EP2427266A1 - Microfluidic apparatus and method for generating a dispersion - Google Patents
Microfluidic apparatus and method for generating a dispersionInfo
- Publication number
- EP2427266A1 EP2427266A1 EP10720042A EP10720042A EP2427266A1 EP 2427266 A1 EP2427266 A1 EP 2427266A1 EP 10720042 A EP10720042 A EP 10720042A EP 10720042 A EP10720042 A EP 10720042A EP 2427266 A1 EP2427266 A1 EP 2427266A1
- Authority
- EP
- European Patent Office
- Prior art keywords
- droplet formation
- dimension
- opening
- formation unit
- feed
- Prior art date
- Legal status (The legal status 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 status listed.)
- Withdrawn
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
- 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
- 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
- B01F25/3142—Injector mixers in conduits or tubes through which the main component flows wherein additional components are introduced at the circumference of the conduit the conduit having a plurality of openings in the axial direction or in the circumferential direction
-
- 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
- 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
- B01J2219/00783—Laminate assemblies, i.e. the reactor comprising a stack of plates
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
- B01J2219/00—Chemical, physical or physico-chemical processes in general; Their relevant apparatus
- B01J2219/00781—Aspects relating to microreactors
- B01J2219/00851—Additional features
- B01J2219/00858—Aspects relating to the size of the reactor
- B01J2219/0086—Dimensions of the flow channels
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
- B01J2219/00—Chemical, physical or physico-chemical processes in general; Their relevant apparatus
- B01J2219/00781—Aspects relating to microreactors
- B01J2219/00889—Mixing
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
- B01J2219/00—Chemical, physical or physico-chemical processes in general; Their relevant apparatus
- B01J2219/00781—Aspects relating to microreactors
- B01J2219/00993—Design aspects
- B01J2219/00995—Mathematical modeling
-
- 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
Definitions
- the invention relates to a system for generating a dispersion.
- the invention also relates to a microchannel apparatus for generating a dispersion, comprising a feed openingfor supplying a to-be- dispersed phase first substance, a guide channel having a second depth which may supply for supplying a continuous phasesubstanceproduct, and a connection channel forming a fluid connection between the feed opening and the guide channel, wherein the connection channel mouths into the guide channel.
- Monodisperse emulsions with droplet size of 0.1-100 ⁇ m are of great importance in both science and industry.
- conventional emulsification techniques yield wide droplet size distributions with typical coefficients of variation (CV) of around 40%.
- CV coefficients of variation
- most of the energy put into the product is dissipated as heat.
- One known class of systems for generating a dispersion that are capable of producing highly monodisperse droplets utilizes so-called single- drop technologies such as flow-focusing devices, co-flowing systems, T-, Y- or cross-junctions and microchannels.
- a feed channel feeds a to-be- dispersed phase substance into a guide channel guiding a continuous phase substance.
- the droplets are formed one at a time (sequentially).
- microchannel Another class of known systems for generating a dispersion is known as so-called microchannel (MC) systems.
- MC microchannel
- an oblong feed channel feeds the to-be-dispersed phase product into a guide channel guiding the continuous phase (product matrix).
- Product matrix continuous phase
- Droplet formation in microchannels is often referred to as spontaneous droplet formation.
- the continuous flow rate is not a parameter suitable for adjusting droplet generation, since droplet formation is not induced by shear forces but by nozzle geometry inducing instabilities in the surface tension on the droplet being formed.
- a low flow rate is still applied for droplet transport from the DFU, since otherwise it would be blocked by the droplets.
- microchannel systems seem to be more suitable for scale-up; especially the straight-through microchannel devices of Kobayashi and co- workers look promising (I. Kobayashi et al., M. Microfluid Nanofluid 2008, 4, 167).
- Kobayashi monodisperse emulsions with droplet diameters of 4.4 - 9.8 ⁇ m with a CV from 5.5 - 2.7% were successfully produced using straight - through MC plates with different channel dimensions.
- the channel efficiency which is the percentage of droplet producing channels, was less than 1% for the plate with the smallest microchannels, and only up to 12.3% for the plates with the larger microchannels. This is probably due to pressure gradients in the system, as was extensively discussed by Abrahamse (A.J.
- Kobayashi also presented submicron channel arrays (I. Kobayashi et al., Colloids & surfaces A 296 (2007), 285) allowing droplets of 1.5 ⁇ m to be generated at a high channel efficiency.
- This system has the disadvantage that the structure is complex, as very small terraces are required having a width of 7.4-8.8 ⁇ m, length of 3.2-5.5 ⁇ m and height of 0.32-1.4 ⁇ m.
- These structures are relatively difficult to produce, especially when the dimensions of all terraces in the system need to be substantially identical (for narrow droplet size distribution).
- a microfluidic apparatus for generating a dispersion comprising a droplet formation unit (DFU) comprising a feed opening for supplying a to-be- dispersed phase first substance to the droplet formation unit, and an oblong droplet formation opening for forming droplets of the to-be-dispersed phase first substance in a continuous phase second substance, the droplet formation opening having a first, smallest dimension, e.g. width, W and a second, largest dimension, e.g. length, L, wherein the second dimension L of the droplet formation opening is more than fifty times the first dimension W of the droplet formation opening, the droplet formation unit having a third dimension, e.g.
- DFU droplet formation unit
- the microfluidic apparatus further comprises a feed structure, in fluid communication with the feed opening for feeding the to-be- dispersed phase first substance to the droplet formation unit, wherein a flow resistance of the droplet formation unit is larger than a flow resistance of the feed structure.
- the to-be-dispersed phase first substance is supplied to the feed opening of the droplet formation unit via the feed structure while the continuous phase second substance is present at or flows across the droplet formation opening.
- the droplet formation opening defines the location where, in use, an interface between the to-be- dispersed phase and the continuous phase is present.
- the droplet formation unit forms the droplets of the first substance in the continuous phase second substance at the droplet formation opening.
- the inventor realised that by providing the droplet formation unit with the oblong droplet formation opening with a second, largest dimension being more than fifty times the first dimension of the opening and having the third dimension being more than two and a half times the first dimension, and having the flow resistance being larger than the flow resistance of the feed structure, it is possible to allow a simultaneous multi-droplet formation mechanism to occur that spontaneously generates many narrowly dispersed droplets simultaneously from one and the same droplet formation unit.
- the droplet formation unit may have a very simple geometry. It will be appreciated that generating a plurality of droplets simultaneously by providing a plurality of droplet formation units, e.g. microchannels, in parallel, e.g. on a single substrate, is also possible, although this will result in a much more complicated geometry than the microfluidic apparatus according to the invention.
