Microdroplet generation apparatus and method

Abstract

A column apparatus for generating microdroplets comprises a hollow tube body (12) and a stereoperiodic cavity structure (18) located within the hollow tube body (12). The stereoperiodic cavity structure (18) is a stereoregular microstructure, or an inverse of a stereoregular microstructure, consisting of multiple stacked spheres (20). The column apparatus (10) allows for the supply of a dispersion system (30) comprising a continuous phase (32) and a dispersed phase (34). As the dispersion system (30) passes through the stereoperiodic cavity structure (18), isolated units of the dispersed phase (34) are sheared into microdroplets under the shear stress of the continuous phase (32) fluid, gradually decreasing in size from the original macrodroplets. These microdroplets, when further matured, have a wide range of applications in many technical fields, as well as a method for generating microdroplets using the aforementioned column apparatus (10).

Description

[Technical Field]

[0001] The present invention relates to a microdroplet generation technology, more specifically to an apparatus capable of shearing a fluid into microdroplets of uniform size and dispersing them in another immiscible fluid, and also to further maturing the generated microdroplets into microspheres. This technology, the microdroplets generated thereby, and the microparticles formed by maturing the microdroplets all have a wide range of applications in various technical fields. [Background technology]

[0002] In the prior art, a device for generating microdroplets is known, as shown in Figures 1A and 1B. In Figure 1A, a first-phase fluid 90 enters a cavity 91 having at least one nozzle 92 on one side, and at least one actuator 93 is positioned inside the cavity 91. This actuator 93 may be a heater that uses the high temperature generated by instantaneous heating to vaporize a portion of the fluid, forming pulsed bubbles 94 of the second phase (Figure 1B). Since the second-phase fluid 94 (bubbles) is immiscible with the first-phase fluid 90, the second-phase bubbles prevent the fluid from entering the right side of the cavity 91 (located below the nozzle), and apply a strong shear pressure to the first-phase fluid 90 below the nozzle. This shear pressure pushes the fluid 90 out of the nozzle 92. Due to the interaction mechanism between the shear pressure and the fluid and the nozzle shape (which creates a complex vortex effect near the nozzle), droplets can be ejected through this interaction process. By repeating the two steps shown in Figures 1A and 1B (stopping the actuator to allow fluid entry, and then starting the actuator to generate pulsed bubbles), continuous droplet generation becomes possible.

[0003] However, this known technology has the following drawbacks: its structure is complex, the actuator design is complex, and it requires the integration of related circuits and systems to control the actuator. The system (of this device) is complex and expensive. Furthermore, when a large number of droplets need to be generated, this method is very energy-intensive, expensive, and completely impractical. In addition, high-temperature actuators are not suitable for all fluids, and the resulting droplets may have different properties from the original fluid. Overcoming and addressing these drawbacks is necessary. Therefore, there is still a strong demand in the relevant industry for microdroplet generators that are simple in structure, easy to operate, and low in cost. [Overview of the project]

[0004] The present invention aims to solve the above problems and thereby provide a column apparatus for generating microdroplets. The apparatus has at least one input end and at least one output end, allowing a dispersion system consisting of a continuous phase and a dispersed phase to be supplied through at least one input end and then discharged through at least one output end. A stereoperiodic cavity structure is arranged within the column apparatus, which may be a stereoregular microstructure consisting of a plurality of packed monodisperse spheres (where the gaps between the spheres form narrow flow channels that allow the dispersion system to pass through), or an inverse stereoregular microstructure (where a plurality of regularly arranged spherical cavities form a stereoregular porous microstructure, and the connecting holes between these spherical cavities form narrow flow channels that allow the dispersion system to pass through). The inventors have found that when the dispersion system is supplied into the column apparatus of the present invention through at least one input end, the continuous phase fluid interacts with the stereoperiodic cavity structure inside the column apparatus, creating a complex vortex effect at the opening of the narrow flow channels. As a result, the dispersed phase gradually decreases in size from the original macrodroplets under the shear stress of the continuous phase fluid and is further sheared into microdroplets. These microdroplets can be separated from the continuous phase fluid after further maturation and used independently.

