Microsphere preparation device and application

Abstract

The application relates to a microsphere preparation device and application, which comprises a driving liquid structure and a micropore array arranged in sequence along the direction of microsphere extrusion, and a liquid flow channel distribution cavity is formed between the driving liquid structure and the micropore array; the driving liquid structure is provided with a piezoelectric film layer for mechanically moving and extruding the liquid flow channel distribution cavity. The application realizes efficient preparation and accurate control of microsphere particle size by combining the micropore array with the driving liquid structure and simultaneously controlling the stacking structure of each film layer, and can be applied to the microsphere preparation scene in the biological and pharmaceutical fields.

Description

TECHNICAL FIELD

[0001] The present application relates to the field of microfluidic technology, and in particular to a microsphere preparation device and application. BACKGROUND

[0002] Microsphere preparation technology is widely used in the fields of biotechnology, basic medical research, diagnostics, pharmacy, etc. At present, the methods for preparing microspheres mainly include mechanical method, atomization method and microfluidic method. The mechanical method mainly uses high-speed rotating mechanical paddles to stir the oil-liquid two-phase liquid at high speed, thereby dispersing the liquid to form an emulsion, and then separating the liquid droplets in the emulsion to obtain microspheres of different sizes; the atomization method is to dry the microspheres by atomizing the liquid into a drying tank through an atomizing nozzle; the microfluidic method is to divide the liquid through a single or multiple flow channels to form different liquid droplets, and then dry the formed liquid droplets.

[0003] CN 114634390A discloses a preparation method of multi-element composite energetic microspheres, comprising the following steps: adding an emulsifier into distilled water, stirring and dissolving to form an aqueous solution; adding explosives, high-activity metal powder and fluoropolymer into an organic solvent containing a binder at a certain mass ratio, mechanically stirring and mixing uniformly to form an oil phase mixture. The oil phase mixture is slowly added to the water phase, stirred and emulsified to form a microemulsion. Heating, the organic solvent in the microemulsion slowly volatilizes, the binder precipitates, and the energetic microspheres are formed by the assembly of explosive, high-activity metal powder and fluoropolymer particles. After separation, washing, filtration and drying, the composite energetic microspheres are obtained. However, the mechanical method has low efficiency, it is difficult to prepare small particle size microspheres, the output is not high, and there are problems such as large particle size distribution of microspheres.

[0004] CN 103521150A discloses a method for preparing cellulose microspheres and chitosan-coated cellulose composite microspheres. First, a transparent sol is prepared by dissolving cellulose in an aqueous solution of sodium hydroxide and urea. Then, the sol is sprayed through a nozzle under certain pressure into a dilute acetic acid or pure water coagulation bath to form gel microspheres. After washing, the gel microspheres are dispersed in distilled water again, and then the gel suspension is dried by a spray dryer. The microspheres obtained by the above-mentioned atomization method need to calculate the droplet size of the atomizing nozzle and the evaporation ratio, which requires a large volume of equipment and high energy consumption.

[0005] Compared with the atomization method, the microfluidic method reduces the use of volatile materials such as solvents and reduces energy consumption. However, the design of the flow channel is highly specialized, and the design flux of the microfluid is usually low. Only high-flux microfluidic design can provide higher microsphere preparation efficiency.

[0006] In view of the deficiencies of the prior art, there is an urgent need to provide a microsphere preparation device that can be used in high-flux scenarios, has high preparation efficiency and precise microsphere particle size control capability. SUMMARY

[0007] The present application aims to provide a microsphere preparation device and application, which realizes efficient preparation and precise control of microsphere particle size by combining a micropore array with a driving liquid structure and simultaneously controlling the stacking structure of each layer of film, and can be applied to the microsphere preparation scene in the biological and pharmaceutical fields.

[0008] To achieve the purpose of the present application, the following technical solutions are adopted:

[0009] In a first aspect, the present application provides a microsphere preparation device, which comprises a driving liquid structure and a micropore array arranged in sequence along the direction of microsphere extrusion, and a liquid flow channel distribution cavity is formed between the driving liquid structure and the micropore array.

