WO2025112628A1 - 一种用于大规模制造单分散乳液液滴的多通道微流体乳化膜及其应用 - Google Patents

一种用于大规模制造单分散乳液液滴的多通道微流体乳化膜及其应用 Download PDF

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WO2025112628A1
WO2025112628A1 PCT/CN2024/110348 CN2024110348W WO2025112628A1 WO 2025112628 A1 WO2025112628 A1 WO 2025112628A1 CN 2024110348 W CN2024110348 W CN 2024110348W WO 2025112628 A1 WO2025112628 A1 WO 2025112628A1
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membrane
emulsification
channel microfluidic
channel
phase
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French (fr)
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王华楠
张昊岳
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Dalian University of Technology
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Dalian University of Technology
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    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
    • B01L3/00—Containers or dishes for laboratory use, e.g. laboratory glassware; Droppers
    • B01L3/50—Containers for the purpose of retaining a material to be analysed, e.g. test tubes
    • B01L3/502—Containers for the purpose of retaining a material to be analysed, e.g. test tubes with fluid transport, e.g. in multi-compartment structures
    • B01L3/5027—Containers for the purpose of retaining a material to be analysed, e.g. test tubes with fluid transport, e.g. in multi-compartment structures by integrated microfluidic structures, i.e. dimensions of channels and chambers are such that surface tension forces are important, e.g. lab-on-a-chip
    • B01L3/502769—Containers for the purpose of retaining a material to be analysed, e.g. test tubes with fluid transport, e.g. in multi-compartment structures by integrated microfluidic structures, i.e. dimensions of channels and chambers are such that surface tension forces are important, e.g. lab-on-a-chip characterised by multiphase flow arrangements
    • B01L3/502784—Containers for the purpose of retaining a material to be analysed, e.g. test tubes with fluid transport, e.g. in multi-compartment structures by integrated microfluidic structures, i.e. dimensions of channels and chambers are such that surface tension forces are important, e.g. lab-on-a-chip characterised by multiphase flow arrangements specially adapted for droplet or plug flow, e.g. digital microfluidics
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
    • B01L3/00—Containers or dishes for laboratory use, e.g. laboratory glassware; Droppers
    • B01L3/02—Burettes; Pipettes
    • B01L3/0241—Drop counters; Drop formers

Definitions

  • the present invention belongs to the technical field of membrane emulsification, and specifically is a multi-channel microfluidic emulsification membrane and an emulsification device designed based on the microfluidic principle, as well as an application method of using the device to mass produce monodisperse emulsion droplets of uniform size.
  • Emulsion technology is widely used to prepare microdroplets for encapsulating bioactive substances (such as bioactive macromolecular drugs or living cells). It has a wide range of applications in chemical, pharmaceutical and biochemistry. Highly uniform microdroplets can also be used as standard droplets in various fields such as high-precision biochemical and immunological experiments, such as tissue engineering, single cell and single molecule research.
  • Common emulsion emulsification methods include membrane emulsification, spraying, stirring emulsification, and the emerging microfluidics method. Among them, membrane emulsification technology has the characteristics of low energy consumption, mild conditions and high production throughput, and has been widely used in various cosmetics, food, drug carrier preparation and other fields.
  • Conventional membrane emulsification technology usually uses the dispersed phase to flow through the membrane structure to the continuous phase.
  • the dispersed phase grows at the membrane pores and leaves the membrane surface to form droplets under the combined action of surface tension, transmembrane pressure, continuous phase drag, buoyancy and other factors. Since conventional membrane emulsification technology relies on the force effect of the liquid phase to complete emulsification in a passive way, the droplet size distribution is relatively wide, so the droplets cannot be used for large-scale production of higher precision emulsion products such as drugs and cell carriers.
  • microfluidics can produce droplet emulsions with higher uniformity and has been widely used in various biochemical studies. This method usually uses two incompatible liquid phases to form a monodisperse emulsion with controllable size under highly controlled microscopic forces.
  • Common microfluidic technologies used for microdroplet production include passive emulsification methods using various structural controls and active emulsification methods that introduce additional forces from external sources.
  • the present invention discloses a multi-channel microfluidic emulsification membrane design based on microfluidics and an application method thereof for high-throughput mass production of monodisperse emulsion droplets.
  • the present invention provides a multi-channel microfluidic emulsification membrane for manufacturing emulsion droplets, comprising at least one through hole, wherein the through hole has a rectangular cross-section, the short side length of the cross-section is 0.005-1.5 mm, and the length ratio of the short side to the long side is 1:2-1:10.
  • the through holes are arranged in a rectangular array, the spacing between the through holes in the first direction is 0.2-20 times the length of the long side, and the spacing between the through holes in the second direction is 0.4-20 times the length of the long side.
  • the thickness of the multi-channel microfluidic emulsification membrane is 0.01mm-10mm, and the depth of the through hole is more than 1 times the length of the long side.
  • the surface of the multi-channel microfluidic emulsification membrane is strongly hydrophobic or strongly hydrophilic.
  • the multi-channel microfluidic emulsification membrane is a tubular, sheet-shaped, or spherical membrane.
  • the multi-channel microfluidic emulsification membrane is made of one or more combinations of glass, silicon, metal, ceramic, organic polymer, or organic-inorganic composite materials, and the through holes are processed by laser, drilling, etching, 3D printing or overall molding.
  • the through hole array is located in the center of the plane of the multi-channel microfluidic emulsification membrane, and a blank area is left at the edge of the membrane without through holes, wherein the straight-line distance between the through holes outside the through hole array and the edge of the membrane is greater than twice the length of the long side.
  • the second aspect of the present invention provides an emulsification device, comprising the aforementioned multi-channel microfluidic emulsification membrane, wherein the multi-channel microfluidic emulsification membrane is encapsulated in a liquid phase chamber to seal the liquid phase chamber, and the emulsification device is provided with an input hole for introducing a dispersed phase into the liquid phase chamber; preferably, when there are multiple liquid phase chambers, the number of input holes is the same as the number of liquid phase chambers, and corresponds one to one; the multiple liquid phase chambers are arranged in layers, and the liquid phase chambers that are not directly connected to the multi-channel microfluidic emulsification membrane are connected to the multi-channel microfluidic emulsification membrane through input channels, and the outlets of the input channels are lower than the upper surfaces of the through holes of the multi-channel microfluidic emulsification membrane, the number of input channels is consistent with the number of through holes of the multi-channel microfluidic emulsification
  • the multi-channel microfluidic emulsion membrane is packaged and sealed by one or more of hot pressing, gluing, laser welding, ultrasonic welding, bolting, anodic bonding, and plasma bonding.
  • the third aspect of the present invention provides a membrane emulsification method, the method comprising using the emulsification device according to claim 7, comprising the following steps:
  • the emulsification control factor is selected from one or more of buoyancy, gravity, centrifugal force, electric field force, hydraulic shear force, magnetic force, temperature, interfacial tension, ultraviolet light irradiation, infrared light irradiation, and laser induction.
  • the density difference between the continuous phase and the dispersed phase is required to be greater than 0.2 g/ml, preferably, the density difference range is 0.3-0.6 g/ml;
  • the multi-channel microfluidic emulsification membrane is placed horizontally, the dispersed phase is placed above the membrane, and the continuous phase is placed below the membrane; otherwise, the positions of the dispersed phase and the continuous phase are swapped;
  • the continuous phase is the gas phase
  • the emulsification control factor is the gravity factor
  • the continuous phase is the gas phase
  • the multi-channel microfluidic emulsification membrane is placed horizontally, the dispersed phase is placed above the membrane, and the continuous phase is placed below the membrane;
  • the emulsification control factor is the centrifugal force factor
  • the density of the dispersed phase must be greater than that of the continuous phase.
  • the density difference ranges from 0.1 to 0.4 g/ml.
  • the surface of the multi-channel microfluidic emulsification membrane needs to be gold-sprayed, or a metal-based multi-channel microfluidic emulsification membrane is used, and insulating materials are selected accordingly;
  • an additional electrostatic generation device is introduced, and a flat electrode with an area larger than the multi-channel microfluidic emulsification membrane is connected to the electrostatic generation device and placed horizontally to the multi-channel microfluidic emulsification membrane, and the multi-channel microfluidic emulsification membrane is grounded;
  • the emulsification control factor is a magnetic factor
  • a magnetic material needs to be introduced into the continuous phase; when preparing the emulsion, a parallel magnetic field perpendicular to the multi-channel microfluidic emulsification membrane is additionally introduced.
  • a fourth aspect of the present invention provides the use of the aforementioned multi-channel microfluidic emulsification membrane or the aforementioned emulsification device in large-scale production of monodisperse emulsion droplets.
  • the present invention has the following beneficial effects:
  • the emulsification membrane with specific through-holes of the present invention realizes the use of membrane emulsification technology in combination with microfluidic droplet technology.