[0005] Therefore, the first embodiment of the present invention provides a column apparatus for generating microdroplets, and the column apparatus is

[0006] A hollow tube body having at least one input terminal and at least one output terminal located on the opposite side of the at least one input terminal,

[0007] The invention comprises a three-dimensional periodic cavity structure disposed inside a hollow tube body, the three-dimensional periodic cavity structure being selected from the group consisting of a three-dimensionally regular microstructure formed by a plurality of packed spheres and an inverse structure of a three-dimensionally regular microstructure. This structure allows a dispersion system to be supplied through at least one input end, pass through the three-dimensional periodic cavity structure, and then discharged through at least one output end. The dispersion system includes a continuous phase and a dispersion phase immiscible with the continuous phase.

[0008] A second embodiment of the present invention provides a method for generating microdroplets using a column apparatus, wherein the column apparatus is

[0009] A hollow tube body having at least one input terminal and at least one output terminal located on the opposite side of the at least one input terminal,

[0010] The invention comprises a stereoperiodic cavity structure disposed within a hollow tube body, the stereoperiodic cavity structure being selected from the group consisting of stereoregular microstructures formed by a plurality of packed spheres and inverse structures of stereoregular microstructures. This structure allows a dispersion system to be supplied through at least one input end, pass through the stereoperiodic cavity structure, and then discharged through at least one output end. The dispersion system includes a continuous phase and a continuous phase immiscible dispersion phase.

[0011] This method,

[0012] A) A step of supplying a dispersion system into at least one input terminal, wherein the dispersed phase in the dispersion system consists of one or more macrodroplets dispersed in a continuous phase,

[0013] B) A step of causing the dispersion system to pass through a three-dimensional periodic cavity structure so that one or more macrodroplets are sheared into multiple microdroplets dispersed in a continuous phase,

[0014] C) The process includes discharging the continuous phase and microdroplets from the column apparatus through at least one output terminal. [Brief explanation of the drawing]

[0015] [Figure 1A] This is a schematic diagram showing a conventional microdroplet generation device and its operating mode. [Figure 1B] This is a schematic diagram showing a conventional microdroplet generation device and its operating mode. [Figure 2] Figure 2 is a schematic diagram of a column apparatus according to one specific embodiment of the present invention. [Figure 3A] This is a schematic diagram of a stereoperiodic cavity structure according to a specific embodiment of the present invention, showing a stereoregular microstructure composed of multiple filled spheres. [Figure 3B] This is a schematic diagram of a three-dimensional periodic cavity structure according to another specific embodiment of the present invention, showing the structure as a three-dimensionally regular porous microstructure. [Figure 4] Figure 4 is a flow chart for generating microdroplets using the column apparatus of the present invention. [Figure 5] Figure 5 shows the relationship between flow rate and dispersed phase microdroplet size for a column apparatus of a specific embodiment of the present invention at different packed sphere diameters and packing lengths. [Figure 6] Figure 6 shows the relationship between flow rate and dispersibility of dispersed phase microdroplet size for a column apparatus of a specific embodiment of the present invention at different packed sphere diameters and packing lengths. [Modes for carrying out the invention]

[0016] The present invention provides a column device for generating microdroplets suitable for treating a dispersion system, in which macro-droplets dispersed in a continuous phase are sheared into micro-droplets of uniform size. FIG. 2 is a schematic view of a column device 10 according to a specific embodiment of the present invention, which includes a hollow tube body 12 having at least one input end 14 and at least one output end 16 disposed on the opposite side of the at least one input end 14. In a specific embodiment, the hollow tube body 12 is made of a material selected from the group consisting of stainless steel, titanium, quartz, glass, hard plastic (such as polypropylene), formed into a cylindrical, rectangular, or polygonal tube, and a three-dimensional periodic cavity structure 18 is disposed inside the hollow tube body 12.

[0017] According to a specific embodiment of the present invention, the three-dimensional periodic cavity structure 18 may be a three-dimensional regular microstructure composed of a plurality of filled spheres 20 as shown in FIG. 3A. The three-dimensional regular microstructure refers to a microstructure composed of spheres 20 arranged in a three-dimensional regular manner. The term "regularly" as used herein means that the distance between the spheres 20 exhibits regular periodicity, preferably the distance between the spheres 20 is substantially equal. The spheres 20 constituting such a microstructure typically have a uniform particle size, shape, chemical composition, internal structure, or surface characteristics in order to facilitate arranging the spheres 20 in a regular lattice-like structure. In a preferred specific embodiment, the spheres 20 have monodispersity, which means that the spheres 20 have a narrow size distribution and their particle sizes are very uniform.