[0010] The driving liquid structure is provided with a piezoelectric film layer for mechanical movement to extrude the liquid flow channel distribution cavity.

[0011] The microsphere preparation device provided by the present application combines a micropore array with a driving liquid structure, which can utilize the micropore array, a microfluidic device, for microsphere generation, and the driving liquid structure is used to provide the driving force for pushing the droplets out of the micropores, thereby performing the preparation process from droplets to microspheres, and finally realizing efficient preparation and precise control of microsphere particle size, which is suitable for the biological or pharmaceutical microsphere preparation field.

[0012] Preferably, the shape of the micropores of the micropore array includes a circle or a polygon.

[0013] Preferably, the polygon includes any one of a quadrilateral, a hexagon or an octagon.

[0014] Preferably, the arrangement mode of the polygon includes a honeycomb structure arrangement or a linear arrangement.

[0015] Preferably, the diameter of the circular micropore of the micropore array is 2-50 μm, for example, it can be 2 μm, 5 μm, 10 μm, 12 μm, 15 μm, 20 μm, 30 μm, 45 μm or 50 μm, but is not limited to the listed values, and other values not listed within the value range are also applicable.

[0016] Preferably, the diameter of the circumscribed circle of the polygonal micropore of the micropore array is 2-50 μm, for example, it can be 2 μm, 5 μm, 10 μm, 12 μm, 15 μm, 20 μm, 30 μm, 45 μm or 50 μm, but is not limited to the listed values, and other values not listed within the value range are also applicable.

[0017] Preferably, the thickness of the microwell array is 15-400 μm, for example, it can be 15 μm, 50 μm, 100 μm, 200 μm or 400 μm, but is not limited to the listed values, and other values not listed in the range are also applicable.

[0018] The thickness of the microwell array is appropriately adjusted according to the strength requirement corresponding to the size of the microwell array. The thickness of the microwell array and the diameter of the microwell determine the diameter of the microdroplet, i.e., indirectly control the particle size of the final microsphere formed. The diameter is reduced by 2-20 times from the microdroplet to the microsphere, which is determined by the amount of mixed solvent.

[0019] Preferably, the material of the microwell array includes quartz glass and / or soda-lime glass.

[0020] In order to ensure that the capillary force can actively fill the liquid, the inner wall of the microwell array needs to be smooth and hydrophilic. Therefore, quartz glass and / or soda-lime glass is selected, and the microwell is prepared by etching.

[0021] Preferably, the surface of the microwell array is provided with a coating.

[0022] The microwell array needs to be coated with a coating for protection, and at the same time, it can ensure that the droplet can be effectively separated after being extruded from the microwell, thereby avoiding the generation of uneven droplets.

[0023] Preferably, the thickness of the coating is 0.001-10 μm, for example, it can be 0.001 μm, 1 μm, 3 μm, 5 μm or 10 μm, but is not limited to the listed values, and other values not listed in the range are also applicable.

[0024] Preferably, the material of the coating includes any one or a combination of at least two of metal oxide, nitride or long-chain fluorocarbon. A typical but non-limiting combination includes a combination of metal oxide and nitride, a combination of nitride and long-chain fluorocarbon, or a combination of metal oxide, nitride and long-chain fluorocarbon.

[0025] Preferably, the metal oxide includes aluminum oxide ceramic.

[0026] Preferably, the nitride includes silicon nitride ceramic and / or aluminum nitride ceramic.

[0027] Preferably, the long-chain fluorocarbon includes polytetrafluoroethylene and / or 1H, 1H, 2H, 2H-perfluorodecyltrichlorosilane.

[0028] Preferably, the driving liquid structure comprises, in sequence from the direction away from the microwell array, a silicon substrate material, a first silicon oxide layer, an intermediate layer, a second silicon oxide layer, a first conductive layer, a piezoelectric film layer, and a second conductive layer, and the first conductive layer and the second conductive layer are respectively and independently connected to a third conductive layer.

