Microneedle preparation device and application method thereof

Abstract

The invention relates to the technical field of microneedle preparation, in particular to a microneedle preparation device and an application method thereof, and the device comprises a microneedle mold and a sealing device. The application method of the microneedle preparation device comprises the steps that the microneedle mold is placed in a sealing device and vacuumized, so that the microneedle mold is converted into a second form from a first form, and the second form is kept through the sealing device; and the fluid is added into the microneedle mold through target driving force, the microneedle mold is gradually filled with the fluid, and the microneedle mold is gradually restored to the first form from the second form under the action of the fluid and air pressure. According to the novel microneedle preparation device and the application method thereof, the novel microneedle preparation device is self-exhausting, easy and convenient to operate and high in adaptability, the operation threshold and technical requirements are remarkably reduced, the process is simplified, and the microneedle preparation efficiency and quality stability (namely, the reliability of the microneedle form is improved, and the defects such as bubbles or notches are reduced) are ensured.

Description

Technical Field

[0001] This invention relates to the field of microneedle preparation technology, specifically to a microneedle preparation device and its application method. Background Technology

[0002] Microneedles are composed of multiple micron-sized needle tips connected in an array on a base. They can penetrate the skin minimally invasively and painlessly without touching blood vessels and nerves. Essentially, they are a cross-interface transmission platform that can serve as a physical channel and functional interface for the transmission of drugs, energy, signals, and samples. They have broad application prospects in medical devices, transdermal drug delivery, medical aesthetics, and biosensing.

[0003] Currently, the mold-based method, as the mainstream technology for microneedle fabrication, faces significant process bottlenecks in its core mold processing stage. This bottleneck is primarily due to the high viscosity and surface tension of polymer materials, which easily generate bubble defects when filling the mold under normal conditions. These micron-sized bubbles directly reduce the quality of microneedle formation. To address this issue, existing technologies employ vacuum degassing during fluid injection. However, the applicant notes that this vacuum fabrication process has at least two limitations: firstly, the process is severely restricted to specialized vacuum equipment, confining microneedle fabrication to specialized manufacturing environments; secondly, existing solutions are difficult to adapt to application needs in resource-constrained scenarios, such as home environments, primary healthcare units, or field operations, where traditional microneedle fabrication methods are almost impossible to implement.

[0004] The applicant argues that this technical predicament has directly limited the application scope of microneedle products and severely hindered the industrialization process of the technology.

[0005] Specifically, the following patent application discloses a two-stage sample addition process based on vacuuming (i.e., adding fluid once before vacuuming and once after vacuuming): For example, patent application CN202410847181.5 discloses a substrate-free ice microneedle and its preparation method, including the following preparation steps: pre-treating a metal core wrapped with heat insulation material, then dissolving polymer powder to make a solution, pouring it into a PDMS microneedle mold groove, performing vacuum treatment to remove air bubbles, and after the solution fills the PDMS microneedle mold groove, placing the pre-treated heat insulation material-wrapped metal core into the bottom surface of the PDMS microneedle mold groove, and finally freezing both in a refrigerator to obtain ice microneedles.

[0006] For example, patent application CN202510523020.5 discloses a method for preparing transdermal microneedles based on gallium-based liquid metal, including the following steps: using a microsyringe or pipette to draw up preheated liquid metal and quickly inject it into a microneedle mold, so that the liquid metal spreads and completely covers the cavity of the needle tip in the mold; transferring the mold to a constant temperature vacuum chamber and degassing under vacuum; during the degassing process, the degassing temperature keeps the liquid metal in a flowing liquid state, and the vacuum is drawn to no higher than 10 Pa; continuing to inject preheated gallium-based liquid metal or injecting a biodegradable polymer solution into the mold to form the substrate of the microneedles.

[0007] For example, patent application CN202510283238.8 discloses a pregabalin sustained-release dissolving microneedle patch based on PLGA microspheres, its preparation method and application. The method includes: uniformly dispersing PLGA@PG microspheres in a hyaluronic acid solution, adding them into a microneedle mold, vacuuming and centrifuging, drying and demolding the microneedles to obtain the dissolving microneedle patch.

[0008] However, the applicant noted that existing mold-based microneedle fabrication methods are complex in operation and place extremely high demands on operators. Therefore, a simpler microneedle fabrication method is urgently needed. Summary of the Invention

[0009] The purpose of this invention is to provide a method for applying microneedle molds, partially solving or alleviating the aforementioned shortcomings of the prior art, and improving the preparation efficiency and quality of microneedles. As mentioned above, the existing technology involves performing a vacuuming operation during fluid injection, which has significant limitations in application. Therefore, this application develops a novel microneedle preparation method that is self-venting, easy to operate, and highly adaptable. This innovation not only simplifies the process but also ensures the quality stability of the microneedle products, thereby expanding application scenarios and scope to meet the practical needs of diverse application scenarios.

[0010] To solve the aforementioned technical problems, the present invention specifically adopts the following technical solution: A first aspect of the present invention provides a method for applying a microneedle mold, wherein the microneedle preparation apparatus includes a microneedle mold, and the microneedle mold includes a mold and a sealing device for encapsulating the mold. Correspondingly, the method includes: S301, providing the mold, the mold having at least one microneedle model space, the microneedle model space being formed by a second molding layer, and a porous network being formed within the second molding layer; S302, placing the mold into the sealing device and performing a vacuum treatment, wherein the porous network changes from a first morphology to a second morphology, so that the porous network... A pressure difference is generated between the network and the ambient air pressure; S303, the sealing port of the sealing device is sealed, and the mold is encapsulated so that the porous network remains in the second form; S304, the sealing effect is released, and fluid is added to the microneedle model space, which includes: using a target driving force to make the fluid gradually fill the microneedle model space, forming a gas zone in the needle tip region of the microneedle model space; under the influence of the pressure difference, the accumulated gas in the gas zone is absorbed by the porous network, thereby guiding the fluid to fill the gas zone; at this time, the porous network gradually recovers from the second form to the first form, and the fluid gradually forms a microneedle shape.

[0011] In some embodiments, the second molding layer is interconnected with the first molding layer, and the material hardness of the second molding layer is less than or equal to the material hardness of the first molding layer. In some embodiments, the vacuum intensity of the vacuuming process is -0.005 to -0.1 MPa, and the vacuuming time is maintained at more than 2 seconds. In some embodiments, the material of the sealing device is one or more of the following: polymer materials, metallic materials, inorganic non-metallic materials, and composite materials.

[0012] In some embodiments, the Shore hardness of the second molding layer is less than 35A, the first molding layer is a polymer material or a composite material, and the Shore hardness of the first molding layer is greater than or equal to 70A.

[0013] In some embodiments, the Shore hardness of the second molding layer is 35-90A. In some embodiments, the target driving force satisfies a first injection model, the first injection model including: ;in, The capillary force on the inner surface of the microneedle model space. The atmospheric pressure difference in the space of the microneedle model after release. This refers to the recovery stress that the microneedle model space can generate after being vacuumed. Driven by the goal.

[0014] In some embodiments, the target driving force further satisfies a second injection model, the second injection model comprising: ; in, The time required for fluid injection The viscosity of the fluid. The tip angle is the microneedle model space.

[0015] In some embodiments, the fluid comprises any one of the following substances, or a combination of any at least two of the following substances: compounds, polymers, bioactive molecules, regulatory factors, cells, cell products, and carriers. In some embodiments, the second molding layer is made of a material that is aerosolizable and breathable. In some embodiments, the aerosolizable and breathable material comprises one or more of the following: rubber, silicone, polydimethylsiloxane, polyurethane, metal-organic framework composites, poly(N-isopropylacrylamide) hydrogel, polyolefins, styrene, fluororubber, and acrylate rubber.

[0016] This invention also provides a microneedle fabrication apparatus, comprising: a microneedle mold, the microneedle mold comprising: a mold comprising: multiple microneedle model spaces provided by multiple second molding layers, wherein a porous network is formed inside the second molding layers; the second molding layers are interconnected with a first molding layer, wherein the hardness of the second molding layer is less than or equal to the hardness of the first molding layer; wherein, under vacuum, the porous network changes from an initial first morphology to a second morphology, thereby creating a pressure difference between the porous network and the ambient air pressure; wherein the vacuum intensity corresponding to the second morphology is -0.005 MPa to -0.1 MPa; a sealing device for sealing the mold, thereby maintaining the porous network in the second morphology; wherein, when a target driving force is used to gradually fill the microneedle model space with fluid, a gas region is formed in the tip region of the microneedle model space; under the influence of the pressure difference, the fluid gradually replaces the accumulated gas, thereby guiding the fluid to fill the gas region; at this time, the porous network gradually returns from the second morphology to the first morphology.

[0017] In some embodiments, the Shore hardness of the second molding layer is less than 35A, the first molding layer is a polymer material or a composite material, and the Shore hardness of the first molding layer is greater than or equal to 70A; or, the Shore hardness of the second molding layer is 35~90A.

[0018] Beneficial Technical Effects: Compared to traditional microneedle mold preparation processes—which require vacuuming or centrifugation during the fluid injection stage to drive liquid filling of the mold, such as the secondary sample addition process based on vacuuming—this application proposes a gentler and more efficient new method: pre-vacuuming the mold and utilizing the inherent gas permeability of its material to achieve rapid and automatic filling based on the internal and external pressure difference when liquid is added. This innovative method significantly simplifies the operation process, avoids potential mechanical damage to cells, exosomes, and other active ingredients during centrifugation or vacuuming, and possesses a "ready-to-use" characteristic, better meeting the needs of rapid clinical preparation and personalized treatment, providing a new solution for the application of microneedles in cell therapy, drug delivery, and other fields.

[0019] In other words, the present invention actually provides a single-sampling process based on pre-vacuuming, which can greatly simplify the on-site preparation difficulty and alleviate the application difficulty in resource-constrained scenarios.

