Fabrication method and device of hollow microneedle array

Abstract

This invention relates to a method and device for fabricating a hollow microneedle array. It includes: providing a microneedle silicon template capable of fabricating a hollow microneedle array; using the microneedle silicon template as a base plate, fabricating a low-melting-point alloy template identical to the microneedle silicon template; fabricating a template polymer layer on the low-melting-point alloy template, the template polymer layer covering the working surface of the low-melting-point alloy template; removing alloy template needles from the working surface of the low-melting-point alloy template; and melting and removing the low-melting-point alloy template to form a polymer hollow microneedle array using the template polymer layer. The polymer hollow microneedle array comprises arrayed polymer microneedles, and each polymer microneedle includes a through-hole, the polymer microneedle hole being coaxially distributed with the polymer microneedle. This invention can effectively realize the fabrication of hollow microneedle arrays, simplify the manufacturing process, and reduce manufacturing costs.

Description

Technical Field

[0001] This invention relates to a preparation method and a device, and more particularly to a preparation method and device for a hollow microneedle array. Background Technology

[0002] Currently, there are many materials available for microneedle fabrication, including monocrystalline silicon, various metals, and various polymers. However, most commonly used microneedle templates are made of monocrystalline silicon. After repeated use, silicon templates become noticeably dirty and cannot be cleaned properly, forcing them to be discarded. This results in high production costs and makes it difficult to meet actual production needs. Summary of the Invention

[0003] The purpose of this invention is to overcome the shortcomings of the prior art and provide a method and device for preparing hollow microneedle arrays, which can effectively realize the preparation of hollow microneedle arrays, simplify the manufacturing process, and reduce manufacturing costs.

[0004] According to the technical solution provided by the present invention, a method for preparing a hollow microneedle array includes:

[0005] Provides a microneedle silicon template for fabricating hollow microneedle arrays;

[0006] Using a microneedle silicon template as a master substrate, a low-melting-point alloy template consistent with the microneedle silicon template was prepared.

[0007] A template polymer layer is prepared on a low-melting-point alloy template, the template polymer layer covering the working surface of the low-melting-point alloy template;

[0008] Remove alloy template needles from the working surface of low-melting-point alloy templates;

[0009] A low-melting-point alloy template is melted and removed to form a polymer hollow microneedle array using the template polymer layer. The polymer hollow microneedle array comprises polymer microneedles arranged in an array.

[0010] For any polymer microneedle, there is a through-hole in the polymer microneedle, which is coaxially distributed with the polymer microneedle.

[0011] The preparation process for low-melting-point alloy templates includes:

[0012] Polymer microneedle negative molds were prepared on microneedle silicon templates using a molding process.

[0013] Under vacuum conditions, a low-melting-point alloy template is prepared by casting on a polymer microneedle negative mold using a low-melting-point alloy. The low-melting-point alloy template includes a number of alloy microneedles and alloy microneedle gap windows for separating adjacent alloy microneedles.

[0014] The distribution of the alloy microneedles on the low-melting-point alloy template is consistent with the distribution of silicon microneedles on the silicon substrate, and the alloy microneedles and silicon microneedles have the same shape.

[0015] The alloy microneedle includes an alloy template needle body integrated with the alloy template needle head, wherein the alloy template needle head is pyramidal and the alloy template needle body is vertical or polygonal.

[0016] The alloy template needle is connected to the low-melting-point alloy template.

[0017] When preparing polymer microneedle negative molds using a molding process, the preparation process includes:

[0018] The working surface of the microneedle silicon template is passivated.

[0019] The polymer mixture is poured into the working surface of the microneedle silicon template, the polymer mixture is vacuum degassed, and then baked until the polymer mixture is cured to prepare the polymer microneedle negative mold. The polymer mixture is a solution of PDMS mixture.

[0020] When passivating the working surface of the microneedle silicon template, the process includes using silane to passivate the microneedle silicon template, so as to assist in the separation of the formed polymer microneedle negative mold from the microneedle silicon template after passivation.

[0021] For low-melting-point alloy templates, the materials of the low-melting-point alloy templates include metals and metal alloys with melting points below 300°C.