[0029] The microwell array mainly functions to cut the liquid, and a pushing force is needed below the microwell array to push the liquid droplet out of the microwell. The driving liquid structure provided by the application mainly relies on the mechanical movement of the piezoelectric film layer under the action of the upper and lower electrodes to generate the up-and-down vibration process, so as to extrude the space after the combination of the microwell array and the driving liquid structure, thereby ensuring the liquid to be extruded out of the microwell array to form a microdroplet. The first conductive layer is connected to the third conductive layer by opening a through slot in the piezoelectric film layer.

[0030] Preferably, the bonding mode of the silicon substrate material and the microwell array includes bonding and / or adhesion.

[0031] Preferably, the thickness of the silicon substrate material is 20-1000 pm, for example, it can be 20 pm, 200 pm, 400 pm, 600 pm or 1000 pm, but is not limited to the listed values, and other values not listed in the value range are also applicable, and preferably 200-600 pm.

[0032] If the thickness of the silicon substrate material is too large, the fluid flow and driving force will decrease, and if the thickness is too small, the preparation difficulty will increase, so the thickness of the silicon substrate material is controlled within a reasonable range.

[0033] Preferably, the thickness of the first silicon oxide layer and the second silicon oxide layer is respectively 100-1000 nm, for example, it can be 100 nm, 200 nm, 500 nm, 800 nm or 1000 nm, but is not limited to the listed values, and other values not listed in the value range are also applicable.

[0034] If the thickness of the first silicon oxide layer and the second silicon oxide layer is too large, the deformation amount will decrease when the piezoelectric driving is performed, and if the thickness is too small, the risk of electric leakage and damage in the manufacturing process will increase.

[0035] Preferably, the thickness of the first conductive layer, the second conductive layer and the third conductive layer is respectively 10-500 nm, for example, it can be 10 nm, 100 nm, 200 nm, 400 nm or 500 nm, but is not limited to the listed values, and other values not listed in the value range are also applicable.

[0036] The thickness of the first, second and third conductive layers is within a reasonable range, which can provide sufficient driving power. Too thick conductive layers will result in a decrease in the deformation of the piezoelectric film when driven.

[0037] Preferably, the material of the first and second conductive layers comprises platinum.

[0038] Preferably, the material of the third conductive layer comprises gold and / or aluminum.

[0039] Preferably, the thickness of the intermediate layer is 500-5000 nm, for example, it can be 500 nm, 1000 nm, 2000 nm, 4000 nm or 5000 nm, but is not limited to the listed values, and other values not listed within the range are also applicable.

[0040] Preferably, the material of the intermediate layer comprises any one of a silicon material, stainless steel, manganese steel, quartz or diamond.

[0041] The material of the intermediate layer can be a silicon material, a metal material or an insulating material.

[0042] Preferably, the thickness of the piezoelectric film layer is 500-10000 nm, for example, it can be 500 nm, 1000 nm, 3000 nm, 6000 nm or 10000 nm, but is not limited to the listed values, and other values not listed within the range are also applicable.

[0043] The thickness of the intermediate layer needs to be matched with the thickness of the piezoelectric film layer. Too thick piezoelectric film thickness results in an increase in driving voltage and driving force; when it is too thin, the reliability of the film will decrease, affecting its service life. The thickness of the piezoelectric film layer is also affected by the cross-sectional area of the individual holes of the micropore array. When the area of the individual micropores is smaller, the required driving force is greater, and accordingly, the thickness of the intermediate layer and the thickness of the piezoelectric film layer are appropriately matched within the above range.

[0044] Preferably, the piezoelectric film layer comprises a lead zirconate titanate film or a lead-free piezoelectric film.

[0045] Preferably, the shape of the piezoelectric film layer and the intermediate layer comprises any one of a circle, an ellipse, a rectangle, a hexagon, a cross, a back-to-back character or a windmill shape.

[0046] The cross shape refers to the pattern remaining after the four corners of a square are cut by arcs.