- the second dimension L of the droplet formation opening is more than eighty times, preferably more than one hundred times, more preferably more than 150 times, most preferably more than 200-500 times the first dimension W of the droplet formation opening. This allows even more droplets to be formed simultaneously from the same feed channel. It will be appreciated that the second dimension L of the droplet formation opening may even be more than 10.000 times the first dimension W provided that the droplet formation unit remains geometrically stable.
- the droplet formation unit has a cross section, measured transverse, preferably perpendicular, to the flow direction from the feed opening to the droplet formation opening in the droplet formation unit, having a first dimension, parallel to the first dimension W of the droplet formation opening, and a second dimension, parallel to the second dimension L of the droplet formation opening, such that the cross section satisfies the condition that the second dimension of the droplet formation unit is at least fifty times the first dimension of the droplet formation unit over a third dimension, here depth, of the droplet formation unit, measured from the droplet formation opening towards the feed opening that, is equal to or more than two and a half (2.5) times the first dimension of the droplet formation unit.
- the droplet formation unit has a cross section, measured transverse, preferably perpendicular, to the flow direction from the feed opening to the droplet formation opening in the droplet formation unit, such that the first dimension of the droplet formation unit is equal to or more than the first dimension of the droplet formation opening and the cross section satisfies the condition that the second dimension of the droplet formation unit is at least fifty times the first dimension of the droplet formation unit over a third dimension, here depth, of the droplet formation unit, measured from the droplet formation opening towards the feed opening, that is equal to or more than two and a half (2.5) times the first dimension of the droplet formation unit.
- such minimum third dimension assists the droplet formation unit in allowing the simultaneous multi-droplet formation mechanism to occur that spontaneously generates many narrowly dispersed droplets simultaneously from one and the same droplet formation unit. It has also been found that if the third dimension is too small, for instance approximately equal to the first dimension of the droplet formation opening simultaneous multi-droplet formation is prevented. It has been found that such minimum third dimension assists the droplet formation unit in allowing the simultaneous multi- droplet formation mechanism to occur that spontaneously generates many narrowly dispersed droplets simultaneously from one and the same droplet formation unit. It has also been found that if the third dimension is too small, for instance approximately equal to the first dimension of the droplet formation opening simultaneous multi- droplet formation is prevented.
- the droplet formation unit may be formed as a chamber, having a hollow interior, forming a fluid communication between the feed opening and the droplet formation opening.
- the chamber then may have a cross section and depth as described in the preceding paragraph.
- the droplet formation unit may have a cross section that is substantially constant.
- the substantially constant cross section may correspond to the dimensions of the droplet formation opening.
- the substantially constant cross section may be substantially rectangular.
- the droplet formation unit has a (substantially) constant rectangular cross section, having a first dimension W corresponding to the first dimension W of the droplet formation opening, and a second dimension L corresponding to the second dimension L of the droplet formation opening.
- the droplet formation unit has the third dimension D, wherein the cross section is (substantially) constant over the entire third dimension D.
- the second dimension L of the droplet formation unit is more than fifty times the first dimension W of the droplet formation unit
- the third dimension D of the droplet formation unit is more than two and a half (2.5) times the first dimension W of the droplet formation unit.
- the microfluidic apparatus is capable of forming multiple droplets simultaneously from one and the same droplet formation unit when the second dimension of the droplet formation opening is more than approximately fifty times the first dimension of the droplet formation opening, i.e. L/W > 50.
- the droplet formation unit has a substantially constant rectangular cross section corresponding to the dimensions of the droplet formation opening (L x W), wherein the droplet formation unit has a depth D in a flow direction from the feed opening to the droplet formation opening, the volume of the connection channel is LxWxD.
- the feed structure can be defined having a width Wfs in a direction parallel to the width W of the droplet formation opening, a length Lf 8 in a direction parallel to the length L of the droplet formation opening, and a depth Df s in a direction parallel to the depth D of the droplet formation unit.
- the width Wfs of the feed structure is substantially equal to the width W of the droplet formation opening.
- the flow resistance RDFU of the droplet formation unit is larger than the flow resistance Rf s of the feed structure if Df 8 ZLf 8 ⁇ DZL.
- the flow resistance of the droplet formation unit may also simply be made larger than the flow resistance of the feed structure is a cross section of the feed structure is (much) larger than the cross section of the droplet formation unit.
- a feed rate at which the to-be- dispersed phase substance is fed into the connection channel via the feed opening is chosen such that the simultaneous formation of the plurality of droplets does not deplete the connection channel from the to-be- dispersed phase substance.
- the inventor has found that several, up to hundreds of, droplets may be formed per microsecond by a single droplet formation unit according to the invention, depending on the length of the droplet formation unit.
- the feed rate of the to-be-dispersed phase substance is at least one hundred times the volume of the droplet to be formed per microsecond.
- the feed rate is preferably at least 11 microliter per second, preferably at least 30 ⁇ l/s. It will be appreciated that the feed rate may be affected by a flow resistance of a feed channel feeding the to-be-dispersed phase substance to the feed opening of the DFU.
- the apparatus according the invention markedly increases the droplet yield per DFU, thus making the apparatus according the invention very well suited for scaling up production of droplets.
- the latter is of benefit for e.g. producing large amounts of dispersions as will be detailed below.
- the flow rate of the continuous phase product is not a ruling parameter for droplet generation, since the shear forces do not play a role and the droplets are generated by instabilities in the surface tension on the forming droplet, possibly induced by the geometry of the droplet formation opening.
- the microfluidic apparatus further comprises a a collection structure for supplying the continuous phase second substance and collecting the formed droplets, wherein the droplet formation opening mouths into the guide structure.
- the droplet formation unit is formed by a plateau having a width corresponding to the first dimension of the droplet formation opening.
- the first dimension of the droplet formation opening e.g. the width of the plateau
- the first dimension of the droplet formation opening is more than ten times smaller than the depth of the collection structure in a direction along the first dimension of the droplet formation opening, more preferably more than fifty times.
- the process of forming small droplets or bubbles at the droplet formation opening is not disturbed by the presence of physical boundaries of the guide channel.
- the smallest, first dimension of the droplet formation opening is between 0.05 and 25 ⁇ m, more preferably between 0.1 and 2 ⁇ m.
- the preferred size range for the first dimension of the droplet formation opening provides droplets within the desired range, e.g. 0.1 to 200 micron.
- the feed structure, collection structure and plateau are covered with a ceiling.