[0020] Furthermore, this invention provides a soft and hard synergistic mold product for single-sample loading processes involving pre-vacuuming. This mold product, through material selection and coordination with a sealing device, as well as through the selection of vacuum processing conditions, can provide a favorable initial environment for microneedle formation. In other words, this synergistic selection of materials and vacuum processing conditions can effectively improve the quality of microneedle formation.

[0021] From another perspective, the invention also provides a bottom-up freezing path / mode that facilitates the fabrication of high-quality microneedles. Specifically, the invention provides a freezing mold based on a bottom-up freezing mode, and it can also introduce a vacuum process to optimize the microneedle forming process. For example, before use, the microneedle model space can be evacuated. When injecting fluid into the microneedle model space, the mold's self-rebound capability helps to achieve a high degree of fluid filling of the microneedle model space, avoiding or reducing the failure of microneedle tip fabrication due to incomplete liquid filling in the narrow tip area. Attached Figure Description

[0022] To more clearly illustrate the technical solutions in the embodiments of the present invention or the prior art, the drawings used in the description of the embodiments or the prior art will be briefly introduced below. In all the drawings, similar elements or parts are generally identified by similar reference numerals. The elements or parts in the drawings are not necessarily drawn to scale. Obviously, the drawings described below are some embodiments of the present invention, and those skilled in the art can obtain other drawings based on these drawings without any creative effort.

[0023] Figure 1This is a schematic diagram of the structure of a refrigeration device in an exemplary embodiment of the present invention; Figure 2 This is a schematic diagram of the molding area in an exemplary embodiment of the present invention; Figure 3 This is a first schematic diagram of the liquid level addition state of the refrigeration device during application in an exemplary embodiment of the present invention; Figure 4 This is a second schematic diagram of the liquid level addition state of the refrigeration device during application in an exemplary embodiment of the present invention; Figure 5 This is a schematic diagram of partial components of a refrigeration apparatus in an exemplary embodiment of the present invention; Figure 6 This is a schematic diagram of the molding area in another exemplary embodiment of the present invention; Figure 7 This is a schematic diagram of a needle-shaped structure in an exemplary embodiment of the present invention; Figure 8 This is a partial schematic diagram of a refrigeration apparatus in an exemplary embodiment of the present invention; Figure 9 This is a schematic diagram of the heat dissipation port of the refrigeration device in an exemplary embodiment of the present invention; Figure 10 This is a schematic diagram of the structure of the moving part in another exemplary embodiment of the present invention; Figure 11 This is a schematic diagram of the structure of the moving part in another exemplary embodiment of the present invention; Figure 12 This is a schematic diagram of the freezing effect of the microneedle model space in an exemplary embodiment of the present invention; Figure 13 Comparison chart of temperature differences between existing technology and the present invention in the freeze crystallization process; Figure 14 This is a schematic diagram of the first structure of the preparation component in an exemplary embodiment of the present invention; Figure 15 This is a schematic diagram of the structure of the third template of the preparation component in an exemplary embodiment of the present invention; Figure 16 This is a schematic diagram of the structure of the first template of the preparation component in an exemplary embodiment of the present invention; Figure 17 This is a schematic diagram of the structure of the second template of the preparation component in an exemplary embodiment of the present invention; Figure 18 This is a partially enlarged schematic diagram of the first template of the preparation component in an exemplary embodiment of the present invention; Figure 19 This is a schematic diagram of gas flow in an exemplary embodiment of the present invention; Figure 20This is a schematic diagram illustrating the fluid filling effect in an exemplary embodiment of the present invention; Figure 21 This is a table showing the test results of a verification embodiment of the present invention; Figure 22 This is a table showing the test results of another confirmatory embodiment of the present invention; Figure 23 This is a table showing the test results of another confirmatory embodiment of the present invention; Figure 24 This is a schematic diagram of the pore distribution inside the molding layer in an exemplary embodiment of the present invention; Figure 25 This is a schematic diagram of the structure of a microneedle; Figure 26 This is a schematic diagram of the structure of the microneedle provided by the present invention; Figure 27 This is a schematic diagram of the deformation of a mold under vacuum conditions in an exemplary embodiment of the present invention; Figure 28 To use separately Figure 26 , Figure 25 The diagram shows the puncture effect after the micro-needle is used to puncture the skin; Figure 29 This is a schematic diagram of the measurement range for Shore hardness.

[0024] Summary of reference numerals in the attached drawings: 2. Freezing mold; 22. Mold frame; 21. Molding area; 211. Second molding layer; 212. First molding layer; 3. Moving part; 31. Connector; 32. Holding part; 31a. First connecting section; 31b. Second connecting section; 311. Limiting part; 312. Guiding part; 2121. Microneedle model space; 41. First contact surface; 42. Second contact surface; 421. Centralized conduction area; 5. Freezing chamber; 6. Cooling module; 61. First conduction surface; 7. Shaped needle body; 71. Main part; 72. Puncture part; 82. Fluid; 81. Gas zone; R1. First gap space; R2. Second gap space; 01. First template; 011. First model; 0111. Second surface; 0112. Third surface; 0112a. First contact surface; 0112b. Second contact surface; 012. Substrate; 013. Connecting space; 0131. First connecting space; 0132. Second connecting space; 02. Second template; 021. Template opening; 022. Connecting part; 03. Third template; 031. Isolation part; 032. Drainage space; 0311. Drainage groove. Detailed Implementation

[0025] To make the objectives, technical solutions, and advantages of the embodiments of the present invention clearer, the technical solutions of the embodiments of the present invention will be clearly and completely described below with reference to the accompanying drawings. Obviously, the described embodiments are only some embodiments of the present invention, not all embodiments. Based on the embodiments of the present invention, all other embodiments obtained by those skilled in the art without creative effort are within the scope of protection of the present invention. In this document, suffixes such as "module," "component," or "unit" used to represent elements are only for the purpose of illustrative purposes and have no specific meaning in themselves. Therefore, "module," "component," or "unit" can be used interchangeably. In this document, the terms "upper," "lower," "inner," "outer," "front," "rear," "one end," "the other end," etc., indicate the orientation or positional relationship based on the orientation or positional relationship shown in the accompanying drawings, and are only for the convenience of describing the present invention and simplifying the description, and do not indicate or imply that the device or element referred to must have a specific orientation, or be constructed and operated in a specific orientation, and therefore should not be construed as a limitation of the present invention. Furthermore, the terms "first" and "second" are used for descriptive purposes only and should not be construed as indicating or implying relative importance.

[0026] In this document, unless otherwise explicitly specified and limited, the terms "installed," "equipped with," "connected," etc., should be interpreted broadly. For example, "connection" can be a fixed connection, a detachable connection, or an integral connection; it can be a mechanical connection, a direct connection, or an indirect connection through an intermediate medium; it can be a connection within two components. Those skilled in the art can understand the specific meaning of the above terms in this invention based on the specific circumstances.

[0027] In this document, "and / or" includes any and all combinations of one or more of the listed related items. "A plurality of" means two or more, i.e., it includes two, three, four, five, etc. As used in this specification, the term "about" typically means + / -5% of the value, more typically + / -4%, more typically + / -3%, more typically + / -2%, even more typically + / -1%, even more typically + / -0.5%. In this specification, certain embodiments may be disclosed in a range format. It should be understood that this "range" description is merely for convenience and brevity and should not be construed as a rigid limitation on the disclosed range. Therefore, the description of the range should be considered as having specifically disclosed all possible subranges and independent numerical values ​​within those ranges. For example, a description of the range 1-6 should be considered as having specifically disclosed subranges such as from 1 to 3, from 1 to 4, from 1 to 5, from 2 to 4, from 2 to 6, from 3 to 6, etc., as well as individual numbers within this range, such as 1, 2, 3, 4, 5, and 6. The above rules apply regardless of the breadth of the range.

[0028] Elastic materials, also referred to as soft materials in this article, are materials that, after being deformed by external forces (tension, pressure, shear, etc., which in this article may be the force generated by vacuum), can completely recover their original shape and size when the external force is completely removed. "Complete recovery" means that the recovered shape of the elastic material is approximately identical to its original shape, with the difference being negligible in practical applications. In other words, elastic materials are materials with self-recovery properties. Examples of elastic materials include rubber (including natural and synthetic rubber), silicone, thermoplastic elastomers, polyurethane, etc. In this article, "vacuum" refers to a gaseous state at a pressure below approximately one atmosphere in a given space. In this article, hydrophilicity of a surface or material refers to molecules on the surface or material having polar groups that have a strong affinity for water, attracting water molecules or readily dissolving in water. Hydrophilicity manifests as the ability of surface (or surface material) molecules to form transient bonds with water through hydrogen bonds. The surface of solid materials formed by molecules with polar groups is easily wetted by water; this property is called hydrophilicity.

[0029] In this paper, the resulting bottom-up cold source transfer path (or tip-to-bottom freezing transfer path) allows the cold source to travel along... Figure 13The cold source is transferred in the direction of the arrows shown in the right-hand diagram. For example, the cold source can be positioned below the freezing mold so that it can be gradually transferred from bottom to top. Alternatively, the cold source can be located below and from the sides of the freezing mold, meaning it can be transferred gradually inwards from the periphery of the tip. In other words, the cold source can be transferred either vertically from bottom to top or obliquely upwards, as long as the microneedles are frozen in a roughly bottom-to-top direction. Or, it simply requires ensuring that during the freezing process, the temperature of the lower end (or cold end) of the microneedle model space is lower than the temperature of the upper end (or hot end).

[0030] The cryo-microneedles of this invention can be used to deliver various live cells and biological products, such as stem cells, immune cells, peptides, nucleic acids, and probiotics, all of which can be stored, transported, and delivered via the cryo-microneedle platform. Furthermore, cryo-microneedles can resist the problem of skin pore closure to a certain extent, and can be completely removed after drug delivery, eliminating the problem of needle residue. Therefore, cryo-microneedles have significant advantages in the field of microneedling applications.

