A device for large-scale preparation of microspheres and its application method

Abstract

This invention discloses a device for the large-scale preparation of microspheres and its application method. Based on two independent liquid storage modules, the microneedle array and micropore array of the two liquid storage modules are coordinated through the connection and positioning of the guide column array and guide hole array to form a coaxial focusing microfluidic channel array. Driven by air pressure, the continuous and discrete phase fluids in the two liquid storage modules automatically converge to the coaxial focusing microfluidic channel array, simultaneously generating a large number of microdroplets or microspheres, thus realizing the large-scale production of microfluidic droplets or microspheres. This invention utilizes the structural design and mutual coordination of independent modules. Through simple mechanical assembly, a synchronous parallel coaxial focusing microfluidic channel array can be formed, enabling the mass production of microspheres. It can conveniently and efficiently realize the preparation of microdroplets or microspheres and can be widely applied in the field of microsphere synthesis technology.

Description

TECHNICAL FIELD

[0001] The present application relates to the technical field of microsphere synthesis, and particularly relates to a microsphere large-scale preparation device and an application method thereof. BACKGROUND

[0002] The porous polymer microsphere is a kind of spherical microparticle condensed by natural and / or artificial synthetic polymer, and has a three-dimensional spatial structure inside, which can provide effective space for cell growth and proliferation.

[0003] At present, in the field of disease treatment, stem cell treatment has broad prospects. Stem cell treatment products have been clinically applied in Alzheimer's disease, myocardial infarction and osteoarthritis and other diseases. However, how to produce and obtain high-quality stem cells on a large scale to meet the needs of clinical application is still a great challenge for the industrialization of stem cells.

[0004] At present, the main method of stem cell culture still adopts the traditional two-dimensional culture process of culture bottles, that is, the stem cells are directly inoculated in the culture bottles or culture dishes for adherent culture, so as to achieve the purpose of cell expansion. However, these methods have the disadvantages of small cell growth area, large cell culture container area, large quality difference between cell batches, large consumption of manpower and time, easy contamination in the culture process and inability to automatically control, etc.

[0005] The suspension culture technology based on the porous polymer microsphere is to inoculate the stem cells on the microspheres, and then to suspend the microspheres loaded with the cells for culture. This technology has the advantages of adherent culture and suspension culture, is convenient for cell expansion and collection, and can solve the difficulties and pain points in the current large-scale expansion and culture process of stem cells. Compared with the traditional two-dimensional culture process, the porous polymer microsphere culture has the advantages of large effective surface area for cell growth, higher cell yield per unit volume of culture solution, easy observation of cell growth, good functional reproducibility between cell batches, simple cell harvesting process, automatic control of the whole process, reduction of labor cost and cell contamination risk, etc., and is a stem cell large-scale culture technology with the most promising development

[0006] The existing methods for preparing microdroplets or microspheres include traditional stirring method, hierarchical assembly technology, membrane emulsification and interfacial polymerization, and methods based on microfluidic chips and off-chip methods. The traditional method can produce microdroplets or microspheres on a large scale, but the uniformity is poor, and generally needs to be subjected to an additional filtration process, thereby causing waste of raw materials and reducing the utilization rate. The methods based on microfluidic chips and off-chip methods can generally achieve good uniformity, but the production efficiency is not high, and the chip or device needs to be packaged and sealed to achieve the stability of the size of the microdroplets or microspheres.

[0007] Therefore, how to realize convenient and efficient preparation of microdroplets or microspheres is a problem to be solved. SUMMARY

[0008] Therefore, the embodiment of the present application provides a microsphere large-scale preparation device and an application method thereof, which can realize convenient and efficient preparation of microdroplets or microspheres.

[0009] In one aspect, the embodiment of the present application provides a microsphere large-scale preparation device, which comprises a first liquid storage module, a second liquid storage module and a collection module.

[0010] The first liquid storage module is provided with a first liquid storage tank, a microneedle array and a guide column array; the first liquid storage tank is used for containing a dispersed phase liquid; the microneedle array is in communication with the bottom of the first liquid storage tank; and the microneedle array is parallel to the guide column array.

[0011] The second liquid storage module is provided with a second liquid storage tank, a micropore array and a guide hole array; the second liquid storage tank is used for containing a continuous phase liquid; and the micropore array is parallel to the guide hole array.