- the microfluidic apparatus e.g. the feed structure, DFU (e.g. the plateau) and collection structure may be machined, e.g. milled, etched, routed, sand blasted and/or injection moulded, in a substrate, or built using spacers on a, e.g. substantially flat, substrate.
- the feed structure, DFU and collection structure are etched (e.g. in an essentially lithographical process) in a semiconductor substrate, such as a silicon substrate, although other substrate materials are possible, such as glass, metal (e.g. stainless steel) or polymers.
- the substrate may be covered with a ceiling, such as a glass plate, e.g. bonded to the substrate to close the respective structures. It is also possible to use a first substrate as the ceiling of a second substrate.
- the droplet forming unit (e.g. the plateau) has a depth D, in a direction perpendicular to the droplet formation opening, such that, in use, the to-be- dispersed phase substance fills the droplet formation unit over substantially the entire second dimension.
- the suitable depth of the droplet formation unit may depend on a surface tension between the to-be- dispersed phase substance and the continuous phase substance optionally including appropriate emulsifiers or stabilisers.
- the suitable depth D of the droplet formation unit may depend on the second dimension of the droplet formation opening, e.g.
- the depth D of the droplet formation unit e.g. corresponding to a depth of the plateau, may be very short, e.g. in the order of several microns.
- the length Lf of the feed opening is much smaller than the second dimension L, the depth D of the droplet formation unit may need to be much longer, e.g. substantially equal to the second dimension L.
- the invention also relates to a system for generating a dispersion comprising a plurality of microfluidic apparatus according to the invention.
- the system comprises a substrate having therein a plurality of microfluidic apparatus according to the invention.
- the feed structures of the respective apparatus are in fluid communication.
- the collection structures of the respective apparatus are in fluid communication.
- the droplet formation units of the respective apparatus are arranged such that the to-be- dispersed phase substance flows through the respective droplet formation units in parallel.
- a system may be obtained having an increased yield. It will be appreciated that also a plurality of such substrates may be connected in series and/or in parallel.
- Fig. 1 shows a schematic representation of a microfluidic apparatus according to the invention
- Fig. 2 shows a schematic representation of an alternative microfluidic apparatus according to the invention
- Figs. 3a-3e show a top plan view of a microfluidic apparatus according to the invention at various stages during its operation;
- Fig. 4a and 4b show schematic representations of examples of systems according to the invention;
- Fig. 5a shows a schematic representation of an alternative apparatus according to the invention
- Fig. 5b shows a schematic representation of an alternative apparatus according to the invention
- Fig. 6 shows size distributions for emulsions produced with exemplary microfluidic systems, the small picture in the corner is a produced emulsion visualized via microscope;
- Figs. 7a- 7h show a typical shape of an interface between the oil and water phases during droplet formation; and Fig. 8 shows a graphic representation of droplet diameter as a function of pressure applied to the feed structure.
- FIG. 1 shows a schematic representation of a microfluidic apparatus
- the apparatus 1 comprises a droplet formation unit (DFU) 3.
- the droplet formation unit 3 comprises a feed opening 2.
- the droplet formation unit 3 also comprises a droplet formation opening 14.
- the droplet formation opening 14 is oblong, more specifically rectangular.
- the droplet formation opening 14 has a first, smallest dimension or width W.
- the droplet formation opening 14 has a second, largest dimension or length L.
- the droplet formation unit 3 is designed as a connection channel 6 forming a fluid connection between the feed opening 2 and the droplet formation opening 14.
- the connection channel 6 is designed as a slot 8' with a substantially constant cross section.
- the cross section of the connection channel 6 in this example corresponds to the dimensions L and W of the droplet formation opening 14.
- the width of the droplet formation unit 3 is in this example equal to the width W of the droplet formation opening 14.
- the length of the droplet formation unit 3 is in this example equal to the length L of the droplet formation opening 14.
- the connection channel 6 has a depth D, defined as the length in the direction from the feed opening 2 to the droplet formation opening 14.
- the depth of the droplet formation unit 3 is equal to the depth D of the connection channel 6.
- the feed opening 2 is smaller than the droplet formation opening 14, it will be appreciated that the feed opening 2 may also be equal to or larger than the droplet formation opening 14.
- Fig. 1 is schematic and is not drawn to scale.
- the length L of the droplet formation opening 14 may for instance be 5500 ⁇ m
- the width W of the droplet formation opening 14 may be 2.6 ⁇ m
- the depth D of the connection channel 6 may be 25 ⁇ m.
- the second, largest dimension L of the droplet formation opening 14 is, hence, much larger, here more than 4500 times larger, than the first dimension W of the droplet formation opening 14.
- the third dimension D of the droplet formation unit 3 is, hence, larger, here more than nine times larger, than the first dimension W of the droplet formation opening 14.
- the length L& of the feed structure 2' may for instance be 5500 ⁇ m, and the width Wf 8 of the feed structure 2' may for instance be 2.6 ⁇ m, while the depth Df s of the feed structure 2'may be 5 ⁇ m.
- the flow resistance of the droplet formation unit 3 of Fig. 1 is approximately 3.1 m 3 .
- the flow resistance of the feed structure 2' of Fig. 1 is approximately 0.62 nr 3 .
- the flow resistance of the droplet formation unit 3 is larger than the flow resistance of the feed structure 2' in this example.
- the droplet formation unit 3, i.e. the feed opening 2, the droplet formation opening 14 and the connection channel 6, is in this example provided in a substrate 10.
- the feed opening 2 is in fluid connection with a feed structure 2' for supplying a to-be- dispersed phase first substance to the droplet formation unit 3.
- the apparatus 1 of Fig. 1 may be arranged such that the droplet formation opening 14 is in fluid communication with a collection structure in which a continuous phase second substance is present, such that the continuous phase second substance is present at or flows across the droplet formation opening 14.
- the microfluidic apparatus 1 as described thus far with respect to Fig. 1, may be operated as follows.
- a to-be- dispersed phase first substance PD is supplied to the feed opening 2.
- the feed rate at which the to-be- dispersed phase substance PD is supplied to the feed opening 2 may in this example be approximately 340 ⁇ l/s.
- a continuous phase second substance Pc is supplied to the collection structure to be present at the droplet formation opening 14.
- the continuous phase may be an aqueous phase.
- the to-be- dispersed phase may be a fat or gas phase.
- a pressure difference is applied such that the to-be-dispersed phase substance PD is at an overpressure with respect to the continuous phase substance Pc.
- the overpressure may be approximately 0.01-10 bar.
- the to-be-dispersed phase substance PD flows via the feed opening 2 into the droplet formation unit 3.