[0031] The applicant noted that traditional cryomicroneedle fabrication processes have significant shortcomings in application: 1) They are inefficient and complex to manufacture, making industrialization difficult. For example, traditional processes cannot produce microneedles in large quantities, requiring substantial human and material resources for actual clinical applications; 2) Cryomicroneedles have relatively simple structures, making it difficult to fabricate needles with irregular shapes, thus limiting their applicability.

[0032] Example 1: In stark contrast to traditional methods of fabricating cryogenic microneedles that transfer the cold source from top to bottom, this invention provides a method for transferring the cold source from tip to bottom (the principle of the fabrication scheme is as follows). Figure 13 As shown), the cryo-microneedle includes: a needle body having a tip for puncture, and the needle body being connected to a movable part. Correspondingly, the method includes: preparing the microneedle using a molding method; and the molding method provides a transmission path for transmitting a cold source from the tip to the bottom of the needle body to cryo-shape the microneedle.

[0033] Preferably, during the freeze-forming process, the temperature of the needle tip is lower than the temperature of the bottom of the needle body. Correspondingly, the needle tip is also referred to as the cold end, while the bottom of the needle body is referred to as the hot end.

[0034] Preferably, the step of preparing the microneedles using a mold method includes: preparing the microneedles using a cryogenic apparatus, wherein the cryogenic apparatus is used to provide at least one microneedle model space 2121 (e.g., Figure 2 As shown in the figure, the microneedle model space is used to assist in the cryogenic shaping of liquid.

[0035] Furthermore, in some embodiments, the method includes the steps of: A freezing device is provided, wherein the freezing device is provided with a microneedle model space 2121, the opening of the microneedle model space is arranged facing the upper end of the freezing device, and a refrigeration module is arranged at the lower end of the freezing device; Liquid is added to the microneedle model space, and a moving part is provided above the microneedle model space; The refrigeration module is activated, creating a bottom-to-top cold source transfer path within the freezing device to cause the liquid to freeze and solidify into the microneedles. The formed microneedles are connected to a movable part and can be removed through the movable part.

[0036] In some embodiments, the method further includes the step of pre-treating the freezing device.

[0037] For example, in some embodiments, the pretreatment may optionally involve evacuating the refrigeration unit.

[0038] Alternatively, in some embodiments, the pretreatment may be a surface pretreatment of the microneedle model space, which is used to improve the surface hydrophilicity of the microneedle model space, thereby making it easier for liquid to fill the microneedle model space.

[0039] In some embodiments, the method further includes the step of centrifuging or vacuuming the freezing device after adding the liquid, thereby causing excess gas in the microneedle model space to be expelled.

[0040] In some embodiments, during the cryogenic molding process, the temperature at the top of the microneedle model space is higher than the temperature at the bottom of the microneedle model space. Therefore, the top and bottom of the microneedle model space can also be referred to as the hot end and the cold end, respectively.

[0041] The bottom-up cryogenic molding solution provided by the present invention will be described below by way of example. It should be understood that this solution is only a preferred embodiment of the present invention and should not be construed as a limitation on the technical solution protected by the present invention. Correspondingly, the method includes the following steps: A freezing device is provided, comprising a microneedle model space with its opening facing upwards. A refrigeration module is located at the lower end of the freezing device. Liquid is added to the microneedle model space, and a moving part is positioned above it. The refrigeration module is kept open, creating a bottom-to-top cold source transfer path within the freezing device to cause the liquid to freeze and solidify into microneedles. The temperature at the top of the microneedle model space is higher than the temperature at the bottom.

[0042] Further, the preferred preparation method includes the step: S100, providing a freezing device, preferably, the freezing device is provided with a cold source transfer path from bottom to top; wherein, see Figures 1-9 As shown, the refrigeration apparatus includes: A refrigeration module 6 has a first conductive surface 61 for transmitting a cold source. The first conductive surface 61 is provided with a concentrated conductive part 4 having a first contact surface 41 and a second contact surface 42, and the first contact surface 41 is in contact with the first conductive surface 61. A freezing mold 2 includes a mold frame 22, which is provided with a forming area 21. The forming area 21 is a recessed area formed by indentation along the surface of the mold frame, and the outer surface of the forming area 21 is in contact with the second contact surface 42. The recessed area of ​​the forming area 21 is provided with a microneedle model space.

[0043] Preferably, the molding area 21 includes: a second molding layer 211, on which a plurality of microneedle model spaces 2121 are formed, and the edge of the second molding layer 211 extends outward and forms a covering area of ​​a first length H1 on the side of the molding area 21, so that the molding surface forms a first auxiliary space I above the microneedle model space 2121; and a moving part 3, the moving part 3 including: a connector 31, the connector 31 having an external shape structure adapted to the first auxiliary space I; wherein, the cold source transmission path arranged from bottom to top is as follows: a first conductive surface 61, a first contact surface 41, a second contact surface 42, the outer surface of the molding area 21, and the microneedle model space; S101, add liquid (or a third raw material, which can typically be a drug solution that needs to be administered) to the molding area 21 so that the liquid surface L is higher than the microneedle model space 2121 and lower than the height of the first molding layer 212 (e.g., lower than the dividing line). S102, the moving part is placed in the molding area 21, while the liquid level is kept lower than the height of the first molding layer 212. S103, the cooling module 6 is activated to perform cooling; at this time, at least a portion of the liquid is gradually frozen and shaped in the microneedle model space 2121 in an order from bottom to top to form a microneedle structure (or needle body), while the remaining portion of the liquid is attached to the connecting surface. S104, Remove the moving part to demold the microneedle structure.

[0044] In some embodiments, the frozen microneedles can be directly demolded from the cryogenic mold to remove them. Alternatively, in some embodiments, the frozen microneedles can be heated before demolding to facilitate easy removal. For example, in some embodiments, the frozen microneedles can be heated by heating the environment within the cryogenic device using a heating module located on the cryogenic equipment, or by heating the centralized conduction section 4 or the cryogenic mold 2 using a heating module, thereby heating the microneedles.

[0045] For example, in some embodiments, during the preparation of cryo-microneedles, the cryo-device (or the internal environment of the cryo-device) can be pre-cooled by external cooling methods (e.g., using a fan or other cooling means) before being cooled by the cryo-device.

[0046] Alternatively, in some embodiments, during the preparation of cryo-microneedles, while the cryo-device is being cooled, an external cooling method can be used to simultaneously cool the cryo-device (such as its internal environment).

[0047] In some embodiments, the process of gradually freezing and shaping at least a portion of the liquid within the microneedle model space 2121 in a bottom-to-top order includes the following steps: At least one bubble is generated in the liquid at the bottom of the microneedle model space 2121 during the freeze-forming process; as the liquid gradually freezes from bottom to top, at least one bubble is discharged upwards in an upward direction. See also Figure 12 As shown, the bubbles generated at the needle tip will move in the direction indicated by the arrow.

[0048] See Figure 13 As shown, Figure 13 The left and right sides respectively show the temperature trend diagrams (or crystallization direction diagrams) of the microneedles in the traditional microneedle freezing scheme and the microneedle freezing scheme of this invention. The arrows indicate the direction of cold source transfer, and the darker the color of the microneedle, the lower the temperature at that location (or the earlier the crystallization sequence). It is worth noting that the applicant found that this top-to-bottom cold source transfer path (i.e., crystallization from top to bottom) easily leads to an increase in the volume of the microneedle at the tip, causing deformation and affecting the strength and effectiveness of the microneedle. For example, during the top-to-bottom cold transfer process, bubbles generated at the upper end tend to move downwards along the crystallization direction, causing an increase in volume at the tip due to bubble accumulation. As another example, the volume of the third raw material in its crystalline state is slightly larger than its volume in its liquid state under the same mass conditions. Therefore, the top-to-bottom crystallization process will cause some liquid to be squeezed to the lower end, resulting in an increase in the liquid volume at the lower end and a certain degree of expansion and deformation.

[0049] It is worth noting that this invention designs a conduction path for transferring the cold source from bottom to top, thereby guiding the liquid within the microneedle model space to freeze and solidify rapidly from bottom to top. Furthermore, during the liquid freezing process, a certain amount of bubbles may be generated; however, through the bottom-to-top freezing path, these bubbles can be guided upwards to escape, thus ensuring that the tip of the microneedle has high strength, i.e., superior microneedle quality (in other words, the microneedles prepared using this invention have higher precision and mechanical strength).

[0050] In some embodiments, during cryogenic molding, the temperature at the top of the microneedle model space is higher than the temperature at the bottom of the microneedle model space.

[0051] Preferably, in some embodiments, in S103, the microneedle model space 2121 is initially in a vacuum state. Specifically, when the microneedle model space 2121 is in a vacuum state, it is in a contracted state. At this time, when liquid is gradually added to the molding area, the liquid can gradually fill the microneedle model space. At this time, the microneedle model space will also gradually return from the contracted state to the standard state. In this embodiment, the vacuum state of the microneedle model space is more conducive to the effective filling of liquid, that is, avoiding defects such as pores and bubbles during the filling process.

[0052] See Figures 1-9 As shown, the present invention provides a cryogenic device that can be used for the efficient preparation of cryogenic microneedles.

[0053] An exemplary embodiment of the present invention provides a refrigeration apparatus, comprising: A freezer housing 5 has a support platform, and a refrigeration module 6 is disposed on the support platform. The refrigeration module 6 has a first conductive surface for transmitting cold energy. A centralized conductive portion 4 is disposed on the first conductive surface, and the centralized conductive portion 4 has a first contact surface 41 and a second contact surface 42. The first contact surface 41 and the first conductive surface 61 are disposed in surface contact. Preferably, the second contact surface 42 may be provided with at least one centralized conductive area 421, which is a region formed by at least a portion of the second contact surface 42 being recessed inward; for example, in some embodiments, see... Figure 5 As shown, the first contact surface 41 of the concentrated conduction section 4 is a flat surface for contacting the first conduction surface, while the second contact surface 42 has multiple recessed areas (i.e., concentrated conduction areas 421) formed therein.