[0012] The collection module is provided with a collection tank and a first outlet; and the first outlet is used for connecting a negative pressure driving device.

[0013] The microneedle array corresponds to the micropore array, and the guide column array corresponds to the guide hole array; the microneedle array penetrates through the second liquid storage tank and enters the micropore array; the pore diameter of the micropore in any corresponding group of microneedles and micropores in the microneedle array and the micropore array is greater than the outer diameter of the microneedle; the second liquid storage module is in sealed connection with the collection module; and the micropore array is in communication with the second liquid storage tank and the collection tank.

[0014] Optionally, the device further comprises a connecting kit, which is used for controlling the longitudinal movement of the first liquid storage module and the second liquid storage module, and adjusting the depth of the microneedle array embedded in the micropore array.

[0015] Optionally, the microneedle array and the micropore array comprise microneedles and micropores of different specifications, so as to form an array of coaxial focusing microchannels of different sizes.

[0016] Optionally, the number of guide columns in the guide column array and the number of guide holes in the guide hole array are at least 2.

[0017] Optionally, the guide holes in the guide hole array are blind holes.

[0018] Optionally, the collection tank comprises a first collection tank and a second collection tank separated by a partition plate; the first collection tank is used for collecting generated microspheres; and the second collection tank is used for containing liquid overflowing from the first collection tank.

[0019] Optionally, the collecting module further comprises a second outlet, which is arranged at the lower end of the second collecting tank, and is used for discharging and recycling the liquid contained in the second collecting tank.

[0020] In another aspect, the application provides a method for using a device for large-scale preparation of microspheres, the device comprising a first liquid storage module, a second liquid storage module, and a collecting module; the first liquid storage module is provided with a first liquid storage tank, a microneedle array, and a guide column array; the first liquid storage tank is used for containing a dispersed phase liquid, the microneedle array is in communication with the bottom of the first liquid storage tank, and the microneedle array is parallel to the guide column array; the second liquid storage module is provided with a second liquid storage tank, a micropore array, and a guide hole array; the second liquid storage tank is used for containing a continuous phase liquid, and the micropore array is parallel to the guide hole array; the collecting module is provided with a collecting tank and a first outlet; the first outlet is used for connecting a negative pressure driving device; wherein the microneedle array corresponds to the micropore array, and the guide column array corresponds to the guide hole array; the microneedle array penetrates through the second liquid storage tank and enters the micropore array; in any corresponding group of microneedles and micropores in the microneedle array and the micropore array, the pore diameter of the micropore is greater than the outer diameter of the microneedle; the second liquid storage module is hermetically connected to the collecting module, and the micropore array communicates the second liquid storage tank and the collecting tank; the method comprises:

[0021] connecting the first liquid storage module and the second liquid storage module through the guide column array and the guide hole array, and maintaining the lateral fixation of the first liquid storage module and the second liquid storage module;

[0022] moving the first liquid storage module and the second liquid storage module longitudinally, so that the ends of the microneedle array enter the micropore array, and a coaxial focusing microchannel array is formed through one-to-one correspondence between the microneedles of the microneedle array and the micropores of the micropore array;

[0023] hermetically connecting the collecting module to the bottom of the second liquid storage module;

[0024] adding a dispersed phase liquid into the first liquid storage tank of the first liquid storage module, and adding a continuous phase liquid into the second liquid storage tank of the second liquid storage module;

[0025] starting and setting the negative pressure driving device connected to the first outlet, so that the dispersed phase liquid and the continuous phase liquid react to generate microspheres in the coaxial focusing microchannel array;

[0026] collecting the microspheres through the collecting tank of the collecting module.

[0027] Optionally, the device further comprises a connecting kit, and the moving the first liquid storage module and the second liquid storage module longitudinally comprises:

[0028] The longitudinal movement of the first liquid storage module and the second liquid storage module is controlled by the connecting kit, and the depth of embedding the microneedle array into the micropore array is adjusted.

[0029] Optionally, the collection tank comprises a first collection tank and a second collection tank separated by a partition, the first collection tank is used for collecting the generated microspheres, and the second collection tank is used for containing the liquid overflowing from the first collection tank, the collection module further comprises a second outlet arranged at the lower end of the second collection tank, and the application method further comprises:

[0030] The liquid contained in the second collection tank is discharged and recovered through the second outlet.