- the to-be-dispersed phase substance PD will displace continuous phase substance Pc present in the droplet formation unit 3, here in the connection channel 6, until the droplet formation unit 3 is substantially entirely filled with the to-be-dispersed phase substance.
- droplet formation will occur at the droplet formation opening 14. Droplet formation may occur at many locations along the length L of the droplet formation opening 14 simultaneously. The size of the droplets formed at the droplet formation opening 14 will be very homogeneous. Upon formation, the droplets will be forced out of the droplet formation unit 3 into the (flow of) the continuous phase substance Pc.
- Fig. 2 shows a schematic representation of an alternative microfluidic apparatus 1 according to the invention.
- the apparatus 1 comprises a feed structure 2'.
- the feed structure 2' has a depth Df s and a first width Wf s .
- the apparatus 1 further comprises a collection structure 4.
- the collection structure has a depth D cs and a second width W cs .
- the apparatus 1 further comprises a droplet formation unit 3 designed as the connection channel 6 forming a fluid connection between the feed structure 2' and the collection structure 4.
- the droplet formation unit 3 is designed as a plateau 8.
- the droplet formation unit 3 and the feed structure 2' are in fluid communication at the feed opening 2.
- the feed structure 2', collection structure 4 and droplet formation unit 3 are in this example provided in a substrate 10.
- connection channel 6 mouths into the collection structure 4 at the oblong droplet formation opening 14.
- a first, smallest dimension or width W of the droplet formation opening 14 in this example corresponds to the width, W P , of the plateau 8. It will be appreciated that a second, largest dimension or length L of the droplet formation opening 14 in this example corresponds to the length, L p , of the plateau 8.
- Fig. 2 is schematic and is not drawn to scale.
- the length L of the droplet formation opening 14 may for instance be 500 ⁇ m
- the width W of the droplet formation opening 14 may be 1.2 ⁇ m
- the depth D of the connection channel 6 may be 200 ⁇ m.
- the second, largest dimension L of the droplet formation opening 14 is, hence, much larger, here more than 190 times larger, than the first dimension W of the droplet formation opening 14. More in general, the second, largest dimension L of the droplet formation opening 14 is much larger, i.e. more than fifty times larger, than the first dimension W of the droplet formation opening 14. It has been found that better results may be achieved if the second dimension L is more than eighty, preferably more than one hundred, times the first dimension W.
- the droplet formation unit has a constant cross section, measured perpendicular to the flow direction from the feed opening to the droplet formation opening in the droplet formation unit.
- the first dimension of the droplet formation unit W P is in this example equal to the first dimension W of the droplet formation opening.
- the cross section satisfies the condition that the second dimension L p of the droplet formation unit is at least fifty times the first dimension of the droplet formation unit W p .
- the third dimension D of the droplet formation unit 3 is larger, here more than 166 times larger, than the first dimension W of the droplet formation opening 14. More in general, the third dimension D of the droplet formation unit is larger, i.e. more than two and a half times larger, than the first dimension W of the droplet formation opening 14. It has been found that better results may be achieved if the third dimension D is more than five, preferably more than ten, times the first dimension W. It will be appreciated that in the example of Fig.
- the cross section (W p , L p ) of the droplet formation unit satisfies the condition that the second dimension L p of the droplet formation unit is at least fifty times the first dimension of the droplet formation unit W p over the third dimension D of the droplet formation unit, measured from the droplet formation opening 14 towards the feed opening 2, wherein this third dimension D is more than two and a half (2.5) times the first dimension of the droplet formation unit W p .
- the width Wf s of the feed structure 2' is substantially equal to the width W of the droplet formation unit 3.
- the length, Lfs of the feed structure 2' is in this example 300 ⁇ m.
- the depth Df s of the feed structure 2' is in this example 40 ⁇ m.
- the flow resistance of the droplet formation unit 3 RDFU
- RDFU K-D/(W 3 -L)
- K is a geometry dependent contant which is 12 in this case (see Perry's 7 th edition, equations 6-36 and 6-51).
- the flow resistance of the droplet formation unit 3 of Fig. 2 is approximately 2.78 nr 3 .
- the flow resistance of the feed structure 2' of Fig. 2 is approximately 0.93 nr 3 .
- the flow resistance of the droplet formation unit 3 is larger than the flow resistance of the feed structure 2' in this example.
- the first, smallest dimension W of the droplet formation opening 14 is smaller than the width W cs of the collection structure 4.
- the first dimension W is more than ten, preferably more than fifty times smaller than the width W csg of the collection structure 4.
- Fig. 2 may be operated as follows.
- a to-be- dispersed phase first substance PD is supplied to the droplet formation unit 3 via the feed structure 2' in the direction of arrow F (see Fig. 3a).
- the feed rate at which the to-be- dispersed phase substance PD is supplied to the feed opening 2 may in this example be approximately 11 ⁇ l/s.
- a continuous phase second substance Pc is supplied to the collection structure 4 in the direction of arrow G (see Fig. 3a).
- the continuous phase may be an aqueous phase.
- the to-be-dispersed phase may be a fat or gas phase.
- a pressure difference is applied such that the to-be- dispersed phase substance PD is at an overpressure with respect to the continuous phase substance Pc.
- the overpressure may be approximately 0.01-10 bar.
- the to-be-dispersed phase substance PD flows through the feed opening 2 onto the plateau 8 (see Fig. 3b).
- the to-be- dispersed phase substance PD will displace continuous phase Pc product present on the plateau 8 until the plateau is substantially entirely covered with the to-be-dispersed phase substance (see Fig. 3c). It is noted that the corners of the plateau 8 may be free of to-be- dispersed phase substance due to Laplace pressure differences.
- the droplet formation unit 3 will then be substantially entirely filled with the to- be-dispersed substance.
- droplet formation will occur at the edge 16 of the plateau 8 (see Fig. 3d).
- Droplet formation may occur at many locations at the edge 16 of the plateau 8 simultaneously. A size of the droplets formed at the edge 16 of the plateau 8 will be very homogeneous. Again, the corners of the plateau 8 may be not used due to Laplace pressure differences. Upon formation, the droplets will enter the collectyion structure 4 and will be forced out of the apparatus 1 by the flow of the continuous phase substance Pc (see Fig. 3e).
- the width difference between plateau 8 (W p ) and collection structure 4 (Wcs) is believed to play a role in spontaneous droplet generation.
- the width W cs of the collection structure 4 is at least ten times larger than the width Wp of the plateau 8, more preferably at least fifty times larger, most preferably at least eighty times larger.