[0022] The template polymer layer is prepared on the working surface of the low-melting-point alloy template by means of spin coating or spray coating.

[0023] The template polymer layer comprises PI (polyimide).

[0024] Methods for removing alloy template needles from the working surface of low-melting-point alloy templates include grinding.

[0025] A hollow microneedle array device includes a polymer hollow microneedle array, wherein the polymer hollow microneedle array is prepared by the above-described preparation method.

[0026] The advantages of this invention are as follows: Using a microneedle silicon template as a master substrate, a polymer microneedle negative mold is prepared through a single molding process, followed by a second molding process to obtain a low-melting-point alloy template. A polymer hollow microneedle array is then fabricated using the low-melting-point alloy template. The process is simple, reliable, and easy to operate. Compared with existing methods for preparing hollow microneedle arrays, this invention has fewer steps, is simpler, requires less time, and has lower costs. Multiple polymer microneedle negative molds can be prepared, resulting in multiple low-melting-point alloy templates. Furthermore, the material of the low-melting-point alloy template can be repeatedly remelted and reused. The low-melting-point alloy template can be used as a sacrificial layer template, utilizing its low-temperature melting characteristics to construct the hollow microneedle array, thus reducing process costs. Attached Figure Description

[0027] Figures 1-9 This is a cross-sectional view of the process steps of one embodiment of the hollow microneedle array of the present invention, wherein,

[0028] Figure 1 This is a cross-sectional view of the microneedle silicon template of the present invention.

[0029] Figure 2 This is a cross-sectional view of the working surface of the microneedle silicon template after passivation treatment according to the present invention.

[0030] Figure 3 This is a cross-sectional view of the polymer microneedle negative mold prepared on a microneedle silicon template according to the present invention.

[0031] Figure 4 This is a cross-sectional view of the low-melting-point alloy plate and the polymer microneedle negative mold after alignment according to the present invention.

[0032] Figure 5 This is a cross-sectional view of the polymer microneedle negative mold after the low melting point alloy plate is used to make the mold according to the present invention.

[0033] Figure 6 This is a cross-sectional view of the low-melting-point alloy template prepared according to the present invention.

[0034] Figure 7 This is a cross-sectional view of the template polymer layer prepared according to the present invention.

[0035] Figure 8 This is a cross-sectional view of the present invention after the alloy template needle has been removed.

[0036] Figure 9 A cross-sectional view of the polymer hollow microneedle array prepared according to the present invention.

[0037] Explanation of reference numerals in the attached figures: 1-Silicon microneedle template, 2-Passivation layer, 3-Polymer microneedle female mold, 4-Low melting point alloy plate, 5-Template polymer layer, 6-Silicon microneedle gap window, 7-Silicon microneedle, 8-Female mold positioning block, 9-Alloy microneedle gap window, 10-Alloy microneedle, 11-Needle body connection base, 12-Polymer microneedle hole, 13-Polymer microneedle, 14-Low melting point alloy template. Detailed Implementation

[0038] The present invention will be further described below with reference to specific accompanying drawings and embodiments.

[0039] To effectively fabricate hollow microneedle arrays, simplify the manufacturing process, and reduce manufacturing costs, in one embodiment of the present invention, the fabrication method for hollow microneedle arrays includes:

[0040] A microneedle silicon template 1 is provided for fabricating hollow microneedle arrays;

[0041] Using the microneedle silicon template 1 as the master plate, a low-melting-point alloy template 14 consistent with the microneedle silicon template 1 was prepared;

[0042] A template polymer layer 5 is prepared on a low-melting-point alloy template 14, the template polymer layer 5 covering the working surface of the low-melting-point alloy template 14;

[0043] Remove the alloy template needle from the working surface of the low-melting-point alloy template 14;

[0044] The low-melting-point alloy template 14 is melted and removed to form a polymer hollow microneedle array using the template polymer layer 5. The polymer hollow microneedle array includes polymer microneedles 13 arranged in an array.

[0045] For any polymer microneedle 13, there is a polymer microneedle hole 12 that penetrates the polymer microneedle hole 12, which is coaxially distributed with the polymer microneedle 13.