[0047] The back-to-back character shape refers to the pattern formed by combining the four isosceles trapezoids obtained by rotating an isosceles trapezoid by 0°, 90°, 180° and 270°.

[0048] The windmill shape refers to a pattern formed by taking a circle as the center, diverging at least 4 semi-circular arcs from the circle outward.

[0049] The size of the piezoelectric film layer is usually 50 μm, 100 μm or 200 μm thin film, and the size will be determined according to the overall shape and volume of the corresponding micro-hole array. In addition to the circular shape, the shapes provided in the present application can also obtain larger film displacement and film driving force. These shapes mainly make different choices between increasing deformation and driving force, and need to balance between the first-order resonance frequency and the second-order resonance frequency when the piezoelectric film deforms. The main principle is to increase the frequency difference between the two, so as to obtain a wider first-order control frequency, and to meet the control requirements of different droplet extrusion speeds.

[0050] In the second aspect, the present application provides an application of the microsphere preparation device according to the first aspect, which is used in the preparation of drug microspheres, atomization device or digital quantitative detection.

[0051] Preferably, the drug in the preparation of drug microspheres includes any one of leuprolide, risperidone, exenatide, octreotide, triptorelin, repaglinide, cimetidine, rosiglitazone, nitrendipine, acyclovir, ranitidine hydrochloride, misoprostol, metformin, aceclofenac, diltiazem, L-dopa or styryl amide fluorouracil.

[0052] Preferably, the liquid used in the digital quantitative detection includes a solution containing nucleic acid and protein or a biological sample liquid to be detected.

[0053] In the digital quantitative detection, the microsphere preparation device provided by the present application is used to prepare oil liquid two-phase microdroplets, i.e. to separate the liquid into inert fluorine oil, so as to perform digital quantitative detection such as polymerase chain reaction detection.

[0054] Preferably, the atomization device includes a biological atomization device or a medical atomization device.

[0055] Preferably, the liquid used in the biological atomization device includes any one of perfume, moisturizer or foundation.

[0056] Preferably, the liquid used in the medical atomization device includes any one of aqueous solution, ethanol solution, solvent-free solution or mixture solution.

[0057] Preferably, the solute in the liquid used in the medical atomization device includes any one of pharmaceutical active substance, substance preparation or substance mixture, preferably any one of substance for treating respiratory diseases and for inhalation administration, its substance preparation or its substance mixture.

[0058] Preferably, the pharmaceutically active substance comprises any one or a combination of at least two of an anticholinergic agent, a B-mimetic, a steroid, a phosphodiesterase IV inhibitor, an LTD4 antagonist, an EGFR kinase inhibitor, an anti-allergic agent, an ergot derivative, a triptan, a CGRP antagonist or a phosphodiesterase V inhibitor, typical but non-limiting combinations including a combination of a B-mimetic and an anticholinergic agent, or a combination of a B-mimetic and an anti-allergic agent.

[0059] Preferably, at least one pharmaceutically active substance in the combination of pharmaceutically active substances comprises chemically bound water.

[0060] The anti-allergic agent comprises cromoglycate disodium or nedocromil.

[0061] The ergot derivative comprises dihydroergotamine or ergotamine.

[0062] Compared with the prior art, the present application has the following beneficial effects:

[0063] (1) The microsphere preparation device provided by the present application uses a micropore array for microsphere generation, and a coating is arranged on the surface of the micropore array, so as to effectively break the liquid droplets and form microspheres; in addition, through the selection of the material of the micropore array, the liquid is self-filled in the capillary holes of the micropore array due to capillary force to form a required liquid droplet volume;

[0064] (2) The microsphere preparation device provided by the present application uses a driving liquid structure to provide a pushing force for pushing the liquid droplets out of the micropore, further proposes the shape design of the piezoelectric film layer, and the piezoelectric film layer can be appropriately selected and matched according to the required volume of the liquid droplets, so as to realize the preparation process from the liquid droplets to the microspheres, and finally achieve the purpose of efficient preparation and precise control of the particle size of the microspheres, which is suitable for the field of biological or drug microsphere preparation. BRIEF DESCRIPTION OF DRAWINGS

