A frozen microneedle manufacturing device

Abstract

The utility model provides a kind of frozen microneedle manufacturing device, including lower template and upper template;Groove is provided with on the top surface of lower template, and upper template is matched and installed in the groove of lower template;Multiple micropores are arrayed and distributed on the bottom surface of groove, and the bottom end of micropore is tip;Upper template includes annular frame and bottom plate fixed to the bottom surface of annular frame, multiple through holes are arrayed and distributed on the bottom plate, and the number and position of through hole and micropore correspond, and each through hole is communicated with one micropore.The mixed solution of biological active substance and low-temperature medium is cast into the inner cavity of annular frame of upper template when frozen microneedle is manufactured, and the mixed solution fills micropore, through hole and annular frame inner cavity.When demolding, researchers exert force on upper template perpendicular to lower template, and due to the overall support formed by bottom plate backing frozen microneedle, the stress of each part of frozen microneedle backing is uniform, so that the frozen microneedle after mixed solution solidification can be separated from lower template together with upper template, and demolding is completed.

Description

Technical Field

[0001] This utility model relates to the field of cryo-microneedle technology, specifically to a cryo-microneedle fabrication device. Background Technology

[0002] Cryomicroneedles, as an emerging and promising transdermal drug delivery strategy, successfully integrate the advantages of microneedle transdermal delivery systems and cryopreservation technology. This enables the transdermal delivery of various cryopreservation-dependent bioactive substances (such as cells, exosomes, vaccines, mRNA, and live bacterial preparations), exhibiting significant minimally invasive, high-efficiency, and targeted delivery characteristics. Cryomicroneedles are made from cryopreservation solutions and include a backing and an array of microneedles arranged in an orderly fashion on the backing surface. Each microneedle typically ranges in length from 50 to 1500 micrometers. During drug delivery, the cryopreserved microneedle patch contacts the epidermis, and appropriate pressure is applied to achieve stratum corneum penetration. Subsequently, the microneedles thaw intradermally, releasing the bioactive components through diffusion.

[0003] The current method for fabricating cryo-microneedles involves researchers pre-suspending the bioactive substance to be delivered in a cryogenic medium, casting the mixture into a PDMS mold, and then solidifying the mixture through a continuous gradient cryogenic freezing process. After demolding, the cryo-microneedles are obtained. (Refer to the attached instruction manual.) Figure 7 This diagram illustrates the current process of demolding cryo-microneedles. Researchers use tweezers to grasp one side of the cryo-microneedle and peel it off from the PDMS mold to the other side. In this method, the tweezers are difficult to control precisely in terms of gripping position and force, requiring extremely high hand stability. Furthermore, because cryo-microneedles are brittle, the small contact area between the tweezers and the microneedle easily leads to stress concentration in certain areas, potentially causing cracks or breakage on the microneedle surface. Therefore, the tweezers demolding method suffers from difficulties in demolding and is prone to damaging the cryo-microneedles during demolding, severely hindering the mass production and clinical application of cryo-microneedles. There is an urgent need to overcome these technological bottlenecks through innovative mold structures. Utility Model Content

[0004] To address the problems mentioned in the background section, this invention provides a combined cryo-microneedle fabrication device that is easy to demold and does not easily damage the cryo-microneedles during demolding.

[0005] The present invention adopts the following technical solution: a cryo-microneedle fabrication device, comprising a lower template and an upper template; a groove is provided on the top surface of the lower template, and the upper template is fitted into the groove of the lower template;

[0006] Multiple micropores are arranged in an array on the bottom surface of the groove, and the bottom end of each micropore is a pointed tip. The upper template includes an annular frame and a base plate fixed to the bottom surface of the annular frame. Multiple through holes are arranged in an array on the base plate. The number and position of the through holes correspond to the number of micropores, and each through hole is connected to a micropore.

[0007] Furthermore, the cryo-microneedle fabrication device also includes a cover plate, a fixing component, and a handle. The cover plate is fixedly installed on the top of the annular frame by at least two fixing components to close the top opening of the annular frame. The handle is fixedly installed in the middle of the top surface of the cover plate.