[0031] The embodiment of the present application provides a microsphere large-scale preparation device, which comprises a first liquid storage module, a second liquid storage module and a collection module; the first liquid storage module is provided with a first liquid storage tank, a microneedle array and a guide column array; the first liquid storage tank is used for containing a dispersed phase liquid, the microneedle array is in communication with the bottom of the first liquid storage tank, and the microneedle array is parallel to the guide column array; the second liquid storage module is provided with a second liquid storage tank, a micropore array and a guide hole array; the second liquid storage tank is used for containing a continuous phase liquid, and the micropore array is parallel to the guide hole array; the collection module is provided with a collection tank and a first outlet; the first outlet is used for connecting a negative pressure driving device; wherein the microneedle array corresponds to the micropore array, and the guide column array corresponds to the guide hole array; the microneedle array penetrates through the second liquid storage tank and enters the micropore array, forming a coaxial focusing microchannel array; in any corresponding group of microneedles and micropores in the microneedle array and the micropore array, the pore diameter of the micropore is greater than the outer diameter of the microneedle; the second liquid storage module is in sealed connection with the collection module, and the micropore array is in communication with the second liquid storage tank and the collection tank. The present application is based on two independent liquid storage modules, the microneedle array and the micropore array of the two liquid storage modules are matched with each other through the connection and positioning of the guide column array and the guide hole array, a coaxial focusing microchannel array is formed, the continuous phase and the dispersed phase fluids in the two liquid storage modules are automatically gathered into the coaxial focusing microchannel array in a gas pressure driven manner, a large number of microdroplets or microspheres are generated synchronously, and the large-scale production of microfluidic droplets or microspheres is realized. The present application utilizes the mechanism design and mutual cooperation of independent modules, and a large number of microspheres can be produced through simple mechanical assembly, so that a coaxial focusing microchannel array in synchronous parallel connection is formed. BRIEF DESCRIPTION OF DRAWINGS

[0032] In order to more clearly illustrate the technical solutions in the embodiments of the present application, the drawings needed to be used in the embodiments will be briefly introduced. Obviously, the drawings in the following description only constitute some embodiments of the present application. For those skilled in the art, other drawings can also be obtained from these drawings without any creative effort.

[0033] Figure 1 A microsphere scale preparation device and an application principle schematic diagram provided by the embodiment of the present application are provided.

[0034] Figure 2 An appearance diagram of a first liquid storage module of a microsphere scale preparation device provided by the embodiment of the present application is provided.

[0035] Figure 3 A top view and a sectional view of the first liquid storage module of the microsphere scale preparation device provided by the embodiment of the present application are provided.

[0036] Figure 4 An appearance diagram of a second liquid storage module of a microsphere scale preparation device provided by the embodiment of the present application is provided.

[0037] Figure 5 A top view and a sectional view of the second liquid storage module of the microsphere scale preparation device provided by the embodiment of the present application are provided.

[0038] Figure 6 An application principle diagram of a collection module of a microsphere scale preparation device provided by the embodiment of the present application is provided.

[0039] Figure 7 A schematic diagram of a microsphere product effect provided by the embodiment of the present application is provided. DETAILED DESCRIPTION

[0040] In order to make the purpose, technical solutions and advantages of the present application more clear, the present application will be further described in detail below in combination with the drawings and embodiments. It should be understood that the specific embodiments described herein are only used to explain the present application, and are not used to limit the present application.

[0041] In order to make the content and technical solutions of the present application more clear, the related terms and meanings are described:

[0042] Co-flow focusing: Co-flow focusing refers to that the continuous phase flow channel and the dispersed phase flow channel form concentric or coaxial parallel flow channels, and the fluids of the continuous phase and the dispersed phase flow in parallel in the flow channels. When the dispersed phase enters the continuous phase flow channel, it is extruded and broken to form droplets under the action of the viscous shear force of the continuous phase fluid.

[0043] On the one hand, with reference to Figure 1The embodiment of the present application provides a microsphere large-scale preparation device, which comprises a first liquid storage module 1, a second liquid storage module 2 and a collection module 3.