  • the emulsification membrane meets the low-energy consumption, high-throughput, and automated production of various types of small-particle-size and narrow-particle-size distribution microemulsions with unique manufacturing requirements under extremely high space utilization conditions (e.g., using an 8cm ⁇ 8cm emulsification membrane, an emulsion droplet with a particle size of 114.3 ⁇ 0.6 ⁇ m is prepared at a flux of 71.2L/h);
  • the through-hole structure of the present invention can achieve high-precision emulsification at an emulsion level comparable to traditional dilute solution emulsification under emulsification conditions without the aid of external force, including but not limited to high-viscosity polymer prepolymer solutions such as alginate and sodium carboxymethyl cellulose, to prepare high-viscosity hydrogel emulsion droplets with small particle size and narrow particle size distribution;
  • the particle size range of the emulsion droplet product obtained by the present invention is 0.01-10mm, and the particle size distribution is less than 5%.
  • the present invention greatly reduces the control parameters required for droplet production. Based on control factors such as buoyancy, gravity, centrifugal force, electric field force, and magnetic force, the preparation of monodisperse emulsions can be achieved without accurately limiting the dispersed phase input flow rate.
  • the multi-channel microfluidic emulsification membrane of the present invention is based on the microfluidic control mechanism of microfluidic droplet technology, which significantly reduces the supporting emulsification factors (shearing equipment, stirring equipment, tangential flow rate), simplifies the production process, and reduces the equipment construction cost;
  • the continuous phase and the dispersed phase have a spontaneous separation effect under different production environments. Therefore, after emulsification is completed, the dispersed phase emulsion droplets can automatically separate from the continuous phase, completing the initial separation step, eliminating the separation steps such as centrifugation and drying in the traditional emulsification process.
  • the independent arrangement of the through holes of the emulsification membrane of the present invention can avoid the possibility of collision and fusion between multiple droplets when droplets are formed, so that each through hole is emulsified relatively independently, avoiding contamination between droplets and uneven product size.
  • Fig. 1 is a schematic diagram of the planar structure of a multi-channel microfluidic emulsification membrane
  • Fig. 2 is a schematic diagram of the three-dimensional structure of a multi-channel microfluidic emulsification membrane
  • FIG3 is a three-dimensional schematic diagram of an emulsification device, wherein 1 is an input hole, 2 is a liquid phase chamber, 3 is a multi-channel microfluidic emulsification membrane, and 4 is an input channel;
  • Fig. 4 is a micrograph of a multi-channel microfluidic emulsification membrane
  • FIG5 is a diagram showing the formation of droplets on the surface of a multi-channel microfluidic emulsification membrane having 30 through holes in Example 1;
  • FIG6 is a microscopic photograph of droplet formation in a single membrane pore when the multi-channel microfluidic emulsification membrane of Example 1 prepares a water-in-oil emulsion;
  • FIG7 is a micrograph of a water-in-oil emulsion product prepared by a multi-channel microfluidic emulsification membrane in Example 1;
  • FIG8 is a microscopic photograph of droplet formation in a single membrane pore when a water-in-oil emulsion is prepared by a multi-channel microfluidic emulsification membrane with different pore sizes in Example 2;
  • FIG9 is a diagram showing the particle size distribution of water-in-oil emulsion droplets prepared by emulsification membranes with different pore sizes in Example 2;
  • FIG10 is a product photo of the PEGDA600 gel obtained by preparing the multi-channel microfluidic emulsification membrane in Example 3 for 1 minute, wherein the upper white emulsion contains the obtained gel product;
  • FIG11 is a diagram showing the size distribution of different types of gel products prepared by multi-channel microfluidic emulsification membrane in Example 3;
  • FIG12 is a schematic diagram of the three-dimensional structure of a multi-channel microfluidic emulsification membrane, wherein X is the pore spacing in the first direction, Y is the pore spacing in the second direction, L is the length of the long side of the pore, h is the length of the short side, and H is the through-hole depth (i.e., membrane thickness);
  • FIG. 13 is a diagram showing the formation of droplets on the surface of a multi-channel microfluidic emulsification membrane containing 300 through holes in Example 1.
  • FIG14 is a schematic diagram of a multilayer emulsification device for producing yin-yang structure microgels
  • FIG15 is a schematic diagram of a multilayer structure emulsification device for producing core-shell structure microgels
  • FIG16 is a cell-carrying microgel having a yin-yang structure obtained by preparing the membrane in Example 8;
  • FIG17 is a dual fluorescent microgel with a yin-yang structure prepared in Example 4.
  • FIG18 is a cell-laden microgel prepared in Example 7, wherein the green bright spots are rat mesenchymal stem cells transfected with green fluorescent protein;
  • FIG19 is a diagram of the E. coli loaded microgel prepared in Example 6.
  • FIG20 is a magnetic particle microgel prepared in Example 9;
  • FIG21 is a PMMA microgel prepared in Example 10.
  • FIG22 is a core-shell structure microgel prepared in Example 5.
  • FIG23 is a polyethylene glycol dimethacrylate microgel prepared in Example 11.
  • FIG24 is a schematic diagram of a preparation device of Example 10.
  • FIG25 is a schematic diagram of a preparation apparatus of Example 11.
  • FIG26 is an electron microscope image of the planar structure of different multi-channel microfluidic emulsification membranes used in Example 12;
  • FIG. 27 is a diagram showing the actual production effect of the multi-channel microfluidic emulsification membrane of structure i-iii shown in FIG. 26 used in Example 12.
  • the multi-channel microfluidic emulsification membrane disclosed in the embodiment of the present invention combines the membrane emulsification concept with the microfluidic droplet technology. Taking the preparation of hydrogel-based polymers as an example, it can continuously and stably prepare a variety of hydrogel emulsion droplets, and can automatically separate the continuous phase and the dispersed phase by using the density difference between the liquid phases.
  • the present invention will be further described in detail below in conjunction with the accompanying drawings and specific embodiments.
  • the multi-channel microfluid emulsification membrane disclosed by the present invention is provided with a plurality of through holes on its substrate to form a rectangular array, the cross section of the through hole is rectangular, the length h of the short side of the cross section is 0.005-1.5mm, the length ratio of the short side to the long side is 1:2-1:10, the through holes are arranged in a rectangular array, the spacing X between the through holes in the first direction is 0.2-20 times the length L of the long side, and the spacing Y between the through holes in the second direction is 0.4-20 times the length L of the long side ( Figure 12).
  • the thickness of the multi-channel microfluid emulsification membrane is 0.01mm-10mm, and the depth H of the through hole is more than 1 times the length of the long side.
  • Figure 4 is a micrograph of the multi-channel microfluid emulsification membrane.
  • the emulsification device includes a multi-channel microfluidic emulsification membrane 3, a liquid phase chamber 2, and the multi-channel microfluidic emulsification membrane is fixedly encapsulated in the liquid phase chamber by a clamp or other encapsulation method, so that the liquid phase chamber is sealed, and the liquid phase chamber side of the multi-channel microfluidic emulsification membrane is completely isolated from the other side of the multi-channel microfluidic emulsification membrane except for the through hole of the multi-channel microfluidic emulsification membrane.
  • the emulsification device also includes an input hole 1, which is connected to the input pipeline of the dispersed phase to introduce the dispersed phase into the liquid phase chamber.
  • the emulsification device is placed as a whole in a continuous phase storage tank, and the multi-channel microfluidic emulsification membrane and the liquid phase chamber are immersed below the continuous phase liquid surface.
  • the emulsification device includes two liquid phase chambers, which are arranged in layers.
  • the multi-channel microfluidic emulsification membrane is fixedly packaged in the upper liquid phase chamber by a clamp or other packaging method, so that the upper and lower liquid phase chambers are sealed, and one side of the liquid phase chamber of the multi-channel microfluidic emulsification membrane is completely isolated from the other side of the multi-channel microfluidic emulsification membrane.
  • Each layer of the liquid phase chamber is provided with an input hole 1, and each input hole is connected to an input pipe of a dispersed phase to introduce different dispersed phases into the two liquid phase chambers.
  • the liquid phase chamber that is not directly connected to the multi-channel microfluidic emulsification membrane is connected to the multi-channel microfluidic emulsification membrane through an input channel 4, and the outlet of the input channel 4 is lower than the upper surface of the through-hole of the multi-channel microfluidic emulsification membrane.
  • the number of input channels is consistent with the number of through-holes of the multi-channel microfluidic emulsification membrane, and the input channels correspond one-to-one to the through-holes of the multi-channel microfluidic emulsification membrane.
  • the dispersed phase Take the case where the density of the continuous phase is greater than that of the dispersed phase. Inject the dispersed phase into the liquid phase chamber to evacuate the residual air inside the liquid phase chamber. Inject the dispersed phase at a set flow rate at a constant speed.