[0008] Furthermore, the fixing assembly includes a hinge seat, a hinge shaft, and a spring-loaded fastening plate. Two hinge seats are fixedly disposed on the outer side of the annular frame at a distance from each other. The hinge shaft is fixedly connected between the two hinge seats. The spring-loaded fastening plate includes an extension and a bending portion. One end of the extension is rotatably connected to the hinge shaft, and the bending portion is fixedly connected to the other end of the extension. The bending portion bends toward the inner side of the annular frame and can abut against the top surface of the cover plate, for fixing the cover plate to the top of the upper template.

[0009] Preferably, the outer diameter of the annular frame matches the groove, and the thickness of the annular frame is greater than the depth of the groove.

[0010] Furthermore, the micropore includes a connected columnar portion and a conical portion, or the micropore is a conical pore.

[0011] Furthermore, the upper template also includes multiple sleeves fixedly installed on the bottom surface of the base plate, with a sleeve coaxially arranged on each through hole, and the inner cavity of the sleeve communicating with the through hole; at least a portion of the sleeve can be fitted into the microhole.

[0012] Furthermore, the lower template is made of silicone material, the upper template is made of metal material, and the cover plate is made of heat-insulating material.

[0013] Beneficial Effects: The cryo-microneedle fabrication device in this patent involves pouring a mixture into the annular cavity of the upper template during cryo-microneedle fabrication. The mixture fills the micropores, through-holes, and the annular cavity. During demolding, researchers apply a force perpendicular to the lower template to the upper template, which detaches the solidified cryo-microneedle along with the upper template, completing the demolding process. Because the base plate provides overall support for the backing of the cryo-microneedle, the force on all parts of the backing is evenly distributed, effectively solving the problems of demolding difficulties and damage to the cryo-microneedles that occur when using tweezers for demolding. Attached Figure Description

[0014] Appendix Figure 1This is a three-dimensional structural diagram of the cryogenic microneedle fabrication device of this utility model.

[0015] Appendix Figure 2 This is a cross-sectional structural diagram of the cryogenic microneedle fabrication device of this utility model.

[0016] Appendix Figure 3 This is a schematic diagram of the structure of the lower template 1 in this utility model.

[0017] Appendix Figure 4 This is a cross-sectional structural diagram of the lower template 1 in this utility model.

[0018] Appendix Figure 5 This is a schematic diagram of the structure of the upper template 2 and the fixing component 4 in this utility model. Figure 1 .

[0019] Appendix Figure 6 This is a schematic diagram of the structure of the upper template 2 and the fixing component 4 in this utility model. Figure 2 .

[0020] Appendix Figure 7 This is a schematic diagram of the current process for demolding cryogenic microneedles.

[0021] The reference numerals in the attached drawings are explained as follows: lower template 1, groove 11, microhole 12, upper template 2, annular frame 21, base plate 22, through hole 23, sleeve 24, cover plate 3, fixing component 4, hinge seat 41, hinge shaft 42, elastic fastener plate 43, handle 5. Detailed Implementation

[0022] To more clearly illustrate the technical solutions in the embodiments of this utility model or the prior art, the drawings used in the description of the embodiments or the prior art will be briefly introduced below. Obviously, the drawings described below are only some embodiments of this utility model. For those skilled in the art, other drawings can be obtained based on these drawings without creative effort. The content of the utility model will be further explained below in conjunction with the drawings:

[0023] Example 1

[0024] Refer to the instruction manual appendix Figure 1 , 2 A cryogenic microneedle fabrication device includes a lower template 1, an upper template 2, a cover plate 3, a fixing component 4, and a handle 5.

[0025] The lower template 1 is made of silicone material, such as polydimethylsiloxane. Polydimethylsiloxane has good biocompatibility, high gas permeability and low surface tension, and is easy to demold frozen microneedles after low-temperature freezing and solidification. The upper template 2 is made of metal material, such as stainless steel. Stainless steel has corrosion resistance, biocompatibility, mechanical properties and is easy to clean and disinfect, and can be reused after cleaning and disinfection.