[0044] Referring to Figure 2 and 3 , the first liquid storage module 1 is provided with a first liquid storage tank 1-1, a microneedle array 1-2 and a guide column array 1-3; the first liquid storage tank 1-1 is used for containing a dispersed phase liquid, the microneedle array 1-2 is in communication with the bottom of the first liquid storage tank 1-1, and the microneedle array 1-2 is parallel to the guide column array 1-3.

[0045] Referring to Figure 4 and 5 , the second liquid storage module 2 is provided with a second liquid storage tank 2-1, a micropore array 2-2 and a guide hole array 2-3; the second liquid storage tank 2-1 is used for containing a continuous phase liquid, the micropore array 2-2 is parallel to the guide hole array 2-3;

[0046] Referring to Figure 1 , the collection module 3 is provided with a collection tank and a first outlet; the first outlet is used for connecting a negative pressure driving device (providing adjustable negative pressure);

[0047] As shown in Figure 1 , the microneedle array corresponds to the micropore array; the guide column array corresponds to the guide hole array; the microneedle array penetrates through the second liquid storage tank and accesses into the micropore array, forming a coaxial focusing microchannel array; in any corresponding group of microneedles and micropores in the microneedle array and the micropore array, the pore diameter of the micropore is greater than the outer diameter of the microneedle; the second liquid storage module is hermetically connected (including threaded fastening, sealing washer pressure fastening and the like) to the collection module, and the micropore array is in communication with the second liquid storage tank and the collection tank. It should be noted that the sealing principle at the connection of the coaxial focusing microchannel array: after the continuous phase liquid is added into the second liquid storage tank of the second liquid storage module, the gap between the microneedle array and the micropore array can be automatically filled with the continuous phase liquid to complete the sealing, so that no additional sealing components are required.

[0048] In some preferred embodiments, the device further comprises a connecting kit for controlling the longitudinal movement of the first liquid storage module and the second liquid storage module, and adjusting the depth of the microneedle array embedded in the micropore array. Specifically, by adding a connecting kit provided with two reverse threads (corresponding threads are arranged outside the first liquid storage module and the second liquid storage module), the vertical (longitudinal) movement of the two liquid storage modules can be controlled by rotating the connecting kit, and the depth of the microneedle array embedded in the micropore array can be adjusted.

[0049] In some preferred embodiments, the microneedle array and the microwell array comprise microneedles and microwells of different specifications to form an array of coaxial focusing microfluidic channels of different sizes. Specifically, multiple levels of aperture can be set in the microwell array based on depth (aperture is set in sections), and when the microneedles penetrate to different depths to reach apertures of different sizes, multiple scales of microspheres are generated based on the change in the oil-water two-phase flow rate ratio. Different specifications of microneedle arrays in multiple first liquid storage modules and / or different specifications of microwell arrays in multiple second liquid storage modules can also be included to achieve an array of coaxial focusing microfluidic channels of different sizes through the combination of different first liquid storage modules and second liquid storage modules.

[0050] In some preferred embodiments, the number of guide columns in the guide column array and the number of guide holes in the guide hole array are at least 2. The guide column array and the guide hole array function to connect and laterally fix the first liquid storage module and the second liquid storage module, and thus at least two sets of guide columns and guide holes are used to prevent the offset of the liquid storage modules from damaging the microneedle array, and to position the microneedle array and the microwell array to enable the microneedle array and the microwell array of the two liquid storage modules to cooperate with each other.

[0051] In some preferred embodiments, the guide holes in the guide hole array are blind holes, and the limited depth of the blind holes prevents the two liquid storage modules from being too tightly fitted (facilitating the reservation of space between the first liquid storage module and the second liquid storage module for the continuous phase liquid to be continuously added) or from being damaged by touching the bottom.

[0052] In some preferred embodiments, with reference to Figure 6 The collection tank comprises a first collection tank 3-2 and a second collection tank 3-3 separated by a partition 3-1, the first collection tank 3-2 is used to collect the generated microspheres, and the second collection tank 3-2 is used to accommodate the overflow liquid from the first collection tank. Specifically, two tanks are provided in the collection module and separated by a baffle, the first collection tank is added with a continuous phase liquid, and the outlet of the microwell array of the second liquid storage module is immersed below the liquid level (to achieve a better sealed reaction environment and prevent the microspheres from directly falling to the bottom of the collection tank and being damaged), the generated microspheres are settled in the first collection tank, and the overflow continuous phase liquid flows into the second collection tank through the baffle.