[0018] Sphere 20 can be made from any inert material that does not undergo substantial physical or chemical reactions with the dispersion system. Non-limiting examples of suitable materials include metallic materials, as well as non-metallic materials such as polymeric and inorganic materials. Examples of metallic materials include, but are not limited to, gold, silver, copper, platinum, aluminum, zinc, cerium, thallium, barium, yttrium, zirconium, tin, titanium, tungsten, cadmium, iron, and their alloys (such as stainless steel). Polymeric materials are preferably thermoplastic polymers. Examples of such materials include, but are not limited to, polymer homopolymers such as polystyrene (PS), polymethyl methacrylate (PMMA), polybutyl methacrylate (PBMA), polymethyl acrylate, poly(ethyl acrylate) (PEA), poly(butyl acrylate) (PBA), polybenzyl methacrylate, poly-α-methylstyrene, polyphenyl methacrylate, polydiphenyl methacrylate, and polycyclohexyl methacrylate, as well as polymer copolymers such as styrene-acrylonitrile copolymer, styrene-methyl methacrylate copolymer, styrene-butyl methacrylate copolymer, and styrene-butyl acrylate copolymer. Examples of inorganic materials include, but are not limited to, titanium dioxide, zinc oxide, cerium oxide, tin oxide, thallium oxide, barium oxide, aluminum oxide, yttrium oxide, zirconium oxide, copper oxide, nickel oxide, silicon oxide, as well as ceramics, glass, and quartz.

[0019] Those skilled in the field of geometric structures will understand that the characteristics and arrangements of the three-dimensional periodic cavity structures described herein can include various filling patterns. In a preferred specific embodiment where the spheres 20 have monodispersity, when the spheres 20 are filled within the hollow tube body 12, they tend to be stacked in the most dense configuration to form a three-dimensional periodic cavity structure 18. That is, adjacent microspheres are in contact with each other, the centers of any three adjacent microspheres form an equilateral triangle, the coordination number of each microsphere is 12, and a plurality of triangular voids are left between adjacent microspheres. At least a portion of the spheres 20 of the three-dimensional periodic cavity structure 18 is preferably arranged in the most dense configuration. That is, at least 50% of the spheres 20 of the three-dimensional periodic cavity structure 18, more preferably at least 60% of the spheres 20, for example at least 70% of the spheres 20, are arranged in the most dense configuration. The most dense configurations include, but are not limited to, three-dimensional hexagonal close packing (hcp), three-dimensional face-centered cubic packing (fcc), three-dimensional body-centered cubic packing (bcc), and combinations thereof. However, due to manufacturing process and material limitations, the spheres 20 cannot achieve an absolutely uniform size, and their configurations are not necessarily limited to perfect spheres and can be, for example, ellipsoids, which will be understood by those skilled in the relevant technical field. Therefore, the three-dimensional periodic cavity structure 18 composed of the spheres 20 has periodicity in a macroscopic and statistically averaged view. Inevitably, crystal-like defects such as voids, displacements, stacking defects, etc. exist in the structure, but these defects do not impair the core concept or intended technical effects of the present invention. The pore system of the three-dimensional periodic cavity structure 18 composed of a plurality of spheres 20 is mainly formed by the voids 22 between the spheres 20, thereby defining narrow flow channels for shearing the dispersion system.