- the volume V of the connection channel 6 of the DFU 3 is approximately 3.575- 10 5 ⁇ m 3 .
- the volume Wop of the droplets to be formed is at least approximately 1150 ⁇ m 3 (65-W 3 ).
- the volume of the connection channel is approximately 310 times the volume of the droplet to be formed.
- the volume V of the connection channel 6 of the DFU is approximately 1.2-10 5 ⁇ m 3 .
- the volume Vdrop of the droplets to be formed is at least approximately 112 ⁇ m 3 (65-W 3 ).
- the volume of the connection channel is approximately 1070 times the volume of the droplet to be formed.
- the volume V of the connection channel 6 is preferably chosen such that it is at least one hundred times the volume Vdrop of the droplet to be formed.
- the connection channel may contain a sufficient amount of the to-be-dispersed phase substance to supply the to-be-dispersed phase substance to the plurality of droplets being formed simultaneously.
- the feed rate at which the to-be- dispersed phase substance PD is fed into the connection channel 6 via the feed opening 2 is at least one hundred times the volume Vdrop of the droplet to be formed per microsecond. It will be appreciated that the feed rate thus, is chosen such that the simultaneous formation of the plurality of droplets does not deplete the connection channel from the to-be- dispersed phase substance.
- the microfluidic apparatus according to the invention is very well suited for scale-up of the process in an efficient way. Manufacturing the slot or plateau is not a serious challenge for the modern etching techniques.
- the microfluidic apparatus 1 can be considered as self-regulating; the droplet formation position along the droplet formation opening 14 can be at many places at the same time. Moreover, operation of the microfluidic apparatus is straightforward. After pressurization, the connection channel 6 fills with the to-be-dispersed phase substance, and even if some disturbing factor (e.g., a speck of dust) is present, which influences the flow pattern, the relatively large length L of the droplet formation opening 14 with respect to its width W, causes the connection channel 6 to fill regularly.
- some disturbing factor e.g., a speck of dust
- the aspect ratio of the droplet formation opening 14 may be increased to increase the area available for droplet formation. It is for instance possible that the length L of the droplet formation opening is more than 150 times the width W, or even more than 250 times or 500 times.
- the feed structure for the droplet formation unit having such large aspect ratio is designed such that the flow resistance of the feed structure is smaller than the flow resistance of the droplet formation unit.
- Fig. 4a shows an example of a system for generating a dispersion comprising a plurality of microfluidic apparatus according to the invention.
- each connection channel 6.i of the plurality of connection channels 6.i forms a plateau 8.i.
- the width Wf 8 of the feed structure 2' is chosen larger than the width W p of the plateaus 8.i, while the length L& of the feed channel of each apparatus is equal to the length L p of the plateau of each apparatus.
- the flow resistance of the feed structure for each apparatus can easily be chosen to be smaller than the feed resistance of each droplet formation unit.
- the system shown in Fig. 4a may comprise a cover 12 as shown in Fig. 2. It is also possible that a plurality of substrates according to Fig. 4a, are stacked, each subsequent substrate forming the cover for the next, underlying substrate. If the stacked substrates are removably connected, e.g. clamped together, the substrates may be removed from one another, allowing easy cleaning of the substrates.
- Fig. 4b shows another example of a system for generating a dispersion comprising a plurality of microfluidic apparatus according to the invention.
- the connection channels 6.i are designed as the slots as in Fig. 1. Also in this example, all connection channels 6.i may be in fluid communication with a common feed structure 2' and/or mouth into a common collection structure 4.
- Fig. 4a the length Lf 8 at which the feed structure 2' opens into the connection channels 6.i is substantially equal to the length L p , at which the connection channel 6 opens into the collection structure 4. It will be appreciated that hence the entire width of the plateau 8.i can easily be filled with the to-be-dispersed phase substance.
- Figs. 2 and 3c where it is shown that also in that case, where the length Lf 8 of the feed structure 2' at the connection channel 6 is smaller than the length L of the droplet formation opening 14.i at the collection structure 4, the entire width of the plateau is filled with the to-be-dispersed product.
- the length Lf 8 of the feed opening at the connection channel 6 is substantially equal to, or larger than, the second dimension L of the droplet formation opening (e.g. the length L p of the plateau 8) the depth D of the connection channel, e.g. corresponding to a depth D p of the plateau 8, may be very short, e.g. in the order of several microns.
- the depth D of the connection channel 6 may need to be much longer, e.g. substantially equal to the second dimension L, to allow the to-be-dispersed phase substance PD to fill the entire length L of the connection channel 6.
- the flow resistance of the droplet formation unit 3 can easily be made to be larger than the flow resistance of the feed structure.
- the system shown in Fig. 4b can be referred to as a plate-like structure 10 having a plurality of slots therein.
- the length L and width W of these slots is chosen such that the length is more than fifty times the width.
- the slots can be designed such that the feed opening of each slot is substantially of equal size as the droplet formation opening 14.i.
- the depth D of each droplet formation unit is equal to a thickness of the plate-like structure 10.
- the depth D of each droplet formation unit is chosen such that the depth D is at least two and a half times the width W of the slot.
- the feed structure may be formed by a hollow space provided at the bottom side of the plate-like structure, adjacent to the feed openings 2, in fluid communication with said feed openings.
- the dimensions of such feed structure can easily be designed such that the flow resistance of the feed structure is smaller than the flow resistance of the combined droplet formation units. Hence, proper filling of the droplet formation units with the to-be-dispersed phase substance can be assured.
- Fig. 5a shows another example of a microfluidic apparatus 1 for generating a dispersion. In Fig.
- the apparatus 1 comprises the droplet formation unit (DFU) 3.
- the droplet formation unit 3 comprises the feed opening 2.
- the droplet formation unit 3 also comprises the droplet formation opening 14.
- the corners in the droplet formation opening 14, where the respective sections join may serve as droplet nucleation structure to aid in forming the plurality of droplets simultaneously. More in general, such nucleation structure may be formed by a change in direction of the droplet formation opening in the plane of the droplet formation opening.
- Fig. 5b shows yet another example of a microfluidic apparatus 1 for generating a dispersion.
- the apparatus 1 comprises the droplet formation unit (DFU) 3.
- the droplet formation unit 3 comprises the feed opening 2.
- the droplet formation unit 3 also comprises the droplet formation opening 14.
- the nucleation structure acts as a preferential site for droplet generation.
- a distance between two adjacent nucleation structures is chosen to be less than a distance at which droplets would
- the distance between two adjacent nucleation structures is preferably chosen to be 8- W or less, more preferably 5-W or less.