  • the dispersed phase passes through the multi-channel microfluidic emulsification membrane through-hole, it advances at a constant curvature interface inside the hole and expands rapidly when it reaches the hole outlet.
  • the dispersed phase drag force and the interfacial tension between the two phases drive the dispersed phase in the membrane hole to quickly enter the droplet at the outlet.
  • the curvature of the interface between the phases inside the membrane pores is rapidly reduced, thereby completing the droplet detachment step.
  • the droplets detach from the membrane surface, they are driven by the density difference between the two phases to be enriched in the upper layer of the continuous phase and remain stable under the action of the surfactant.
  • the surface enriched emulsion droplets are collected to obtain the microemulsion product.
  • the multi-channel microfluidic emulsification membrane can be made of one or more combinations of glass, silicon, metal, organic polymer, or organic-inorganic composite materials.
  • the processing method can be laser, drilling, etching, 3D printing ( Figure 4) or overall molding, and hydrophilic or hydrophobic treatment can be performed according to the target emulsion properties.
  • the multi-channel microfluidic emulsification membrane based on microfluidic droplet technology disclosed in the present invention and its application have simple supporting equipment and concise production process, and can adapt to the preparation of different types of hydrogel microemulsions; use microfluidic droplet technology to ensure the continuous formation of emulsion droplets; and use the physical properties of the dispersed phase itself to complete the separation of the emulsion.
  • the present invention combines the idea of membrane emulsification and designs a multi-channel microfluidic emulsification membrane. Under the condition of maintaining the microgel particle size distribution, it greatly shortens the production time of the microgel emulsion, simplifies the production process, and greatly improves the production throughput, providing an efficient platform for the production of polymer microemulsions.
  • Example 1 Preparation of water-in-oil droplets using multi-channel microfluidic emulsification membranes containing 30 and 300 through-holes
  • the membrane pore size is 60 ⁇ 300 ⁇ m, the pore depth is 500 ⁇ m, and the spacing between the pores in the first and second directions is 300 ⁇ m.
  • Ultrapure water is used as the dispersed phase, and HFE7500 containing 1% Krytox-COOH is used as the continuous phase.
  • the dispersed phase is input into the liquid phase chamber through the input hole 1 in advance to evacuate the gas inside the dispersed phase.
  • the emulsification device is placed so that the emulsification membrane is placed horizontally and the membrane holes are kept facing upward.
  • the dispersed phase is input into the liquid phase chamber through the input hole 1 at a flow rate of 1 ml/min.
  • the droplet formation on the surface of the multi-channel microfluidic emulsification membrane containing 30 through holes is shown in Figure 5
  • the droplet formation on the surface of the multi-channel microfluidic emulsification membrane containing 300 through holes is shown in Figure 13, where the droplet formation in a single emulsification hole is shown in Figure 6.
  • the droplets generated by emulsification are automatically enriched on the liquid surface of the emulsification tank, as shown in Figure 7.
  • the product can be obtained by taking the upper emulsion droplets.
  • the membrane pore specifications are 500 ⁇ 150 ⁇ m, 1000 ⁇ 200 ⁇ m, 1440 ⁇ 340 ⁇ m, 3000 ⁇ 600 ⁇ m, 4000 ⁇ 800 ⁇ m, 6000 ⁇ 1200 ⁇ m, 8000 ⁇ 1600 ⁇ m, pore depth 500-8000 ⁇ m, pore depth is equal to the length of the long side of the membrane pore, and the spacing between the holes in the first and second directions is the length of the long side.
  • the multi-channel microfluidic emulsification membrane is sealed in the liquid phase chamber to obtain an emulsification device. Ultrapure water is used as the dispersed phase, and HFE7500 containing 1% Krytox-COOH is used as the continuous phase.
  • the dispersed phase is pre-input through the input hole to evacuate the gas inside the liquid phase chamber.
  • the continuous phase is injected into the emulsification pool, it is placed in the emulsification device so that the multi-channel microfluidic emulsification membrane is placed horizontally and the membrane pores are kept facing upward.
  • the dispersed phase is input through the input hole, and the formation of droplets of membrane pores of different sizes is shown in Figure 8.
  • the droplets generated by emulsification are automatically enriched on the liquid surface of the emulsification pool, and the product can be obtained by taking the upper layer of emulsion droplets.
  • the size distribution of emulsion droplets obtained from membranes of different specifications is shown in Figure 9.
  • the prepolymerization liquid formulas of alginate (Alg) and polyethylene glycol diacrylate (PEGDA) are:
  • Alginic acid 1% alginate solution dissolved with 50 mM calcium EDTA;
  • Polyethylene glycol dimethacrylate 10% polyethylene glycol diacrylate (PEGDA600) solution with a molecular weight of 600 dissolved in 1% photoinitiator 2959.
  • the above hydrogel prepolymer is used as the dispersed phase, and HFE7500 containing 1% Krytox-COOH is used as the continuous phase.
  • the membrane pore size is 2000 ⁇ 400 ⁇ m, the pore depth is 2000 ⁇ m, the spacing between the pores in the first direction is 400 ⁇ m, and the spacing between the pores in the second direction is 800 ⁇ m.
  • the multi-channel microfluidic emulsification membrane is sealed in the liquid phase chamber and encapsulated to obtain an emulsification device.
  • the dispersed phase is pre-input through the input hole to evacuate the gas inside the liquid phase chamber.
  • the continuous phase is injected into the emulsification tank, it is placed in the emulsification device so that the emulsification membrane is placed horizontally and the membrane pores are kept upward.
  • the dispersed phase is input through the input hole, and the emulsified droplets are automatically enriched on the liquid surface of the emulsification tank.
  • Different curing methods are used to induce hydrogel curing (alginate: add glacial acetic acid solution to the emulsification tank; PEGDA600: irradiate the emulsion with ultraviolet light with a wavelength of 365nm and a power of 2W/ cm2 ), and the desired hydrogel product can be obtained after separation, as shown in Figure 10.
  • the size distribution of different types of gels is shown in Figure 11.
  • alginate (Alg) prepolymer solution is:
  • Alginate A 1% 5-aminofluorescein-modified alginate solution dissolved in 50 mM calcium ethylenediaminetetraacetate;
  • Alginate B 1% rhodamine B modified alginate solution dissolved in 50 mM calcium ethylenediaminetetraacetate;
  • the above hydrogel prepolymer is used as the dispersed phase, and HFE7500 containing 1% Krytox-COOH is used as the continuous phase.
  • the membrane pore size is 2000 ⁇ 400 ⁇ m, the pore depth is 2000 ⁇ m, and the spacing between the pores in the first and second directions is 2000 ⁇ m.
  • Alginate A and alginate B are placed in two different liquid phase chambers, respectively. The two liquid phase chambers are arranged up and down.
  • the upper chamber of alginate A is directly connected to the multi-channel microfluidic emulsification membrane, and the lower chamber of alginate B is connected to each through hole of the multi-channel microfluidic emulsification membrane through an 800 ⁇ 400 ⁇ m input channel, and the outlet of the input channel is lower than the upper surface of the multi-channel microfluidic emulsification membrane ( Figure 14).
  • the multi-channel microfluidic emulsification membrane is sealed in the upper liquid phase chamber and encapsulated to obtain an emulsification device.
  • the dispersed phase is pre-input into the two liquid phase chambers through different input holes to exhaust the air in the liquid phase chamber.
  • the emulsification device After the continuous phase is injected into the emulsification tank, the emulsification device is placed so that the emulsified membrane is placed horizontally and the membrane holes are kept facing upward. Alginate A and alginate B are respectively input into the two liquid phase chambers through different input holes. By controlling the flow rates of different dispersed phases, multi-petal microgels with different chamber ratios are obtained. The emulsified droplets are automatically enriched on the liquid surface of the emulsification tank. Glacial acetic acid solution is added to the emulsification tank to induce the cross-linking of the yin-yang structure alginate microgel. After separation, the desired hydrogel product can be obtained, as shown in Figure 17.
  • alginate (Alg) shell prepolymer solution 1% 5-aminofluorescein-modified alginate solution dissolved with 50 mM calcium ethylenediaminetetraacetate;
  • the core prepolymer solution formula is: 10% rhodamine-modified dextran solution
  • the above prepolymer is used as the dispersed phase, and HFE7500 containing 1% Krytox-COOH is used as the continuous phase.
  • the membrane pore size is 2000 ⁇ 400 ⁇ m, the pore depth is 2000 ⁇ m, the spacing between the pores in the first and second directions is 2000 ⁇ m, the shell prepolymer liquid and the core prepolymer liquid are placed in different liquid phase chambers respectively, the chamber of the shell prepolymer liquid is connected to the multi-channel microfluidic emulsification membrane, and the chamber of the core prepolymer liquid is connected to each through hole of the multi-channel microfluidic emulsification membrane through the input channel, the outlet of the input channel is lower than the upper surface of the multi-channel microfluidic emulsification membrane, and the input channel is placed at the center of each through hole (Figure 15) to ensure that the shell prepolymer liquid enters the two sides of the through hole, and the core prepolymer liquid enters the middle; each through hole has three 500 ⁇ 400 ⁇
  • the multi-channel microfluidic emulsification membrane is encapsulated in a liquid phase chamber and sealed to obtain an emulsification device.