[0053] In some preferred embodiments, with reference to Figure 6 The collection module further comprises a second outlet 3-4 provided at the lower end of the second collection tank 3-3 (the position of the first outlet is higher than that of the second outlet), and the second outlet 3-4 is used to discharge and recover the liquid accommodated in the second collection tank 3-3.

[0054] The present application is implemented by using the mechanism design and mutual cooperation of independent modules. Through simple mechanical assembly, a coaxial focusing micro-channel array in parallel can be formed. By continuously adding corresponding reaction liquid in the first and second liquid storage tanks of the device, microdroplets or microspheres can be continuously produced in large quantities. By replacing modules with different size specifications of micropore and microneedle array and adjusting the pressure, microsphere products of different sizes can be produced. In addition, the device does not need to be packaged and can be used immediately. It can be disassembled and cleaned for repeated use, which is convenient and fast, and is expected to quickly realize the commercial application of microsphere products.

[0055] In another aspect, the present application provides a method for using a microsphere scale preparation device. The device includes a first liquid storage module, a second liquid storage module, and a collection module. The first liquid storage module is provided with a first liquid storage tank, a microneedle array, and a guide column array. The first liquid storage tank is used to contain a dispersed phase liquid. The microneedle array is in communication with the bottom of the first liquid storage tank. The microneedle array is parallel to the guide column array. The second liquid storage module is provided with a second liquid storage tank, a micropore array, and a guide hole array. The second liquid storage tank is used to contain a continuous phase liquid. The micropore array is parallel to the guide hole array. The collection module is provided with a collection tank and a first outlet. The first outlet is used to connect a negative pressure driving device. The microneedle array corresponds to the micropore array, and the guide column array corresponds to the guide hole array. The microneedle array passes through the second liquid storage tank and enters the micropore array. The micropore has a larger diameter than the microneedle. The second liquid storage module is in sealed connection with the collection module. The micropore array connects the second liquid storage tank and the collection tank. The method includes connecting the first liquid storage module and the second liquid storage module through the guide column array and the guide hole array, maintaining the horizontal fixation of the first liquid storage module and the second liquid storage module, moving the first liquid storage module and the second liquid storage module longitudinally, making the end of the microneedle array enter the micropore array, forming a coaxial focusing micro-channel array through the one-to-one correspondence of the microneedle of the microneedle array and the micropore of the micropore array, sealing the collection module to the bottom of the second liquid storage module, adding a dispersed phase liquid in the first liquid storage tank of the first liquid storage module, adding a continuous phase liquid in the second liquid storage tank of the second liquid storage module, starting and setting the negative pressure driving device connected to the first outlet, making the dispersed phase liquid and the continuous phase liquid react to generate microspheres in the coaxial focusing micro-channel array, and collecting the microspheres through the collection tank of the collection module.

[0056] In some preferred embodiments, the device further comprises a connecting kit, and the longitudinal movement of the first liquid storage module and the second liquid storage module comprises: controlling the longitudinal movement of the first liquid storage module and the second liquid storage module through the connecting kit, and adjusting the depth of embedding of the microneedle array into the micropore array.

[0057] In some preferred embodiments, the collection tank comprises a first collection tank and a second collection tank separated by a partition, the first collection tank is used for collecting the generated microspheres, and the second collection tank is used for containing the liquid overflowing from the first collection tank, the collection module further comprises a second outlet arranged at the lower end of the second collection tank, and the application method further comprises: discharging and recycling the liquid contained in the second collection tank through the second outlet.