- the distance between two adjacent nucleation structures is not less than Ddrop.
- the droplet formation unit 3 is designed as the slot 8'. It will be appreciated that it is also possible to provide the nucleation structures in the droplet formation unit designed as the plateau 8.
- the examples shown thus far may have been produced by etching the connection channels 6, and optionally the feed structure 2'and collection structure 4, into the substrate 10 from the top side.
- the top side of all structures 2',4,6, may extend in one plane (e.g. the bottom plane of the cover 12) while the bottom side of the structures may extend at different planes due to differences in widths of the respective structures.
- the feed structure 2' and connection channel 6 are machined through the thickness of the substrate 10.
- the connection channel 6 mouths into the collection structure 4 at the oblong opening 14.
- the colection structure 4 is partially bounded by a top surface 22 of the substrate.
- different geometries are also conceivable.
- the continuous phase product flows through the collection structure 4 in a direction substantially parallel to the largest dimension L of the droplet formation opening 14.
- the continuous phase product may flow through the collection structure 4 in a direction substantially parallel to the smallest dimension W of the droplet formation opening 14.
- a silicon microchip substrate 10 of 1.5 x 1.5 cm was provided.
- the structures, also referred to aschannels, 2', 4, 6 were etched in the silicon microchip with the Deep Reactive Ion Etching (DRIE) technique (Micronit Microfluidics, The Netherlands).
- a glass plate 12 was bonded on top of the microchip to close the channels. Hydrophilic surfaces needed for oil-in-water emulsion production were formed in the channels 2', 4, 6, in this way by the silicon and the glass.
- the microfluidic apparatus comprised an oil feed channel 2' of 200 ⁇ m wide (Wf 8 ) and 100 ⁇ m deep (Df 8 ).
- the continuous phase collection channel 4 was also 200 ⁇ m wide (W C8 ) and 100 ⁇ m deep (D C8 ).
- a digital pressure controller (Bronkhorst, The Netherlands) was used to set and control the applied pressure. The pressure needed for hexadecane to flow onto the plateau 8 is determined by Laplace's law.
- Droplet formation at the edge 16 of the plateau 8 occurs at many locations at the edge of the plateau simultaneously, albeit that the corners of the plateau 8 are not used due to Laplace pressure differences.
- monodisperse hexadecane droplets can be formed at frequencies of more than 300 Hz per droplet formation unit.
- the droplet sizes of emulsions produced with both the tested systems have been analyzed through image analysis and with a Mastersizer 2000 (Malvern Instruments Ltd., United Kingdom). The resulting droplet size distributions are depicted in Fig. 6.
- Figs. 7a- 7h show a typical shape of an interface between the oil and water phases during droplet formation. In use the interface between the oil phase and the water phase is present at the droplet formation opening. Each of the Figs. 7a- 7h bears an indication of the time at which the image was taken.
- the droplet grows in time, which results in a decrease in Laplace pressure in the droplet.
- the droplet in Figs. 7a-7h is still connected to the plateau through a neck N.
- the local pressure in the neck N will be approximately equal to the Laplace pressure in the droplet.
- the curvature in the x-y plane (R P 2) can have different values and has to become negative if the droplet radius (Rd) becomes twice as large as the fixed curvature (Rpi) on the plateau 8, due to the decrease of the pressure in the growing droplet.
- Rd droplet radius
- Rpi fixed curvature
- 2 ⁇ / Rd(t) ⁇ / Rp 1 - ⁇ / R P 2(t).
- R P 2 is very large before a droplet has been formed, it assumes a much smaller value as soon as the droplet is present.
- the counter-pressure ⁇ / R P 2(t) stabilizes the neck N, which therefore can be stable for some time.
- the dynamics of the interface between the to-be- dispersed phase product and the continuous phase product at droplet formation opening induce the necking, and are different from the dynamics in prior art microchannel systems.
- the interface between the to-be- dispersed phase and the continuous phase is present at the droplet formation opening. It will be clear that the interface bulges outwardly of the droplet formation unit into the continuous phase product at locations where the droplets are formed and may recede adjacent to these droplet formation locations. Nevertheless, on average the interface between the to-be- dispersed phase and the continuous phase is present at the droplet formation opening.
- Ddrop has in this example been determined with image analysis software (Image Pro Plus), and 100 droplets have been measured.
- An increase in applied pressure results in a substantially constant Ddrop (around 7 ⁇ m) at lower pressures.
- a broad practical pressure range is available at which a monodisperse emulsion can be formed. In this pressure range, 250-350 mbar in this example, the oil supply over the plateau is small compared to the flow into the droplet.
- the droplet diameter increases with the applied pressure.
- the pressure range in which the droplet diameter is substantially constant is larger if the difference between the flow resistance of the feed structure and the droplet formation unit is larger.
- This pressure range may also be enlarged by providing the droplet formation unit having a larger flow resistance at its droplet formation opening than at its feed opening, e.g. a droplet formation unit which has a length L which decreases when going from the feed opening to the droplet formation opening.
- Figs. 4a and 4b the feed structure 2' and the collection structure 4 are substantially parallel. It is for instance also possible that that the feed structure forms branches and the collection structure circumscribes the branches. In such embodiment the connection channels may be substantially radially oriented or otherwise.
- the width of the feed structure is substantially identical to the width of the connection channel.
- the width of the feed structure is substantially identical to the width of the collection structure. It will be appreciated that the width of the feed structure may be chosen to suit the application. Preferably, the width of the feed structure is chosen such that the feed structure does not form such flow restriction as to cause an undue pressure drop in the to-be-dispersed phase product.
- the to-be- dispersed phase product is a liquid fat or oil phase product (or air) and the continuous phase product is a liquid aqueous phase product. It will be appreciated that also other products may be used.
- the to-be- dispensed phase is an aqueous substance and the continuous phase is an oil
- a dispersion of e.g. water in oil.
- a dispersion comprising a solid substance in oil (nano suspension) in water, a (biodegradable) polymer solution into water, a solution of a (biodegradable) polymer and a drug into water, a mixture of a lipid (melt) and a drug into water, a monomer (solution) into water, an oligomer (solution ) into water, a mixture of oil/solvent, cosolvent, polymer, oil, lipids, actives into water.
- the dispersion to be formed may e.g. be any lipophilic fluid mixture and/or solution and/or suspension into any hydrophilic fluid mixture and/or solution and/or suspension and vice versa.
- droplets formed with the microfluidic apparatus according to the invention are transformed into micro particles or nano particles or capsules.
