CN113520986A - Random curved surface polymer microneedle array and preparation method thereof - Google Patents
Random curved surface polymer microneedle array and preparation method thereof Download PDFInfo
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- A61M37/00—Other apparatus for introducing media into the body; Percutany, i.e. introducing medicines into the body by diffusion through the skin
- A61M37/0015—Other apparatus for introducing media into the body; Percutany, i.e. introducing medicines into the body by diffusion through the skin by using microneedles
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- A61M37/00—Other apparatus for introducing media into the body; Percutany, i.e. introducing medicines into the body by diffusion through the skin
- A61M37/0015—Other apparatus for introducing media into the body; Percutany, i.e. introducing medicines into the body by diffusion through the skin by using microneedles
- A61M2037/0053—Methods for producing microneedles
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Abstract
The invention discloses an arbitrary curved surface polymer micro-needle array and a preparation method thereof, the arbitrary curved surface (a needle point surface) polymer micro-needle array on a plane substrate provided by the invention is attached to a human skin curve by changing the curvature of the needle point surface of a micro-needle, so that the conditions of uneven stress, easy breakage of side micro-needles and the like are avoided, and the preparation method of the arbitrary curved surface polymer micro-needle array has the advantages of simple processing technology and low cost, and is suitable for batch production.
Description
Technical Field
The invention belongs to the technical field of biomedical engineering, and particularly relates to an arbitrarily curved polymer microneedle array and a preparation method thereof.
Background
Subcutaneous injection is widely used for injecting vaccines and injections in clinical practice, but pain feeling during injection is always an unsolved problem, particularly for some special users such as old people, children and the like. In contrast, microneedle-based transdermal delivery allows for minimally invasive contact with the skin, minimizing access to the dermal cortex and nerve endings, and thus significantly reducing sampling pain. The application of microneedle array technology in the fields of drug delivery, medical cosmetology, tissue fluid extraction, and biosensing has attracted increasing attention in recent years. Since the target of action is the human skin surface, microneedles need to be able to conform to rough skin and have a certain mechanical strength to pierce the stratum corneum of the skin.
Common microneedle materials include polymers, silicon, metals, and the like. Polymeric microneedles are generally biosafety high but mechanical strength insufficient to pierce the stratum corneum; although the silicon is hard, it is brittle and easy to break; metals have the advantage of low processing costs but are less biocompatible. The general structure of the microneedle array is composed of solid or hollow microneedle arrays with different shapes and a substrate supporting the microneedle structures. The conventional microneedle array processing method is generally based on semiconductor processes such as photolithography, machining and etching, and methods such as chemical etching or laser micromachining to fabricate single crystal silicon microneedles or metal microneedles, or metal templates of polymer microneedles (CN104970804A, CN101507857A, CN108325065A, etc.). However, these processes are complicated and expensive to manufacture. More importantly, most fabrication processes are directed to planar microneedle arrays (with tips in the same plane). However, the skin surface of the human body is not flat but has undulation and elasticity. The planar microneedle array has the problems of uneven stress on human skin, incomplete insertion of microneedles into the stratum corneum and the like, and the application range is not wide. More and more researches are focused on manufacturing microneedles with the same height on a flexible or curved substrate to be attached to a fluctuant human body surface, the microneedles can be relatively and completely inserted into a skin cuticle, but the problems that the curved substrate is complex in processing process and uneven in stress during use still exist, for example, when the microneedle patch is torn off, the microneedles on the side edge can be more easily broken due to larger shearing force and even remain in the skin; and when the skin is faced with some narrow folds, the insufficient elasticity or curvature of the curved surface of the substrate can also cause partial microneedles to be incapable of penetrating the skin completely. Therefore, developing a simpler and lower-cost manufacturing method to prepare curved microneedle arrays in batches would be of great value for practical application of microneedle technology.
Disclosure of Invention
In order to overcome the disadvantages and shortcomings of the prior art, a primary object of the present invention is to provide an arbitrarily curved polymer microneedle array.
The invention also provides a preparation method of the polymer microneedle array with the any curved surface, which is characterized in that the curvature of the tip surface of the microneedle is changed to be attached to the curve of the human skin, the planar substrate is kept, the prepared polymer microneedle array with the any curved surface is uniformly stressed when being pressed, and the microneedle is only stressed axially, so that the conditions of uneven stress, easy breakage of the microneedle at the side edge and the like are avoided.
The primary purpose of the invention is realized by the following technical scheme:
the polymer microneedle array with the arbitrary curved surface comprises a microneedle array and a substrate perpendicular to the microneedle array, wherein the microneedles are erected on the substrate and arranged on the substrate in parallel, and the substrate comprises a substrate thin layer and a substrate main body.
