CN115178198B - Polymer microsphere preparation device and preparation method - Google Patents
Polymer microsphere preparation device and preparation method Download PDFInfo
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- CN115178198B CN115178198B CN202210602401.9A CN202210602401A CN115178198B CN 115178198 B CN115178198 B CN 115178198B CN 202210602401 A CN202210602401 A CN 202210602401A CN 115178198 B CN115178198 B CN 115178198B
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- 239000004005 microsphere Substances 0.000 title claims abstract description 162
- 229920000642 polymer Polymers 0.000 title claims abstract description 120
- 238000002360 preparation method Methods 0.000 title claims abstract description 51
- 239000007788 liquid Substances 0.000 claims description 60
- 238000005406 washing Methods 0.000 claims description 27
- 239000011159 matrix material Substances 0.000 claims description 25
- 238000000034 method Methods 0.000 claims description 24
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 24
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 20
- 238000006116 polymerization reaction Methods 0.000 claims description 19
- 230000005684 electric field Effects 0.000 claims description 18
- 239000000203 mixture Substances 0.000 claims description 12
- 238000000464 low-speed centrifugation Methods 0.000 claims description 9
- 239000011259 mixed solution Substances 0.000 claims description 8
- 239000000178 monomer Substances 0.000 claims description 8
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 claims description 7
- 238000007789 sealing Methods 0.000 claims description 7
- 238000004519 manufacturing process Methods 0.000 claims description 6
- 239000002086 nanomaterial Substances 0.000 claims description 6
- 230000009471 action Effects 0.000 claims description 5
- 239000007850 fluorescent dye Substances 0.000 claims description 4
- 108091006047 fluorescent proteins Proteins 0.000 claims description 4
- 102000034287 fluorescent proteins Human genes 0.000 claims description 4
- 230000001678 irradiating effect Effects 0.000 claims description 3
- 239000002904 solvent Substances 0.000 claims description 3
- 238000005516 engineering process Methods 0.000 abstract description 6
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- 239000012071 phase Substances 0.000 description 76
- 239000000243 solution Substances 0.000 description 7
- 239000000463 material Substances 0.000 description 6
- 229920001109 fluorescent polymer Polymers 0.000 description 4
- 239000000126 substance Substances 0.000 description 4
- 230000003197 catalytic effect Effects 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- 238000003780 insertion Methods 0.000 description 3
- 230000037431 insertion Effects 0.000 description 3
- 239000000523 sample Substances 0.000 description 3
- 229910000831 Steel Inorganic materials 0.000 description 2
- 239000008346 aqueous phase Substances 0.000 description 2
- 239000003795 chemical substances by application Substances 0.000 description 2
- 239000004205 dimethyl polysiloxane Substances 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 239000002245 particle Substances 0.000 description 2
- 229920000435 poly(dimethylsiloxane) Polymers 0.000 description 2
- -1 polydimethylsiloxane Polymers 0.000 description 2
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- 102000004144 Green Fluorescent Proteins Human genes 0.000 description 1
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- 230000015572 biosynthetic process Effects 0.000 description 1
- 239000000969 carrier Substances 0.000 description 1
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- GNBHRKFJIUUOQI-UHFFFAOYSA-N fluorescein Chemical compound O1C(=O)C2=CC=CC=C2C21C1=CC=C(O)C=C1OC1=CC(O)=CC=C21 GNBHRKFJIUUOQI-UHFFFAOYSA-N 0.000 description 1
- 229940020947 fluorescein sodium Drugs 0.000 description 1
- 239000005090 green fluorescent protein Substances 0.000 description 1
- 238000011065 in-situ storage Methods 0.000 description 1
- 238000004020 luminiscence type Methods 0.000 description 1
- WPBNNNQJVZRUHP-UHFFFAOYSA-L manganese(2+);methyl n-[[2-(methoxycarbonylcarbamothioylamino)phenyl]carbamothioyl]carbamate;n-[2-(sulfidocarbothioylamino)ethyl]carbamodithioate Chemical compound [Mn+2].[S-]C(=S)NCCNC([S-])=S.COC(=O)NC(=S)NC1=CC=CC=C1NC(=S)NC(=O)OC WPBNNNQJVZRUHP-UHFFFAOYSA-L 0.000 description 1
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- 238000007254 oxidation reaction Methods 0.000 description 1
- SOQBVABWOPYFQZ-UHFFFAOYSA-N oxygen(2-);titanium(4+) Chemical compound [O-2].[O-2].[Ti+4] SOQBVABWOPYFQZ-UHFFFAOYSA-N 0.000 description 1
- 230000005408 paramagnetism Effects 0.000 description 1
- 239000004038 photonic crystal Substances 0.000 description 1
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Classifications
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
- B01J13/00—Colloid chemistry, e.g. the production of colloidal materials or their solutions, not otherwise provided for; Making microcapsules or microballoons
- B01J13/02—Making microcapsules or microballoons
- B01J13/06—Making microcapsules or microballoons by phase separation
- B01J13/14—Polymerisation; cross-linking
-
- 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
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
- B01L2200/00—Solutions for specific problems relating to chemical or physical laboratory apparatus
- B01L2200/02—Adapting objects or devices to another
- B01L2200/026—Fluid interfacing between devices or objects, e.g. connectors, inlet details
- B01L2200/027—Fluid interfacing between devices or objects, e.g. connectors, inlet details for microfluidic devices
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
- B01L2300/00—Additional constructional details