[0026] Refer to the instruction manual appendix Figure 3 , 4 A square groove 11 is provided on the top surface of the lower template 1. Multiple micropores 12 are distributed in a matrix on the bottom surface of the groove 11.

[0027] The micropore 12 comprises, from top to bottom, a connected cylindrical portion and a conical portion. Specifically, the cylindrical portion is cylindrical or prismatic, and the conical portion is conical or pyramidal. The bottom end of the micropore 12 is pointed. After the mixture cast into the micropore 12 is cryogenically frozen and solidified, the bottom end of the microneedle becomes pointed, facilitating skin penetration. Although the accompanying drawings only show the form of the micropore 12 comprising a connected cylindrical hole and a conical hole from top to bottom, those skilled in the art can conceive of other forms of micropore 12 based on the above description, which will not be elaborated here.

[0028] Naturally, the groove 11 can also be designed as a circle, ellipse, polygon or other shapes as needed; the microhole 12 can also be designed as a conical hole, specifically a conical hole or a pyramidal hole.

[0029] Refer to the instruction manual appendix Figure 5 , 6 The upper template 2 includes an annular frame 21 and a base plate 22 fixed to the bottom surface of the annular frame 21. Multiple through holes 23 are distributed in a matrix on the base plate 22. The annular frame 21 matches the shape of the groove 11 and is installed in the groove 11 of the lower template 1. The number and position of the through holes 23 correspond to the micro holes 12, and each through hole 23 is connected to a micro hole 12.

[0030] The groove 11 is used to position and install the annular frame 21, so that the through hole 23 corresponds to the micro hole 12. The inner cavity of the annular frame 21, the through hole 23 and the micro hole 12 together form the casting space of the mixture. The mixture is poured into the casting space from the inner cavity of the annular frame 21 and fills the casting space. After the mixture in the casting space is frozen and solidified at low temperature, it forms a frozen microneedle.

[0031] In order to facilitate the separation of the upper template 2 and the lower template 1 for demolding and to keep the frozen microneedles inside the annular frame 21 warm, the cover plate 3 is fixedly installed on the top of the annular frame 21 by four fixing components 4 to close the top opening of the annular frame 21, and the handle 5 is fixedly installed in the middle of the top surface of the cover plate 3.

[0032] The thickness of the annular frame 21 is greater than the depth of the groove 11, as shown in the attached instruction manual. Figure 5 , 6 The fixing component 4 includes a hinge seat 41, a hinge shaft 42, and a spring-loaded fastening plate 43. Two hinge seats 41 are fixedly disposed on the outer side of the annular frame 21 at a distance from each other. The hinge shaft 42 is fixedly connected between the two hinge seats 41. The spring-loaded fastening plate 43 includes an extension and a bent portion. One end of the extension is rotatably connected to the hinge shaft 42. Specifically, a sleeve is formed at one end of the extension, and the hinge shaft 42 passes through the sleeve, allowing the extension to rotate around the hinge shaft 42. The bent portion is fixedly connected to the other end of the extension and bends towards the inside of the annular frame 21. When the extension rotates around the hinge shaft 42 until the bent portion is above the cover plate 3, the bent portion can abut against the top surface of the cover plate 3, so that the cover plate 3 is fixedly installed on the top of the upper template 2.

[0033] Four fixing components 4 are respectively set on the four outer sides of the annular frame 21, providing uniform and stable fixing force to the cover plate 3. The cover plate 3 serves two purposes: firstly, it facilitates the application of a force perpendicular to the lower template to the upper template via the handle 5, allowing the frozen microneedles, after the mixture has solidified, to detach from the lower template along with the upper template, thus completing the demolding process; secondly, when the cover plate 3 is made of heat-insulating materials (such as polyurethane, extruded polystyrene board (XPS), foamed silicate board, etc.), it can provide heat insulation for the frozen microneedles and prevent the temperature of the researcher's hands from affecting the frozen microneedles inside the annular frame 21 during demolding.