  • the dispersed phase is pre-input into the two liquid phase chambers through different input holes to exhaust the air in the liquid phase chamber.
  • the continuous phase is injected into the emulsification tank, it is placed in the emulsification device so that the emulsification membrane is placed horizontally and the membrane holes are kept facing upward.
  • the dispersed phase is input into the two liquid phase chambers through different input holes.
  • the emulsified droplets are automatically enriched on the liquid surface of the emulsification tank.
  • Glacial acetic acid solution is added to the emulsification tank to induce the cross-linking of the yin-yang structure alginate microgel. After separation, the desired hydrogel product can be obtained, as shown in Figure 22.
  • alginate (Alg) prepolymer solution 1% alginate solution with 50 mM calcium ethylenediaminetetraacetate in a concentration of 10 10 /ml of E. coli;
  • the above hydrogel prepolymer is used as the dispersed phase, and HFE7500 containing 1% Krytox-COOH is used as the continuous phase.
  • the membrane pore size is 3000 ⁇ 1500 ⁇ m, the pore depth is 10000 ⁇ m, and the spacing between the pores in the first and second directions is 200 ⁇ m.
  • glacial acetic acid solution is added to the emulsification tank to induce cross-linking of the alginate microgel, and the desired hydrogel product can be obtained after separation, as shown in FIG19 .
  • Example 7 Preparation of alginate microgels carrying rat mesenchymal stem cells using an integrated multi-channel microfluidic emulsification membrane
  • alginate (Alg) prepolymer solution 1% alginate solution containing 50 mM calcium ethylenediaminetetraacetate, with a concentration of 4x10 6 /ml of rat mesenchymal stem cells transfected with green fluorescent protein;
  • the above hydrogel prepolymer is used as the dispersed phase, and HFE7500 containing 1% Krytox-COOH is used as the continuous phase.
  • the membrane pore size is 50 ⁇ 5 ⁇ m, the pore depth is 50 ⁇ m, and the spacing between the pores in the first and second directions is 1000 ⁇ m.
  • glacial acetic acid solution is added to the emulsification tank to induce the cross-linking of the yin-yang structure alginate microgel, and the desired hydrogel product can be obtained after separation, as shown in Figure 18.
  • Example 8 Preparation of alginate yin-yang (Janus) structured cell-laden microgels using an integrated multi-channel microfluidic emulsification membrane
  • alginate (Alg) prepolymer solution is:
  • Alginate A 1% 5-aminofluorescein-modified alginate solution dissolved with 50 mM calcium ethylenediaminetetraacetate, containing 2 ⁇ 10 6 /ml rat mesenchymal stem cells;
  • Alginate B Arginine-glycine-aspartate fragment-modified alginate solution dissolved with 50 mM calcium ethylenediaminetetraacetate, containing 2 ⁇ 10 6 /ml green fluorescent protein-transfected HeLa cells;
  • the above hydrogel prepolymer is used as the dispersed phase, and HFE7500 containing 1% Krytox-COOH is used as the continuous phase.
  • the membrane pore size is 2000 ⁇ 400 ⁇ m, the pore depth is 2000 ⁇ m, and the spacing between the pores in the first and second directions is 2000 ⁇ m.
  • Alginate A and alginate B are placed in different liquid phase chambers respectively.
  • the chamber of alginate A is directly connected to the multi-channel microfluidic emulsification membrane, and the chamber of alginate B is connected to each through hole of the multi-channel microfluidic emulsification membrane through an input channel of 800 ⁇ 400 ⁇ m, and the outlet of the input channel is lower than the upper surface of the multi-channel microfluidic emulsification membrane ( Figure 14).
  • glacial acetic acid solution is added to the emulsification tank to induce cross-linking of the yin-yang structure alginate microgel, and the desired cell-carrying microgel product can be obtained after separation, as shown in Figure 16, wherein the nucleus of rat mesenchymal stem cells is stained with DAPI to show blue fluorescence.
  • alginate (Alg) prepolymer solution 1% alginate solution containing 1% ferroferric oxide nanoparticles and 50 mM calcium ethylenediaminetetraacetate;
  • the above hydrogel prepolymer is used as the dispersed phase, and 93 soybean oil containing 1% TWEEN-80 is used as the continuous phase.
  • the membrane pore size is 500 ⁇ 100 ⁇ m, the pore depth is 1000 ⁇ m, and the spacing between the pores in the first and second directions is 1000 ⁇ m.
  • the emulsification device is placed in the emulsification tank, so that the multi-channel microfluidic emulsification membrane is placed horizontally and the membrane pores are kept facing downward and facing the rubidium magnet, and a parallel magnetic field is introduced in a direction perpendicular to the multi-channel microfluidic emulsification membrane.
  • the dispersed phase is input through the input hole, and the emulsified droplets are automatically enriched at the bottom of the emulsification tank.
  • Glacial acetic acid solution is added to the emulsification tank to induce cross-linking of alginate microgels. After separation, the desired hydrogel product can be obtained, as shown in Figure 20.
  • PMMA prepolymer solution 1% by mass of photoinitiator 1173, 20% by mass of methyl methacrylate dissolved in toluene solution;
  • the above prepolymer is used as the dispersed phase, and the HFE7500 fluorinated liquid containing 1% perfluoropolyether surfactant is used as the continuous phase.
  • the membrane pore size is 400 ⁇ 80 ⁇ m, the pore depth is 1000 ⁇ m, the spacing between the first and second directions of the pores is 600 ⁇ m, and the membrane surface is silver-plated.
  • the emulsification tank is placed on a high-voltage flat electrode, the voltage is adjusted to 20kV, and the emulsification device is placed in the emulsification tank, so that the multi-channel microfluidic emulsification membrane is placed horizontally and the membrane pores are kept facing downward, as shown in Figure 24.
  • the dispersed phase is input, and the emulsified droplets are automatically enriched at the bottom of the emulsification tank.
  • the emulsion at the bottom of the emulsification tank is irradiated with an ultraviolet light source, and the desired microparticle product can be obtained after separation, as shown in Figure 21.
  • PEGDA polyethylene glycol dimethacrylate
  • EGDMA ethylene glycol diacrylate
  • the above-mentioned prepolymer is used as the dispersed phase, and the aqueous solution containing 20% polyvinyl alcohol is used as the continuous phase.
  • the membrane pore specifications are 400 ⁇ 80 ⁇ m, the pore depth is 1000 ⁇ m, and the spacing between the first and second directions of the pores is 600 ⁇ m.
  • an emulsification device is obtained.
  • the input hole of the emulsification device is connected to the input pipeline of the dispersed phase, and the dispersed phase is pre-input to empty the gas inside the dispersed phase.
  • the emulsification tank is placed on the centrifugal device, and the emulsification device is placed in the emulsification tank.
  • the multi-channel microfluidic emulsification membrane is perpendicular to the centrifugal radius direction, the centrifugal device is started, the dispersed phase is input, and the emulsification process is started, as shown in Figure 25.
  • the centrifuge is turned off, and the emulsion product naturally settles to the bottom of the emulsification tank.
  • the emulsion at the bottom of the emulsification tank is irradiated with an ultraviolet light source. After separation, the desired microparticle product can be obtained, as shown in Figure 23.
  • Example 12 Preparation of water-in-oil droplets using a multi-channel microfluidic emulsification membrane with irregularly arranged rectangular holes
  • the membrane pore size is 300 ⁇ 60 ⁇ m, and the pore depth is 500 ⁇ m.
  • Each through hole is independently randomly arranged, as shown in Figure 26.
  • Figure 26 shows three emulsified membranes formed by random arrangement. These three multi-channel microfluidic emulsified membranes are sealed in the liquid phase chamber to obtain an emulsifying device. Ultrapure water is used as the dispersed phase, and HFE7500 containing 1% Krytox-COOH is used as the continuous phase. The dispersed phase is pre-input through the input hole to empty the gas inside the liquid phase chamber.
  • the continuous phase is injected into the emulsification pool, it is placed in the emulsification device, so that the multi-channel microfluidic emulsified membrane is placed horizontally and the membrane pores are kept facing upward, and the dispersed phase is input through the input hole.
  • the droplets generated by emulsification are automatically enriched on the liquid surface of the emulsification pool, and the product can be obtained by taking the upper emulsion droplets.
  • the droplet size distributions produced by the membrane structures formed by the three different random arrangements of rectangular holes are the same and similar to the droplet products obtained by the through holes arranged in an array of the same specifications ( Figure 13).