- B01L2300/08—Geometry, shape and general structure
- B01L2300/0861—Configuration of multiple channels and/or chambers in a single devices
Landscapes
- Chemical & Material Sciences (AREA)
- Dispersion Chemistry (AREA)
- Organic Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Health & Medical Sciences (AREA)
- Analytical Chemistry (AREA)
- General Health & Medical Sciences (AREA)
- Hematology (AREA)
- Clinical Laboratory Science (AREA)
- Manufacturing Of Micro-Capsules (AREA)
Abstract
The application relates to the technical field of microsphere preparation, and discloses a polymer microsphere preparation device and a preparation method, wherein the preparation device comprises a microsphere generation assembly and a collection container; the microsphere generating assembly comprises a continuous phase runner, a discrete phase runner, a main runner, a first conduit, a second conduit, a third conduit and a working electrode; the continuous phase flow channel and the discrete phase flow channel are crossed and converged to the main flow channel; the working electrodes are arranged on two sides of the main runner and are close to the initial end of the main runner; the first conduit, the second conduit and the third conduit are respectively inserted into corresponding flow passages; the second conduit is of a conductive structure; the collection device conduit is connected to the third conduit. The micro-fluidic chip is coupled with the electrospray technology, and the prepared microsphere has the advantages of large size controllable range, good dispersibility and monodispersity and excellent uniformity, and can be suitable for preparing various fluorescent microspheres with fluorescent matrixes; the application has simple structure and convenient preparation, and is beneficial to wide popularization and application.
Description
Technical Field
The application relates to the technical field of polymer microsphere preparation, in particular to a polymer microsphere preparation device and a polymer microsphere preparation method.
Background
Compared with other materials, the polymer microsphere has unique physical and chemical properties, and is widely applied to fields of photonic crystals, drug targeting delivery carriers, catalysts, environment protection materials, bionic materials and the like in recent years, and the fluorescent polymer microsphere with fluorescent markers added into the polymer is widely applied to a plurality of fields of medical imaging, biosensing, environment monitoring, fluorescent instrument correction and the like. However, most of the current fluorescent polymer microsphere preparation processes are divided into microsphere preparation and fluorescent modification, which is time-consuming and labor-consuming, and has the problem that the fluorescent activity of the marker is irreversibly damaged by various reagents introduced by multi-step reactions.
With the development of microfluidic technology, high-precision control of micro-scale fluid by means of microfluidic technology can obtain polymer monomer droplets with controllable size and uniform particle size, but most of current synthetic methods based on microfluidic technology still cannot break through the limitation of chip geometry on droplet size adjustment due to the fact that the runner structure and the nozzle size of a finished microfluidic chip are fixed.
Disclosure of Invention
The application mainly aims to provide a polymer microsphere preparation device and a polymer microsphere preparation method, and aims to solve the technical problems that the polymer microsphere size control range is small, and the fluorescent polymer microsphere preparation is complex and low in universality.
In order to achieve the above object, the present application provides a polymer microsphere preparation device, which is characterized in that the polymer microsphere preparation device comprises a microsphere generation assembly and a collection container;
the microsphere generating assembly comprises a continuous phase runner, a discrete phase runner, a main runner, a first conduit, a second conduit, a third conduit and a working electrode; the second conduit is of a conductive structure;
the continuous phase flow channels and the discrete phase flow channels are crossly converged into the main flow channel; according to the flow direction, the working electrodes are arranged on two sides of the main runner and are close to the starting end of the main runner; the first conduit is inserted into the continuous phase flow channel, the second conduit is inserted into the discrete phase flow channel, and the third conduit is inserted into the end of the primary flow channel;
the collection vessel is connected to the third conduit by a conduit.
Optionally, in an embodiment, the collection container is a transparent container.
Optionally, in an embodiment, the microsphere generating assembly includes a microfluidic chip and a working electrode disk;
the continuous phase flow channel, the discrete phase flow channel and the main flow channel are arranged in the micro-fluidic chip;
the working electrode is arranged on the surface of the working electrode disc;
the microfluidic chip is attached to the working electrode plate, and the working electrode is positioned between the microfluidic chip and the working electrode plate.
Optionally, in an embodiment, the microfluidic chip includes a chip main body and a sealing film, where a continuous phase runner groove, a discrete phase runner groove and a main runner groove are provided on the chip main body, and the sealing film is attached to a side of the chip main body where the runner groove is provided, so as to form the continuous phase runner, the discrete phase runner and the main runner.