- various techniques may be applied such as cooling, solvent extraction, solvent evaporation, phase separation, (suspension) polymerization, or other chemical reactions.
- the droplets may serve as seed as part of seed swelling techniques for generating particles.
- the particles formed out of droplets produced with the microfluidic apparatus according to the invention may be used for controlled release drug delivery and/or for application in separation processes in the life sciences industries. Examples are PLGA microsphere based drug delivery systems, magnetic polymer or glass beads. Particle based contrast agents.
- the droplets may also act as reaction chambers in processes such as emulsion PCR.
- the to-be-dispersed phase product is a gas (mixture) or vapour, so as to manufacture a dispersion of bubbles in a (liquid) continuous phase product.
- the continuous phase product is a gas (mixture) or vapour, so as to manufacture a mist of droplets, e.g. in air.
- Such droplets may e.g. be dried so as to yield a spray dried to-be-dispersed product.
- the to-be-dispersed phase product already is a dispersion.
- the to-be-dispersed phase product is a dispersion of an aqueous phase product, such as water, in a fat phase product, such as an oil.
- the microfluidic apparatus may then yield a fine dispersion of water filled oil droplets in e.g. an aqueous continuous phase product, for instance for use in so-called "light" food products.
- the water within the oil droplets may comprise an additive such as a flavour, colorant and/or medicine.
- the to-be-dispersed product is a pre-mix, such as a course dispersion comprising large droplets. Feeding the pre-mix through the droplet formation opening of the microfluidic apparatus according to the invention, causes the large droplets in the premix to be broken up into small droplets dispersed into the continuous phase product. Reducing the droplet size of the pre-mix in this way is herein also considered to constitute generating a dispersion, viz. having smaller droplets and/or a narrower droplet size distribution.
- any reference signs placed between parentheses shall not be construed as limiting the claim.
- the word 'comprising' does not exclude the presence of other features or steps then those listed in a claim.
- the words 'a' and 'an' shall not be construed as limited to 'only one', but instead are used to mean 'at least one', and do not exclude a plurality.
- the mere fact that certain measures are recited in mutually different claims does not indicate that a combination of these measures cannot be used to advantage.
Abstract
Description
Claims
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
NL2002862A NL2002862C2 (en) | 2009-05-08 | 2009-05-08 | Microfluidic apparatus and method for generating a dispersion. |
PCT/NL2010/050268 WO2010128858A1 (en) | 2009-05-08 | 2010-05-10 | Microfluidic apparatus and method for generating a dispersion |
Publications (1)
Publication Number | Publication Date |
---|---|
EP2427266A1 true EP2427266A1 (en) | 2012-03-14 |
Family
ID=41479285
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
EP10720042A Withdrawn EP2427266A1 (en) | 2009-05-08 | 2010-05-10 | Microfluidic apparatus and method for generating a dispersion |
Country Status (4)
Country | Link |
---|---|
EP (1) | EP2427266A1 (en) |
CN (1) | CN102458630B (en) |
NL (1) | NL2002862C2 (en) |
WO (1) | WO2010128858A1 (en) |
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US20210362159A1 (en) * | 2018-10-23 | 2021-11-25 | Shenzhen Biorain Biotechnology Co., Ltd. | Microfluidic chip |
Families Citing this family (15)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2014018562A1 (en) * | 2012-07-23 | 2014-01-30 | Bio-Rad Laboratories, Inc. | Droplet generation system with features for sample positioning |
US9409174B2 (en) * | 2013-06-21 | 2016-08-09 | Bio-Rad Laboratories, Inc. | Microfluidic system with fluid pickups |
CN103343090B (en) * | 2013-07-12 | 2014-09-17 | 湖南工程学院 | Integrated multifunctional controllable cell control and analysis micro-fluidic chip and application thereof |
EP2962751B1 (en) * | 2014-07-03 | 2017-04-05 | Helmholtz-Zentrum Geesthacht Zentrum für Material- und Küstenforschung GmbH | Method of forming droplets in a multiple-phase system |
US10544413B2 (en) | 2017-05-18 | 2020-01-28 | 10X Genomics, Inc. | Methods and systems for sorting droplets and beads |
CN117143960A (en) | 2017-05-18 | 2023-12-01 | 10X基因组学有限公司 | Method and system for sorting droplets and beads |
US10610865B2 (en) | 2017-08-22 | 2020-04-07 | 10X Genomics, Inc. | Droplet forming devices and system with differential surface properties |
WO2019083852A1 (en) | 2017-10-26 | 2019-05-02 | 10X Genomics, Inc. | Microfluidic channel networks for partitioning |
US20190321791A1 (en) * | 2018-04-19 | 2019-10-24 | President And Fellows Of Harvard College | Apparatus and method for forming emulsions |
US11130120B2 (en) * | 2018-10-01 | 2021-09-28 | Lifeng XIAO | Micro-pipette tip for forming micro-droplets |
WO2020176882A1 (en) * | 2019-02-28 | 2020-09-03 | 10X Genomics, Inc. | Devices, systems, and methods for increasing droplet formation efficiency |
US11919002B2 (en) | 2019-08-20 | 2024-03-05 | 10X Genomics, Inc. | Devices and methods for generating and recovering droplets |
EP4119221A4 (en) * | 2020-03-13 | 2024-04-17 | Japan Science & Tech Agency | Microdroplet/bubble generation device |
US20230122421A1 (en) | 2020-04-01 | 2023-04-20 | Merck Patent Gmbh | Emulsification device |
CN113278494A (en) * | 2021-05-07 | 2021-08-20 | 深圳市第二人民医院(深圳市转化医学研究院) | Digital PCR microdroplet generation chip |
Family Cites Families (14)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
MY110990A (en) * | 1993-06-03 | 1999-07-31 | Atomaer Pty Ltd | Multiphase staged passive reactor |
DE19541266A1 (en) * | 1995-11-06 | 1997-05-07 | Bayer Ag | Method and device for carrying out chemical reactions using a microstructure lamella mixer |
JP2981547B1 (en) * | 1998-07-02 | 1999-11-22 | 農林水産省食品総合研究所長 | Cross-flow type microchannel device and method for producing or separating emulsion using the device |
DE19917148C2 (en) * | 1999-04-16 | 2002-01-10 | Inst Mikrotechnik Mainz Gmbh | Process and micromixer for producing a dispersion |
