first and second lateral flow channels may have a depth ranging from about 1 ⁇ m to about 1 mm, a width ranging from about 1 ⁇ m to about 1 mm, and a length ranging from about 1 ⁇ m to about 5 mm.
  • the lateral flow channels have a depth of 25 ⁇ m, a width of about 50 ⁇ m and a length of 3 mm.
  • the central flow chamber may have a depth ranging from about 1 ⁇ m to about 1 mm, a width ranging from about 1 ⁇ m to about 1 mm and a length ranging from about 1 ⁇ m to about 5 mm. In one exemplary embodiment, the central flow chamber has a depth of 25 ⁇ m, a width of 100 ⁇ m, and a length of 3 mm.
  • the first and second nozzles may have a depth ranging from about 1 ⁇ m to about 1 mm, a width ranging from about 1 ⁇ m to about 1 mm. In another exemplary embodiment, the first and second nozzles have a depth of 25 ⁇ m, a width of 50 ⁇ m. In one exemplary embodiment the distance between the first and second nozzles is about 1 ⁇ m to about 1 mm. In another exemplary embodiment, the distance between the first and second nozzles is 100 ⁇ m.
  • the coalescence module may have a depth ranging from about 1 ⁇ m to about 1 mm, a width ranging from about 1 ⁇ m to about 1 mm, and a length of 1 ⁇ m to about 1 mm. In another exemplary embodiment, the coalescence module has a depth of 25 ⁇ m, a width of 60 ⁇ m. In yet another exemplary embodiment, the coalescence module may further comprise one or more electrodes connected to an electrical source. In another embodiment, the coalescence module may further comprise a microwave heating source.
  • the collection module may comprise any material and volume suitable for use in storing either temporarily, or for an extended time, the fused droplet pairs produced by the device of the present invention.
  • the collection module has a volume ranging from about 1 pL to about 5 L.
  • the collection module further comprises a cooling means or a heating means.
  • the collection module further comprises a means for re -injecting the fused droplet into the first or second lateral channel of the device.
  • the present invention is directed to a method of forming nanoparticles comprising the steps of: a) formation of a first droplet set comprising a first reaction solution and a second droplet set comprising a second reaction solution; b) fusion of the first droplet set and second droplet set to form a fused droplet set, wherein fusion of the first and second droplet sets initiates synthesis of a nanoparticles; and c) collection of the fused droplet set.
  • Droplet formation can be accomplished using any of a number of prior art methods.
  • the fusion of the first and second droplet set can be initiated by methods known in the art including, but not limited to, electrocoalescense, passive fusion, change or absence of surfactant concentration, and heat.
  • the preset invention is directed to a method for forming and fusing droplet pairs using the device of the present invention to form picoliter to nanoliter reactors, the method comprising the steps of: a) injecting a first reaction solution into the first lateral flow chamber, a second reaction solution into the second lateral flow chamber, and a carrier solution into the central flow chamber; b) forming a first droplet set comprising the first reaction solution and a second droplet set comprising the second reaction solution at the first and second nozzles respectfully; c) fusion of the first and second droplet sets in the coalescence module to form a fused droplet set; and d) collection of the fused droplet set.
  • the first and second reaction mixtures are aqueous phase reaction mixtures and the carrier solution comprises an oil phase solution.
  • the first and second reaction mixtures comprise oil phase reaction mixtures and the carrier solution comprises a aqueous phase solution.
  • the droplets produced have a volume ranging from about 10 pL to about 500 pL. In another exemplary embodiment, the droplets have a volume ratio between droplets ranging from about 1 : 1 to about 1 :7.
  • the method is used to carry out a biochemical or chemical reaction. In another exemplary embodiment, the method is used to synthesize a nanoparticle.
  • the fusion of the first and second droplet initiates, quenches, or modifies a chemical or biological reaction.
  • the fusion of the first and second droplets initiates, quenches, or modifies the synthesis of a nanoparticles.
  • the present invention provides a means for compartmentalizing and handling solid objects for further microfluidic processing.
  • the present invention can be used to functionalize the surface of a nanoparticle formed by the present method, or other means, by adding or exchanging a ligand or polymer coating present on the nanoparticle surface.