[0020] According to another specific embodiment of the present invention, the stereoperiodic cavity structure 18 may be the inverse of the stereoregular microstructure described above, which is structurally a stereoregular porous microstructure. As shown in Figure 3B, the stereoregular porous microstructure has a plurality of regularly arranged spherical cavities 24 and a plurality of connecting holes 26 connecting the spherical cavities 24. As used herein, the term “regular” means that the distances between the spherical cavities 24 exhibit regular periodicity, preferably the distances between the spherical cavities 24 are approximately equal. The pore system of the stereoregular porous microstructure consists of the spherical cavities 24 and the connecting holes 26. As described below, these connecting holes 26 constitute narrow flow channels for shearing the dispersion system. In a preferred specific embodiment, at least a portion of the spherical cavities 24 in the stereoperiodic cavity structure 18 are arranged in the most densely packed configuration. That is, at least 50%, more preferably at least 60%, of the spherical cavities 24 in the three-dimensional periodic cavity structure 18, for example, at least 75%, are arranged in the most densely packed configuration. The most densely packed configuration includes, but is not limited to, three-dimensional hexagonal close packing (hcp), three-dimensional face-centered cubic packing (fcc), three-dimensional body-centered cubic packing (bcc), and combinations thereof. However, due to limitations in the manufacturing process and materials, the spherical cavities 24 cannot achieve an absolutely uniform size, and their configuration is not necessarily limited to perfect spherical cavities, but could be, for example, elliptical cavities, as will be understood by those skilled in the art. Thus, the three-dimensional periodic cavity structure 18 formed by the combination of spherical cavities 24 and connecting holes 26 has periodicity in a macroscopic and statistically averaged view. Inevitably, crystal-like defects such as voids, misalignments, and stacking faults are present in the structure, but these defects do not impair the core concept or intended technical effect of the present invention.

[0021] A method for producing a stereoregular porous microstructure may include the following steps: First, multiple spheres 20 are stacked to form the stereoregular microstructure described above. Next, the stereoregular microstructure is used as a template, and the inverse material penetrates into the voids of the template to form the inverse structure. Finally, the template is removed by calcination, extraction, or other methods to produce a stereoregular porous microstructure. The inverse material may include, but is not limited to, metals such as gold, silver, copper, nickel, platinum, and nickel-tungsten alloys; oxides such as zinc oxide, silica, and cuprous oxide; and polymer materials such as polystyrene, polyacrylate, polymethacrylate, acrylamide, polypyrrole, polyethylene, polypropylene, polyvinyl chloride, and silica gel. The filling of the inverse material can be carried out by centrifugation, vacuum extraction, pressure extrusion, sputtering, electroplating, chemical vapor deposition, atomic layer deposition, and other methods. If the inverse material is a polymer material, monomers or precursors of the polymer material may be filled into the voids before maturation and molding.

[0022] As used herein, the term “dispersion system” refers to a system comprising a continuous phase and a dispersed phase that is immiscible with the continuous phase. As used herein, the “continuous phase” refers to interconnected phases of the same substance that can accommodate some isolated heterogeneous substances. The dispersed phase is a phase consisting of isolated substances dispersed in the aforementioned continuous phase, with each isolated unit surrounded by the continuous phase. In one specific embodiment, the continuous phase and the dispersed phase are immiscible fluids (which can be liquids or gases), and the dispersion system is in the form of a water-in-oil emulsion or an oil-in-water emulsion. In another specific embodiment, the continuous phase is an aqueous liquid or an oily liquid, while the dispersed phase is a gas. In a particular specific embodiment, individual dispersed units in the dispersed phase may themselves contain two immiscible phases; that is, the dispersed units themselves may be an oil-in-water emulsion or a water-in-oil emulsion.

[0023] Figure 4 is a flowchart of a method for generating microdroplets using the column apparatus of the present invention. The method includes step A of supplying a dispersion system into the column apparatus via an input terminal; step B of passing the dispersion system through a three-dimensional periodic cavity structure inside the column apparatus to shear one or more macrodroplets in the dispersion system into microdroplets; and step C of discharging the continuous phase and microdroplets from the column apparatus via an output terminal.