[0046] Specifically, the provided microneedle silicon template 1 can be used to prepare hollow microneedle arrays. The ability to prepare hollow micro arrays specifically means that hollow micro arrays can be directly prepared using the microneedle silicon template 1. However, as can be seen from the above description, the microneedle silicon template 1 generally needs to be scrapped after multiple uses, resulting in high costs and other problems.

[0047] Figure 1 The image shows a schematic diagram of a microneedle silicon template 1. Figure 1 In the process, a number of silicon microneedles 7 are distributed on the silicon template 1, that is, the silicon microneedles 7 are distributed in an array. The silicon microneedle array is generally formed on the silicon substrate using a series of processes such as photolithography, dry etching or wet etching. Figure 1In this design, the head of the silicon microneedle 7 is a pyramidal structure, and the body of the silicon microneedle 7 is a vertical or polygonal pyramidal structure. Adjacent silicon microneedles 7 are separated by silicon microneedle gap windows 6. Of course, the microneedle silicon substrate 1 can also adopt other embodiments. The form of the microneedle silicon substrate 1 can be selected as needed to meet the requirements for fabricating the hollow microneedle array.

[0048] In specific implementation, the microneedle silicon template 1 is used as the master plate to prepare a low melting point alloy template 14 that is consistent with the microneedle silicon template 1. Generally, the low melting point alloy template 14 can be 1:1 with the microneedle silicon template 1, that is, the low melting point alloy template 14 is a complete replica of the microneedle silicon template 1. The difference between the two is that the materials are different, that is, the low melting point alloy template 14 is made of low melting point alloy.

[0049] In order to prepare a low-melting-point alloy template 14 using the microneedle silicon template 1 as a base plate, in one embodiment of the present invention, the preparation process of the low-melting-point alloy template 14 includes:

[0050] A polymer microneedle negative mold 3 was prepared on a microneedle silicon template 1 using a molding process;

[0051] Under vacuum conditions, a low-melting-point alloy template 14 is prepared by casting on a polymer microneedle negative mold 3 using a low-melting-point alloy. The low-melting-point alloy template 14 includes a plurality of alloy microneedles 10 and alloy microneedle gap windows 9 for separating adjacent alloy microneedles 10.

[0052] Specifically, when preparing the polymer microneedle negative mold 3 using the molding process, the preparation process includes:

[0053] The working surface of the microneedle silicon template 1 is passivated.

[0054] The polymer mixture is poured into the working surface of the microneedle silicon template 1, the polymer mixture is vacuum degassed, and then baked. After the polymer mixture is cured, the polymer microneedle negative mold 3 is obtained. The polymer mixture is a solution of PDMS mixture.

[0055] In one embodiment of the present invention, the passivation treatment of the working surface of the microneedle silicon template 1 specifically refers to using silane to passivate the working surface of the microneedle silicon template 1, which helps the template to be demolded from the microneedle silicon template 1 after the polymer microneedle negative mold 3 is prepared.

[0056] In specific implementation, trimethylchlorosilane (TMCS) is selected as the silane. TMCS is dispersed in an isopropanol solution at a volume ratio of 2:98. An appropriate amount of 2% silane mixed solution is poured into a glass petri dish, and the microneedle silicon template 1 is placed in it and immersed for 10-15 minutes. Then, the microneedle silicon template 1 is removed and placed on a hot plate for baking at 100-110°C for 5-10 minutes. After passivation treatment, a passivation layer 2 is formed on the working surface of the microneedle silicon template 1, such as... Figure 2 As shown.

[0057] When the polymer mixture used to prepare the polymer microneedle negative mold 3 is a solution of PDMS (polydimethylsiloxane) mixture, the specific process for preparing the polymer microneedle negative mold 3 includes:

[0058] Pour a commonly used PDMS mixture into a beaker to form a solution of 110ml–220ml. Stir the solution thoroughly with a glass rod. At this point, a large number of bubbles will appear in the PDMS mixture. Then, pour the PDMS mixture into 20ml centrifuge tubes and centrifuge at 3000 rpm for 20–30 minutes. The PDMS mixture is generally obtained commercially; the specific type should be chosen based on the ability to prepare the required polymer microneedle negative mold.