  • the present invention may be used to prepare core/shell structures such as, but not limited to, quantum dots, metal/metaloxides, and alloys in order to provide improved or enhanced properties (e.g. fluorescence properties, magnetic properties, electrical properties, and/or catalytic properties).
  • core/shell structures such as, but not limited to, quantum dots, metal/metaloxides, and alloys in order to provide improved or enhanced properties (e.g. fluorescence properties, magnetic properties, electrical properties, and/or catalytic properties).
  • the present invention may be used to form nanoparticles from materials including, but not limited to, metals, oxides, alloys, sulfides, ceramics, polymers, or a combination thereof.
  • Nanoparticles that may be synthesized using the present invention include, but are not limited to, ZnS, CdS, CoPt, TiO 2 , V 2 O 5 , SiO 2 , PbSe, InAs, ZnIn 2 S 4 , ZnO, CoAu, Au, FePt, Ag, Pt, Pd, Ni, BaTiO 3 , and CoFe 2 O 3 .
  • Nanoparticles synthesized according to the present invention may have shapes including, but not limited to, spherical, with or without a core shell structure, isopolygonal plates, sheets, rods, wires, tubes, or dendrites.
  • Figure 1 is a schematic diagram of an embodiment of the device of the present invention
  • Figure 2 a-b is picture showing the synchronized formation of droplets in the nozzle arms of the present invention
  • Figure 3 is graph plotting the measurement of droplet frequency as a function of the carrier solution flow rate.
  • Figure 4 a-d are graphs plotting the measure of droplet production frequencies for the symmetric case and asymmetric case.
  • Figure 5 a is diagram showing splitting of the carrier solution flow in the asymmetric case
  • Figure 5 b-c are graphs showing decomposition of the asymmetric case into two symmetric cases.
  • Figure 5 d is graph showing the geometrical determination of the droplet production frequency in the asymmetric case.
  • Figure 6 is a graph showing the frequencies measured for various carrier solution flow rates and aqueous phases.
  • Figure 7 a-b is a picture showing the synchronization and coalescence modules of an embodiment of the presently claimed invention.
  • Figure 8 a-b is diagram showing the mixing of droplets in a co-flow and in-line droplet fusion micro fluidic set-up.
  • Figure 9 is a picture showing the formation of iron oxide nanoparticles after fusion of droplet pairs.
  • Figure 10 a is a TEM micrograph showing formation of iron oxide particles
  • Figure 10 b is a HRTEM image of particle showing the particle's spinal plances
  • Figure 10 c is graph showing the electron diffraction pattern indicating the spinel structure.
  • Microfluidic systems are a powerful tool to study and optimize a wide range of biological and chemical reactions [19], and their use for the synthesis of nanoparticles is attracting increasing attention. Compared to conventional bulk synthesis strategies, microfluidic systems allow more precise control of the reaction conditions which can lead to reductions in nanoparticle size and polydispersity [20]. Controlling the synthesis conditions of these particles is critical since this determines their physical properties [25].
  • droplet-based microfluidic systems overcome these limitations by fast mixing in spatially isolated microreactors (droplets) containing well defined quantities of materials [26, 27, 28], and therefore provide a high-level of control of the synthesis conditions [29, 39].
  • reagents are generally brought together in a co-flowing stream just before droplet formation, the reaction occurring later in the microdroplet [26].
  • this method is unsuitable for aggressive or fast reactants which generate precipitates.
  • the present invention utilizes the pre-compartmentalization of reagents into two separate droplet pairs, which are later fused to initiate synthesis of a nanoparticle.
  • the compartmentalization of reagents into separate droplet pairs allows for increased control over the initiation of fast reactions.
  • pre-compartmentalization avoids reagent interaction with the walls of a microfluidic device, as well as premature formation of channel clogging precipitants.
  • Fig 1. provides an embodiment of the device of the present invention.
  • the device 100 comprises a synchronization module 109 and a coalescence module 106, which are in fluid communication with each other.
  • the synchronization module 109 comprises two spatially separated nozzles arms 104 and 105, which are hydrodynamically coupled by the flow of fluid through the central flow channel 101.