[0024] Referring simultaneously to Figures 2 and 4, the dispersion system 30 includes a continuous phase 32 and a dispersion phase 34 that is immiscible with the continuous phase 32, the dispersion phase 34 consisting of one or more dispersion units dispersed within the continuous phase 32. Due to surface tension, these dispersion units are dispersed within the continuous phase 32 in the form of macrodroplets 36. The dispersion system 30 may be supplied into the column apparatus 10 via the input end 14. As previously mentioned, the stereoperiodic cavity structure 18 is provided within the column apparatus. As the dispersion system 30 enters and flows through the stereoperiodic cavity structure 18, the fluid of the continuous phase 32 applies shear stress (shear force) to the macrodroplets 36 while flowing. If the shear stress is sufficiently large, the macrodroplets 36 are sheared into smaller microdroplets 38. The continuous phase 32, along with the microdroplets 38, is then discharged from the column apparatus 10 via the output end 16. In particular, the geometric size of the microdroplets 38 depends on the structural shape of the column apparatus 10 and parameters such as the fluid properties and flow rate of the continuous phase fluid 32. These parameters are described in more detail below.

[0025] As an example, the three-dimensional periodic cavity structure 18 is formed by the filling of multiple spheres 20 shown in Figure 3A, and according to the academic paper by Barth et al. (see HG Barth & FJ Carlin Jr., Journal of Liquid Chromatography, (1984) 7: 9, 1717-1738), the shear stress generated in the three-dimensional periodic cavity structure 18 can be described by the following equation.

[0026] Shear stress (τ), fluid viscosity (η), and shear rate (

number

[0027]

number

[0028] Also, shear rate (

number

[0029]

number

[0030] Equivalent radius of the flow path (R h ) and the diameter (D) of the filled sphere 20 p The relationship between ( ) and the porosity (ε) of the column apparatus 10 is as follows:

[0031] R h = D p ε / 3(1-ε)...... (3)

[0032] Within a fluid channel, velocity gradients generated by the contraction or expansion of the flow path in the fluid flow induce shear stress, which stretches and breaks the dispersed phase 34 when the shear rate is sufficiently high. Generally, the magnitude of the shear stress acting on a solute or dispersed droplet is positively correlated with its size. According to research by Bird et al. (Bird, R. Byron et al., Dynamics of Polymeric Liquids, (1977): 593), there is no quantitative theory or method for evaluating the stability of the dispersed phase or solute under such shear stress, and the relationships between various parameters can only be determined experimentally under strictly defined conditions.

[0033] Therefore, the relationship between the flow rate (Q) and the shear stress (τ) can be derived as equation (4).

[0034] τ = 4ηQ / εAR h ...... (4)

[0035] In other words, as the dispersion system 30 flows through the three-dimensional periodic cavity structure 18, the macro droplets 36 within the dispersion stage 34 are subjected to a shear stress (τ) applied by the fluid in the continuous stage 32, and this shear stress (τ) is directly proportional to the flow rate (Q) of the dispersion system 30.

[0036] The inventors further conducted practical tests to obtain microdroplets 38 in the dispersion stage 34 by varying the size (diameter) of the silicon oxide spheres 20 within the three-dimensional periodic cavity structure 18 and passing the dispersion system 30 through the three-dimensional periodic cavity structure 18 at different flow rates under the same tube diameter conditions. Subsequently, the microdroplets 38 were solidified and separated from the continuous phase 32, thereby determining the particle size (D) of the microdroplets 38 generated after the dispersion system 30 was sheared by the column apparatus 10. v50)The relationship between the diameter of the silicon oxide spheres 20 in the three-dimensional periodic cavity structure 18 and the flow rate was observed. The results are shown in FIG. 5. The dotted line shown in FIG. 5 represents the relationship between the flow rate and the particle size (D v50 ) of the microdroplets 38 in column devices having different packing lengths under the condition of the same sphere diameter (for example, 273 μm, 385 μm, or 500 μm). This mathematical relationship was found to conform to the following formula (5):

[0037] D V50 =Aln(flow rate)+B....(5)

[0038] In the formula, D V50 is the median value of the particle size distribution of the solidified microdroplets 18 (unit: μm), the flow rate refers to the flow rate of the dispersion system 30 passing through the three-dimensional periodic cavity structure 18, A is the slope (unit: μm / ln(mL / min)), and B is the intercept.[[ID=IP15]]

[0039] Therefore, in a preferred specific embodiment of the present invention, the column device of the present invention conforms to the above formula (5), and the slope A is -10 to -30 μm / ln(mL / min), more preferably -12 to -25 μm / ln(mL / min). Further, the length of the region in the column device filled with the spheres 20, that is, the length of the three-dimensional periodic cavity structure 18 along the flow direction of the dispersion system 30 is 1 cm or more in one embodiment, 2 cm or more in another embodiment, and 3 cm or more in still another embodiment.