[0034] The method of using the cryogenic microneedle fabrication device in this embodiment is as follows: the upper template 2 is installed in the groove 11 of the lower template 1, and each through hole 23 corresponds to and is connected to a micro hole 12; the bioactive ingredient to be delivered is pre-suspended in a low-temperature medium, and the mixture is poured into the inner cavity of the annular frame 21 to fill the inner cavity of the annular frame 21, the through holes 23 and the micro holes 12; the cover plate 3 is placed on the top of the annular frame 21, and the cover plate 3 is fixedly installed on the top of the annular frame 21 by four fixing components 4, and the mixture is quickly solidified by a continuous gradient low-temperature freezing process (before the low-temperature freezing operation, the bioactive ingredient can be concentrated to the microneedle part under the action of gravity by centrifugation or vacuuming, or centrifugation or vacuuming can be omitted, so that the bioactive ingredient exists in both the backing and the microneedle).

[0035] When cryomicroneedling is needed, researchers hold the handle 5 and apply a force perpendicular to the lower template to the upper template, causing the frozen microneedles, after the mixture has solidified, to detach from the lower template along with the upper template, thus completing the demolding process. The frozen microneedles, along with the upper template, are then placed on the target treatment area of ​​the skin, and appropriate pressure is applied to allow the microneedles to penetrate the skin. Once inside the skin, the microneedles melt intradermally, directly releasing the loaded bioactive ingredients into the skin through diffusion. After treatment, the upper template can be removed.

[0036] Example 2

[0037] The inventors discovered that in the current process of manufacturing cryomicroneedles, the bioactive ingredients are concentrated into the microneedle part under the action of gravity through centrifugation or vacuuming. The drug-carrying part of cryomicroneedles is mainly the microneedles, but the drug loading capacity of a single microneedle is only in the microgram range. Compared with traditional subcutaneous and intravenous injections, its drug loading capacity is relatively limited. Therefore, further research is needed to improve the drug loading efficiency of cryomicroneedles.

[0038] Currently, some researchers are fabricating cryomicroneedles without using centrifugation or vacuuming. In this method, the drug-loaded portion of the cryomicroneedle covers the entire backing and the microneedle, increasing the drug loading capacity. However, new problems arise during the use of cryomicroneedles: after the microneedles penetrate the skin, they melt rapidly. Because the transdermal delivery channels created by the microneedles are very small, and the skin itself has a certain degree of elasticity, as the cryomicroneedles melt, the microchannels on the skin gradually close. The residual bioactive ingredients in the backing are difficult to effectively penetrate the epidermal layer of the skin. Therefore, optimizing the transdermal delivery efficiency of bioactive ingredients in cryomicroneedles is another key challenge.

[0039] The cryogenic microneedle fabrication device provided in this embodiment can solve the above problems.

[0040] Refer to the instruction manual appendix Figure 6 Similar to Embodiment 1, the upper template 2 also includes multiple sleeves 24 fixedly installed on the bottom surface of the base plate 22. Each through hole 23 has a sleeve 24 coaxially disposed thereon, and the inner cavity of the sleeve 24 communicates with the through hole 23. The shape of the sleeve 24 matches the micropore 12, and the sleeve 24 can be fitted into the micropore 12. The sleeve 24 is made of stainless steel, possessing corrosion resistance, biocompatibility, good mechanical properties, and ease of cleaning and disinfection, allowing for reuse after cleaning and disinfection.

[0041] The sleeve 24 can penetrate the skin along with the microneedles. After the microneedles melt rapidly, the sleeve 24 can serve as a delivery channel for bioactive ingredients, delivering the bioactive ingredients in the backing into the skin to improve the transdermal efficiency of the bioactive ingredients.

[0042] In this embodiment, the method of using the cryogenic microneedle fabrication device is as follows: the upper template 2 is matched and installed in the groove 11 of the lower template 1, and each sleeve 24 is fitted into a micropore 12; the bioactive ingredient to be delivered is pre-suspended in a low-temperature medium, and the mixture is poured into the inner cavity of the annular frame 21 to fill the inner cavity of the annular frame 21, the through hole 23 and the micropore 12; the cover plate 3 is placed on the top of the annular frame 21, and the cover plate 3 is fixedly installed on the top of the annular frame 21 by four fixing components 4, and the mixture is quickly solidified by a continuous gradient low-temperature freezing process.