[0058] In some specific embodiments, a mixture of paraffin oil and a surfactant is used as the dispersed phase liquid, and an aqueous solution of methyl methacrylated gelatin is used as the continuous phase liquid, and the method for preparing microspheres by using the microsphere scaling preparation device comprises the following steps:

[0059] 1. The first liquid storage module has an outer diameter of 0.2 mm and an inner diameter of 0.1 mm, and the second liquid storage module has a micropore array with a pore diameter of 0.3 mm;

[0060] 2. The first liquid storage module and the second liquid storage module are connected and assembled along the guide column, the guide column reaches the bottom of the guide hole, the tip of the microneedle array enters the micropore array, and the microneedle array and the micropore array are kept concentric / coaxial;

[0061] 3. 2 mL of an aqueous solution of methyl methacrylated gelatin is added to the first liquid tank, and the aqueous solution contains 0.5% (w / v) LAP photoinitiator in PBS solution;

[0062] 4. 10 mL of a mixture of paraffin oil and a surfactant is added to the second liquid tank;

[0063] 5. The collection module is connected and fastened to the second liquid storage module, the collection module container is made of transparent glass material, an ultraviolet light source is arranged outside the collection module, the wavelength of the light source is 405 nm, and the outlet of the collection module is connected to a negative pressure pump;

[0064] 6. The negative pressure is adjusted to -40 kPa, the ultraviolet light source is turned on, the flow limiting valve is opened, and the photocured gelatin microspheres are automatically generated and collected.

[0065] 7. As shown in Figure 7 , the collected gelatin microspheres are observed under a microscope, and the particle size is 210 ± 3 μm.

[0066] In summary, the embodiment of the application is based on two independent liquid storage modules, the two modules are cooperated with each other through the array of guide columns for connection and positioning, the coaxial focusing micro-channel array is formed, the continuous phase and the dispersed phase fluid in the two liquid storage modules are automatically converged to the coaxial focusing micro-channel array through the gas pressure driving mode, and a large number of micro-droplets or microspheres are synchronously generated, so that the large-scale production of micro-fluidic droplets or microspheres is realized.

[0067] In some alternative embodiments, the functions / operations mentioned in the block diagrams can not occur in the order mentioned in the operation diagram. For example, depending on the functions / operations involved, two blocks shown in succession can actually be executed substantially simultaneously with each other, or the blocks can sometimes be executed in reverse order. Furthermore, the embodiments presented and described in the flowcharts of the present application are provided by way of example only, and are not intended to provide an exhaustive description of techniques of the present application. The disclosed methods are not limited to the operations and logical flows presented in this specification. Alternative embodiments are contemplated in which the order of various operations is changed, and in which sub-operations described as part of a larger operation are independently executed.

[0068] In the description of the present specification, the description of the terms "one embodiment", "some embodiments", "example", "specific example", or "some examples" and the like means that the specific features, structures, materials or characteristics described in connection with the embodiment or example are included in at least one embodiment or example of the present application. In the present specification, the illustrative description of the above terms does not necessarily refer to the same embodiment or example. Moreover, the specific features, structures, materials or characteristics described can be combined in any suitable manner in one or more embodiments or examples.

[0069] Although the embodiments of the present application have been shown and described, those skilled in the art can understand that various changes, modifications, replacements and variations can be made to the embodiments without departing from the principles and spirit of the present application, and the scope of the present application is defined by the claims and their equivalents.

[0070] The above is a specific description of the preferred embodiment of the present application, but the present application is not limited to the described embodiments, and those skilled in the art can make various equivalent modifications or replacements without departing from the spirit of the present application, and these equivalent modifications or replacements are all included in the scope defined by the claims of the present application.

Claims

1. A microsphere scale-up production apparatus characterized by comprising: The device comprises a first liquid storage module, a second liquid storage module and a collection module. The first liquid storage module is provided with a first liquid storage tank, a microneedle array and a guide column array; the first liquid storage tank is used for containing discrete phase liquid; the microneedle array is in communication with the bottom of the first liquid storage tank; and the microneedle array is parallel to the guide column array. The second liquid storage module is provided with a second liquid storage tank, a micropore array and a guide hole array; the second liquid storage tank is used for containing continuous phase liquid; the micropore array is parallel to the guide hole array. The collection module is provided with a collection tank and a first outlet; the first outlet is used for connecting a negative pressure driving device. The microneedle array corresponds to the micropore array; the guide column array corresponds to the guide hole array; the microneedle array penetrates through the second liquid storage tank and accesses the micropore array, thereby forming a coaxial focusing microchannel array; in any corresponding group of microneedles and micropores in the microneedle array and the micropore array, the pore diameter of the micropore is greater than the outer diameter of the microneedle; the second liquid storage module is hermetically connected to the collection module; and the micropore array is in communication with the second liquid storage tank and the collection tank.