  • the droplet size difference coefficients are all ⁇ 3%, as shown in Figure 27.

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Abstract

本发明属于膜乳化技术领域，具体是一种用于大规模制造单分散乳液液滴的多通道微流体乳化膜及其应用。乳化膜包括至少一个贯穿孔，所述贯穿孔横截面为长方形，其截面短边长为0.005-1.5mm，短边与长边的边长比为1:2-1:10。本发明的乳化膜，实现了将膜乳化技术结合微流控液滴技术使用，通过矩阵排列、自由塑形的方式，满足各类具有独特制造要求的小粒径窄粒径分布微乳液的低能耗、高通量、自动化生产；基于微流控液滴技术，本发明的贯穿孔结构可实现不借助外力的乳化条件下，以媲美传统稀溶液乳化的乳液水平高精度乳化。

Description

一种用于大规模制造单分散乳液液滴的多通道微流体乳化膜及其应用 技术领域
本发明属于膜乳化技术领域，具体是一种基于微流控原理设计的多通道微流体乳化膜及其乳化装置设计，以及使用该装置进行大批量生产尺寸均一的单分散乳液液滴的应用方法。
背景技术
乳液技术被广泛用于制备包封生物活性物质(如生物活性大分子药物或者活体细胞)的微液滴，在化工、制药和生物化学中有广泛的应用，高度均一的微液滴也可以作为标准液滴应用于各类高精度生化免疫实验等领域，如组织工程，单细胞、单分子研究等。常见的乳液乳化方法如膜乳化法、喷雾法、搅拌乳化，以及新兴出现的微流控法等。其中，膜乳化技术具有低能耗、条件温和、高生产通量的特点，已广泛应用于各类化妆品、食品、药物载体制备等领域中。常规的膜乳化技术通常利用分散相经过膜结构向连续相流动，分散相在膜孔处形成长大，受表面张力、跨膜压力、连续相曳力、浮力等因素综合作用后离开膜表面形成液滴。由于常规膜乳化技术均依赖于液相受力效果以被动的方式完成乳化，液滴粒径分布相对较宽，因而液滴无法应用于更高精度乳液产品，如药物、细胞载体等的产品的大规模生产。同时，由于被动乳化原理限制，对高粘度分散相乳化时将更难实现小粒径乳液的高通量生产，因此更加难以应用于如水凝胶等粘性微凝胶生产。
相比之下，微流控法能够得到均一性更高的液滴乳液，因而已广泛用于各类生化研究中。该方法通常利用两种不相容液相，在高度受控的微观作用力控制下形成尺寸可控的单分散乳液。常见的用于微液滴生产的微流控技术包括利用各种结构控制的被动乳化法以及外源引入额外作用力的主动乳化法。然而这些常规的微流控液滴技术存在以下问题：1)通常需要高度精密的微流控芯片完成液滴生产，芯片设备成本高(CN 105641743A，CN104511320A)；2)基于各类微通道的微流控液滴生产技术的液滴生产通量较低(<1L/h)，完成一定剂量的均匀微乳液液滴生产通常需要消耗较长时间(CN112275336A，CN110038656A)；3)乳液形成过程高度依赖各个液相的流速，对生产流程中各液相的实时控制要求较高，因而在实际应用之中难以实现大规模应用(CN107930542A，CN107511189A)。
因此，如何实现高粘度分散相的高通量制备，仍是突破载生物活性物质微颗粒应用于临床或是其他领域的关键问题。
发明内容
为解决现有技术存在的问题，本发明一种基于微流控的多通道微流体乳化膜设计及其高通量量产单分散乳液液滴的应用方法。
为实现上述发明目的，本发明采用以下技术方案：
本发明一方面提供了一种用于乳化液滴制造的多通道微流体乳化膜，包括至少一个贯穿孔，所述贯穿孔横截面为长方形，其截面短边长为0.005-1.5mm，短边与长边的边长比为1:2-1:10。
上述技术方案中，进一步地，所述贯穿孔成矩形阵列排布，所述贯穿孔之间第一方向上的间距为长边边长的0.2-20倍，所述贯穿孔之间第二方向上的间距为长边边长的0.4-20倍。
上述技术方案中，进一步地，所述多通道微流体乳化膜厚度为0.01mm-10mm，所述贯穿孔深度为长边边长的1倍以上。
上述技术方案中，进一步地，所述多通道微流体乳化膜表面为强疏水型或强亲水型。
上述技术方案中，进一步地，所述多通道微流体乳化膜为管状、片状、球状膜。
上述技术方案中，进一步地，所述多通道微流体乳化膜材质为玻璃、硅、金属、陶瓷、有机高分子聚合物、或有机-无机复合材料中的一种或多种组合，所述贯穿孔由激光、钻孔、蚀刻、3D打印或整体倒模的方式加工。
上述技术方案中，进一步地，所述贯穿孔阵列位于多通道微流体乳化膜平面中央，膜边缘留有空白区域不设置贯穿孔，其中，贯穿孔阵列外侧贯穿孔距膜边缘的直线距离大于长边边长的2倍。
本发明第二方面提供了一种乳化装置，包括前述多通道微流体乳化膜，所述多通道微流体乳化膜封装于液相腔室使液相腔室密封，所述乳化装置设有输入孔用以向液相腔室通入分散相；优选地，当液相腔室为多个时，输入孔数量与液相腔室数量相同，并一一对应；多个液相腔室层层排列，不直接连接多通道微流体乳化膜的液相腔室通过输入通道连通至多通道微流体乳化膜，所述输入通道的出口处低于所述多通道微流体乳化膜贯穿孔的上表面，输入通道的数量与多通道微流体乳化膜贯穿孔的数量一致，输入通道与多通道微流体乳化膜贯穿孔一一对应。
上述技术方案中，进一步地，所述多通道微流体乳化膜封装方式采用热压、胶粘、激光焊接、超声焊接、螺栓对接、阳极键合、等离子键合中的一种或多种方式进行封装密封。
本发明第三方面提供了一种膜乳化的方法，所述方法包括使用权利要求7所述乳化装置，包括以下步骤：
(1)将乳化装置置于连续相乳液中，使分散相与连续相分别置于多通道微流体乳化膜两侧；
(2)向液相腔室通入分散相，分散相经多通道微流体乳化膜的贯穿孔进入连续相，在乳化控制因素诱导下完成连续乳化；优选地，所述乳化控制因素选自浮力、重力、离心力、电场力、水力剪切力、磁力、温度、界面张力、紫外光辐照、红外光辐照、激光诱导中的一种或几种。
上述技术方案中，进一步地，所述乳化控制因素选用浮力因素时，要求连续相与分散相之间的密度差大于0.2g/ml，优选的，密度差范围0.3-0.6g/ml；乳液制备时，若分散相密度大于连续相，则所述多通道微流体乳化膜膜面水平放置，分散相置于膜上方，连续相置于膜下方；反之，则调换分散相与连续相的位置；
所述乳化控制因素选用重力因素时，连续相选用气相；乳液制备时，所述多通道微流体乳化膜膜面水平放置，分散相置于膜上方，连续相置于膜下方；
所述乳化控制因素选用离心力因素时，要求连续相与分散相之间存在密度差，且分散相密度需大于连续相，优选的，密度差范围0.1-0.4g/ml；乳液制备时，需额外引入离心设备，所述多通道微流体乳化膜膜面垂直于离心半径放置，分散相置于膜靠近离心圆心方向，连续相置于远离离心圆心方向；
所述乳化控制因素选用电场力因素时，所述多通道微流体乳化膜表面需进行喷金处理，或使用金属基多通道微流体乳化膜，且连续相应选用绝缘材料；乳液制备时，额外引入静电生成设备，并将一块面积大于所述多通道微流体乳化膜的平板电极链接至所述静电生成设备，水平于所述多通道微流体乳化膜放置，同时所述多通道微流体乳化膜接地处理；
所述乳化控制因素选用磁力因素时，连续相内需引入磁性材料；乳液制备时，额外引入垂直于所述多通道微流体乳化膜的平行磁场。
本发明第四方面提供了前述多通道微流体乳化膜或前述乳化装置在大规模制造单分散乳液液滴中的应用。
与现有技术相比，本发明的有益效果：
1)本发明具有特定贯穿孔的乳化膜，实现了将膜乳化技术结合微流控液滴技术使用，通过贯穿孔独立设置，随机排布或矩阵排列，乳化膜在极高空间利用率条件下满足各类具有独特制造要求的小粒径窄粒径分布微乳液的低能耗、高通量、自动化生产(如使用8cm×8cm乳化膜，以71.2L/h的通量制备粒径为114.3±0.6μm的乳液液滴)；