[0065] Figure 1 is a structural schematic diagram of the microsphere preparation device provided by Embodiment 1 of the present application;

[0066] 1, micropore array; 2, liquid flow channel distribution cavity; 3, alumina ceramic coating; 4, silicon substrate material; 5, first silicon oxide layer; 6, silicon material layer; 7, second silicon oxide layer; 8, first conductive layer; 9, piezoelectric film layer; 10, second conductive layer; 11, third conductive layer. DETAILED DESCRIPTION

[0067] The technical solutions of the present application will be further described below through specific embodiments. Those skilled in the art should understand that the embodiments are only used to help understand the present application and should not be regarded as specific limitations on the present application.

[0068] Embodiment 1

[0069] The embodiment provides a microsphere preparation device, which comprises, in the direction of microsphere extrusion, a driving liquid structure and a micropore array 1 arranged in sequence, and a liquid flow channel distribution cavity 2 formed by surrounding the driving liquid structure and the micropore array 1. Figure 1

[0070] The micropore of the micropore array 1 is circular in shape and has a diameter of 20 μm; the micropore array 1 has a thickness of 200 μm and is made of quartz glass; and the surface of the micropore array 1 is provided with an alumina ceramic coating 3 with a thickness of 3 μm.

[0071] In the direction away from the micropore array 1, the driving liquid structure comprises, in sequence, a silicon substrate material 4, a first silicon oxide layer 5, a silicon material layer 6, a second silicon oxide layer 7, a first conductive layer 8, a piezoelectric film layer 9 and a second conductive layer 10, and the first conductive layer 8 and the second conductive layer 10 are respectively and independently connected to a third conductive layer 11; the piezoelectric film layer 9 is provided with a through groove for connecting the third conductive layer 11 and the first conductive layer 8; and the piezoelectric film layer 9 is used for mechanical movement to extrude the liquid flow channel distribution cavity 2.

[0072] The silicon substrate material 4 is bonded to the micropore array 1; the thickness of the silicon substrate material 4 is 400 μm; the thicknesses of the first silicon oxide layer 5 and the second silicon oxide layer 7 are 200 nm and 100 nm respectively; the middle part of the silicon substrate material 4 and the first silicon oxide layer 5 is provided with a through groove for accommodating liquid; the thicknesses of the first conductive layer 8, the second conductive layer 10 and the third conductive layer 11 are 200 nm, 300 nm and 350 nm respectively; the materials of the first conductive layer 8 and the second conductive layer 10 are both platinum, and the material of the third conductive layer 11 is gold; the thickness of the silicon material layer 6 is 500 nm; the thickness of the piezoelectric film layer 9 is 1000 nm and the material is a lead zirconate titanate film; and the shapes of the piezoelectric film layer 9 and the silicon material layer 6 are both circular.

[0073] Embodiment 2

[0074] The embodiment provides a microsphere preparation device, which comprises, in the direction of microsphere extrusion, a driving liquid structure and a micropore array 1 arranged in sequence, and a liquid flow channel distribution cavity 2 formed by surrounding the driving liquid structure and the micropore array 1.

[0075] The micropore of the micropore array 1 is hexagonal in shape and arranged in a honeycomb structure, and the circumscribed circle diameter of the hexagonal micropore is 2 μm; the micropore array 1 has a thickness of 15 μm and is made of quartz glass; and the surface of the micropore array 1 is provided with a silicon nitride ceramic coating with a thickness of 0.001 μm.​

[0076] In the direction away from the micropore array 1, the driving liquid structure comprises, in sequence, a silicon substrate material 4, a first silicon oxide layer 5, a silicon material layer 6, a second silicon oxide layer 7, a first conductive layer 8, a piezoelectric film layer 9, and a second conductive layer 10, the first conductive layer 8 and the second conductive layer 10 are also respectively independently connected to a third conductive layer 11; the piezoelectric film layer 9 is provided with a through slot to connect the third conductive layer 11 and the first conductive layer 8; the piezoelectric film layer 9 is used to perform mechanical movement to extrude the liquid flow channel distribution cavity 2;