Optionally, in an embodiment, the polymer microsphere generating assembly further includes an electrical connection disc, where the electrical connection disc is disposed on a surface of the working electrode disc and is located outside the microfluidic chip; the power receiving disc is electrically connected with the working electrode, and the power receiving disc is electrically connected with the alternating current output end of the power amplifier.
Optionally, in an embodiment, the first, second and third conduits have an outer diameter of 0.1mm to 10mm;
the first, second and third conduits are in a straight line.
In order to achieve the above object, the present application provides a method for preparing polymer microspheres, which is applied to any one of the above polymer microsphere preparation devices; the preparation method of the polymer microsphere comprises the following steps:
preparing a prepolymerization mixed solution;
injecting a continuous phase liquid from the first conduit into the continuous phase flow channel, and simultaneously injecting the prepolymerization mixed liquid from the second conduit into the discrete phase flow channel;
setting voltage intensity and frequency output by a power amplifier, inputting current to the second conduit and the working electrode, and presetting the voltage intensity and frequency applied to the second conduit and the working electrode so as to enable a preset alternating current electric field to be generated at the intersection of water and oil phases, and enabling the prepolymerization mixed solution to form liquid drops with target size in the microsphere generating assembly;
and collecting the solution containing the liquid drops flowing out of the third conduit through a transparent container, irradiating ultraviolet light into the transparent container through an ultraviolet lamp, and solidifying the liquid drops into polymer microspheres under the irradiation of the ultraviolet light.
Optionally, in an embodiment, after the droplets are solidified into polymer microspheres under the irradiation of ultraviolet light, the polymer microsphere preparation method further includes washing the polymer microspheres;
the polymer microsphere washing steps are as follows:
a) Washing the polymer microsphere for 2 times by using cyclohexane through a low-speed centrifugation method to obtain a cyclohexane-washed polymer microsphere;
b) Washing the polymer microsphere washed by cyclohexane for 2 times by using ethanol through a low-speed centrifugation method to obtain the polymer microsphere washed by ethanol;
c) Washing the polymer microsphere washed by the ethanol for 2 times by using water through a low-speed centrifugation method to obtain a polymer microsphere washed by the water, and adding the water into the polymer microsphere washed by the water to obtain the polymer microsphere suspended in the water.
Optionally, in an embodiment, the pre-polymerization mixture includes a polymer monomer, a photoinitiator, and a solvent.
Optionally, in an embodiment, the pre-polymerization mixture further includes a functionalized matrix, wherein the functionalized matrix includes one or more of a magnetic matrix, a fluorescent matrix, a chemiluminescent matrix, and a biomolecular matrix.
Optionally, in an embodiment, the fluorescent matrix comprises one or more of a fluorescent dye, a fluorescent protein, and a fluorescent nanomaterial.
According to the technical scheme provided by the application, the polymer microsphere preparation device is used for skillfully coupling an alternating current spraying technology and a microfluidic technology, and the power amplifier is used for adjusting the alternating current voltage and frequency, so that the size of the generated polymer liquid drops is adjusted and controlled, and the size adjustment range of the liquid drops is large and reaches approximately three orders of magnitude. The polymer microsphere preparation device is used for preparing polymer microspheres. Because the fluorescent matrix or other functional matrixes such as magnetic matrixes can be directly added into the prepolymerization mixed solution, the preparation of the fluorescent microspheres or the magnetic microspheres can be directly completed in one step, and the preparation flow of the fluorescent microspheres is simplified. The method has good applicability to different types of matrixes (such as organic small molecules, proteins and nano materials) and has great application potential. In addition, the method for washing the microspheres obtained by the method is simple and has good effect. The polymer microsphere obtained by the method has good monodispersity and excellent uniformity.
Drawings
One or more embodiments are illustrated by way of example and not limitation in the figures of the accompanying drawings, in which like references indicate similar elements, and in which the figures of the drawings are not to scale, unless expressly stated otherwise.
FIG. 1 is a schematic diagram showing the connection relationship between a schematic structure of an embodiment of a polymer microsphere preparation device and a power supply system;
FIG. 2 is a schematic top view of a microsphere forming assembly according to an embodiment of the apparatus for preparing polymeric microspheres of the present application;
FIG. 3 is a schematic flow chart of one embodiment of a method for preparing polymeric microspheres according to the present application.
Description of the drawings:
1. a continuous phase flow path; 2. a discrete phase flow path; 3. a main flow passage; 4. a working electrode; 5. a first conduit; 6. a second conduit; 7. a third conduit; 8. a microfluidic chip; 9. a working electrode plate; 10. a transparent container; 11. a power-on disc; 100. a power supply system; 101 high voltage ac power supply; 102. a power amplifier; 103. an oscilloscope; 200. a microsphere generation assembly; 300. a polymer microsphere preparation device.