2)基于微流控液滴技术，本发明的贯穿孔结构可实现不借助外力的乳化条件下，以媲美传统稀溶液乳化的乳液水平高精度乳化，包括但不限于海藻酸、羧甲基纤维素钠等高粘度高分子预聚体溶液，制备小粒径窄粒径分布的高粘度水凝胶乳液液滴；本发明得到的乳液液滴产品粒径范围为0.01-10mm，粒径分布小于5％。
3)区别于传统微流控液滴技术中的被动乳化方案，本发明大幅减少了液滴生产时所需的控制参数，基于浮力、重力、离心力、电场力、磁力等控制因素，可在不精确限定分散相输入流速的条件下实现单分散乳液的制备。
4)相较于传统高精度膜乳化生产微球、微液滴(CN 1939281A，CN105246580A)的工艺，本发明所述多通道微流体乳化膜基于微流控液滴技术的微流体控制机制，显著减少配套助乳化因素(剪切设备、搅拌设备、切向流速)，简化生产工艺，降低设备搭建成本；
5)使用本发明所述多通道微流体乳化膜连续生产乳液液滴时，连续相与分散相在不同生产环境下均存在自发分离效应，因而完成乳化后，分散相乳液液滴可自动与连续相分层，完成初步分离步骤，免去传统乳化流程中离心、干燥等分离工序。
6)本发明乳化膜的贯穿孔的独立设置，可避免液滴形成时多个液滴间所发生的碰撞融合可能性，使每个贯穿孔乳化相对独立，避免液滴间污染以及产品尺寸不均的问题。
附图说明
图1多通道微流体乳化膜的平面结构示意图；
图2多通道微流体乳化膜的三维结构示意图；
图3是乳化装置三维示意图，其中1输入孔，2为液相腔室，3为多通道微流体乳化膜，4为输入通道；
图4多通道微流体乳化膜的显微照片；
图5是是实施例1中含有30个贯穿孔的多通道微流体乳化膜表面液滴形成状况；
图6是实施例1多通道微流体乳化膜制备油包水乳液时单个膜孔内液滴形成状况的显微照片；
图7是实施例1多通道微流体乳化膜制备油包水乳液产品的显微照片；
图8是实施例2不同孔径多通道微流体乳化膜制备油包水乳液时单个膜孔内液滴形成状况的显微照片；
图9是实施例2不同孔径乳化膜制备油包水乳液液滴的粒径分布状况；
图10是实施例3多通道微流体乳化膜制备1分钟所获得的PEGDA600凝胶的产品照片，其中上层白色乳液内包含所获得的凝胶产品；
图11是实施例3多通道微流体乳化膜制备不同种凝胶产品的尺寸分布；
图12多通道微流体乳化膜的三维结构示意图，其中X为第一方向孔间距，Y为第二方向孔间距，L为孔的长边边长，h为短边边长，H为贯穿孔深度(即膜厚度)；
图13是实施例1中含有300个贯穿孔的多通道微流体乳化膜表面液滴形成状况
图14用于阴阳结构微凝胶生产的多层结构乳化装置结构示意图；
图15用于核壳结构微凝胶生产的多层结构乳化装置结构示意图；
图16是实施例8膜制备获得的具有阴阳结构的载细胞微凝胶；
图17是实施例4制备获得的具有阴阳结构的双荧光微凝胶；
图18是实施例7制备获得的载细胞微凝胶，其中绿色亮点为绿色荧光蛋白转染的大鼠间充质干细胞；
图19是实施例6制备获得的载大肠杆菌微凝胶；
图20是实施例9制备获得的载磁性颗粒微凝胶；
图21是实施例10制备获得的PMMA微凝胶；
图22是实施例5制备获得的核壳结构微凝胶；
图23是实施例11制备获得的聚乙二醇二甲基丙烯酸酯微凝胶；
图24是实施例10的制备装置示意图；
图25是实施例11的制备装置示意图；
图26是实施例12所使用的不同多通道微流体乳化膜的平面结构电镜图；
图27是实施例12所使用的、图26所示i-iii结构的多通道微流体乳化膜对应的实际生产效果图。
具体实施方式
以下结合具体实施例对本发明作进一步说明，但不以任何方式限制本发明。
本发明实施例中所公开的多通道微流体乳化膜通过结合膜乳化理念与微流控液滴技术，以制备水凝胶基高分子为例，可以持续稳定的制备多种水凝胶乳液液滴，并可以借由液相间密度差自动完成连续相与分散相的分离，下面将结合附图与具体实施方式对本发明作进一步详细说明。
本发明公开的多通道微流体乳化膜，如图1，2所示，其基片上设置有多个贯穿孔形成矩形阵列，贯穿孔横截面为长方形，截面短边长h为0.005-1.5mm，短边与长边的边长比为1:2-1:10，贯穿孔成矩形阵列排布，贯穿孔之间第一方向上的间距X为长边边长L的0.2-20倍，所述贯穿孔之间第二方向上的间距Y为长边边长L的0.4-20倍(图12)。多通道微流体乳化膜厚度为0.01mm-10mm，贯穿孔深度H为长边边长的1倍以上。图4为多通道微流体乳化膜的显微照片。
如图3所示，乳化装置包括多通道微流体乳化膜3，液相腔室2，并由夹具或其他封装方式将多通道微流体乳化膜固定封装于液相腔室，使液相腔室密封，保持除多通道微流体乳化膜的贯穿孔外，多通道微流体乳化膜的液相腔室一侧与多通道微流体乳化膜的另一侧区域完全隔离，乳化装置还包括输入孔1，输入孔1连接分散相的输入管道，用以向液相腔室中通入分散相。将乳化装置整体置于含有连续相储液槽中，多通道微流体乳化膜及液相腔室均浸没于连续相液面之下。如图14或15所示，乳化装置包括2个液相腔室，液相腔室层层排列，由夹具或其他封装方式将多通道微流体乳化膜固定封装于上层液相腔室，使上下两层液相腔室均密封，多通道微流体乳化膜的液相腔室一侧与多通道微流体乳化膜的另一侧区域完全隔离，每一层液相腔室均设有输入孔1，每一个输入孔连接一个分散相的输入管道，用以向两个液相腔室中通入不同的分散相，不直接连接多通道微流体乳化膜的液相腔室通过输入通道4连通至多通道微流体乳化膜，输入通道4的出口处低于所述多通道微流体乳化膜贯穿孔的上表面，输入通道的数量与多通道微流体乳化膜贯穿孔的数量一致，输入通道与多通道微流体乳化膜贯穿孔一一对应。
以连续相密度大于分散相为例。向液相腔室中注入分散相，排空液相腔室内部的残余空气。以设定流速匀速注入分散相，分散相经过多通道微流体乳化膜贯穿孔时在孔内部以恒定曲率界面推进，并在到达孔出口处时迅速膨胀，由分散相曳力与两相间界面张力驱使膜孔内分散相迅速进入出口处的液滴之中， 使膜孔内部相间界面曲率迅速降低，进而完成液滴脱离步骤。液滴脱离膜表面后，经由两相密度差驱使，在连续相上层富集，并在表面活性剂作用下保持稳定。收集表层富集乳液液滴，即可获得微乳液产品。
其中，多通道微流体乳化膜材质可为玻璃、硅、金属、有机高分子聚合物、或有机-无机复合材料中的一种或多种组合，加工方式可选用激光、钻孔、蚀刻、3D打印(图4)或整体倒模的形式加工，并根据目标乳液特性进行亲水或疏水处理。
由此可见，本发明所公开的基于微流控液滴技术的多通道微流体乳化膜及其应用，其配套设备简单，生产工序简洁，可以适应不同种水凝胶微乳液的制备；利用微流控液滴技术保证乳液液滴的连续形成；利用分散相自身物理特性完成乳液的分离。相较于传统微流控液滴技术，本发明结合膜乳化思路，通过多通道微流体乳化膜的设计，在保持微凝胶粒径分布的条件下，极大地缩短了微凝胶乳液的生产时间，简化了生产流程，大幅提高了生产通量，为高分子微乳液的生产提供了一个高效的平台。
实施例1分别使用含有30，300个贯穿孔的多通道微流体乳化膜制备油包水液滴
膜孔规格采用60×300μm，孔深500μm，第一、第二方向孔间间距均为300μm。以超纯水为分散相，以含有1％Krytox-COOH的HFE7500作为连续相。
经输入孔1预先向液相腔室输入分散相排空分散相内部的气体。将连续相注入乳化池后，置入乳化装置，使乳化膜水平放置并且保持膜孔朝上。以1ml/min的流量经输入孔1向液相腔室输入分散相，含有30个贯穿孔的多通道微流体乳化膜表面液滴形成状况如图5所示，含有300个贯穿孔的多通道微流体乳化膜表面液滴形成状况如图13所示，其中单个乳化孔内的液滴形成状况如图6所示。乳化产生液滴自动富集于乳化池液面上，如图7所示。取上层乳液液滴即可获得产品。