2. The microsphere scaling-up preparation device according to claim 1, characterized in that, The device further comprises a connecting kit, which is used for controlling the longitudinal movement of the first liquid storage module and the second liquid storage module and adjusting the depth of the microneedle array embedded in the micropore array.

3. The microsphere scaling-up preparation device according to claim 1, characterized in that, The microneedle array and the micropore array comprise microneedles and micropores of different specifications, so as to form coaxial focusing microchannel arrays of different sizes.

4. The microsphere scaling-up preparation device according to claim 1, characterized in that, The number of guide columns in the guide column array and the number of guide holes in the guide hole array are at least 2.

5. The microsphere scaling-up preparation device according to claim 1, wherein, The guide holes in the guide hole array are blind holes.

6. The microsphere scaling device of claim 1, wherein, The collection tank comprises a first collection tank and a second collection tank separated by a partition; the first collection tank is used for collecting generated microspheres; and the second collection tank is used for containing liquid overflowing from the first collection tank.

7. The microsphere scaling-up preparation device according to claim 6, characterized in that, The collection module further comprises a second outlet, which is arranged at the lower end of the second collection tank; the second outlet is used for discharging and recycling the liquid contained in the second collection tank.

8. A method of using a microsphere scale-up production apparatus, characterized by, The device comprises a first liquid storage module, a second liquid storage module and a collection module; the first liquid storage module is provided with a first liquid storage tank, a microneedle array and a guide column array; the first liquid storage tank is used for containing discrete phase liquid; the microneedle array is in communication with the bottom of the first liquid storage tank; and the microneedle array is parallel to the guide column array. The second liquid storage module is provided with a second liquid storage tank, a micropore array and a guide hole array; the second liquid storage tank is used for containing continuous phase liquid; the micropore array is parallel to the guide hole array; the collection module is provided with a collection tank and a first outlet; the first outlet is used for connecting a negative pressure driving device; wherein the microneedle array corresponds to the micropore array; the guide column array corresponds to the guide hole array; the microneedle array penetrates through the second liquid storage tank and accesses the micropore array; in any corresponding group of microneedles and micropores in the microneedle array and the micropore array, the pore diameter of the micropore is greater than the outer diameter of the microneedle; the second liquid storage module is hermetically connected to the collection module; and the micropore array is in communication with the second liquid storage tank and the collection tank; and the application method comprises: connecting the first liquid storage module and the second liquid storage module through the guide post array and the guide hole array, keeping the first liquid storage module and the second liquid storage module transversely fixed; moving the first liquid storage module and the second liquid storage module longitudinally, so that the tips of the microneedle array enter the microwell array, and through the one-to-one correspondence between the microneedles of the microneedle array and the microwells of the microwell array, an array of coaxial focusing microfluidic channels is formed; sealingly connecting the collection module to the bottom of the second liquid storage module; adding a dispersed phase liquid into the first liquid storage tank of the first liquid storage module, and adding a continuous phase liquid into the second liquid storage tank of the second liquid storage module; starting and setting a negative pressure driving device connected to the first outlet, so that the dispersed phase liquid and the continuous phase liquid react to generate microspheres in the array of coaxial focusing microfluidic channels; collecting the microspheres through the collection tank of the collection module.

9. The use of a microsphere scale-up production apparatus according to claim 8, characterized in that, The device further comprises a connecting kit, and the moving the first liquid storage module and the second liquid storage module longitudinally comprises: controlling the longitudinal movement of the first liquid storage module and the second liquid storage module through the connecting kit, and adjusting the depth of the embedding of the microneedle array into the microwell array.

10. The use of a microsphere scale-up production apparatus according to claim 8, characterized in that, The collection tank comprises a first collection tank and a second collection tank separated by a partition, the first collection tank is used to collect the generated microspheres, and the second collection tank is used to accommodate the liquid overflowed from the first collection tank, the collection module further comprises a second outlet, and the second outlet is arranged at the lower end of the second collection tank, and the application method further comprises: discharging and recycling the liquid accommodated in the second collection tank through the second outlet.

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