[0054] The freezing mold 2 includes a mold frame 22 made from a first raw material. The mold frame 22 has forming areas 21 spaced apart from the concentrated conduction area 421. The forming areas 21 extend inward and downward along the surface of the mold frame (e.g., towards...). Figure 2 The area formed by the protrusion (in the direction indicated by the middle arrow) and the outer surface of the molding area 21 is adapted to the shape of the concentrated conduction area 421 (that is, the protruding part of the molding area can be inserted into the concentrated conduction area), so as to achieve face-to-face contact with the concentrated conduction area, so as to enable the molding area 21 to conduct cold source in a surface-wrapped manner; this surface-wrapped contact method is beneficial to improve the conduction efficiency of the cold source.

[0055] The molding area 21 includes: a second molding layer 211 prepared from a second raw material, on which a plurality of microneedle model spaces 2121 are formed, and the edge of the second molding layer 211 extends outward and forms a covering area of ​​a first length H1 on the side of the molding area 21, so that the molding surface forms a first auxiliary space I above the microneedle model space 2121; a first molding layer 212 disposed on the second molding layer, and the inner wall of the first molding layer 212 correspondingly forms a second auxiliary space II; for example, in some embodiments, a second length H2 extends outward along the edge of the second molding layer to form the first molding layer. Preferably, the second length H2 may be less than or equal to the first length H1.

[0056] The movable part 3 includes a connector 31, which has an external shape structure adapted to the first auxiliary space I, and the connecting surface of the external shape structure is preferably set as a rough surface. When the moving part is disposed in the centralized conduction area 421 and the centralized conduction area 421 stores a third raw material, when the refrigeration module 6 performs refrigeration, a portion of the third raw material can fill the microneedle model space 2121 and form a microneedle structure under the action of the cold source, while another portion of the third raw material can at least partially fill the first auxiliary space I to form a connecting freezing structure, and the connecting freezing structure can be attached to the rough surface.

[0057] In this paper, a rough surface refers to a surface with small peaks and valleys (e.g., wavelength <1 mm) and microscopic geometric irregularities, whose peak-valley height differences (e.g., Ra, Rz parameters) can be formed through processing or naturally.

[0058] In some embodiments, the movable part further includes a gripping part 32 connected to the connector 31; the gripping part 32 can be used to connect the importing device for operation, or it can be configured to be easy to hold with a hand or tweezers. For example, the importing device can be a medical importing device such as a microneedle importing device or a medical aesthetic importing device. Alternatively, in some embodiments, the connecting surface of the external structure can also be configured as a smooth surface.

[0059] Preferably, the second raw material is a soft material, such as an elastic material, which facilitates high-quality and efficient demolding of the product (i.e., cold-operated microneedles). For example, the elastic properties of the soft material can reduce damage to the needle body during the user's demolding process to a certain extent. The surface of the second molding layer 211 can also be referred to as a soft contact surface. Preferably, the second raw material can be a material with a hardness between approximately 10A and 50A.

[0060] Preferably, in some embodiments, the width of the second auxiliary space II is greater than the width of the first auxiliary space I.

[0061] Preferably, in some embodiments, the molding area has a first opening above it, and its internal width gradually decreases in the direction away from the first opening, for example, see... Figure 2 As shown, the cross-section of the forming area is a trapezoidal structure. For example, in some embodiments, the width of the concentrated conduction area 421 gradually decreases along the direction away from its second opening; correspondingly, the outer surface of the forming area 21 is an extended structure formed by protruding outwards along the outer surface away from the outer surface, and the extended structure gradually decreases along the direction away from the first opening, so that the extended structure is uniformly surrounded by the inner surface of the concentrated conduction area 421.

[0062] It is worth noting that this embodiment provides a multi-layer structure design suitable for high-efficiency cryogenic microneedles. The molding area in the cryogenic mold 2 uses a first and second molding layer in combination, and a first auxiliary space I and a second auxiliary space II are planned within the molding area. The first auxiliary space I focuses on the precise positioning of the moving part 3. Simultaneously, the soft material under the first auxiliary space (i.e., the surface of the second molding layer 211) is used to guide the formation of the connecting cryogenic structure, allowing the cryogenic microneedle to connect more tightly with the moving part 3 through the connecting cryogenic structure. Furthermore, the soft material in the first auxiliary space also facilitates better demolding of the connecting cryogenic structure later. Meanwhile, the second auxiliary space is wider than the first auxiliary space, thereby creating a certain gap between the walls of the moving part and the second auxiliary space. This gap allows for a certain degree of deviation when the moving part is inserted into the molding area.

[0063] For example, in some embodiments, see Figure 10As shown, the movable part includes a connector 31 and a gripper 32, wherein the connector 31 includes a first connecting segment 31a and a second connecting segment 31b. A first end of the first connecting segment 31a is connected to the gripper, and a second end is connected to the first end of the second connecting segment 31b. Preferably, the width of the first connecting segment 31a is greater than the width of the second connecting segment 31b.

[0064] For example, in some embodiments, the width of the second connecting segment 31b gradually decreases along its direction from the first end to the second end, that is, the shape of the second connecting segment 31b is adapted to the first auxiliary space I to achieve the positioning purpose. For example, in some embodiments, the first connecting segment 31a can be set as a columnar structure so that a certain gap is formed between the second connecting segment 31b and the wall of the second auxiliary space II. It is understood that during the molding process, in order to separate the model surface from the molding area, the user may shake the moving part 3, that is, demold by shaking. In this regard, the parting space design in this embodiment can reserve a certain operating space for the user.

[0065] See Figure 4 As shown, a first gap space R1 and a second gap space R2 are formed between the connector 31 of the moving part and the second molding layer 211 and the first molding layer 212, respectively. In some embodiments, the width of the second gap space R2 is greater than the width of the first gap space R1. Here, the width of the gap space refers to the interval between the connecting surface of the connector 31 and the molding layer.

[0066] Preferably, in some embodiments, the freezing mold can control the liquid level of the third raw material during use by utilizing the first auxiliary space and the second auxiliary space. For example, in some embodiments, a dividing line can be provided between the first auxiliary space and the second auxiliary space, that is, a dividing line can be provided between the first forming layer and the second forming layer 211. In some embodiments, the frozen material can be formed below the dividing line. Preferably, in steps S102-S103, only the first auxiliary space I is filled with liquid, while the second auxiliary space II remains unfilled. The layered forming space design can control the amount of liquid used and improve the forming quality.

[0067] Understandably, the application process of cryomicroneedles involves using the puncture properties of microneedles to create puncture channels in the skin of a target (such as a patient), allowing medication (such as the medication formed after the cryomicroneedle thaws) to enter the skin through these channels, thus completing the drug delivery process. Therefore, the strength and morphology of the cryomicroneedle are crucial to the drug delivery process.

[0068] The parting space design with a soft contact surface used in this embodiment allows the main structure of the microneedle (especially the tip) to contact the soft contact surface. Therefore, even if the user experiences hand tremors or shaking during the molding process, the soft contact surface can effectively protect the structure and prevent damage to the tip. On the other hand, the parting space design also functions as a precise positioning and coarse limiting mechanism. It ensures close contact between the moving part and the bottom of the molding area, allowing for accurate contact between the bottom surface of the moving part and the molding area. This also helps control the thickness of the connecting structure to a certain extent, reducing the consumption of the medication. Furthermore, the coarse limiting mechanism, while assisting in positioning, provides sufficient operating space for molding and limits shaking during the molding process, protecting the needle structure.

[0069] Furthermore, it is worth noting that the parting space design proposed in this application has significant advantages in the fabrication of irregularly shaped needles. Specifically, this soft-hard synergistic parting space design helps reduce the risk of damage to the irregularly shaped needles during the molding process.

[0070] See Figure 6 , Figure 7 As shown, the freezing apparatus in this embodiment can be used to prepare irregularly shaped needles. For example... Figure 7 The images show the structures of a conventional needle body (left) and an irregularly shaped needle body (right). The irregularly shaped needle body 7 includes a main body 71 and a puncture portion 72 connected to the main body 71. The width of the puncture portion 72 gradually decreases from its first end to its second end, meaning the second end of the puncture portion 72 is used to form a needle tip structure. The width of the first end of the puncture portion is slightly larger than the width of the main body 71 to form a barb structure. For example, in some embodiments, the difference between the width of the first end of the puncture portion and the width of the main body 71 is approximately within 0.1 millimeters (mm).

[0071] It is worth noting that when this irregularly shaped needle pierces the skin's surface, its barbed structure provides a certain degree of restraint, thereby further ensuring that the melted medication is efficiently absorbed by the skin and reducing medication loss to some extent. On the other hand, this needle, with its slightly short puncture section, possesses a certain puncture capability, while also differing from conventional needles (such as...). Figure 7 As shown, the width of its needle body gradually decreases from its first end to its second end. Compared to other needles, it has higher strength, meaning that the needle tip is less likely to be damaged during storage and retrieval.

[0072] However, the applicant noted that traditional cryogenic microneedle fabrication processes cannot produce irregularly shaped needles. This is because the barbed structure of the irregularly shaped needles would cause damage during the molding process, leading to their failure. Furthermore, it is understandable that, from another perspective, this application adopts a completely different technical approach compared to traditional refrigeration solutions (such as the ice microneedle manufacturing apparatus disclosed in patent application CN119327019A).