[0043] When cryo-microneedling is needed, researchers hold handle 5 and apply a force perpendicular to the lower template to the upper template, causing the frozen microneedles, after the mixture has solidified, to detach from the lower template along with the upper template, thus completing the demolding process. The frozen microneedles, along with the upper template, are then placed on the target treatment area of ​​the skin, and appropriate pressure is applied to allow the microneedles and sleeve 24 to penetrate the skin. The microneedles melt intradermally, directly releasing the loaded bioactive ingredients into the skin through diffusion. The bioactive ingredients in the cryo-microneedle backing are delivered into the skin through sleeve 24. After treatment, the upper template can be removed.

[0044] Obviously, modifications and / or additions can be made to the above-described cryo-microneedle fabrication apparatus and corresponding methods without departing from the scope and domain of this utility model.

[0045] It is equally clear that, although the present invention has described the cryo-microneedle fabrication apparatus in detail, those skilled in the art will certainly be able to obtain many other equivalent forms of cryo-microneedle fabrication apparatuses and corresponding methods that have the features described in the claims and are therefore within the scope of protection defined herein.

Claims

1. A cryogenic microneedle fabrication device, characterized in that: It includes a lower template (1) and an upper template (2); a groove (11) is provided on the top surface of the lower template (1), and the upper template (2) is matched and installed in the groove (11) of the lower template (1); Multiple microholes (12) are arranged in an array on the bottom surface of the groove (11), and the bottom end of each microhole (12) is a pointed tip. The upper template (2) includes an annular frame (21) and a base plate (22) fixed on the bottom surface of the annular frame (21). Multiple through holes (23) are arranged in an array on the base plate (22). The number and position of the through holes (23) correspond to the number of microholes (12), and each through hole (23) is connected to a microhole (12).

2. The cryo-microneedle fabrication apparatus according to claim 1, characterized in that: The cryo-microneedle fabrication device further includes a cover plate (3), a fixing component (4), and a handle (5). The cover plate (3) is fixedly installed on the top of the annular frame (21) by at least two fixing components (4) to close the top opening of the annular frame (21). The handle (5) is fixedly installed in the middle of the top surface of the cover plate (3).

3. The cryo-microneedle fabrication apparatus according to claim 2, characterized in that: The fixing component (4) includes a hinge seat (41), a hinge shaft (42), and an elastic fastening plate (43). The two hinge seats (41) are fixedly disposed on the outer side of the annular frame (21) at a distance from each other. The hinge shaft (42) is fixedly connected between the two hinge seats (41). The elastic fastening plate (43) includes an extension and a bending part. One end of the extension is rotatably connected to the hinge shaft (42). The bending part is fixedly connected to the other end of the extension. The bending part bends toward the inner side of the annular frame (21) and can abut against the top surface of the cover plate (3) for fixing the cover plate (3) on the top of the upper template (2).

4. The cryo-microneedle fabrication apparatus according to claim 1, characterized in that: The outer diameter of the annular frame (21) matches the groove (11), and the thickness of the annular frame (21) is greater than the depth of the groove (11).

5. The cryo-microneedle fabrication apparatus according to claim 1, characterized in that: The micropore (12) includes a columnar portion and a conical portion that are connected, or the micropore (12) is a conical pore.

6. The cryo-microneedle fabrication apparatus according to claim 1, characterized in that: The upper template (2) also includes a plurality of sleeves (24) fixedly installed on the bottom surface of the base plate (22). Each through hole (23) is coaxially provided with a sleeve (24), and the inner cavity of the sleeve (24) is connected to the through hole (23). At least a part of the sleeve (24) can be fitted into the micro hole (12).

7. The cryo-microneedle fabrication apparatus according to claim 2, characterized in that: The lower template (1) is made of silicone material, the upper template (2) is made of metal material, and the cover plate (3) is made of heat insulation material.

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