  • a first 102 and second 103 lateral flow channel run adjacent to the central flow channel and are in fluid communication with the first 104 and second 105 nozzle, respectively.
  • the device 100 may further comprises a flow control module 107 for introducing and controlling the flow rate of aqueous and non-aqueous fluids into the central and lateral flow channels.
  • the flow control module may be integrated into the microfluidic device ("on-chip"), or separable from the microfluidic device ("off chip”).
  • the flow control module may comprise any system suitable for the controlled injection of aqueous and/or oil based fluids into the lateral and central flow channels of the microfluidic device.
  • the flow control module comprises one or more syringe pumps.
  • the device 100 may also further comprise a collection module 108 in fluid communication with the coalescence module.
  • the collection module may comprise any material and volume suitable for use in storing either temporarily, or for an extended time, the fused droplet pairs produced by the device of the present invention.
  • the collection module has a volume ranging from about 1 pL to 5 L or more.
  • the capacity of the coalescence module is determined by the type and amount of product to by synthesized and can readily be determined by one of ordinary skill in the art.
  • the collection module, and/or microfluidic device further comprises a cooling means or a heating means.
  • the collection module further comprises a means for re -injecting the fused droplet into the first or second lateral channel of the device.
  • the device 100 may optionally include a detection module for detecting the formation of particlulates or other reaction products.
  • Suitable detection means include confocal microscopy, fluorescence detectors, magnetic detectors, or any other suitable means known in the art for monitoring nanoparticle formation.
  • the type of detection system used will depend on the type of nanoparticles or other products being synthesized for which detection is desired.
  • a carrier solution is injected into the central flow channel and a first and second reaction solution are injected into the first and second lateral flow channels respectively.
  • the carrier solution is non-aqueous and the first and second reaction solutions are aqueous.
  • the carrier solution may be an aqueous solution and the first and second reactions solutions are non-aqueous.
  • the device of the present invention may be prepared using any standard microfabrication technique known in the art.
  • the device may be prepared, for example, on poly(dimethylsiloxane) (PDMS) using a soft lithography technique.
  • PDMS poly(dimethylsiloxane)
  • the device may also be fabricated from other substrates including, but not limited to, glass, silicon, and poly (methyl methylacyrlate).
  • the present invention provides a method for synthesizing a solid object, such as nanoparticles, on a microfluidic device.
  • the method employs the use of pre- compartmentalization of reagents into two separate droplet pairs. This pre-compartmentalization prevents undesirable interactions between the wall of the microfluidic device, as well the premature formation of channel blocking precipitants.
  • the pre-compartmentalization of reagents also allows for greater control over initiation and quenching of reactions through the controlled initiation of fusion between droplet pairs.
  • the ability to synthesize solid objects, such as nanoparticles, in a compartmentalized form allows for further processing of products.
  • the encapsulated nanoparticle can be reinjected into a microfluidic device and further processed and modified, such as required for the building of core-shell-particles.
  • the separation of a bulk reactions into multiple identical small volume reactions also allows for increased homogeneity of the reaction.
  • a correlation has been shown between the degree of homogeneity of nucleation and the degree of polydispersity of nanoparticles sizes in nanoparticle synthesis [42].
  • the present device allows for the production of nanoparticles of well defined structure and reduced polydispersity.
  • the methods of the present invention require the formation of a first and second set of droplet pairs comprising a first and second reaction solution respectively.
  • the formation of separate droplet pairs may be carried out using any suitable microfluidic device, including the device of the present invention.