实施例2使用不同尺寸贯穿孔的多通道微流体乳化膜制备油包水液滴
膜孔规格采用500×150μm、1000×200μm、1440×340μm、3000×600μm、 4000×800μm、6000×1200μm、8000×1600μm，孔深500-8000μm，孔深均等于膜孔长边边长，第一、第二方向孔间间距均为长边边长。多通道微流体乳化膜密封于液相腔室封装后获得乳化装置。以超纯水为分散相，以含有1％Krytox-COOH的HFE7500作为连续相。经输入孔预先输入分散相排空液相腔室内部的气体。将连续相注入乳化池后，置入乳化装置，使多通道微流体乳化膜水平放置并且保持膜孔朝上。经输入孔输入分散相，不同尺寸膜孔液滴形成状况如图8所示。乳化产生液滴自动富集于乳化池液面上，取上层乳液液滴即可获得产品，不同规格膜制得的乳液液滴尺寸分布如图9所示。
实施例3使用乳化膜制备海藻酸、聚乙二醇微凝胶
海藻酸(Alg)、聚乙二醇二丙烯酸酯(PEGDA)预聚液配方分别为：
海藻酸：溶有50mM乙二胺四乙酸钙的1％海藻酸溶液；
聚乙二醇二甲基丙烯酸酯：溶有1％光引发剂2959的10％分子量为600的聚乙二醇二丙烯酸酯(PEGDA600)溶液。
以上述水凝胶预聚体为分散相，以含有1％Krytox-COOH的HFE7500作为连续相。膜孔规格采用2000×400μm，孔深2000μm，第一方向孔间间距400μm、第二方向孔间间距为800μm，多通道微流体乳化膜密封于液相腔室封装后获得乳化装置。经输入孔预先输入分散相排空液相腔室内部的气体。将连续相注入乳化池后，置入乳化装置，使乳化膜水平放置并且保持膜孔朝上。经输入孔输入分散相，乳化产生液滴自动富集于乳化池液面上，分别采用不同的固化方式诱导水凝胶固化(海藻酸：于乳化槽中加入冰醋酸溶液；PEGDA600：以波长为365nm，功率为2W/cm2的紫外光照射乳液)，分离后即可获得所需水凝胶产品，如图10所示。不同种类凝胶尺寸分布如图11所示。
实施例4使用一体式多层乳化膜制备海藻酸阴阳(Janus)结构微凝胶
海藻酸(Alg)预聚液配方为：
海藻酸A：溶有50mM乙二胺四乙酸钙的1％5-氨基荧光素修饰海藻酸溶液；
海藻酸B：溶有50mM乙二胺四乙酸钙的1％罗丹明B修饰海藻酸溶液；
以上述水凝胶预聚体为分散相，以含有1％Krytox-COOH的HFE7500作为连续相。膜孔规格采用2000×400μm，孔深2000μm，第一、第二方向孔间间距均为2000μm，海藻酸A和海藻酸B分别置于不同两个液相腔室中，两个液相腔室上下排列，海藻酸A的上层腔室直接连接多通道微流体乳化膜，海藻酸B的下层腔室通过800×400μm的输入通道一一连接至多通道微流体乳化膜的每一个贯穿孔，且输入通道的出口低于多通道微流体乳化膜上表面(图14)，将多通道微流体乳化膜密封于上层液相腔室封装后获得乳化装置。通过不同的输入孔分别向两个液相腔室预输入分散相排空液相腔室空气。将连续相注入乳化池后，置入乳化装置，使乳化膜水平放置并且保持膜孔朝上。通过不同的输入孔分别向两个液相腔室输入海藻酸A和海藻酸B，通过控制不同分散相通入的流速不同，获得具有不同腔室比例的多瓣微凝胶。乳化产生液滴自动富集于乳化池液面上，于乳化槽中加入冰醋酸溶液诱导阴阳结构海藻酸微凝胶交联，分离后即可获得所需水凝胶产品，如图17所示。
实施例5使用一体式多层乳化膜制备海藻酸核壳结构微凝胶
海藻酸(Alg)壳层预聚液配方为：溶有50mM乙二胺四乙酸钙的1％5-氨基荧光素修饰海藻酸溶液；
核芯预聚液配方为：10％罗丹明修饰的葡聚糖溶液；
以上述预聚体为分散相，以含有1％Krytox-COOH的HFE7500作为连续相。膜孔规格采用2000×400μm，孔深2000μm，第一、第二方向孔间间距均为2000μm，壳层预聚液与核芯预聚液分别置于不同液相腔室中，壳层预聚液的腔室与多通道微流体乳化膜连接，核芯预聚液的腔室通过输入通道连接至多通道微流体乳化膜的每一个贯穿孔，输入通道的出口低于多通道微流体乳化膜上表面，输入通道置于每个贯穿孔的中心位置(图15)，以保证贯穿孔的两侧进入的是壳层预聚液，中间进入的是核芯预聚液；每个贯穿孔中分别具有三个500×400μm的乳化通道，其中两侧乳化通道输入壳层预聚液，中间乳化通道与输入通道连通输入核心预聚液。将多通道微流体乳化膜封装于液相腔室密封后获得乳化装置。通过不同的输入孔分别向两个液相腔室预输入分散相排空液相腔室空气。将连续相注入乳化池后，置入乳化装置，使乳化膜水平放置并且保持膜孔朝上。通过不同的输入孔分别向两个液相腔室输入分散相，乳化产生液滴自动富集于乳化池液面上，于乳化槽中加入冰醋酸溶液诱导阴阳结构海藻酸微凝胶交联，分离后即可获得所需水凝胶产品，如图22所示。
实施例6使用一体式多通道微流体乳化膜制备搭载大肠杆菌的海藻酸微凝胶
海藻酸(Alg)预聚液配方为：大肠杆菌浓度为1010/ml，溶有50mM乙二胺四乙酸钙的1％海藻酸溶液；
以上述水凝胶预聚体为分散相，以含有1％Krytox-COOH的HFE7500作为连续相。膜孔规格采用3000×1500μm，孔深10000μm，第一、第二方向孔间间距均为200μm，同实施例3，于乳化槽中加入冰醋酸溶液诱导海藻酸微凝胶交联，分离后即可获得所需水凝胶产品，如图19所示。
实施例7使用一体式多通道微流体乳化膜制备搭载大鼠间充质干细胞的海藻酸微凝胶
海藻酸(Alg)预聚液配方为：绿色荧光蛋白转染的大鼠间充质干细胞浓度为4x106/ml，溶有50mM乙二胺四乙酸钙的1％海藻酸溶液；
以上述水凝胶预聚体为分散相，以含有1％Krytox-COOH的HFE7500作为连续相。膜孔规格采用50×5μm，孔深50μm，第一、第二方向孔间间距均为1000μm，同实施例3，于乳化槽中加入冰醋酸溶液诱导阴阳结构海藻酸微凝胶交联，分离后即可获得所需水凝胶产品，如图18所示。
实施例8使用一体式多通道微流体乳化膜制备海藻酸阴阳(Janus)结构载细胞微凝胶
海藻酸(Alg)预聚液配方为：
海藻酸A：溶有50mM乙二胺四乙酸钙的1％5-氨基荧光素修饰海藻酸溶液，内含2×106/ml大鼠间充质干细胞；
海藻酸B：溶有50mM乙二胺四乙酸钙的精氨酸-甘氨酸-天冬氨酸片段修饰海藻酸溶液，内含2×106/ml绿色荧光蛋白转染的海拉细胞；
以上述水凝胶预聚体为分散相，以含有1％Krytox-COOH的HFE7500作为连续相。膜孔规格采用2000×400μm，孔深2000μm，第一、第二方向孔间间距均为2000μm，海藻酸A和海藻酸B分别置于不同液相腔室中，海藻酸A的腔室直接连接多通道微流体乳化膜，海藻酸B的腔室通过800×400μm的输入通道连接至多通道微流体乳化膜的每一个贯穿孔，且输入通道的出口低于多通道微流体乳化膜上表面(图14)，同实施例4，于乳化槽中加入冰醋酸溶液诱导阴阳结构海藻酸微凝胶交联，分离后即可获得所需载细胞微凝胶产品，如图16所示，其中大鼠间充质干细胞的细胞核由DAPI进行染色，显示蓝色荧光。
实施例9使用一体式单层多通道微流体乳化膜制备搭载磁性颗粒的海藻酸微凝胶
海藻酸(Alg)预聚液配方为：溶有质量分数为1％四氧化三铁纳米颗粒，50mM乙二胺四乙酸钙的1％海藻酸溶液；
以上述水凝胶预聚体为分散相，以含有1％TWEEN-80的九三大豆油作为连续相。膜孔规格采用500×100μm，孔深1000μm，第一、第二方向孔间间距均为1000μm。多通道微流体乳化膜密封于液相腔室封装后获得乳化装置，将乳化装置的输入孔连接分散相的输入管道，预先输入分散相排空分散相内部的气体。将连续相注入乳化池后，将乳化池置于铷磁铁上方。乳化装置置入乳化池，使多通道微流体乳化膜水平放置并且保持膜孔朝下并且正对铷磁铁，在垂直于多通道微流体乳化膜的方向引入平行磁场。经输入孔输入分散相，乳化产生液滴自动富集于乳化池底部，于乳化槽中加入冰醋酸溶液诱导海藻酸微凝胶交联，分离后即可获得所需水凝胶产品，如图20所示。