DE19928123A1 (en) * | 1999-06-19 | 2000-12-28 | Karlsruhe Forschzent | Static micromixer has a mixing chamber and a guiding component for guiding fluids to be mixed or dispersed with slit-like channels that widen in the direction of the inlet side |
JP3511238B2 (en) * | 2000-10-13 | 2004-03-29 | 独立行政法人食品総合研究所 | Microsphere manufacturing method and manufacturing apparatus |
KR100932418B1 (en) * | 2003-06-11 | 2009-12-17 | 아사히 가라스 가부시키가이샤 | Method for producing inorganic spheres and apparatus |
JP4520166B2 (en) * | 2004-02-02 | 2010-08-04 | 独立行政法人農業・食品産業技術総合研究機構 | Resin microchannel substrate and manufacturing method thereof |
US20070160474A1 (en) * | 2004-02-06 | 2007-07-12 | Kazuhiro Iida | Regulation structure, separation device and gradient forming device, and microchip using the same |
EP1804964A1 (en) * | 2004-10-01 | 2007-07-11 | Velocys Inc. | Multiphase mixing process using microchannel process technology |
JP3723201B1 (en) * | 2004-10-18 | 2005-12-07 | 独立行政法人食品総合研究所 | Method for producing microsphere using metal substrate having through hole |
JP3772182B2 (en) * | 2004-10-18 | 2006-05-10 | 独立行政法人食品総合研究所 | Microsphere manufacturing apparatus and manufacturing method |
KR20080073934A (en) * | 2007-02-07 | 2008-08-12 | 삼성전자주식회사 | Valve filler and valve unit with the same |
US20090023189A1 (en) * | 2007-05-18 | 2009-01-22 | Applera Corporation | Apparatus and methods for preparation of subtantially uniform emulsions containing a particle |
-
2009
- 2009-05-08 NL NL2002862A patent/NL2002862C2/en not_active IP Right Cessation
-
2010
- 2010-05-10 WO PCT/NL2010/050268 patent/WO2010128858A1/en active Application Filing
- 2010-05-10 EP EP10720042A patent/EP2427266A1/en not_active Withdrawn
- 2010-05-10 CN CN201080030504.8A patent/CN102458630B/en not_active Expired - Fee Related
Non-Patent Citations (1)
Title |
---|
See references of WO2010128858A1 * |
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US20210362159A1 (en) * | 2018-10-23 | 2021-11-25 | Shenzhen Biorain Biotechnology Co., Ltd. | Microfluidic chip |
Also Published As
Publication number | Publication date |
---|---|
CN102458630B (en) | 2014-08-13 |
NL2002862C2 (en) | 2010-11-09 |
CN102458630A (en) | 2012-05-16 |
WO2010128858A1 (en) | 2010-11-11 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
NL2002862C2 (en) | Microfluidic apparatus and method for generating a dispersion. | |
US8100348B2 (en) | Device for generating microspheres from a fluid, method of injecting at least one first fluid into a second fluid, and an injection plate | |
Serra et al. | Microfluidic‐assisted synthesis of polymer particles | |
van Dijke et al. | Simultaneous formation of many droplets in a single microfluidic droplet formation unit | |
Sahin et al. | Partitioned EDGE devices for high throughput production of monodisperse emulsion droplets with two distinct sizes | |
JP5886329B2 (en) | Multiphase mixing process using microchannel process technology | |
Vladisavljević et al. | Effect of dispersed phase viscosity on maximum droplet generation frequency in microchannel emulsification using asymmetric straight-through channels | |
Kobayashi et al. | Straight-through microchannel devices for generating monodisperse emulsion droplets several microns in size | |
JP2019089067A (en) | Device and method for forming droplet with relatively single dispersion | |
EP3359293B1 (en) | Microfluidic droplet generator with controlled break-up mechanism | |
US20180085762A1 (en) | Droplet Generator Based on High Aspect Ratio Induced Droplet Self-Breakup | |
Liu et al. | Microfluidic step emulsification techniques based on spontaneous transformation mechanism: A review | |
KR19990067311A (en) | Process for preparing dispersions and performing chemical reactions in the dispersed phase | |
EP2827979A1 (en) | Apparatus and method for mass producing a monodisperse microbubble agent | |
JP2005144356A (en) | Micro flow path structure and method for producing fine particle using the same | |
CA3111609A1 (en) | A micro-pipette tip for forming micro-droplets | |
EP3600639B1 (en) | Device and method for generating droplets | |
US20170151537A1 (en) | Mixing of Fluids | |
JP2006239594A (en) | Emulsification apparatus, continuous emulsification apparatus and emulsification method | |
JP2005279523A (en) | Microchannel structure | |
Deydier et al. | Scaled-up droplet generation in parallelised 3D flow focusing junctions | |
JP4470640B2 (en) | Fine particle manufacturing method and microchannel structure therefor | |
Hoppe et al. | A new technology for producing mono-disperse macroemulsions | |
Izumida et al. | Production of quasi-monodisperse emulsions with large droplets using a micromachined device | |
Vladisavljević et al. | Emulsion Formation in membrane and microfluidic devices |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
PUAI | Public reference made under article 153(3) epc to a published international application that has entered the european phase |
Free format text: ORIGINAL CODE: 0009012 |
|
17P | Request for examination filed |
Effective date: 20111202 |
|
AK | Designated contracting states |
Kind code of ref document: A1 Designated state(s): AL AT BE BG CH CY CZ DE DK EE ES FI FR GB GR HR HU IE IS IT LI LT LU LV MC MK MT NL NO PL PT RO SE SI SK SM TR |
|
DAX | Request for extension of the european patent (deleted) | ||
17Q | First examination report despatched |
Effective date: 20120925 |
|
GRAP | Despatch of communication of intention to grant a patent |
Free format text: ORIGINAL CODE: EPIDOSNIGR1 |
|
RIC1 | Information provided on ipc code assigned before grant |
Ipc: B01J 19/00 20060101ALI20141007BHEP Ipc: B01F 3/08 20060101ALI20141007BHEP Ipc: B01F 5/04 20060101ALI20141007BHEP Ipc: B01F 13/00 20060101ALI20141007BHEP Ipc: B01L 3/00 20060101AFI20141007BHEP |
|
INTG | Intention to grant announced |
Effective date: 20141023 |
|
GRAP | Despatch of communication of intention to grant a patent |
Free format text: ORIGINAL CODE: EPIDOSNIGR1 |
|
INTG | Intention to grant announced |
Effective date: 20150212 |
|
STAA | Information on the status of an ep patent application or granted ep patent |
Free format text: STATUS: THE APPLICATION IS DEEMED TO BE WITHDRAWN |
|
18D | Application deemed to be withdrawn |
Effective date: 20150623 |