[0040] One application example of the present invention can be found in U.S. Patent Application Publication No. 2024 / 0033713, assigned to the applicant of the present invention, titled "A Porous Microsphere, a Stationary Phase Medium, and an Adsorption Chromatography Column Comprising the Porous Microsphere." In the adsorption chromatography column disclosed in this U.S. Patent Application Publication, the packed porous microspheres can be produced using the column apparatus of the present invention. In detail, this U.S. Patent Application Publication involves first preparing a first emulsion and then dispersing the first emulsion in a third phase fluid to obtain a macroemulsion containing macrodroplets. The macroemulsion is preferably a water-in-oil (W / O / W) emulsion in which water functions as a continuous phase as described in Figures 2 and 4, and the water-in-oil (W / O) emulsion corresponds to the macrodroplets described in Figures 2 and 4. Subsequently, the macroemulsion is supplied into the column apparatus of the present invention as a dispersion system as described herein, so that the macrodroplets dispersed in the macroemulsion are sheared into microdroplets by the stereoperiodic cavity structure inside the column apparatus. Finally, these microdroplets are matured to obtain porous microspheres that can be used as a stationary phase medium for chromatography. In the embodiments of this application, the particle size of the porous microspheres is preferably less than 500 μm, more preferably less than 300 μm, and even less than 200 μm, in order to maintain the convective transport properties of the porous microspheres for adsorption chromatography column applications. In this U.S. Patent Application Publication, porous microspheres with a median particle size of about 50 μm were further prepared, and experimental data demonstrated that adsorption chromatography columns packed with such porous microspheres exhibit excellent convective transport adsorption performance.Based on this characteristic, for example, if a flow rate of 40 mL / min is taken, and it is desirable to obtain microdroplets smaller than 500 μm using the column apparatus of the present invention, the diameter of the packed spheres used must be less than 1.3 mm, and the packed length of the spheres must be greater than 1 cm. Naturally, the above example of applications does not imply that the column apparatus of the present invention is suitable only for these applications. As long as the process involves mixing at least two fluid phases and is intended to form small droplets from at least one of the fluid phases, the process can be achieved using the column apparatus of the present invention. Furthermore, the microdroplets produced by the column apparatus of the present invention can be matured for applications such as adsorption chromatography, microcarriers, biological scaffolds, and the purification of various biological, medical, and chemical preparations.

[0041] The inventors further packed the column apparatus of the present invention with spheres of different diameters (i.e., 253.5, 335, and 500 μm). After the dispersion system 30 passed through the column apparatus having different packing lengths (i.e., the length of the stereoperiodic cavity structure 18 along the flow direction of the dispersion system 30) at different flow rates, the microdroplets 38 flowing out of the column apparatus were matured into microspheres and separated from the continuous phase 32. This experiment demonstrated the dispersibility (Span / D) of the microspheres. V50 , where Span=D V90 ~D V10 This was carried out to observe the relationship between the diameter, packing length, and flow rate of the packed spheres in the dispersion system within the column apparatus of the present invention. The results are shown in Figure 6. Microspheres (Span / D v50 As can be seen in Figure 6, the dispersibility of the microspheres increases with increasing flow rate, and as the flow rate increases, the resulting particle size distribution of the microspheres becomes wider. Conversely, as the flow rate decreases, the particle size distribution tends to become more uniform, and this relationship shows an almost linear correlation.

[0042] Y = aX + b...... (6)

[0043] In the formula, Y is the dispersibility of the microspheres, X is the flow rate of the dispersion system (mL / min), a is the gradient, and b is the intercept.

[0044] Accordingly, in another preferred specific embodiment of the present invention, the matured microsphere conforms to formula (6) above, and the gradient a (unit: min / mL) is 0.005 to 0.009 min / mL, more preferably 0.006 to 0.008 min / mL. Furthermore, the packing length of the spheres 20 in the column apparatus, i.e., the length of the stereoperiodic cavity structure 18 along the flow direction of the dispersion system 30, is 1 cm or more in one embodiment, 2 cm or more in another embodiment, and 3 cm or more in yet another embodiment.