  • the first and second droplet sets are then fused to initiate, quench, or modify a reaction between the reagents of the first and second reaction mixtures. Fusion between droplet pairs can be achieved using standard techniques in the art including, but not limited to, electrocoalescence, heat, changes in concentration of absence of surfactant, or passive fusion (e.g. altering the geometry of a coalescence module).
  • Nanoparticles that may be synthesized using the present invention include, but are not limited to, ZnS, CdS, CoPt, TiO 2 , V 2 O 5 , SiO 2 , PbSe, InAs, ZnIn 2 S 4 , ZnO, CoAu, Au, FePt, Ag, Pt, Pd, Ni, BaTiO 3 , and CoFe 2 O 3 , CdSe, boehmite, iron oxide, Au, Co, Ag, Pd, Cu, BaSO 4 , and CdSe-ZnS core shell nanoparticles.
  • the type of nanoparticle to be synthesized will determine the selection of reagents for the first and second reaction solutions as well as an appropriate carrier solution.
  • the first reaction solution may contain a mixture of FeCl 2 and FeCl 3 salts and the second reaction mixture may comprise a mixture of ammonium hydroxide.
  • a suitable carrier solution may include a solution of a perfluorocarbon oil FC40 and a surfactant.
  • the methods of the present invention may be used to modulate the self-assembly of nanoparticles and the shape by mixing of charged nanoparticles with oppositely charged homopolymers, bloc copolymers or statistical copolymers.
  • the shape of the nanoparticle can be designed by changing, over multiple fusions, reagent concentrations, ionic strength, pH, polymer length, solvent, surfactant/polymer structure, or reaction temperature.
  • the methods of the present invention may be used to functionalize the surface of a nanoparticle by transferring it to a polar or non-polar solvent, by ligand exchange (e.g. citrates, oleic acids, CTAB, DTAB, TOPO) or polymer coating (e.g. polyvinylpyrolidone, polyacid acrylic, polylysine and polysine derivatives, polyethylene glycol and polyethylene glycol derivatives).
  • ligand exchange e.g. citrates, oleic acids, CTAB, DTAB, TOPO
  • polymer coating e.g. polyvinylpyrolidone, polyacid acrylic, polylysine and polysine derivatives, polyethylene glycol and polyethylene glycol derivatives.
  • the methods of the present invention may also be used to prepare core/shell structures such as, but not limited to, quantum dots, metals/metaloxides and alloys, to combine physical properties or enhance properties such as fluorescence, magnetic properties, electrical properties, or catalytic properties.
  • core/shell structures such as, but not limited to, quantum dots, metals/metaloxides and alloys, to combine physical properties or enhance properties such as fluorescence, magnetic properties, electrical properties, or catalytic properties.
  • the synthesis of solid objects the methods of the present invention may be used to conduct biochemical and chemical reactions as well as provide a means for studying those reactions at the single molecule or single cell level.
  • PDMS poly(dimethylsiloxane)
  • Sylgard 184 Dow Corning
  • the PDMS was bound to a glass slide after treatment in an oxygen plasma.
  • the channels were coated with a commercial surface coating agent (Aquapel, PPG Industries) to increase hydrophobicity and subsequently dried with N 2 . Volumetric flow rates were controlled by syringe pumps (PHD2000, Harvard Apparatus).
  • PPD2000 syringe pumps
  • the microfluidic device consists of two adjacent nozzles coupled together by the use of a single central oil stream (Fig. 2).
  • the oil stream comprised a perfluorocarbon oil FC40 (3M) with 2.5% (w/w) of surfactant, made of the ammonium salt of a perfluorinated polyether (PFPE) (Krytox FSL, Dupont) [17] and flowing at a rate Qo.
  • PFPE perfluorinated polyether
  • Two aqueous phases, a mixture of phosphate buffered saline solution (PBS; Sigma) containing either 50 ⁇ M resorufm, or 10 ⁇ M fluorescein are dispensed through the lateral channels x and y at volumetric flow rate rates Qx and Qy.
  • a 488nm laser source focused in the channels through a x40 microscope objective (Leica) excited the droplets.
  • Fluorescent emission intensities were measured simultaneously on two photomultiplier tubes (Hammamatsu) in the range of 495- 520nm (green, fluorescein detection) and 578-657nm (orange, resorufin detection) respectively. Fluorescent detection coupled to a data-acquisition device (Labview - National Instruments) allowed signal processing for droplet frequency measurements and statistical analysis. Additionally, sequences of images were recorded with a high speed camera (Phantom V4.2 at 2 - 10 ⁇ 4 frames per second).