Further, the material adopted by the micro-needle is at least one of polydimethylsiloxane, polylactic acid, lactic acid/glycolic acid copolymer, polyvinylpyrrolidone and polyacrylamide polymer.
Further, the substrate thin layer is made of a material consistent with that of the microneedle material, and the substrate main body is made of at least one of glass, metal, polyethylene, rubber, latex and polydimethylsiloxane.
The second purpose of the invention is realized by the following technical scheme:
a preparation method of an arbitrarily curved polymer microneedle array comprises the following steps:
1) preparation of a metal microneedle array prototype: two or more conical stainless steel needles with the diameter of 0.2 mm or 0.1 mm or 0.3 mm or 0.4 mm are tightly fixed together on a magnet to obtain a metal microneedle array prototype with the same spatial characteristics as the target polymer microneedle array;
2) preparing a template: preparing a template by using the metal microneedle array prototype obtained in the step 1) and a template material;
3) removing the metal micro-needle array prototype from the template;
4) pouring the polymer mixed solution into the template of the metal microneedle array prototype removed in the step 3);
5) vacuumizing to make the polymer mixed liquid poured into the template completely fill the pores without leaving bubbles;
6) drying to solidify and mold the polymer mixed liquid material poured into the template to obtain the microneedle array part and the substrate thin layer part of the polymer microneedle array;
7) connecting the microneedle array part of the microneedle array prepared in the step 6) with the substrate thin layer and the substrate main body material together to obtain the polymer microneedle array with any curved surface.
Further, the tip surface of the metal microneedle array prototype in the step 1) may be a plane, an inclined surface, an arc surface, an arbitrary curved surface, or the like.
Further, the template material in the step 2) is at least one of polyethylene, polytetrafluoroethylene, polydimethylsiloxane and gypsum.
Further, when the template material in step 2) is polyethylene, polytetrafluoroethylene and gypsum, the metal microneedle array prototype in step 1) is used to press and punch holes on a thin plate made of the material.
Further, when the template material in the step 2) is polydimethylsiloxane, pouring polydimethylsiloxane mixed liquor into the prepared container, inserting the metal microneedle array prototype until the mixed liquor slightly submerges the needle tip surface, vacuumizing for 15-30 minutes until no bubbles exist in the container, and then putting the container into a 70 ℃ oven for curing for 3-4 hours.
Further, the polymer mixed solution in the step 4) is at least one of polydimethylsiloxane, polylactic acid, lactic acid/glycolic acid copolymer, polyvinylpyrrolidone and polyacrylamide polymer.
Further, when the polymer mixed solution in the step 4) is polydimethylsiloxane, the polydimethylsiloxane is prepared by a polymer and a cross-linking agent according to a mass ratio of 10: 1.
The polydimethylsiloxane (Poly (dimethylsiloxane), Sylgard 184), was purchased from Dow Corning, Inc. and includes a polymer (composition of a mixture of a metallic platinum catalyst and a vinyl-containing dimethylsiloxane polymer precursor) and a cross-linking agent (composition of a vinyl-and Si-H-containing dimethylsiloxane precursor).
Further, when the polymer mixed solution in the step 4) is at least one of polylactic acid, a lactic acid/glycolic acid copolymer, polyvinylpyrrolidone and a polyacrylamide polymer, the mass percentage of the polymer in the polymer mixed solution is 20-80%.
Further, in the step 6), the drying temperature is 20-70 ℃.
Further, the substrate body material in step 7) is at least one of glass, metal, polyethylene, rubber, latex and polydimethylsiloxane.
The invention has the beneficial effects that:
(1) the polymer micro-needle array with the arbitrary curved surface prepared by the invention has different heights, and the whole needle point surface is the arbitrary curved surface, so that the fit of different curves on the surface of the skin can be met;
(2) the microneedles in the polymer microneedle array with any curved surface prepared by the method are high in mechanical strength and can penetrate through the stratum corneum of the skin;
(3) the prepared random curved surface polymer microneedle array is a planar substrate microneedle array, and compared with other curved surface or flexible substrate microneedles, the curved surface polymer microneedle array is not only attached to the skin, but also stressed more uniformly and is not easy to break;
(4) the microneedles in the polymer microneedle array with any curved surface prepared by the method are good in consistency, safe and durable;
(5) the preparation method of the polymer microneedle array with any curved surface has simple integral process and is beneficial to large-scale production.