[0045] The specific embodiments described above also demonstrate that the present invention is suitable for generating a large number of monodisperse microdroplets, and that the size of the microdroplets can be adjusted by selecting the diameter and packing length of the spheres in the column apparatus.

[0046] According to the present invention, in a method for generating microdroplets, an additional step of maturing the microdroplets may follow step C. Here, “maturation” refers to the process of converting the microdroplets into microspheres having a stable, independent structure. For example, in a specific embodiment in which the microdroplets contain a polymerizable monomer, the maturation step may include heating the microdroplets and / or irradiating them with light of an appropriate wavelength, or further including adding an accelerator to enable the polymerizable monomer to undergo polymerization to form a polymer, thereby achieving maturation into a solid form.

[0047] A separation step may also be included after the maturation step to separate the matured microspheres from the continuous phase fluid. A suitable separation process may include all conventional solid-liquid separation processes. In one preferred specific embodiment, the microspheres may be separated by a filtration method such as sieving, membrane filtration, vacuum suction, wet filtration, or filtration using a sieve shaker. The separated microspheres may be washed several times with water (e.g., deionized water, pure water) and / or an alcohol-based solvent (e.g., ethanol, isopropanol) to remove any residual continuous phase fluid. [Explanation of symbols]

[0048] 10: Columnar apparatus 12: Hollow tube body 14: Input terminal 16: Output terminal 18: Three-dimensional periodic cavity structure 20: Sphere 22: Gap 24: Spherical cavity 26: Connection hole 30: Distributed system 32: Continuous Phase 34: Dispersed phase 36: Macro droplets 38: Microdroplets 90: First phase fluid 91: Hollow 92: Nozzle 93: Actuator 94:Second phase fluid

Claims

1. A column apparatus for generating microdroplets, comprising a hollow tube having at least one input terminal and at least one output terminal opposite to the at least one input terminal, and a three-dimensional periodic cavity structure disposed inside the hollow tube, The system comprises a stereoregular microstructure formed by filling multiple spheres, and a stereoperiodic cavity structure selected from the group consisting of the stereoregular microstructure and the inverse structure of the stereoregular microstructure, The column apparatus is configured such that a dispersion is supplied through the at least one input terminal, passes through the three-dimensional periodic cavity structure, and is then discharged through the at least one output terminal. The dispersion system comprises a continuous phase and a dispersion phase consisting of one or more macrodroplets that are immiscible with the continuous phase. As the dispersion system enters and flows within the three-dimensional periodic cavity structure, the continuous phase applies shear stress to one or more macrodroplets, thereby shearing them into a plurality of microdroplets dispersed in the continuous phase. Matured microdroplets satisfy the following equation (5): D V50 =Aln (flow rate) + B.... (5) In the formula, D V50 D is the median of the particle size distribution of the matured microdroplets, the flow rate refers to the flow rate of the dispersion system passing through the three-dimensional periodic cavity structure, and D is the ratio of the flow rate. V50 The slope A is -10 to -30 μm / ln (mL / min), and B is the intersection. A column apparatus in which the length of the three-dimensional periodic cavity structure along the flow direction of the dispersion system is 1 cm or more.

2. The column apparatus according to claim 1, wherein the slope A is -12 to -25 μm / ln (mL / min).

3. The column apparatus according to claim 1, wherein the length of the three-dimensional periodic cavity structure along the flow direction of the dispersion system is 2 cm or more.

4. The column apparatus according to claim 3, wherein the length of the three-dimensional periodic cavity structure along the flow direction of the dispersion system is 3 cm or more.

5. The column apparatus according to claim 1, wherein the three-dimensional periodic cavity structure is a three-dimensionally regular microstructure formed by filling a plurality of spheres, and at least 50% of the spheres in the three-dimensional periodic cavity structure are arranged in the most densely packed arrangement.

6. The column apparatus according to claim 5, wherein the three-dimensional periodic cavity structure is a three-dimensionally regular microstructure formed by filling a plurality of spheres, and at least 60% of the spheres in the three-dimensional periodic cavity structure are arranged in the most densely packed arrangement.