[0059] The centrifuged PDMS mixture was poured onto the working surface of the passivated microneedle silicon template 1 and then molded. Specifically, the microneedle silicon template 1 was placed in a glass culture dish with its working surface facing upwards. The centrifuged PDMS mixture solution from the centrifuge tube was poured into the glass culture dish, covering the working surface of the microneedle silicon template 1, taking care to avoid generating air bubbles.

[0060] Next, place the glass culture dish entirely in a vacuum desiccator to remove residual air bubbles. If large air bubbles form on the surface of the PDMS mixture during the debubbling process, debubble slowly to prevent the PDMS mixture from foaming again. Continue placing the glass culture dish in the vacuum desiccator until no air bubbles are visible, ensuring that the PDMS mixture completely fills the silicon microneedle gap window 6 of the microneedle silicon template 1.

[0061] After degassing, remove the glass culture dish from the vacuum desiccator and place it on a hot plate. Set the hot plate temperature to 120℃ and bake for 20–30 minutes. Wait for the PDMS to completely cure to form the polymer microneedle negative mold 3, as shown below. Figure 3As shown. After that, the glass culture dish was removed from the hot plate and allowed to cool to room temperature. The polymer microneedle negative mold 3 was then cut open at the outer edge of the pattern with a blade. The entire polymer microneedle negative mold 3 was carefully pried up from the cut edge for subsequent processes.

[0062] When preparing a low-melting-point alloy template 14 using a polymer microneedle negative mold 3, a low-melting-point alloy plate 4 is first required. The low-melting-point alloy plate 4 generally requires a low-melting-point metal or a low-melting-point metal alloy. The melting point of the low-melting-point alloy plate 4 is below 300℃. The low-melting-point metal is typically composed of low-melting-point metal elements such as Bi, Sn, Pb, and In. These alloys are commonly used to manufacture plastic molds, deep-drawing dies, and forming dies. The low-melting-point alloy plate 4 uses a certain proportion of elements such as bismuth, cadmium, tin, lead, dysprosium, and indium as the main components to form different eutectic low-melting-point alloys. The manufacturing cost of the low-melting-point alloy template is low, the alloy material can be repeatedly remelted and reused, the manufacturing process is simplified, and it can also be used as a sacrificial layer template.

[0063] In one embodiment of the present invention, the low melting point alloy plate 4 may be a bismuth-tin alloy with 58% bismuth and 42% tin, and a melting point of about 140°C.

[0064] When using the low-melting-point alloy plate 4 for mold making, a vacuum bonding machine is used. The bonding machine maintains a vacuum state inside, and its upper cover has a flat metal pressure head that can be heated within a range of room temperature to 350°C. The polymer microneedle mold 3 is placed on the lower pressure head (which also serves as the stage) inside the bonding machine cavity. The bellows is opened, and the lower pressure head of the bonding machine is lowered. The low-melting-point alloy plate 4 is then placed above the polymer microneedle mold 3. Figure 4 As shown.

[0065] Afterwards, the bonding machine is shut down, a vacuum is drawn, and once a certain vacuum level is reached, the heating function of the metal pressure head on the top cover of the bonding machine is activated, raising the temperature to 140℃~160℃. The high temperature of the upper pressure head melts the low-melting-point alloy plate 4. The bellows is then closed, and the lower pressure head rises and applies pressure of 0.08Mpa~0.12Mpa. Under vacuum conditions, the low-melting-point alloy plate 4 can slowly fill the entire polymer microneedle mold 3. After maintaining this temperature for 20min~30min, the heating of the upper pressure head is turned off, and the pressure is maintained at 0.08Mpa~0.12Mpa. Once the temperature of the upper pressure head drops to about 60℃, the pressure can be released, the vacuum is turned off, the bonding machine is opened, and the polymer microneedle mold 3 and the bismuth low-melting-point alloy plate 4 are removed. At this point, the temperature is close to room temperature, the low-melting-point alloy plate 4 has solidified, and the polymer microneedle mold 3 can be peeled off. The low-melting-point alloy template 14 is then formed through the solidified low-melting-point alloy plate 4. Figure 5 and Figure 6 As shown.