  • the idea behind the design presented in Fig. 2 is that the synchronization is promoted by the formation and presence of a droplet in one of the two nozzle arms forcing the oil through the second arm. Above a certain size limit, the influence of the droplet on the fluidic resistance [18] is strong enough to force droplet breakup in the opposite channel leading to an alternating oil flow.
  • the asymmetric case (Qx Qy) was studied using the same method and, as before, the droplet production frequency was equal in both nozzle arms (Fig. 2 (b)).
  • the measured frequencies lie in between the frequencies obtained in the symmetric case with the corresponding aqueous flow rates (see Fig. 3).
  • deriving an equivalent of the power-law of Eq. 1 for the asymmetric case is not straight-forward.
  • the asymmetric case can be modeled as a combination of two symmetric cases: each side of the device behaves as a symmetric nozzle with oil flow rates 2 eQo and 2(1- e)Qo respectively.
  • the frequency fxy (Qo ) is the solution of Eq. 3:
  • Fig. 4(d) illustrates the geometrical interpretation of Eq. 3 leading to frequency determination: the distances BAxx and BAyy are equal.
  • This construction has been applied to the experimental data of Fig. 3. In all studied cases, the geometrical construction predicts accurately the frequencies of the asymmetric case.
  • the present analysis characterizes a microfluidic module for the controlled production of droplet pairs.
  • the size ratio between paired droplets is directly controlled by the flow rates of the aqueous streams.
  • a well-defined regime of flow rates corresponding to droplet pairing can be achieved when the droplets are wider than the channel width.
  • droplet production frequencies (and volumes) display a power-law behavior with the flow rates - determined experimentally in the symmetric case and generalized to the asymmetric case - which enable the prediction of frequencies and droplet volumes.
  • the 25 ⁇ m deep structures used for fluid channels and electrodes were patterned into poly(dimethylsiloxane) (PDMS) using soft-lithography [39]. Electrodes used for fusion were patterned into the same layer and in close vicinity to the fluidic channels [40].
  • a commercial surface coating agent (Aquapel, PPG Industries) was used to coat the channels.
  • Harvard Apparatus syringe pumps (PHD2000) controlled the flow rates.
  • the continuous oil phase was a perfluorocarbon oil FC40 (3M) with 2.5% (w/w) of surfactant, made of the ammonium salt of a perfluorinated poly ether (PFPE) (Krytox FSL - Dupont) [41].
  • TEM and HRTEM images were recorded with a TOPCON 002B transmission electron microscope, operating at 200 kV, with a point to point resolution of 0.18 nm.
  • Magnetic measurements were performed using a Superconducting Quantum Interference Device Magnetometer (SQUID) magnetometer (Quantum Design MPMS- XL) at 200 K.
  • SQUID Superconducting Quantum Interference Device Magnetometer
  • Magnetic spinel iron oxide nanoparticles were synthesized by co-precipitation of Fe ⁇ /Fe i ⁇ salt solutions by addition of a base. This co-precipiatation leads first to magnetite (Fe3O4) which oxidizes readily subsequently to maghemite (gamma-Fe2 03) when in contact with air [24, 25]. The co-precipitation is so fast that it immediately forms particles and blocks the channels in a co-flow system especially at higher concentrations (data not shown). Droplet fusion can potentially overcome this problem [33], but in the absence of surfactant [33], it is extremely difficult to achieve controlled pairwise droplet fusion [36].
  • the present experiment demonstrates a robust and flexible microfluidic module for the controlled production of droplet pairs based on hydrodynamic coupling.
  • the level of control obtained allows the realization of highly sensitive and reproducible experiments in microreactors, as demonstrated for the precipitation of iron oxide nanoparticles.
  • Such on-chip synthesized particles could potentially be functionalized by an additional droplet fusion step to synthesize core-shell particles optimized for bio-compatibility, drug anchoring, and cell targeting [20].
  • magnetite Fe3O4
  • maghemite ⁇ -Fe2O3
  • This system can be used to control and study a wide range of millisecond kinetic reactions in chemistry and biology and is therefore an additional tool that extends the capabilities of and complements other preexisting microfluidic modules for droplet manipulation.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Dispersion Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Physics & Mathematics (AREA)
  • Fluid Mechanics (AREA)
  • Organic Chemistry (AREA)
  • Analytical Chemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Hematology (AREA)
  • Clinical Laboratory Science (AREA)
  • Physical Or Chemical Processes And Apparatus (AREA)