[0077] The bonding mode of the silicon substrate material 4 and the micropore array 1 is bonding; the thickness of the silicon substrate material 4 is 200 μm; the thicknesses of the first silicon oxide layer 5 and the second silicon oxide layer 7 are 100 nm respectively; the middle part of the silicon substrate material 4 and the first silicon oxide layer 5 is provided with a through slot for accommodating liquid; the thicknesses of the first conductive layer 8, the second conductive layer 10, and the third conductive layer 11 are 10 nm respectively; the materials of the first conductive layer 8 and the second conductive layer 10 are platinum, and the material of the third conductive layer 11 is gold; the thickness of the silicon material layer 6 is 1000 nm; the thickness of the piezoelectric film layer 9 is 1200 nm, and the material is lead zirconate titanate film; the shapes of the piezoelectric film layer 9 and the silicon material layer 6 are hexagonal.

[0078] Embodiment 3

[0079] The embodiment provides a microsphere preparation device, in the direction of microsphere extrusion, the microsphere preparation device comprises, in sequence, a driving liquid structure and a micropore array 1, and a liquid flow channel distribution cavity 2 is surrounded between the driving liquid structure and the micropore array 1;

[0080] The micropore shape of the micropore array 1 is quadrilateral, arranged in a linear structure, and the diameter of the circumscribed circle of the quadrilateral micropore is 50 μm; the thickness of the micropore array 1 is 400 μm, and the material is sodium potassium glass; the surface of the micropore array 1 is provided with a polytetrafluoroethylene coating with a thickness of 10 μm;

[0081] In the direction away from the micropore array 1, the driving liquid structure comprises, in sequence, a silicon substrate material 4, a first silicon oxide layer 5, a silicon material layer 6, a second silicon oxide layer 7, a first conductive layer 8, a piezoelectric film layer 9, and a second conductive layer 10, the first conductive layer 8 and the second conductive layer 10 are also respectively independently connected to a third conductive layer 11; the piezoelectric film layer 9 is provided with a through slot to connect the third conductive layer 11 and the first conductive layer 8; the piezoelectric film layer 9 is used to perform mechanical movement to extrude the liquid flow channel distribution cavity 2;

[0082] The bonding mode of the silicon substrate material 4 and the micropore array 1 is bonding; the thickness of the silicon substrate material 4 is 600 μm; the thickness of the first silicon oxide layer 5 and the second silicon oxide layer 7 is 1000 nm respectively; a through slot is arranged in the middle of the silicon substrate material 4 and the first silicon oxide layer 5, which is used for accommodating liquid; the thickness of the first conductive layer 8, the second conductive layer 10 and the third conductive layer 11 is 500 nm respectively; the material of the first conductive layer 8 and the second conductive layer 10 is platinum, and the material of the third conductive layer 11 is aluminum; the thickness of the silicon material layer 6 is 5000 nm; the thickness of the piezoelectric film layer 9 is 2000 nm, and the material is lead zirconate titanate film; the shape of the piezoelectric film layer 9 and the silicon material layer 6 is cross-shaped.

[0083] Example 4

[0084] The embodiment provides a microsphere preparation device, which is different from example 1 in that, except that the thickness of the silicon substrate material 4 is adjusted to 20 μm, the rest is the same as example 1.

[0085] Example 5

[0086] The embodiment provides a microsphere preparation device, which is different from example 1 in that, except that the thickness of the silicon substrate material 4 is adjusted to 1000 μm, the rest is the same as example 1.

[0087] Example 6

[0088] The embodiment provides a microsphere preparation device, which is different from example 1 in that, except that the thickness of the first silicon oxide layer 5 and the second silicon oxide layer 7 is adjusted to 50 nm respectively, the rest is the same as example 1.