Detailed Description
In order that the application may be readily understood, a more particular description thereof will be rendered by reference to specific embodiments that are illustrated in the appended drawings. It will be understood that when an element is referred to as being "fixed" to another element, it can be directly on the other element or one or more intervening elements may be present therebetween. When an element is referred to as being "connected" to another element, it can be directly connected to the other element or one or more intervening elements may be present therebetween. The terms "vertical," "horizontal," "left," "right," "inner," "outer," and the like are used in this specification for purposes of illustration only. In the description of the present application, the terms "first", "second" are used for descriptive purposes only and are not to be construed as indicating relative importance or implicitly indicating the number of technical features indicated. Thus, unless otherwise indicated, features defining "first", "second" may include one or more such features either explicitly or implicitly; the meaning of "plurality" is two or more. The terms "comprises," "comprising," and any variations thereof, are intended to cover a non-exclusive inclusion, such that one or more other features, integers, steps, operations, elements, components, and/or groups thereof may be present or added.
Furthermore, unless explicitly specified and limited otherwise, the terms "mounted," "connected," and "connected" are to be construed broadly, and may be either fixedly connected, detachably connected, or integrally connected, for example; can be mechanically or electrically connected; either directly or indirectly through intermediaries, or in communication with each other. All technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this application belongs. The terminology used in the description of the application herein is for the purpose of describing particular embodiments only and is not intended to be limiting of the application. The term "and/or" as used in this specification includes any and all combinations of one or more of the associated listed items.
Furthermore, the term "droplets" in the present application is a reference to tiny incompatible droplets formed by water-in-oil, and is not a description of the size of the droplets, but is not to be construed as limiting the size of the droplets.
In addition, the technical features mentioned in the different embodiments of the application described below can be combined with one another as long as they do not conflict with one another.
Referring to fig. 1 and 2, an embodiment of a polymer microsphere preparation device 300 is provided, wherein the polymer microsphere preparation device 300 comprises a microsphere formation assembly 200 and a collection container 10; wherein the microsphere generation assembly 200 comprises a microfluidic chip 8, a working electrode 4, a working electrode disk 9, a first conduit 5, a second conduit 6 and a third conduit 7; wherein the second conduit 6 is an electrically conductive structure; the micro-fluidic chip 8 is internally provided with a continuous phase runner 1, a discrete phase runner 2 and a main runner 3; the continuous phase runner 1 and the discrete phase runner 2 are crossed and converged to the main runner 3, the continuous phase runner 1 is shaped like a Chinese character 'kou', the discrete phase runner 2 and the main runner 3 are shaped like a Chinese character 'yi', and the tail end of the discrete phase runner 2 is perpendicularly crossed with the continuous phase runner 1. The first conduit 5 is inserted into the continuous phase flow channel 1, the second conduit 6 is inserted into the discrete phase flow channel, the third conduit 7 is inserted into the end of the main flow channel 3, the first conduit 5, the second conduit 6, the third conduit 7 are in line, and the collection vessel 10 is connected to said third conduit 7 by means of a conduit.
The working electrode 4 is arranged on the surface of the working electrode disk 9 in a magnetic resonance sputtering mode, and the shape of the working electrode 4 can be preset according to the requirement. The micro-fluidic chip 8 is attached to the working electrode disk 9, the working electrode 4 is located between the micro-fluidic chip 8 and the working electrode disk 9, and when the micro-fluidic chip 8 is attached, the flow direction of liquid according to the discrete phase flow channel 2 is ensured, and the working electrode 4 is located at two sides of the main flow channel 3 and is close to the starting end of the main flow channel 3. The microfluidic chip 8 and the working electrode 4 are of non-integral structure, so that the microfluidic chip 8 and the working electrode 4 can be manufactured separately and then assembled, the manufacturing complexity of the microsphere generating assembly 200 can be effectively reduced, and the device is beneficial to mass production, thereby being beneficial to popularization of application.
The second conduit 6 is of a conductive structure, and is electrified to the second conduit 6, so that an electric field can be generated at the initial end of the discrete phase flow channel 2 after the second conduit 6 is electrified; after the working electrode 4 at the starting end of the main runner 3 is powered on, another electric field is generated at the starting end of the main runner 3. At the intersection and junction of the discrete phase flow channel 2 and the continuous phase flow channel 1, the surface tension of the liquid of the pre-polymerization mixed liquid and the electrostatic force generated by the externally applied electric field applied from the second conduit 6 are balanced, so that the pre-polymerization mixed liquid forms a taylor cone at the junction, and the conical liquid is thrown off into discrete liquid drops under the high-speed stretching of the electric field force generated by the working electrode 4, namely the sample solution in the discrete phase flow channel 2 generates the liquid drops under the action of the electric field force and the surface tension. Adjusting the intensity and frequency of the energizing voltage of the second conduit 6 and the working electrode 4 can thus vary the size of the droplets formed.