实施例10使用一体式多通道微流体乳化膜，基于电场力制备聚甲基丙烯酸甲酯(PMMA)微颗粒
聚甲基丙烯酸甲酯(PMMA)预聚液配方为：溶有质量分数为1％的光引发剂1173，20％甲基丙烯酸甲酯的甲苯溶液；
以上述预聚体为分散相，以含有1％全氟聚醚表面活性剂的HFE7500氟化液作为连续相。膜孔规格采用400×80μm，孔深1000μm，第一、第二方向孔间间距均为600μm，膜面镀银。密封于液相腔室封装后获得乳化装置，将乳化装置的输入孔连接分散相的输入管道，预先输入分散相排空分散相内部的气体，并在分散相的液相腔室内引入接地线，将分散相接地。将连续相注入乳化池后，将乳化池置于高压平板电极上，调节电压至20kV，乳化装置置入乳化池，使多通道微流体乳化膜水平放置并且保持膜孔朝下，如图24所示。输入分散相，乳化产生液滴自动富集于乳化池底部，使用紫外光源照射乳化池底部乳液，分离后即可获得所需微颗粒产品，如图21所示。
实施例11使用单层多通道微流体乳化膜，基于离心力高通量制备聚乙二醇二甲基丙烯酸酯(PEGDA)微颗粒
聚乙二醇二甲基丙烯酸酯(PEGDA)预聚液配方为：溶有质量分数为1％的光引发剂614的乙二醇二丙烯酸酯(EGDMA)溶液；
以上述预聚体为分散相，以含有20％聚乙烯醇的水溶液为连续相。膜孔规格采用400×80μm，孔深1000μm，第一、第二方向孔间间距均为600μm，密封于液相腔室封装后获得乳化装置，将乳化装置的输入孔连接分散相的输入管道，预先输入分散相排空分散相内部的气体。乳化池置于离心装置上，乳化装置置于乳化池中，使多通道微流体乳化膜垂直于离心半径方向，启动离心装置，输入分散相，启动乳化流程，如图25所示。完成乳化后关闭离心机，乳液产品自然沉降于乳化池底部，使用紫外光源照射乳化池底部乳液，分离后即可获得所需微颗粒产品，如图23所示。
实施例12使用具有不规则排布矩形孔的多通道微流体乳化膜制备油包水液滴
膜孔规格采用300×60μm，孔深500μm。每一贯穿孔独立随机排布，如图26所示，图26展示了随机排布形成的3种乳化膜，分别将这3种多通道微流体乳化膜密封于液相腔室封装后获得乳化装置。以超纯水为分散相，以含有1％Krytox-COOH的HFE7500作为连续相。经输入孔预先输入分散相排空液相腔室内部的气体。将连续相注入乳化池后，置入乳化装置，使多通道微流体乳化膜水平放置并且保持膜孔朝上，经输入孔输入分散相。乳化产生液滴自动富集于乳化池液面上，取上层乳液液滴即可获得产品。3种不同矩形孔随机排布形成的膜结构所产出的液滴尺寸分布相同，且均类似于同规格阵列排布贯穿孔所获得液滴产品(图13)，液滴粒径差异系数均<3％，如图27所示。
对于任何熟悉本领域的技术人员而言，在不脱离本发明技术方案范围情况下，都可利用上述揭示的技术内容对本发明技术方案作出许多可能的变动和修饰，或修改为等同变化的等效实施例。因此，凡是未脱离本发明技术方案的内容，依据本发明的技术实质对以上实施例所做的任何简单修改、等同变化及修饰，均应仍属于本发明技术方案保护的范围内。

Claims (10)

  1. 一种用于制造单分散乳液液滴的多通道微流体乳化膜，其特征在于，包括至少一个贯穿孔，所述贯穿孔横截面为长方形，其截面短边长为0.005-1.5mm，优选地，截面短边长为0.01-0.5mm，短边与长边的边长比为1:2-1:10。
  2. 根据权利要求1所述的多通道微流体乳化膜，其特征在于，所述贯穿孔独立随机排布或成矩形阵列独立排布；优选地，贯穿孔成矩形阵列排布，贯穿孔之间第一方向上的间距为长边边长的0.2-20倍，所述贯穿孔之间第二方向上的间距为长边边长的0.4-20倍。
  3. 根据权利要求1所述的多通道微流体乳化膜，其特征在于，所述多通道微流体乳化膜厚度为0.01mm-10mm，所述贯穿孔深度为长边边长的1倍以上。
  4. 根据权利要求1所述的多通道微流体乳化膜，其特征在于，所述多通道微流体乳化膜材质为玻璃、硅、金属、陶瓷、有机高分子聚合物、或有机-无机复合材料中的一种或多种组合，所述贯穿孔由激光、钻孔、蚀刻、3D打印或整体倒模的方式加工。
  5. 根据权利要求1所述的多通道微流体乳化膜，其特征在于，所述贯穿孔阵列位于多通道微流体乳化膜平面中央，膜边缘留有空白区域不设置贯穿孔，其中，贯穿孔阵列外侧贯穿孔距膜边缘的直线距离大于长边边长的2倍。
  6. 一种基于多通道微流体乳化膜的单分散乳液液滴制备装置，其特征在于，包括权利要求1所述多通道微流体乳化膜，所述多通道微流体乳化膜封装于液相腔室使液相腔室密封，所述乳化装置设有输入孔用以向液相腔室通入分散相。
  7. 根据权利要求6所述的基于多通道微流体乳化膜的单分散乳液液滴制备装置，其特征在于，当液相腔室为多个时，输入孔数量与液相腔室数量相同，并一一对应；多个液相腔室层层排列，不直接连接多通道微流体乳化膜的液相腔室通过输入通道连通至多通道微流体乳化膜，所述输入通道的出口处低于所述多通道微流体乳化膜贯穿孔的上表面，输入通道的数量与多通道微流体乳化膜贯穿孔的数量一致，输入通道与多通道微流体乳化膜贯穿孔一一对应；优选地，所述输入通道置于每个贯穿孔的中心位置。
  8. 一种单分散乳液液滴大规模制备的方法，其特在在于，所述方法包括使用权利要求6或7所述乳化装置，包括以下步骤：
    (1)将乳化装置置于连续相中，使分散相与连续相分别置于多通道微流体乳化膜两侧；
    (2)向液相腔室通入分散相，分散相经多通道微流体乳化膜的贯穿孔进入连续相，在乳化控制因素诱导下完成连续乳化；所述乳化控制因素选自浮力、重力、离心力、电场力、磁力中的一种或几种。
  9. 根据权利要求8所述的单分散乳液液滴大规模制备的方法，其特在在于，所述乳化控制因素为浮力因素时，连续相与分散相之间的密度差大于0.2g/ml，优选的，密度差范围0.3-0.6g/ml；若分散相密度大于连续相，则所述多通道微流体乳化膜膜面水平放置，分散相置于膜上方，连续相置于膜下方；反之，则调换分散相与连续相的位置；
    所述乳化控制因素为重力因素时，连续相选用气相；所述多通道微流体乳化膜膜面水平放置，分散相置于膜上方，连续相置于膜下方；
    所述乳化控制因素为离心力因素时，以离心设备提供离心力，分散相密度大于连续相，优选的，密度差范围0.1-0.4g/ml；所述多通道微流体乳化膜膜面垂直于离心半径放置，分散相置于膜靠近离心圆心方向，连续相置于远离离心圆心方向；
    所述乳化控制因素为电场力因素时，以静电生成设备产生电场，所述多通道微流体乳化膜表面进行喷金处理，或使用金属基多通道微流体乳化膜，连续相为绝缘材料；将一块面积大于所述多通道微流体乳化膜的平板电极链接至所述静电生成设备，水平于所述多通道微流体乳化膜放置，同时所述多通道微流体乳化膜接地处理；
    所述乳化控制因素为磁力因素时，连续相内引入磁性材料，垂直于所述多通道微流体乳化膜引入平行磁场。
  10. 权利要求1所述多通道微流体乳化膜或权利要求6、7所述装置在大规模制造单分散乳液液滴中的应用。
PCT/CN2024/110348 2023-11-29 2024-08-07 一种用于大规模制造单分散乳液液滴的多通道微流体乳化膜及其应用 Pending WO2025112628A1 (zh)

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