Abstract

La présente invention concerne des procédés de synthèse d’objets solides, comme des nanoparticules, dans un système microfluidique. En outre, la présente invention concerne un nouveau dispositif microfluidique pour la formation et la fusion de paires de gouttelettes par couplage hydrodynamique de deux buses séparées dans l’espace. Le dispositif et les procédés de la présente invention utilisent la pré-compartimentalisation de solutions de réactif pour accroître le contrôle sur le début et la fin des réactions ainsi qu’un moyen pour capturer les précipités solides ou d’autres objets solides formés après la fusion des paires de gouttelettes.
PCT/IB2009/006478 2008-05-05 2009-05-05 Production microfluidique de paires de gouttelettes WO2009136300A2 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US5045708P 2008-05-05 2008-05-05
US61/050,457 2008-05-05

Publications (2)

Publication Number Publication Date
WO2009136300A2 true WO2009136300A2 (fr) 2009-11-12
WO2009136300A3 WO2009136300A3 (fr) 2010-01-21

Family

ID=41265099

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/IB2009/006478 WO2009136300A2 (fr) 2008-05-05 2009-05-05 Production microfluidique de paires de gouttelettes

Country Status (1)

Country Link
WO (1) WO2009136300A2 (fr)

Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB2524608A (en) * 2012-04-25 2015-09-30 Agilent Technologies Inc Prevention of phase separation upon proportioning and mixing fluids
CN106148159A (zh) * 2015-03-23 2016-11-23 西南大学 一种快速生长微藻藻株高通量筛选系统和方法
CN108273454A (zh) * 2016-12-27 2018-07-13 中国科学院微生物研究所 一种小型反应管中纳升级微液滴融合的方法
WO2021240177A1 (fr) * 2020-05-29 2021-12-02 Ucl Business Ltd Synthèse de nanoparticules
US20220032247A1 (en) * 2018-12-06 2022-02-03 Glaxosmithkline Biologicals Sa Microfluidic devices
CN116425190A (zh) * 2023-04-04 2023-07-14 华东师范大学 一种基于微流控芯片原位生长氧化锌纳米棒的方法

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2004091763A2 (fr) * 2003-04-10 2004-10-28 President And Fellows Of Harvard College Formation et regulation d'especes fluidiques
US20050221339A1 (en) * 2004-03-31 2005-10-06 Medical Research Council Harvard University Compartmentalised screening by microfluidic control

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2004091763A2 (fr) * 2003-04-10 2004-10-28 President And Fellows Of Harvard College Formation et regulation d'especes fluidiques
US20050221339A1 (en) * 2004-03-31 2005-10-06 Medical Research Council Harvard University Compartmentalised screening by microfluidic control

Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB2524608A (en) * 2012-04-25 2015-09-30 Agilent Technologies Inc Prevention of phase separation upon proportioning and mixing fluids
CN106148159A (zh) * 2015-03-23 2016-11-23 西南大学 一种快速生长微藻藻株高通量筛选系统和方法
CN108273454A (zh) * 2016-12-27 2018-07-13 中国科学院微生物研究所 一种小型反应管中纳升级微液滴融合的方法
US20220032247A1 (en) * 2018-12-06 2022-02-03 Glaxosmithkline Biologicals Sa Microfluidic devices
WO2021240177A1 (fr) * 2020-05-29 2021-12-02 Ucl Business Ltd Synthèse de nanoparticules
CN116425190A (zh) * 2023-04-04 2023-07-14 华东师范大学 一种基于微流控芯片原位生长氧化锌纳米棒的方法
CN116425190B (zh) * 2023-04-04 2024-04-12 华东师范大学 一种基于微流控芯片原位生长氧化锌纳米棒的方法

Also Published As

Publication number Publication date
WO2009136300A3 (fr) 2010-01-21

Similar Documents

Publication Publication Date Title
Abou‐Hassan et al. Microfluidics in inorganic chemistry
Krishna et al. Lab-on-a-chip synthesis of inorganic nanomaterials and quantum dots for biomedical applications
Leong et al. Unified view of magnetic nanoparticle separation under magnetophoresis
Zhang et al. On-chip manipulation of continuous picoliter-volume superparamagnetic droplets using a magnetic force
Lu et al. Microfluidic hydrodynamic focusing for synthesis of nanomaterials
Mosayebi et al. Synthesis, functionalization, and design of magnetic nanoparticles for theranostic applications
Al-Hetlani et al. Continuous magnetic droplets and microfluidics: generation, manipulation, synthesis and detection
Azimi et al. Using magnetically excited nanoparticles for liquid–liquid two-phase mass transfer enhancement in a Y-type micromixer
WO2009136300A2 (fr) Production microfluidique de paires de gouttelettes
Uson et al. Single phase microreactor for the continuous, high-temperature synthesis of< 4 nm superparamagnetic iron oxide nanoparticles
Hung et al. Alternating droplet generation and controlled dynamic droplet fusion in microfluidic device for CdS nanoparticle synthesis
Stephens et al. Analytical methods for separating and isolating magnetic nanoparticles
CN103930210A (zh) 微流体系统
WO2009029229A2 (fr) Émulsions de ferrofluides, particules, ainsi que systèmes et procédés de production et d&#39;utilisation de celles-ci
Misuk et al. Micro magnetofluidics: droplet manipulation of double emulsions based on paramagnetic ionic liquids
Yu et al. 3D droplet-based microfluidic device easily assembled from commercially available modules online coupled with ICPMS for determination of silver in single cell
Asfer et al. Retention of ferrofluid aggregates at the target site during magnetic drug targeting
Yang et al. Integration of microfluidic systems with external fields for multiphase process intensification
Mohammadrashidi et al. Experimental and theoretical investigation on the dynamic response of ferrofluid liquid marbles to steady and pulsating magnetic fields
KR20090059837A (ko) 등자기영동 기술을 이용한 미세입자 분리 장치 및등자기영동 기술을 이용한 미세입자 분리 방법
Shah et al. Manipulation of Taylor bubble flow in a magneto-fluidic system
Huang et al. Controlled formation and coalescence of paramagnetic ionic liquid droplets under magnetic field in coaxial microfluidic devices
Singh 3D-printed device for synthesis of magnetic and metallic nanoparticles
CN110914544B (zh) 用于使液体循环的装置和方法
Varma Development of magnetic structures by micro-magnetofluidic techniques

Legal Events

Date Code Title Description
NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 09742473

Country of ref document: EP

Kind code of ref document: A2