In order to facilitate the insertion of the first, second and third conduits 5, 6, 7, the microsphere generating assembly 200 is provided with through holes at the inlet of the continuous phase flow channel 1, the inlet of the discrete phase flow channel 2 and the outlet of the main flow channel, and the first, second and third conduits 5, 6, 7 are inserted into the corresponding through holes, respectively, so that the first conduit 5 is inserted into the continuous phase flow channel 1, the second conduit 6 is inserted into the discrete phase flow channel, and the third conduit 7 is inserted into the main flow channel 3. The outer diameters of the first conduit 5, the second conduit 6 and the third conduit 7 are tightly attached to the inner diameters of the respective through holes to form a seal, wherein the outer diameters of the first conduit 5, the second conduit 6 and the third conduit 7 are 0.1mm-10mm. The through holes provide accurate insertion positions for the first, second, and third conduits 5, 6, 7, making assembly of the microsphere-generating assembly 200 simpler.
In particular, the second conduit 6 is an electrically conductive structure, and in some embodiments the second conduit 6 may be a hollow steel needle, which not only facilitates its insertion into the discrete phase flow channel, but also has good electrical conductivity, and is of a low cost and readily available material. The first conduit 5 and the third conduit 7 may likewise be hollow steel needles.
Referring to fig. 1, when a polymer microsphere preparation apparatus performs polymer microsphere preparation, a high voltage ac power supply 101, an oscilloscope 103 and a power amplifier 102 constitute a power supply system 100 of the polymer microsphere preparation apparatus; the high-voltage alternating current power supply 101 and the oscilloscope 103 are respectively and electrically connected with the power amplifier 102, the power amplifier 102 is provided with two output lines, one output line is connected to the second conduit 6, the other output line is connected to the working electrode 4, wherein the output line ports can be clip-shaped and can be directly clamped to the second conduit 6, so that the connection is simple and convenient. Wherein the high voltage ac power supply 101 provides high voltage ac power, the power amplifier 102 is capable of adjusting the voltage and frequency of the output ac power, and the oscilloscope 103 is capable of displaying the frequency, voltage, or other parameters of the ac power output by the power amplifier 102. The output voltage and frequency are adjusted through the power amplifier, namely, the voltage intensity and frequency applied to the second conduit 6 and the working electrode 4 are preset through the adjustment of the output voltage and frequency through the power amplifier, so that a preset alternating current electric field is generated at the junction of the water phase and the oil phase. The polymer microsphere preparation device 300 can greatly adjust the size of the liquid drops formed in the polymer microsphere generation assembly 200, can generate super-uniform liquid drops within the range of nearly three orders of magnitude under the optimal condition, can obtain polymer liquid drops with the required size of a target, has high universality, and can visualize the microsphere preparation parameters.
In the polymer microsphere preparation device, continuous phase liquid of the polymer microsphere is injected into a continuous phase runner 1 from a first conduit 5, discrete phase of the polymer microsphere, namely pre-polymerization mixed liquid, is injected into a discrete phase runner 2 from a second conduit 6, the continuous phase liquid flows to the intersection of the continuous phase runner 1 and the discrete phase runner 2 along the continuous phase runner 1 under the pushing of air pressure, and the pre-polymerization mixed liquid flows to the intersection of the continuous phase runner 1 and the discrete phase runner 2 along the discrete phase runner 2. The continuous phase liquid is water-insoluble liquid, namely an oil phase, the pre-polymerization mixed liquid is an aqueous phase sample, and the pre-polymerization mixed liquid forms a Taylor cone at the junction due to the balance of the liquid surface tension difference of the oil phase sample and the aqueous phase sample and the electrostatic force generated by the external electric field applied from the second conduit 6, and the cone tip liquid is thrown off into discrete liquid drops under the high-speed stretching of the electric field force generated by the working electrode 4, namely the sample solution in the discrete phase flow channel 2 generates the liquid drops under the action of the electric field force and the surface tension. Adjusting the intensity and frequency of the energizing voltage of the second conduit 6 and the working electrode 4 can thus vary the size of the droplets formed. The droplets and the continuous phase liquid flow in the main flow channel 3 and out of the third conduit 7 at the end of the main flow channel 3.
In one embodiment, the collection container is a transparent container. The transparent shell of the transparent container facilitates the passage of ultraviolet light, so that in order to solidify the polymer droplets, ultraviolet light can be irradiated into the collection container 10 by an ultraviolet lamp, and the ultraviolet light irradiation promotes polymerization of the polymerized monomers in the prepared droplets, thereby causing the droplets to be solidified and forming stable polymer microspheres.
In one embodiment, the microfluidic chip 8 is composed of a chip body and a sealing film, wherein the chip body is provided with a continuous phase runner 1 groove, a discrete phase runner 2 groove and a main runner 3 groove, and the sealing film is attached to one side of the chip body where the runner grooves are arranged so as to form the continuous phase runner 1, the discrete phase runner 2 and the main runner 3. When the closed flow channel is manufactured, the flow channel groove is firstly manufactured in the chip main body, and then the flow channel groove is closed by the closed film, so that the closed flow channel is formed, and the difficulty in manufacturing the microfluidic chip 8 can be obviously reduced. In the embodiment, the microfluidic chip 8 is a polydimethylsiloxane chip, and the sealing film is a polydimethylsiloxane film.