[0073] Specifically, existing ice microneedle manufacturing devices use thermally conductive copper rods as the primary cold source, directly providing the necessary environment for ice microneedle fabrication to the microneedle mold. This results in very low cold source utilization efficiency, relatively slow microneedle formation speed, and low strength. Furthermore, using the thermally conductive copper rod as a handle is inconvenient, as its low-temperature surface can easily cause frostbite to the user. In contrast, this application utilizes a multi-layered structure to create a centralized, enclosed cooling mode. This improves the microneedle formation rate and quality (i.e., increases freezing intensity) during efficient cold source transfer, while maintaining a relatively high surface area on the handle end of the moving part (such as a grip), allowing for convenient manual operation without any issues.

[0074] Alternatively, the existing technology uses a top-down cold source transfer method, but this top-down transfer method has at least the following problems: First, the size of the microneedle patch is limited, making it difficult to prepare large-size or batch microneedle patches; Second, the operation is very inconvenient, as the thermally conductive copper rod needs to be moved during freezing and needle removal, and the thermally conductive copper rod has defects such as being easily damaged by freezing.

[0075] Conversely, the movable part 3 in this invention is preferably made of a non-metallic lightweight material to improve the convenience and safety of operation.

[0076] Preferably, in some embodiments, the hardness of the first raw material is greater than the hardness of the second raw material. Preferably, in some embodiments, the first molding layer 212 is prepared using the second raw material. Alternatively, in some embodiments, the first molding layer 212 can also be prepared using the first raw material.

[0077] In some embodiments, see Figure 11 As shown, the connecting surface is provided with a guide portion 312 corresponding to at least one of the microneedle model spaces. The guide portion is cylindrical or conical. The guide portion 312 can play a certain role in guiding the flow, that is, guiding the third material to fill the microneedle model space as soon as possible and reducing the generation of air bubbles. On the other hand, it can also save the amount of the third material to a certain extent.

[0078] See Figure 11As shown, in some embodiments, the connecting surface includes a second bottom surface for abutting against a first bottom surface of the molding area, and a side surface connected thereto. The side surface is provided with a plurality of limiting portions 311, wherein the limiting portions 311 can be spherical or columnar protrusions that bulge outward along their side surfaces, which can improve the gripping force between the connecting structure and the moving part, thereby improving the success rate of mold removal.

[0079] In some embodiments, the cross-section of the second molding layer 211 is arranged in a near-square shape. "Near-square" includes squares with chamfered corners at adjacent sides, or squares with adjacent sides connected by arcs, such as near-quadrilaterals, like rectangles (where the apex corners of a rectangle are replaced with arcs), near-squares (where the apex corners of a square are replaced with arcs), etc. Specifically, the cross-section of the second molding layer 211 is arranged in a near-rectangular shape, meaning that the connection between the bottom and side surfaces of the second molding layer is chamfered.

[0080] In some embodiments, the first conductive surface is a flat surface. In some embodiments, the centralized conductive part 4 is made of one or more of the following materials: metal, graphite, glass, ceramic. In some embodiments, the connecting surface is made of a hydrophilic material. In some embodiments, the moving part is made of a thermal insulation material, wherein the thermal insulation material includes a polymer. For example, in some embodiments, the thermal insulation material may include one or more of the following: polyurethane, polyimide, polyethylene, glass wool, rock wool, polystyrene foam (such as extruded polystyrene foam board XPS).

[0081] In some embodiments, the freezer housing 5 is provided with a heat dissipation module, which can rapidly dissipate the heat generated by the refrigeration module by promoting gas convection. Alternatively, the heat dissipation module can also transfer heat to a lower-temperature object or medium through direct contact. For example, in some embodiments, the heat dissipation module can be one or more of the following: air-cooled radiator, water-cooled radiator, heat pipe radiator, liquid-cooled radiator, or semiconductor refrigeration radiator. In some embodiments, the heat dissipation module can be located at the bottom of the freezer housing, i.e., on the side away from the freezing mold. In some embodiments, the freezing device further includes: a heat dissipation section, which is located on the side away from the first conductive surface 61, and the freezer housing 5 is provided with a heat dissipation vent. In some embodiments, a control unit connected to the refrigeration module 6 is used to control the refrigeration parameters of the refrigeration module.

[0082] In some embodiments, the refrigeration device further includes a disinfection module, such as an ultraviolet germicidal lamp disposed inside the chamber. In some embodiments, the refrigeration device also includes a digitally displayed adjustable temperature / timer module. In some embodiments, the refrigeration module 6 includes one or more of the following: thermoelectric refrigeration devices, liquid nitrogen refrigeration devices, vapor compression refrigeration devices, absorption refrigeration devices, adsorption refrigeration devices, vapor jet refrigeration devices, and magnetic refrigeration devices. It is understood that in this embodiment, one type of refrigeration device can be used for refrigeration. Alternatively, in other embodiments, to improve refrigeration efficiency, any two or more of the above-mentioned refrigeration devices can be used simultaneously for combined refrigeration.

[0083] In this invention, the designed freezing mold 2 has a protruding structure, which allows it to fit into the centralized conduction part 4, achieving five-sided contact and thus achieving efficient cooling. Furthermore, this five-sided enclosed freezing design not only improves cooling efficiency but also reduces material waste and optimizes production costs.

[0084] In some embodiments, the freezer enclosure is further provided with a lighting module. For example, in some embodiments, a light is provided inside the freezer enclosure (such as inside the lid or around the enclosure), which automatically turns on when the freezer enclosure is opened to provide illumination. Alternatively, it may have a control switch, allowing the operator to manually select whether to turn it on or off. In some embodiments, the freezer enclosure is further provided with a disinfection module, which may be, for example, an ultraviolet germicidal lamp, an ozone disinfection module, or a plant extract deodorizing module, etc.

[0085] In some embodiments, the freezing chamber is further equipped with a spray module for spraying a heat exchange medium. This heat exchange medium accelerates the cooling of the environment and speeds up the ice needle formation process. For example, in some embodiments, the heat exchange medium can be dry ice or other non-toxic gases. At room temperature and pressure, dry ice rapidly sublimates from a solid to a gas, absorbing a large amount of heat and causing a rapid decrease in the surrounding temperature. In some embodiments, the freezing device may also be equipped with a display screen, which can be connected to a control unit. The display screen can show the operating parameters of the freezing device (such as freezing time, freezing temperature, etc.) and may also have interactive functions, such as allowing users to touch the display screen to complete function settings (such as starting the freezing program, turning on the freezing device, removing the mold, etc.).

[0086] Correspondingly, this invention also provides a cryomicroneedle product, which is prepared using the method described in any one of the present invention. In some embodiments, the cryomicroneedle contains functional components, including one or more of the following: drugs, vaccines, cells, bacteria, nanolabels, and color additives. For example, in some embodiments, additives with specific colors can be added to the microneedle. For example, in some applications, colored microneedles can assist operators (such as doctors) in observing drug delivery. For example, in some embodiments, one or more functional components can be directly added to the liquid raw material of the cryomicroneedle. In some scenarios, microneedles can serve as a transdermal drug delivery technology that provides physical penetration. By using functional matrix materials and carrying antibacterial, anti-inflammatory, and growth factor drugs, they can produce effects such as hemostasis, antibacterial activity, reduction of inflammatory response, promotion of angiogenesis, cell migration, and collagen deposition, playing an important role in the entire wound healing process.

[0087] For example, in some embodiments, soluble microneedles can be prepared by solidifying a drug solution with healing properties for wound healing. As another example, in some embodiments, soluble microneedles can be prepared by solidifying a drug solution with properties other than antibacterial, analgesic, or hemostatic effects, and applied to wounds to achieve a therapeutic effect.

[0088] Furthermore, the present invention also provides an application of cryo-microneedles in the preparation of delivery or stimulating materials.

[0089] For example, microneedles containing functional materials can deliver drugs, cells, bacteria, and other substances. For instance, these microneedles can be used to prepare transdermal drug delivery systems. Furthermore, microneedles can also serve as stimulants to stimulate biological skin and wounds. In some embodiments, the cryo-microneedles provided by this invention can be used in various medical fields such as aesthetic medicine (e.g., skin injection), infectious disease treatment, and postoperative tissue regeneration. It is understood that the microneedles provided by this invention have good biocompatibility and can be used in various applications to meet specific medical needs; this invention does not limit their application.

[0090] Preferably, the second material is an elastic material, thus enabling the microneedle model space to change from a standard shape to a contracted shape. Specifically, during use, when liquid is gradually added to the molding area, the liquid can gradually fill the microneedle model space. At this time, the microneedle model space will also gradually recover from the contracted shape to the standard shape. In this embodiment, the vacuum state of the microneedle model space is more conducive to the effective filling of liquid, that is, avoiding defects such as pores and bubbles during the filling process.

[0091] The standard form refers to the initial form of the microneedle model space when it is not subjected to external forces, that is, the design form of the microneedle model space. The contracted form refers to the physical form exhibited by the microneedle model space due to contraction and deformation under external forces (such as the suction force generated by vacuuming).

[0092] In some embodiments, low-pressure pretreatment of the second raw material can reduce the number of pores in the second raw material.

[0093] Preferably, the present invention uses a vacuum sealing method to maintain the frozen mold, keeping it under negative pressure (i.e., vacuum) before use.

[0094] In this embodiment, materials with excellent sealing properties, such as PE, PP, PET, PA, PVA, aluminum foil composites, and multilayer composites (such as PE+PET, PE+PA), are preferably selected to wrap and seal the freezing mold to ensure airtightness and stability during long-term storage. In this embodiment, materials with a hardness between 10A and 50A in their solid state are preferably selected to ensure structural stability and achieve efficient demolding. In some embodiments, the second raw material is polydimethylsiloxane or silicone.