[0089] Example 7

[0090] The embodiment provides a microsphere preparation device, which is different from example 1 in that, except that the thickness of the first silicon oxide layer 5 and the second silicon oxide layer 7 is adjusted to 1100 nm respectively, the rest is the same as example 1.

[0091] Example 8

[0092] The embodiment provides a microsphere preparation device, which is different from example 1 in that, except that the thickness of the silicon material layer 6 is adjusted to 300 nm, and the thickness of the piezoelectric film layer 9 is adjusted to 300 nm, the rest is the same as example 1.

[0093] Example 9

[0094] The embodiment provides a microsphere preparation device, which is different from the embodiment 1 in that, in addition to that the thickness of the siliceous material layer 6 is adjusted to 6000 nm and the thickness of the piezoelectric film layer 9 is adjusted to 11000 nm, the rest is the same as the embodiment 1.

[0095] Embodiment 10

[0096] The embodiment provides a microsphere preparation device, which is different from the embodiment 1 in that, the surface of the micropore array 1 is not provided with the alumina ceramic coating 3, and the rest is the same as the embodiment 1.

[0097] Comparative example 1

[0098] The comparative example provides a microsphere preparation device, which is different from the embodiment 1 in that, an acceleration generating device disclosed in CN104741158A is used as the driving liquid structure in the microsphere preparation device, and the rest is the same as the embodiment 1.

[0099] The microspheres are prepared by using the microsphere preparation devices provided in the embodiment 1-10 and the comparative example 1, the error rate of the designed particle size is calculated according to the generated droplet and the volume of the microspheres obtained according to the test sample result curve, and the flux of the microsphere preparation device is tested according to the liquid volume consumed by continuous driving after a fixed time, and the obtained result is shown in Table 1.

[0100] Table 1

[0101] Microsphere size error rate (%) Flux (μL / s) Example 1 2.8 0.16 Example 2 4.5 0.12 Example 3 5.7 0.0875 Example 4 5.7 0.12 Example 5 6.1 0.16 Example 6 3.2 0.16 Example 7 3.3 0.16 Example 8 4.2 0.072 Example 9 3.9 0.016 Example 10 10.5 0.08 Comparative Example 1 30 0.1

[0102] As shown in Table 1, the microspheres prepared by using the microsphere preparation device provided in the application can realize accurate control of the particle size of the microspheres, and have high microsphere preparation efficiency.

[0103] In conclusion, the microsphere preparation device provided in the application uses the micropore array to generate the microspheres, and sets a coating on the surface of the micropore array, so that the droplets are effectively disconnected and form the microspheres; in addition, the material of the micropore array is selected, so that the liquid is self-filled in the capillary hole of the micropore array due to capillary force to form a required droplet volume.

[0104] The microsphere preparation device provided in the application uses the driving liquid structure to provide a pushing force for pushing the droplets out of the micropore, further proposes the shape design of the piezoelectric film layer, and the piezoelectric film layer can be appropriately selected and matched according to the required volume of the droplets, so that the preparation process from the droplets to the microspheres is realized, and the purpose of high-efficiency preparation and accurate control of the particle size of the microspheres is finally achieved, and the microsphere preparation device is suitable for the field of biological or drug microsphere preparation.

[0105] The above merely describes the specific embodiments of the present application, but the protection scope of the present application is not limited thereto, and it should be understood by those skilled in the art that any changes or replacements within the technical scope disclosed by the present application can be easily conceived by those skilled in the art, and all such changes and replacements fall within the protection scope and disclosure scope of the present application.