[0066] Figure 4In the process, the polymer microneedle female mold 3 includes a female mold positioning block 8, wherein the female mold positioning block 8 corresponds to the silicon microneedle gap window 6 and the silicon microneedle 7. Figure 6 The low-melting-point alloy template 14 formed in the process has the same shape as the microneedle silicon template 1. The distribution of the alloy microneedles 10 on the low-melting-point alloy template 14 is consistent with the distribution of the silicon microneedles 7 on the microneedle silicon substrate 1, and the alloy microneedles 10 and the silicon microneedles 7 have the same shape.

[0067] The alloy microneedle 10 includes an alloy template needle body integrally formed with the alloy template needle head. The alloy template needle head is pyramidal in shape, and the alloy template needle body is vertical or polygonal in shape. The alloy template needle body is connected to the low melting point alloy template 14.

[0068] Figure 6 In the process, the alloy microneedles 10 and 9 are separated by an alloy microneedle gap window. The alloy template needle body and the low melting point alloy template 14 are integrally formed. Of course, the alloy template needle head and the alloy template needle body are also integrally formed, that is, both are formed by the aforementioned low melting point alloy plate 4.

[0069] After preparing the low-melting-point alloy template 14, a template polymer layer 5 is prepared on the working surface of the low-melting-point alloy template 14. The polymer material of the template polymer layer 5 specifically refers to a moldable and curable material. The advantage of polymers is that they can be easily formed into ideal shapes using various techniques, such as solution casting, melt molding, or machining. The manufacturing cost of polymers is relatively low. In one embodiment of the present invention, the template polymer layer 5 comprises PI (polyimide). The template polymer layer 5 is prepared on the working surface of the low-melting-point alloy template 14 by spin coating or spraying. A specific preparation process for the template polymer layer 5 is given below:

[0070] Using a low-melting-point alloy template 14 as the working plate, with the working surface of the template facing upwards, a layer of PI is sprayed onto it, with a thickness of 20μm to 50μm, and cured after spraying. PI is sprayed using a glue spraying machine, with PI and thinner mixed according to a preset ratio. The glue spraying pressure is set to 0.1–0.15 MPa, the spraying temperature to 80℃, and the purging pressure to 0.2 MPa. The spraying thickness is 20–50 μm, the baking temperature is 120℃, and the time is 40–60 min. The state of the PI template polymer layer 5 on the working surface of the low-melting-point alloy template 14 is as follows. Figure 7 As shown. Specifically, the diluent can be 99% acetone, and the volume ratio of PI to diluent can be 1:9.

[0071] To create a hollow structure, the alloy template needles on the working surface of the low-melting-point alloy template 14 are removed. Specifically, the removal of the alloy template needles involves grinding. When removing the alloy template needles by grinding, a grinding machine is used to grind the alloy template needles using a planar grinding method, ensuring that the grinding direction is parallel to the plane of the low-melting-point alloy template 14; the grinding flatness requirement is ±10μm; after grinding, the low-melting-point alloy template 14 needs to be exposed, ensuring that the needle tip is composed of alloy in the middle and surrounded by the template polymer layer 5. This way, after removing the low-melting-point alloy template 14, the polymer microneedles 13 will be hollow. Figure 8 and Figure 9 As shown

[0072] Because low-melting-point alloys possess low-temperature melting characteristics, they can be melted and removed after reaching a certain temperature. After grinding, the low-melting-point alloy template 14, covering the solidified template polymer layer 5, is placed in a high-temperature resistant melting pot. The melting pot is heated to 140℃~160℃, causing the bismuth-tin alloy-based low-melting-point alloy template 14 to melt. After the low-melting-point alloy template 14 melts, a polymer hollow microneedle array is obtained, such as... Figure 9 As shown.

[0073] Figure 9 In this structure, the polymer hollow microneedle array includes polymer microneedles 13 arranged in an array. Each polymer microneedle 13 includes a through-hole 12, which is coaxially distributed with the polymer microneedle 13. Furthermore, the bottoms of the polymer microneedles 13 are connected as a single unit via a needle body connecting base 11.

[0074] As can be seen from the above description, a hollow microneedle array device can be obtained. In one embodiment of the present invention, a polymer hollow microneedle array is included, wherein the polymer hollow microneedle array is prepared by the above-described preparation method.