[0095] Example 2: The present invention also provides a method for applying a microneedle mold, the microneedle mold comprising: a mold, and a sealing device for encapsulating the mold; correspondingly, the method comprises: S301, Provide the mold, the mold having at least one microneedle model space, the microneedle model space being formed by a second molding layer 211, and a porous network being formed within the second molding layer 211; S302, Place the mold into the sealing device and perform a vacuum treatment, wherein the porous network changes from a first form to a second form, so that a pressure difference is generated between the porous network and the ambient air pressure; S303, Seal the sealing port of the sealing device and encapsulate the mold, so that the porous network remains in the second form; S304, Release the sealing effect and add fluid to the microneedle model space, including: using a target driving force to gradually fill the microneedle model space with the fluid, forming a gas zone in the needle tip region of the microneedle model space; Under the influence of the pressure difference, the accumulated gas in the gas zone is absorbed by the porous network, so that the fluid gradually replaces the accumulated gas, thereby guiding the fluid to fill the gas zone; At this time, the porous network gradually returns from the second form to the first form, and the fluid gradually forms a microneedle shape.

[0096] For example, in some embodiments, see Figure 24As shown, the mold is mainly made of aerosol and breathable polymer materials, and its interior is actually arranged to form a mesh structure, which can also be called a porous network.

[0097] In this embodiment, the mold and sealing device are sealed and preserved under vacuum conditions, so that the mold can change from the first form to the second form without excessive deformation of the overall structure of the mold.

[0098] like Figure 20 As shown, fluid 82 is injected into the microneedle model space. In the initial stage, fluid 82 cannot completely fill the microneedle model space, so a gas region 81 is formed at the top of the microneedle model space. Furthermore, on the one hand, due to the pressure difference between the internal pores of the mold (especially the second molding layer) and the external environment (such as the gas region 81), and on the other hand, the fluid 82 will also compress the gas region 81 to a certain extent under the action of gravity. Therefore, the gas in the gas region 81 will gradually diffuse into the pores, thereby realizing the replacement of the gas in the gas region 81 by the fluid 82.

[0099] It should be noted that, unlike the conventional technical approach of the prior art—that is, a two-stage sample addition approach involving vacuuming during fluid injection (such as fluid addition operations before and after vacuuming)—this invention provides a single sample addition operation with pre-vacuuming. Specifically, this invention pre-vacuums the mold separately (and uses a sealing device to preserve it under vacuum). During the microneedle molding process, only one continuous sample addition is needed in the microneedle model space to promote the natural formation of the microneedles and substrate shape by the fluid.

[0100] This pre-vacuum single-sample addition operation not only simplifies the user's preparation process, but also optimizes the preparation quality of microneedles (reducing the impact of the vacuum process on the shape of the mold, thereby optimizing the shape of the microneedles).

[0101] In this embodiment, the porous network formed by the polymer material refers to the network structure formed inside the polymer compound through processes such as foaming and cross-linking, consisting of interconnected or closed pores. The pore boundaries are supported by pillars or films formed by the bonding of polymer chain segments or branches. Its pore structure can present a two-dimensional honeycomb structure (polygonal pore planar aggregation) or a three-dimensional foam structure (polyhedral pore spatial aggregation), and the pore size distribution covers micropores (<2nm), mesopores (2-50nm), and macropores (>50nm), etc.

[0102] In some embodiments, multiple second molding layers are connected by a first molding layer (or, the second molding layers are interconnected with the first molding layer), and the material hardness of the second molding layer is less than or equal to the material hardness of the first molding layer. In some embodiments, the vacuuming intensity (or suction pressure) of the vacuuming process is -0.005 to -0.1 MPa, and the processing time is at least 2 seconds. Preferably, the vacuuming intensity is -0.04 to -0.08 MPa, and the time is 15 seconds to 300 seconds, so as to ensure that the porous network and the environment can effectively form a pressure difference, while avoiding excessive deformation of the second forming layer, which would affect the microneedle forming.

[0103] In this embodiment, a combined hard and soft mold structure is also provided for the single sample addition operation with pre-vacuuming. This combined hard and soft mold structure ensures that the mold has sufficiently strong autonomous rebound performance (i.e., autonomously displacing fluid and air based on pressure difference, such as...). Figure 19 , Figure 20 As shown in the figure, on the other hand, it can ensure that the mold has a certain degree of morphological stability during the deformation process (avoiding excessive deformation).

[0104] In some embodiments, the sealing device is made of aluminum foil composite material or plastic material.

[0105] In some embodiments, the Shore hardness of the second molding layer is less than 35A, and the first molding layer is a polymer material or composite material, with a Shore hardness greater than or equal to 70A. In this embodiment, the selection of material hardness helps to prevent overall mold deformation, thus ensuring the integrity of the mold microneedle morphology. Alternatively, in some embodiments, the Shore hardness of the second molding layer is 35~90A.

[0106] It is understood that the mold used in this embodiment can be any of the implementation schemes in Embodiment 1, as can be found in [reference needed]. Figures 1-29 As shown, the present invention does not impose any limitations on this.

[0107] In some embodiments, the target driving force satisfies a first injection model, the first injection model comprising: ; in, The capillary force on the inner surface of the microneedle model space. The atmospheric pressure difference in the space of the microneedle model after release. This refers to the recovery stress that the microneedle model space can generate after being vacuumed. Driven by the goal.

[0108] It is understandable that the capillary force is related to the material properties of the microneedle model's spatial surface (i.e., determined by the second molding layer), the atmospheric pressure difference is determined by the vacuum processing, and the recovery stress is determined by a combination of capillary action and atmospheric pressure difference. In other words, the parameter values ​​in this first injection model can be obtained in advance during the fabrication process.

[0109] In this embodiment, the applicant noted that by making reasonable selections of material type and vacuum level, fluid filling and injection can be completed by a target driving force of appropriate magnitude (e.g., fluid can be injected into the microneedle model space by means of external force, or fluid can be autonomously poured into the microneedle model space).

[0110] From another perspective, the magnitude of the target driving force is to some extent constrained by the vacuum level of the material.

[0111] In some embodiments, the target driving force further satisfies a second injection model, the second injection model comprising: ; in, The time required for fluid injection The viscosity of the fluid. The tip angle is the microneedle model space.

[0112] In this embodiment, to reasonably improve the efficiency of microneedle fabrication, the selection of material type, the setting of microneedle model space, and the setting of vacuum degree can be coordinated to complete fluid injection within a reasonable time. It is understood that the limitations of the injection model in this embodiment can provide guidance for the fabrication of different types of microneedles. For example, taking a pharmaceutical agent as an example, its viscosity value can be obtained through measurement methods specified in the art or from existing databases. Accordingly, different types of vacuum degrees can be pre-treated on the mold to suit different agent types.

[0113] In some embodiments, the second molding layer is made of a polymeric material. In some embodiments, the second molding layer is made of an elastic material. In some embodiments, the elastic material includes one or more of the following: rubber, silicone, polydimethylsiloxane, and polyurethane. In some embodiments, the fluid includes one or more of the following substances: small molecules, polymeric substances, biomacromolecules, growth factors, cells, and enzymes.

[0114] Figure 26 The microneedles prepared using the preparation method provided in this invention are shown. Figure 25 A schematic diagram of a microneedle with poor morphology (its tip is blunt) is shown. Below, the present invention demonstrates its quality optimization effect in the microneedle fabrication process through first and second verification examples: First, the quality of microneedle forming is mainly judged comprehensively from the perspectives of microneedle defects and strength. This forming quality can be determined by the results of microscopic observations (such as...). Figure 25 , Figure 26 A schematic diagram of the microstructure of the prepared microneedles is shown, which illustrates that... Figure 26The microneedles shown have almost no obvious defects and have relatively sharp tips, indicating good quality. The puncture effect of the microneedles after use can be comprehensively judged, and professional technicians can give evaluation results on a scale of poor or excellent. Vacuum packaging quality can be evaluated on a scale of poor or good.

[0115] See Figure 28 As shown, it illustrates the use of Figure 26 The microneedles shown Figure 25 The diagram shows the acupuncture effect created by microneedles piercing the skin. Figure 28 As shown in the middle left image, the microneedle successfully punctured the skin (it can be seen that...). Figure 26 The prepared microneedles have sharp tips and are of high quality, thus enabling them to penetrate skin pores smoothly. Figure 25 The tips of the microneedles shown are blunt, making it difficult for them to penetrate the skin.

[0116] Figure 21 The test data for the first verification example are shown. The implementation scheme adopted is as follows: the first molding material is thermoplastic polyurethane elastomer (TPU) with a Shore hardness of 70A, the second molding material is silicone with a Shore hardness of 20A, and the material of the sealing layer (i.e. the sealing device) is a composite of polyethylene terephthalate (PET) and polyethylene (PE).

[0117] This verification example uses different combinations of vacuum conditions (including vacuum intensity and vacuum processing time) to vacuum the mold and tests the microneedle forming quality under different combinations.

[0118] from Figure 21 The experimental data shown indicates that when the mold is vacuum-treated with a vacuum strength (or suction force) of -0.005 MPa for a duration of 2 seconds or more, the final microneedles formed by the mold exhibit superior quality. Figure 27 The left and right images respectively illustrate the vacuuming effects of the mold and sealing device under improper and optimal vacuuming conditions. It can be seen that by rationally selecting the materials, vacuum intensity, and time, the mold will not easily deform, thus meeting the requirements for microneedle fabrication. It should be understood that the mold is usually transparent. Figure 27 The purpose of dyeing the mold material is to distinguish the mold from the sealing device (i.e., the sealed packaging bag) so as to visually display the deformation effect.

[0119] Figures 22-23Test data for the second verification example are shown, which uses the same vacuum conditions to test different combinations of the first molding layer (corresponding to a hard material) and the second molding layer (corresponding to a soft material). The vacuum conditions used are: vacuum intensity of -0.06 MPa and vacuum treatment time of 15 s.