7. The column apparatus according to claim 6, wherein the three-dimensional periodic cavity structure is a three-dimensionally regular microstructure formed by filling a plurality of spheres, and at least 70% of the spheres in the three-dimensional periodic cavity structure are arranged in the most densely packed configuration.

8. A column apparatus according to claim 1, wherein the matured microdroplets are of the following formula (6): Y = aX + b .... (6) A column apparatus that further satisfies the following equation (wherein Y is the dispersibility of the particle size distribution of the microdroplets, X is the flow rate of the dispersion system, the gradient a of Y with respect to X is 0.005 to 0.009 min / mL, and b is the intercept).

9. The column apparatus according to claim 8, wherein the slope a is 0.006 to 0.008 mins / mL.

10. A method for generating microdroplets using a column apparatus, wherein the column apparatus is A hollow tube having at least one input terminal and at least one output terminal opposite to the at least one input terminal, A three-dimensional periodic cavity structure arranged inside a hollow tube, comprising a three-dimensional periodic cavity structure selected from the group consisting of a three-dimensionally regular microstructure formed by filling with a plurality of spheres, and an inverse structure of the three-dimensionally regular microstructure, The column apparatus is configured such that the dispersed system is supplied through at least one input terminal, The length of the three-dimensional periodic cavity structure along the flow direction of the dispersion system is 1 cm or more. The method described above is A) A step of supplying the dispersion system to at least one input terminal, wherein the dispersion system includes a continuous phase and a dispersion phase consisting of one or more macrodroplets that are immiscible with the continuous phase, B) A step of passing the dispersion system through the three-dimensional periodic cavity structure, wherein as the dispersion system enters and flows inside the three-dimensional periodic cavity structure, the continuous phase applies shear stress to one or more macrodroplets, thereby shearing them into a plurality of microdroplets dispersed in the continuous phase, and the matured microdroplets are given by the following formula (5): D v50 =Aln(flow rate)+B... (5) (In the formula, D V50 D is the median of the particle size distribution of the matured microdroplets, the flow rate refers to the flow rate of the dispersion system passing through the three-dimensional periodic cavity structure, and D is the ratio of the flow rate. v50 The process involves passing the sample through a gradient A of -10 to -30 μm / ln (mL / min), where B is the section, C) A method comprising the step of discharging the continuous phase and the microdroplets from the column apparatus through at least one output terminal.

11. The method according to claim 10, wherein step C is followed by a step of maturing the microdroplets into microspheres.

12. The method according to claim 10, wherein the dispersion system is selected from the group consisting of water-in-oil emulsions and oil-in-water emulsions.

13. The method according to claim 10, wherein the gradient A is -12 to -25 μm / ln (mL / min).

14. The method according to claim 10, wherein the three-dimensional periodic cavity structure has a length of 2 cm or more along the flow direction of the dispersion system.

15. The method according to claim 14, wherein the three-dimensional periodic cavity structure has a length of 3 cm or more along the flow direction of the dispersion system.

16. The method according to claim 10, wherein the three-dimensional periodic cavity structure is a three-dimensionally regular microstructure formed by filling a plurality of spheres, and at least 50% of the spheres in the three-dimensional periodic cavity structure are arranged in the most densely packed arrangement.

17. The method according to claim 16, wherein the three-dimensional periodic cavity structure is a three-dimensionally regular microstructure formed by filling a plurality of spheres, and at least 60% of the spheres in the three-dimensional periodic cavity structure are arranged in the most densely packed arrangement.

18. The method according to claim 17, wherein the three-dimensional periodic cavity structure is a three-dimensionally regular microstructure formed by filling a plurality of spheres, and at least 70% of the spheres in the three-dimensional periodic cavity structure are arranged in the most densely packed arrangement.

19. The method according to claim 10, wherein the matured microdroplets are of the following formula (6): Y = aX + b .... (6) A method that further satisfies the following equation (wherein Y is the dispersibility of the particle size distribution of the microdroplets, X is the flow rate of the dispersion system, the gradient a of Y with respect to X is 0.005 to 0.009 min / mL, and b is the intercept).

20. The method according to claim 19, wherein the incline a is 0.006 to 0.008 mins / mL.

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