In an embodiment, the polymer microsphere preparation device 200 further includes a power receiving disc 11, where the power receiving disc 11 is disposed on the working electrode disc 9 and is located outside the microfluidic chip 8 and electrically connected to the working electrode 4, and the power receiving disc 11 is connected to the power supply system 100, that is, the power receiving disc 11 is used for electrically connecting the electrical output end of the power amplifier 102 and the working electrode 4. The power receiving disc 11 is connected with the two working electrodes 4, has a bridge-like structure shape in the middle of expanding at two ends, and the electric output end of the power supply system 100 is in a clip shape and is clamped and connected to the position of the bridge-like structure, so that the connection between the working electrodes 4 and the electric output end of the power supply system 100 is convenient and simple.
As shown in FIG. 3, the application also provides an embodiment of a method for preparing polymer microspheres, which uses the polymer microsphere preparation device to prepare polymer microspheres; the preparation method of the polymer microsphere comprises the following steps:
step S1: preparing a prepolymerization mixed solution;
step S2: injecting a continuous phase liquid from the first conduit into the continuous phase flow channel, and simultaneously injecting the prepolymerization mixed liquid from the second conduit into the discrete phase flow channel;
step S3: setting voltage intensity and frequency output by a power amplifier, inputting current to the second conduit and the working electrode, and presetting the voltage intensity and frequency applied to the second conduit and the working electrode so as to enable a preset alternating current electric field to be generated at the intersection of water and oil phases, and enabling the prepolymerization mixed solution to form liquid drops with target size in the polymer microsphere preparation device;
step S4: and collecting the solution containing the liquid drops flowing out of the third conduit through a transparent container, irradiating ultraviolet light into the transparent container through an ultraviolet lamp, and solidifying the liquid drops into polymer microspheres under the irradiation of the ultraviolet light.
In step S1, a pre-polymerization mixture is formulated to include a polymer monomer, a photoinitiator, and a solvent. Wherein the polymer monomer is the main component of the microsphere; under the irradiation of ultraviolet light, the photoinitiator promotes the polymerization of the polymer monomers, so that microspheres are formed.
In some embodiments, the pre-polymerization mixture further comprises a functionalized matrix, which is a substance capable of imparting a specific functional effect to the polymeric microspheres, the functionalized matrix comprising one or more of a magnetic matrix, a fluorescent matrix, a chemiluminescent matrix, and a biomolecular matrix. Wherein the magnetic matrix can endow the polymer microsphere with paramagnetism, the fluorescent matrix can endow the polymer microsphere with fluorescence emission capability, and the chemiluminescent matrix can endow the microsphere with a function of generating luminescence through specific oxidation reaction, and the like. Different functional matrixes endow the microspheres with different functions, and after being combined with the properties of the polymer microspheres, the polymer microspheres with different functions can play a unique role in a plurality of fields of biomedicine, separation, chemical industry, analytical chemistry and the like, and have higher irreplaceability. Besides the substances, some nano materials can be used as functionalized matrixes of polymer microspheres, such as nano catalytic materials of nano manganese, nano titanium dioxide and the like, can endow the polymer microspheres with in-situ catalytic functions, and have excellent catalytic effects.
When the functionalized matrix is one, single-function microspheres such as magnetic microspheres, fluorescent microspheres, microspheres containing biomolecules, chemiluminescent microspheres or the like can be prepared; when the functionalized substrates are various, the functionalized substrates can be combined in various ways to prepare and obtain multifunctional microspheres, such as magnetic fluorescent microspheres, multicolor fluorescent microspheres or fluorescent-labeled biomolecule microspheres.
In some embodiments, the fluorescent matrix comprises one or more of a fluorescent dye, a fluorescent protein, and a fluorescent nanomaterial. The method can prepare fluorescent microspheres containing single fluorescent matrixes and can also prepare multicolor fluorescent microspheres containing multiple fluorescent matrixes. The fluorescent polymer microsphere can be prepared by taking three representative fluorescent markers of fluorescein sodium, green fluorescent protein and CdTe quantum dot as fluorescent dye, fluorescent protein and fluorescent nano material respectively and taking polyethylene glycol diacrylate (PEGDA) as an encapsulating material according to the preparation method of the polymer microsphere, and the prepared microsphere shows excellent particle size uniformity and high fluorescence intensity, so that the preparation method of the polymer microsphere is simple and rapid and has good universality.
In the step S2, the air pressure is precisely output by a proportional valve, the continuous phase liquid and the prepared prepolymerization mixture solution are introduced into a microfluidic chip in an air pressure driving mode, and the continuous phase liquid and the prepared prepolymerization mixture solution are slightly regulated to form liquid drops stably.