[0120] See Figure 29 As shown, Shore A is selected as the unit of measurement for hardness in this embodiment to facilitate a proper description of the material hardness within the selectable range. That is to say, in some other embodiments, Shore 00 or Shore D can also be used to characterize the hardness, and this invention does not limit this. Wherein, when Figures 22-23 When “hardness of hard material” is filled in as “ / ”, it means that the first molding layer (i.e., hard material) and the second molding layer are integrally molded from the same material, and there is no distinction between the two.

[0121] from Figures 22-23 The results show that the present invention can provide two different implementation schemes: Scheme 1) The first molding layer and the second molding layer use different material types: For example, preferably, when the Shore hardness of the second molding layer is less than 35A and the Shore hardness of the first molding layer is greater than or equal to 70A, the molding requirements can usually be met. Scheme 2) When the Shore hardness of the material of the second molding layer is greater than or equal to 35A, there is no need to set an additional first molding layer with a higher hardness, or the second molding layer and the first molding layer can be integrally molded using the same type of material. Preferably, when the first molding layer and the second molding layer are integrally molded, the Shore hardness of the selected material is 35A~90A.

[0122] From another perspective, based on the above-described mold preparation method, the present invention can also provide a microneedle mold, comprising: multiple microneedle model spaces 2121 provided by multiple second molding layers 211, wherein a porous network is formed inside the second molding layers; the multiple second molding layers 211 are connected by a first molding layer 212, wherein the hardness of the second molding layer 211 is less than the hardness of the first molding layer 212; wherein the porous network changes from an initial first form to a second form under vacuum, so as to generate a pressure difference between the porous network and the ambient air pressure; wherein the vacuum strength corresponding to the second form is -0.005 MPa to -0.1 MPa; and a sealing device for encapsulating the mold so that the porous network remains in the second form. Specifically, when a target driving force is used to gradually fill the microneedle model space with fluid, a gas region is formed in the tip region of the microneedle model space; under the influence of the pressure difference, the accumulated gas in the gas region is absorbed by the porous network, so that the fluid gradually replaces the accumulated gas, thereby guiding the fluid to fill the gas region; at this time, the porous network gradually recovers from the second form to the first form.

[0123] In some embodiments, the Shore hardness of the second molding layer is less than 35A, and the Shore hardness of the first molding layer is greater than or equal to 70A. In some embodiments, the second molding layer is made of a material that is aerosolizable and breathable. In some embodiments, the material that is aerosolizable and breathable includes one or more of the following: rubber, silicone, polydimethylsiloxane, polyurethane, metal-organic framework (MOF) composites, poly(N-isopropylacrylamide) hydrogel, polyolefins, styrene, fluororubber, and acrylate rubber.

[0124] In some embodiments, during the process of the microneedle model space gradually returning to the first shape from the second shape, the fluid moves from top to bottom and gradually fills the microneedle model space. In some embodiments, after the microneedle model space is evacuated, the mold is sealed with a sealing bag.

[0125] It should be noted that, in some scenarios, during the process of fluid filling the microneedle model space, there may be a certain air region at the top of the microneedle model space (i.e., the area used to form the needle tip). This air region may make it difficult to form the needle tip, or the air region may cause excessive air bubbles to form inside the needle, thereby reducing the quality of the microneedle (e.g., reducing its strength) due to the presence of air bubble defects. In this invention, the self-rebound capability of the elastic material can be used to reduce the air region to a certain extent, or in other words, it can guide the fluid to penetrate deeper into the microneedle model space to a certain extent, thereby improving the product quality of the microneedle.

[0126] In some embodiments, the mold can be made of one or more materials. For example, the microneedle model space portion of the mold can be made of a soft material (or a material with resilience) to ensure that it can undergo a certain degree of compression deformation during vacuuming and rebound autonomously during recovery, thus guiding the fluid deeper. Other parts of the mold, such as those connecting or supporting the individual microneedle model spaces, can be made of a hard material (such as plastic). Especially when it comes to the simultaneous fabrication of batches of cryogenic microneedles, this combination of soft and hard materials combines the advantages of both, facilitating both overall use and high-quality cryogenic molding of microneedles within individual spaces. Specifically, the soft material is rubber.

[0127] In some embodiments, the fluid comprises any one of the following substances, or a combination of any two or more of the following substances: compounds, polymers, bioactive molecules, regulatory factors, cells, cell products, and carriers. For example, the fluid may comprise one or more of the following substances: chemical substances (i.e., compounds, such as small molecule compounds, inorganic salts, organic solvents), polymers (such as synthetic polymers, natural polymers, biodegradable polymers), bioactive molecules (such as proteins, nucleic acids, polysaccharides and their compounds), regulatory factors (such as growth factors, cytokines, chemokines, hormones, signaling molecules), enzymes (such as enzymes, coenzymes, ribozymes), cells (such as primary cells, stem cells, immune cells, engineered cells, microorganisms), cell products (such as exosomes, microvesicles, extracellular matrix, cell secretions), and carriers (such as viral vectors, non-viral vectors, nanoparticles, liposomes, micelles); or the fluid may be a combination of any two or more of the above substances (i.e., mixtures, complexes, conjugates, or derivatives of any of the above categories). For example, in some embodiments, the small molecule may be a synthetic compound or a natural extract. For example, in some embodiments, the polymer can be a soluble or insoluble polymer. For example, in some embodiments, the biomacromolecule can be a large protein, polypeptide, nucleic acid, etc.

[0128] The applicant noted that due to the special nature of cryo-microneedles—cryo- ...

[0129] Understandably, frozen microneedles offer unique advantages in drug delivery. Traditional injection methods often cause pain and discomfort for patients and may pose a risk of infection. Frozen microneedles, with their tiny size, can easily penetrate the stratum corneum of the skin. Utilizing their low-temperature properties, they freeze the surrounding skin tissue at the moment of puncture, reducing nerve signal transmission and minimizing pain. Simultaneously, they can carry drugs, accurately delivering them to specific layers of the skin, improving drug absorption efficiency and enhancing therapeutic efficacy. For example, in vaccination scenarios, they can enable vaccines to enter the body more effectively and activate the immune system.

[0130] In the beauty industry, the skin's absorption capacity limits the effectiveness of many skincare products. Cryo-microneedling can create microchannels on the skin surface without damaging the overall skin structure, allowing the active ingredients in skincare products to better penetrate and exert their effects. Furthermore, the low-temperature stimulation promotes blood circulation and stimulates cell vitality, significantly improving skin texture, reducing wrinkles, and brightening skin tone, thus enhancing skin health and appearance. Therefore, the cryo-microneedles and their preparation method in this invention can be applied to various fields such as medicine and beauty. Furthermore, the mold in this invention can also be used for other types of microneedles, such as those formed by drying; this invention does not limit this application.

[0131] Example 3: See Figures 14-18 As shown, in order to realize the mass application of cryogenic microneedles, the present invention also provides a preparation process for preparing mass production molds.

[0132] The present invention also provides a method for preparing a freezing mold using the aforementioned freezing mold preparation component, comprising the steps of: S200, providing a mold preparation assembly, the mold preparation assembly comprising: First template 01, comprising: substrate 012, on which a plurality of first models 011 are spaced apart, the first models 011 being structures that protrude upward along the first surface of the substrate 012, and adjacent first models 011 are spaced apart to form a connection space 013, the connection space having a first connection space 0131 and a second connection space 0132 formed in a direction away from the substrate; a plurality of microneedle models are disposed on the second surface of the first models. The second template 02 has multiple template openings 021 corresponding to the multiple first models 011, and the template openings 021 are connected by connecting parts 022. The third template 03 is provided with multiple drainage spaces 032 corresponding to the multiple first models 011, and an isolation part 031 is provided adjacent to the drainage space 032. The lower end of the isolation part is provided with a drainage groove 0311 with a first height. When the first template, the second template, and the third template are sequentially fitted together, the first model passes through the template opening, and the second template fills the first connecting space 0131. The drainage groove is connected to the connecting part 022 to form a drainage port. The wall of the isolation part can isolate the adjacent second connecting space 0132. S201, assemble the first template, the second template and the third template into a sequentially fitted state; S202, inject the second material into the plurality of drainage spaces 032 respectively; wherein, at least a portion of the second material can cover the surface of the first model 011 and form a microneedle model space 2121 under the guidance of the microneedle model, a portion of the second material can at least partially cover the surface of the connecting part 022, and another portion of the second material can move to the drainage port and form a connection with the second material under the adjacent drainage space; S203, which keeps the second raw material in shape at the molding temperature to form the corresponding frozen mold.

[0133] In some embodiments, the edge of the first template 01 has a raised side extending in a direction away from the first surface. In this embodiment, the raised side can accommodate the second material, avoiding waste of the second material.

[0134] In some embodiments, the method further includes step S204, which involves vacuuming the frozen mold to reduce the air volume in the microneedle model space 2121, and the microneedle model space will undergo a certain degree of deformation during the vacuuming process.

[0135] Preferably, the second raw material in this embodiment is an elastic material with aerosol and breathability, thus enabling the microneedle model space to change from a standard shape to a contracted shape. Specifically, during use, when liquid is gradually added to the molding area, the liquid can gradually fill the microneedle model space. At this time, the microneedle model space will also gradually recover from the contracted shape to the standard shape. In this embodiment, the vacuum state of the microneedle model space is more conducive to the effective filling of liquid, that is, avoiding defects such as pores and bubbles during the filling process.

[0136] The standard form refers to the initial form of the microneedle model space when it is not subjected to external forces, that is, the design form of the microneedle model space. The contracted form refers to the physical form exhibited by the microneedle model space due to contraction and deformation under external forces (such as the suction force generated by vacuuming).