[0075] Specifically, hollow microneedle array devices refer to devices including polymer hollow microneedle arrays. The polymer hollow microneedle arrays are prepared by the preparation method described above. For specific preparation methods, please refer to the above description, which will not be repeated here.

[0076] This invention utilizes a microneedle silicon template 1 as a master substrate. A polymer microneedle negative mold 3 is prepared through a single molding process, followed by a second molding process to obtain a low-melting-point alloy template 14. A polymer hollow microneedle array is then fabricated using the low-melting-point alloy template 14. The process is simple, reliable, and easy to operate. Compared to existing methods for preparing hollow microneedle arrays, this invention has fewer steps, is simpler, requires less time, and has lower costs. Multiple polymer microneedle negative molds 3 can be prepared, resulting in multiple low-melting-point alloy templates 14. Furthermore, the material of the low-melting-point alloy template 14 can be repeatedly remelted and reused. The low-melting-point alloy template 14 can be used as a sacrificial layer template, utilizing its low-temperature melting characteristics to construct the hollow microneedle array, thus reducing process costs.

Claims

1. A method of fabricating a hollow microneedle array, characterized by, The preparation method includes: Provides a microneedle silicon template for fabricating hollow microneedle arrays; Using a microneedle silicon template as a master substrate, a low-melting-point alloy template consistent with the microneedle silicon template was prepared. A template polymer layer is prepared on a low-melting-point alloy template, the template polymer layer covering the working surface of the low-melting-point alloy template; Remove alloy template needles from the working surface of low-melting-point alloy templates; A low-melting-point alloy template is melted and removed to form a polymer hollow microneedle array using the template polymer layer. The polymer hollow microneedle array comprises polymer microneedles arranged in an array. For any polymer microneedle, there is a through-hole in the polymer microneedle, which is coaxially distributed with the polymer microneedle.

2. The method for preparing the hollow microneedle array according to claim 1, characterized in that, The preparation process for low-melting-point alloy templates includes: Polymer microneedle negative molds were prepared on microneedle silicon templates using a molding process. Under vacuum conditions, a low-melting-point alloy template is prepared by casting on a polymer microneedle negative mold using a low-melting-point alloy. The low-melting-point alloy template includes a number of alloy microneedles and alloy microneedle gap windows for separating adjacent alloy microneedles.

3. The method for preparing the hollow microneedle array according to claim 2, characterized in that, The distribution of the alloy microneedles on the low-melting-point alloy template is consistent with the distribution of silicon microneedles on the silicon substrate, and the alloy microneedles and silicon microneedles have the same shape. The alloy microneedle includes an alloy template needle body integrated with the alloy template needle head, wherein the alloy template needle head is pyramidal and the alloy template needle body is vertical or polygonal. The alloy template needle is connected to the low-melting-point alloy template.

4. The method for preparing the hollow microneedle array according to claim 2, characterized in that, When preparing polymer microneedle negative molds using a molding process, the preparation process includes: The working surface of the microneedle silicon template is passivated. The polymer mixture is poured into the working surface of the microneedle silicon template, the polymer mixture is vacuum degassed, and then baked until the polymer mixture is cured to prepare the polymer microneedle negative mold. The polymer mixture is a solution of PDMS mixture.

5. The method for preparing the hollow microneedle array according to claim 4, characterized in that, When passivating the working surface of the microneedle silicon template, the process includes using silane to passivate the microneedle silicon template, so as to assist in the separation of the formed polymer microneedle negative mold from the microneedle silicon template after passivation.

6. The method for preparing the hollow microneedle array according to any one of claims 1 to 5, characterized in that, For low-melting-point alloy templates, the materials of the low-melting-point alloy templates include metals and metal alloys with melting points below 300°C.

7. The method for preparing the hollow microneedle array according to any one of claims 1 to 5, characterized in that, The template polymer layer is prepared on the working surface of the low-melting-point alloy template by means of spin coating or spray coating.

8. The method for preparing the hollow microneedle array according to any one of claims 1 to 5, characterized in that, The template polymer layer includes PI.

9. The method for preparing the hollow microneedle array according to any one of claims 1 to 5, characterized in that, Methods for removing alloy template needles from the working surface of low-melting-point alloy templates include grinding.

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