Claims

1. A microsphere preparation apparatus, characterized in that, Along the direction of microsphere extrusion, the microsphere preparation apparatus includes a driving liquid structure and a micropore array arranged sequentially, with the driving liquid structure and the micropore array surrounding each other to form a liquid flow channel distribution cavity; the micropore shape of the micropore array includes circular or polygonal; the diameter of the circular micropores in the micropore array is 2-50 μm; the circumcircle diameter of the polygonal micropores in the micropore array is 2-50 μm; the thickness of the micropore array is 15-400 μm; the material of the micropore array includes quartz glass and / or sodium-potassium glass; Along a direction away from the micropore array, the driving liquid structure includes a silicon substrate material, a first silicon oxide layer, an intermediate layer, a second silicon oxide layer, a first conductive layer, a piezoelectric thin film layer, and a second conductive layer arranged sequentially. The first conductive layer and the second conductive layer are also independently connected to a third conductive layer. The piezoelectric thin film layer of the driving liquid structure is used to mechanically move and squeeze the liquid flow channel distribution cavity.

2. The microsphere preparation apparatus according to claim 1, characterized in that, The polygon includes any one of quadrilaterals, hexagons, or octagons.

3. The microsphere preparation apparatus according to claim 1, characterized in that, The surface of the microporous array is coated.

4. The microsphere preparation apparatus according to claim 3, characterized in that, The thickness of the coating is 0.001-10 μm.

5. The microsphere preparation apparatus according to claim 3, characterized in that, The coating material includes any one or a combination of at least two of the following: metal oxides, nitrides, or long-chain fluorocarbons.

6. The microsphere preparation apparatus according to claim 5, characterized in that, The metal oxide includes alumina ceramic.

7. The microsphere preparation apparatus according to claim 5, characterized in that, The nitrides include silicon nitride ceramics and / or aluminum nitride ceramics.

8. The microsphere preparation apparatus according to claim 5, characterized in that, The long-chain fluorocarbons include polytetrafluoroethylene and / or 1H,1H,2H,2H-perfluorodecyltrichlorosilane.

9. The microsphere preparation apparatus according to claim 1, characterized in that, The silicon substrate material is bonded to the micropore array via bonding and / or adhesive bonding.

10. The microsphere preparation apparatus according to claim 1, characterized in that, The thickness of the silicon substrate material is 20-1000 μm.

11. The microsphere preparation apparatus according to claim 10, characterized in that, The thickness of the silicon substrate material is 200-600 μm.

12. The microsphere preparation apparatus according to claim 1, characterized in that, The thicknesses of the first silicon oxide layer and the second silicon oxide layer are 100-1000 nm, respectively.

13. The microsphere preparation apparatus according to claim 1, characterized in that, The thicknesses of the first conductive layer, the second conductive layer, and the third conductive layer are 10-500 nm, respectively.

14. The microsphere preparation apparatus according to claim 1, characterized in that, The materials of the first conductive layer and the second conductive layer include platinum.

15. The microsphere preparation apparatus according to claim 1, characterized in that, The material of the third conductive layer includes gold and / or aluminum.

16. The microsphere preparation apparatus according to claim 1, characterized in that, The thickness of the intermediate layer is 500-5000 nm.

17. The microsphere preparation apparatus according to claim 1, characterized in that, The intermediate layer can be made of any one of the following materials: silicon, stainless steel, or diamond.

18. The microsphere preparation apparatus according to claim 1, characterized in that, The thickness of the piezoelectric thin film layer is 500-10000 nm.

19. The microsphere preparation apparatus according to claim 1, characterized in that, The piezoelectric thin film layer includes a lead zirconate titanate thin film or a lead-free piezoelectric thin film.

20. The microsphere preparation apparatus according to claim 1, characterized in that, The piezoelectric thin film layer and the intermediate layer are respectively shaped as any one of the following: circle, ellipse, rectangle, hexagon, cross, square, or windmill; the cross is the shape remaining after the four corners of a square are cut off by arcs; the square is the shape formed by four isosceles trapezoids obtained by rotating an isosceles trapezoid by 0°, 90°, 180°, and 270°; the windmill is the shape formed by at least four semicircular arcs radiating outward from the circle as the center.

21. The application of the microsphere preparation apparatus according to any one of claims 1-20, characterized in that, The microsphere preparation device is used in the preparation of drug microspheres, atomization devices, or digital quantitative detection.

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