[0137] In some embodiments, before S202, the method further includes step S205, which involves low-pressure pretreatment of the second raw material. In this embodiment, low-pressure pretreatment of the second raw material can reduce the number of pores within it. Preferably, the present invention uses a vacuum sealing method to maintain the freezing mold, keeping it under negative pressure (i.e., vacuum) before use. Preferably, in this embodiment, the preferred setting range for the negative pressure state during storage is -0.005 to -0.1 MPa, and the negative pressure / vacuum treatment time is more than 2 seconds, allowing for direct use after unpacking without the need for additional vacuuming steps.

[0138] In this embodiment, materials with excellent sealing properties, such as PE, PP, PET, PA, PVA, aluminum foil composites, and multilayer composites (such as PE+PET, PE+PA), are preferably selected to wrap and seal the freezing mold to ensure long-term storage airtightness and stability. In this embodiment, materials with a hardness between 10A and 50A in the solid state are preferably selected to ensure structural stability and achieve efficient demolding (it should be noted that the selection of materials can be adapted to different preparation requirements, such as different components or different microneedle types).

[0139] See Figure 14 As shown, the present invention provides a preparation assembly for preparing a freezing mold, comprising: a first template 01, the first template 01 comprising: a substrate 012, wherein a plurality of first models 011 are spaced apart on the substrate 012, the first models 011 being arranged upward along a first surface of the substrate 012 (e.g., ...). Figure 12 The structure is formed by the protrusion (indicated by the middle arrow), and a certain interval is formed between adjacent first models 011 to form a connection space 013. The connection space 013 has a first connection space 0131 and a second connection space 0132 formed in the direction away from the substrate (see...). Figure 16 As shown); a plurality of microneedle models (not shown in the figure) are provided on the second surface of the first model; a second template 02 is provided on the second template 02 corresponding to the plurality of first models 011, and the template openings 021 are connected by connecting parts 022; a third template 03 is provided on the third template 03 corresponding to the plurality of first models 011, and an isolation part 031 is provided adjacent to the drainage space 032, and a drainage groove 0311 with a first height is provided at the lower end of the isolation part; When the first template, the second template, and the third template are sequentially fitted together, the first model passes through the template opening, and the second template fills the first connecting space 0131. The drainage groove is connected to the connecting part 022 to form a drainage port. The wall of the isolation part 031 can isolate the adjacent second connecting space 0132.

[0140] It is understood that in other embodiments, the second mold, i.e. the mold frame, is a component of the freezing mold.

[0141] In some embodiments, the width of the first model 011 gradually decreases in the direction away from the first surface. In some embodiments, the first model 011 includes a second surface 0111 (on which a microneedle model is disposed), and a plurality of third surfaces 0112 disposed around the second surface, and a transition surface is disposed at the connection between any two surfaces in the first model, the transition surface being an arc-shaped surface.

[0142] Specifically, during the mold preparation process, when the second raw material is poured into the flow space 032, the second raw material will diffuse and flow from the second surface 0111 to the third surface 0112. The transition surface between the two surfaces can balance and control the flow rate of the second raw material, avoiding excessive changes in flow rate when the raw material enters different areas. This relatively balanced flow rate alleviates defects such as pores in the raw material. In other words, in this embodiment, the transition surface can reduce turbulence.

[0143] In some embodiments, the third surface 0112 is provided with a first contact surface 0112a and a second contact surface 0112b sequentially along the direction from the lower end to the upper end (see...). Figure 16 As shown), correspondingly, the first contact surface arranged opposite to each other forms the first connection space 0131, while the second contact surface arranged opposite to each other forms the second connection space 0132; wherein, when the second template is fitted onto the first template, the side of the connecting part 022 contacts the first contact surface 0112a (in other words, the second template is embedded in the first connection space).

[0144] In some embodiments, the lower opening of the drainage space 032 is larger than the template opening 021. When the first template, the second template, and the third template are sequentially fitted together, a portion of the surface of the connecting portion 022 can be covered by the third template 03, while a portion of the surface is exposed through the drainage space 032. The exposed edge of the connecting portion 022 will be covered by the added second material. In some embodiments, the edge of the substrate 012 protrudes in a direction away from the first surface to form a baffle.

[0145] In some embodiments, the second raw material is polydimethylsiloxane or silica gel.

[0146] It should be noted that, in this document, the terms "comprising," "including," or any other variations thereof are intended to cover non-exclusive inclusion, such that a process, method, article, or apparatus that comprises a list of elements includes not only those elements but also other elements not expressly listed, or elements inherent to such a process, method, article, or apparatus. Without further limitations, an element defined by the phrase "comprising one..." does not exclude the presence of other identical elements in the process, method, article, or apparatus that includes that element. Through the above description of the embodiments, those skilled in the art can clearly understand that the methods of the above embodiments can be implemented by means of software plus necessary general-purpose hardware platforms, and of course, they can also be implemented by hardware, but in many cases the former is a preferred implementation. Based on this understanding, the technical solution of the present invention, or the part that contributes to the prior art, can be embodied in the form of a software product. This computer software product is stored in a storage medium (such as ROM / RAM, magnetic disk, optical disk) and includes several instructions to cause a computer terminal (which may be a mobile phone, computer, server, or network device, etc.) to execute the methods described in the various embodiments of the present invention.

[0147] The embodiments of the present invention have been described above with reference to the accompanying drawings. However, the present invention is not limited to the specific embodiments described above. The specific embodiments described above are merely illustrative and not restrictive. Those skilled in the art can make many other forms under the guidance of the present invention without departing from the spirit and scope of the claims. All of these forms are within the protection scope of the present invention.

Claims

1. A method for applying a microneedle preparation device, characterized in that, The microneedle fabrication apparatus includes a microneedle mold, and the microneedle mold includes a mold and a sealing device for encapsulating the mold. Correspondingly, the method includes: S301, the mold is provided, the mold having at least one microneedle model space, the microneedle model space being formed by a second molding layer (211), and a porous network being formed within the second molding layer (211); S302, the mold is placed into the sealing device and vacuum is applied, wherein the porous network changes from a first form to a second form so that a pressure difference is generated between the porous network and the ambient air pressure. S303, the sealing port of the sealing device is sealed, and the mold is encapsulated so that the porous network is maintained in the second morphology; S304, release the seal and add fluid into the microneedle model space, including: The fluid is gradually filled into the microneedle model space by using a target driving force, forming a gas zone in the needle tip region of the microneedle model space; Under the influence of the pressure difference, the accumulated gas in the gas region is absorbed by the porous network, thereby guiding the fluid to fill the gas region; at this time, the porous network gradually returns from the second form to the first form, and the fluid gradually forms a microneedle shape.

2. The application method of the microneedle preparation device according to claim 1, characterized in that, The second molding layer is connected to the first molding layer, and the material hardness of the second molding layer is less than or equal to the material hardness of the first molding layer. And / or, the vacuum intensity of the vacuuming process is -0.005~-0.1 MPa, and the vacuuming time is maintained at more than 2 seconds; And / or, the sealing device is made of one or more of the following materials: polymer materials, metallic materials, inorganic non-metallic materials, and composite materials.

3. The application method of the microneedle preparation device according to claim 2, characterized in that, The Shore hardness of the second molding layer is less than 35A, the first molding layer is a polymer material or composite material, and the Shore hardness of the first molding layer is greater than or equal to 70A.

4. The application method of the microneedle preparation device according to claim 1, characterized in that, The Shore hardness of the second molding layer is 35~90A; And / or, the target driving force satisfies a first injection model, the first injection model including: ； in, The capillary force on the inner surface of the microneedle model space. The atmospheric pressure difference in the space of the microneedle model after release. This refers to the recovery stress that the microneedle model space can generate after being vacuumed. Driven by the goal.

5. The application method of the microneedle preparation device according to claim 4, characterized in that, The target driving force also satisfies a second injection model, which includes: ； in, The time required for fluid injection The viscosity of the fluid. The tip angle is the microneedle model space.

6. The application method of the microneedle preparation device according to claim 1, characterized in that, The fluid includes any one of the following substances, or a combination of any two of the following substances: compounds, polymers, bioactive molecules, regulatory factors, cells, cell products, and carriers.

7. The application method of the microneedle preparation device according to claim 6, characterized in that, The second molding layer is made of a material that is aerosolizable and breathable.

8. The application method of the microneedle preparation device according to claim 7, characterized in that, The materials with aerosol and breathability include one or more of the following: rubber, silicone, polydimethylsiloxane, polyurethane, metal-organic framework composites, poly(N-isopropylacrylamide) hydrogel, polyolefins, styrene, fluororubber, and acrylate rubber.

9. A microneedle preparation device, characterized in that, The microneedle fabrication device includes a microneedle mold, and the microneedle mold includes a mold, the mold including a plurality of microneedle model spaces (2121) provided by a plurality of second molding layers (211) respectively, and the interior of the second molding layers forms a porous network; the second molding layers (211) are interconnected with the first molding layer (212), wherein the hardness of the second molding layer (211) is less than or equal to the hardness of the first molding layer (212); Under vacuum, the porous network changes from an initial first state to a second state, thereby creating a pressure difference between the porous network and the ambient air pressure; wherein the vacuum intensity corresponding to the second state is -0.005 MPa to -0.1 MPa. A sealing device for encapsulating the mold so that the porous network remains in the second morphology; Specifically, when a target driving force is used to gradually fill the microneedle model space with fluid, a gas region is formed in the needle tip region of the microneedle model space; under the influence of the pressure difference, the fluid gradually replaces the accumulated gas, thereby guiding the fluid to fill the gas region; at this time, the porous network gradually recovers from the second morphology to the first morphology.

10. A microneedle preparation device according to claim 9, characterized in that, The Shore hardness of the second molding layer is less than 35A, the first molding layer is a polymer material or composite material, and the Shore hardness of the first molding layer is greater than or equal to 70A; or, the Shore hardness of the second molding layer is 35~90A.

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