In step S3, the voltage intensity and frequency output by the power amplifier are set, and a current is input to the second conduit and the working electrode, so as to preset the voltage intensity and frequency applied to the second conduit and the working electrode, so that a preset alternating current electric field is generated at the junction of the water phase and the oil phase, and the prepolymerization mixed solution forms droplets with a target size in the microsphere generating assembly. When the polymer microsphere is prepared, a high-voltage alternating-current power supply, an oscilloscope and a power amplifier form a power supply system of the polymer microsphere preparation device, and the power amplifier is an electric output end of the power supply system. The high-voltage alternating current power supply and the oscilloscope in the power supply system are connected to a power amplifier together, and the power amplifier is provided with two electric output lines which are respectively connected to the second conduit and the working electrode. Because the power amplifier is directly connected to the second conduit and the working electrode, the voltage intensity and the frequency applied to the second conduit and the working electrode can be preset through the adjustment of the output voltage and the frequency by the power amplifier, so that a preset alternating current electric field is generated at the junction of the water phase and the oil phase. Therefore, the size of the droplets formed by the pre-polymerization mixed liquid in the polymer microsphere preparation device can be controlled by setting the output voltage intensity and frequency of the output line of the power amplifier. The pre-polymerized mixture can be formed into droplets of a target size in the microsphere-generating assembly by adjusting the voltage strength and frequency of the output of the set power amplifier. Before production, a specific functional relation between the output voltage intensity and frequency of the power amplifier and the size of the prepared polymer microsphere in the method is often required to be obtained through a pre-experiment, so that when the polymer microsphere is prepared, the output parameters of the power amplifier are ensured to be correctly set, so that a second conduit and a working electrode excite a proper electric field, and a pre-polymerized mixed liquid drop with a target size is obtained.
In step S4, droplets of the pre-polymerization mixture are collected by a transparent container, and ultraviolet light is irradiated into the transparent container by an ultraviolet lamp. Since the droplets formed in step S3 are driven by air pressure to flow into the transparent container along the third conduit together with the continuous phase liquid, the droplets are irradiated with ultraviolet light during the process of dropping from the top of the transparent container. The irradiation of ultraviolet light can promote polymerization of the polymer monomers in the droplets formed by the pre-polymerization mixture, so that the droplets are solidified into polymer microspheres.
After the droplets are solidified into polymer microspheres under the irradiation of ultraviolet light, the continuous phase liquid and the surfactant remain on the surfaces of the polymer microspheres, so that the polymer microspheres also need to be washed to obtain the polymer microspheres capable of being monodisperse in water. The polymer microsphere washing steps are as follows:
a) Washing the polymer microsphere for 2 times by using cyclohexane through a low-speed centrifugation method to obtain a cyclohexane-washed polymer microsphere;
b) Washing the polymer microsphere washed by cyclohexane for 2 times by using ethanol through a low-speed centrifugation method to obtain the polymer microsphere washed by ethanol;
c) Washing the polymer microsphere washed by the ethanol for 2 times by using water through a low-speed centrifugation method to obtain a polymer microsphere washed by the water, and adding the water into the polymer microsphere washed by the water to obtain the polymer microsphere suspended in the water.
Specifically, before washing, firstly, absorbing the polymer microsphere solution irradiated by an ultraviolet lamp in a transparent container to a centrifuge tube, centrifuging at a low speed to enable the polymer microsphere to sink into the bottom under the action of centrifugal force, and absorbing the upper continuous phase liquid to obtain the polymer microsphere to be washed. The single washing operation is that firstly, a washing agent is added into a centrifuge tube with polymer microspheres settled at the bottom, the mixture is uniformly mixed by shaking, the polymer microspheres are centrifuged at a low speed, the polymer microspheres sink into the bottom of a solution (namely the bottom end of the centrifuge tube) under the action of centrifugal force, and the washing agent at the upper layer of the centrifuge tube is sucked to finish one-time washing. In performing the washing, it is required that the volume of the washing liquid to be added should be approximately equal to the volume of the liquid sucked out before the washing. After washing with cyclohexane, ethanol and water twice in sequence according to the above washing operation, the polymer microspheres suspended in water can be finally obtained. The detergent can wash away the residual continuous phase liquid and surfactant on the surface of the polymer microsphere. The three-step washing of the application completes the washing process, so that the polymer microsphere is transferred from the oil phase to the water phase, and has good monodispersity.
The above embodiments are only for illustrating the technical solution of the present application, and are not limiting; the technical features of the above embodiments or in the different embodiments may also be combined within the idea of the application, the steps may be implemented in any order, and there are many other variations of the different aspects of the application as described above, which are not provided in detail for the sake of brevity; although the application has been described in detail with reference to the foregoing embodiments, it will be understood by those of ordinary skill in the art that: the technical scheme described in the foregoing embodiments can be modified or some technical features thereof can be replaced by equivalents; such modifications and substitutions do not depart from the spirit of the application.
Claims (10)
1. A polymeric microsphere preparation device, characterized in that the polymeric microsphere preparation device comprises a microsphere generation component and a collection container;
the microsphere generating assembly comprises a continuous phase runner, a discrete phase runner, a main runner, a first conduit, a second conduit, a third conduit and a working electrode; the second conduit is of a conductive structure;
the continuous phase flow channels and the discrete phase flow channels are crossly converged into the main flow channel; the working electrodes are arranged on two sides of the main runner and close to the initial end of the main runner; the first conduit is inserted into the continuous phase flow channel and is used for injecting continuous phase liquid into the continuous phase flow channel; the second conduit is inserted into the discrete phase flow channel and is used for injecting a pre-polymerization mixed solution into the discrete phase flow channel; the third conduit is inserted into the tail end of the main flow channel; the second conduit and the working electrode are respectively used for communicating two poles of alternating current so as to enable the intersection of the continuous phase liquid and the prepolymerization mixed liquid to generate an alternating current electric field, and the prepolymerization mixed liquid generates discrete liquid drops in the main flow channel under the action of surface tension and the electric field force of the alternating current electric field;
the collection vessel is connected to the third conduit for collecting the discrete droplets to solidify the discrete droplets into the polymeric microspheres.
2. The polymer microsphere preparation device according to claim 1, wherein the microsphere generation assembly comprises a microfluidic chip and a working electrode disk;
the continuous phase flow channel, the discrete phase flow channel and the main flow channel are arranged in the micro-fluidic chip;
the working electrode is arranged on the surface of the working electrode disc;
the microfluidic chip is attached to the working electrode plate, and the working electrode is positioned between the microfluidic chip and the working electrode plate.
3. The polymer microsphere preparation device according to claim 2, wherein the microfluidic chip comprises a chip body and a sealing film, the chip body is provided with a continuous phase runner groove, a discrete phase runner groove and a main runner groove, and the sealing film is attached to one side of the chip body where the runner groove is provided so as to form the continuous phase runner, the discrete phase runner and the main runner.
4. The polymer microsphere preparation device according to claim 3, wherein the microsphere generation assembly further comprises an electrical disc, the electrical disc being disposed on the surface of the working electrode disc and located outside the microfluidic chip; the power receiving disc is electrically connected with the working electrode, and the power receiving disc is electrically connected with the alternating current output end of the power amplifier; the power amplifier is electrically connected with an alternating current power supply to regulate the voltage and frequency of the alternating current.
5. The polymer microsphere preparation device according to claim 1, wherein the first, second and third conduits have an outer diameter of 0.1mm to 10mm;
and/or the first, second and third conduits are in a straight line.
6. A method for producing polymer microspheres, characterized in that it is carried out by the polymer microsphere production apparatus according to any one of claims 1 to 5; wherein the collecting container is a transparent container; the preparation method of the polymer microsphere comprises the following steps:
preparing a prepolymerization mixed solution;
injecting a continuous phase liquid from the first conduit into the continuous phase flow channel, and simultaneously injecting the prepolymerization mixed liquid from the second conduit into the discrete phase flow channel;
setting voltage intensity and frequency output by a power amplifier, inputting current to the second conduit and the working electrode, and presetting the voltage intensity and frequency applied to the second conduit and the working electrode so as to enable the intersection of the continuous phase liquid and the prepolymerization mixed liquid to generate a preset alternating current electric field and enable the prepolymerization mixed liquid to form liquid drops with target size in the microsphere generating assembly;
and collecting the continuous phase liquid containing the liquid drops flowing out of the third conduit by using the transparent container, irradiating ultraviolet light into the transparent container by using an ultraviolet lamp, and solidifying the liquid drops into polymer microspheres under the irradiation of the ultraviolet light.
7. The method for preparing polymer microspheres according to claim 6, wherein after the droplets are solidified into polymer microspheres under the irradiation of ultraviolet light, the method further comprises washing the polymer microspheres;
the polymer microsphere washing steps are as follows:
a) Washing the polymer microsphere for 2 times by using cyclohexane through a low-speed centrifugation method to obtain a cyclohexane-washed polymer microsphere;
b) Washing the polymer microsphere washed by cyclohexane for 2 times by using ethanol through a low-speed centrifugation method to obtain the polymer microsphere washed by ethanol;
c) Washing the polymer microsphere washed by the ethanol for 2 times by using water through a low-speed centrifugation method to obtain a polymer microsphere washed by the water, and adding the water into the polymer microsphere washed by the water to obtain the polymer microsphere suspended in the water.
8. The method of claim 6, wherein the pre-polymerization mixture comprises a polymer monomer, a photoinitiator, and a solvent.
9. The method of any one of claims 6-8, wherein the pre-polymerization mixture further comprises a functionalized matrix comprising one or more of a magnetic matrix, a fluorescent matrix, a chemiluminescent matrix, and a biomolecular matrix.
10. The method of claim 9, wherein the fluorescent matrix comprises one or more of a fluorescent dye, a fluorescent protein, and a fluorescent nanomaterial.
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