Drawings
Fig. 1 is a schematic view of a microneedle array in example 1;
FIG. 2 is a schematic view of the structure of a microneedle array according to example 1;
FIG. 3 is a schematic view of the structure of a microneedle array of example 1;
fig. 4 is a schematic view of a microneedle array in example 2;
fig. 5 is a schematic view of a microneedle array of example 3;
fig. 6 is a schematic view of a microneedle array of example 4;
FIG. 7 is a schematic view of the structure of a microneedle array according to example 4;
fig. 8 is a schematic view of a microneedle array of example 5;
fig. 9 is a schematic view of the structure of the microneedle array of example 5.
Detailed Description
The present invention will be described in further detail with reference to examples and drawings, but the present invention is not limited thereto.
Example 1
Fig. 1 shows a polymer microneedle array of the present embodiment. The polymer microneedle array comprises a substrate body 1, wherein a substrate thin layer 2 and microneedles 3 standing on the substrate thin layer for penetrating into a skin epidermal layer are connected to the substrate body 1.
Sequentially adding a polymer and a cross-linking agent into the disposable cup according to the weight ratio of 10:1, stirring the mixture by using a fork for 10-15 minutes, uniformly mixing the mixture, putting the mixture into a vacuum pump, and vacuumizing for 15-30 minutes until bubbles are removed; tightly fixing 100 prepared stainless steel needles with the diameter of 0.2 mm or 0.1 mm or 0.3 mm or 0.4 mm and the length of 40 mm by using a circular tube, and vertically standing the needle points on a magnet with the needle point surfaces facing downwards so that all the needle points are in the same plane; adding a small amount of polydimethylsiloxane into the tube, and putting the tube into a 70 ℃ oven for curing for 1-2 h to tightly connect and fix the needle and the circular tube; and drying to obtain the planar metal microneedle array prototype.
Pouring polydimethylsiloxane into the prepared container, inserting the metal microneedle array prototype until the mixed liquid slightly exceeds the needle point (shown in figure 2, comprising the metal microneedle array prototype 1 and the polydimethylsiloxane template 2), vacuumizing for 15-30 minutes until no bubbles exist, and then putting the metal microneedle array prototype into a 70 ℃ oven for curing for 3-4 hours; and (3) separating the metal microneedle array prototype from the polydimethylsiloxane template to obtain the polydimethylsiloxane template, as shown in figure 3. And (3) treating the template for 5-10 minutes by using a plasma cleaner, and dropwise adding a small amount of 1H,1H,2H, 2H-perfluorooctyl trichlorosilane beside the template into a chemical fume hood overnight to uniformly deposit the trichlorosilane on the surface of the template.
Pouring polydimethylsiloxane into the template, vacuumizing for 30 minutes till no bubbles exist, covering the substrate glass slide which is treated by a plasma cleaning machine on the template, and putting the substrate glass slide into a 70 ℃ oven for curing for 1 hour; and (4) separating the micro-needle array from the template to obtain the polydimethylsiloxane micro-needle array.
Example 2
Fig. 4 shows a polymer microneedle array of the present embodiment. The polymer microneedle array comprises a substrate body 1, wherein a substrate thin layer 2, and microneedles 3 and a microneedle body 4 which are erected on the substrate thin layer and are used for penetrating into a skin epidermal layer are connected to the substrate body 1.
The tip face was changed to a bevel as in example 1. The specific method comprises the following steps:
the stainless steel needle fixed with a round tube was slightly tilted when it was placed on a magnet to ensure that all the tips of the needles touched the bottom surface. Adding a small amount of polydimethylsiloxane into the tube, putting the tube into an oven at 70 ℃ for 1-2 h, and tightly connecting and fixing the needle and the circular tube; and drying to obtain the inclined plane metal microneedle array prototype.
Pouring polydimethylsiloxane into the prepared container, inserting the metal microneedle array prototype until the mixed liquid slightly submerges the needle point, vacuumizing for 15-30 minutes until no bubbles exist, and then putting the metal microneedle array prototype into a 70 ℃ oven for curing for 3-4 hours; and (3) separating the metal micro-needle array prototype from the polydimethylsiloxane template to obtain the polydimethylsiloxane template. And (3) treating the template for 5-10 minutes by using a plasma cleaner, and dropwise adding a small amount of 1H,1H,2H, 2H-perfluorooctyl trichlorosilane beside the template into a chemical fume hood overnight to uniformly deposit the trichlorosilane on the surface of the template.
Pouring polydimethylsiloxane into the template, vacuumizing for 30 minutes till no bubbles exist, covering the substrate glass slide which is treated by a plasma cleaning machine on the template, and putting the substrate glass slide into a 70 ℃ oven for curing for 1 hour; and (3) separating the microneedle array from the template to obtain the polydimethylsiloxane microneedle array shown in the figure 4.
Example 3
Fig. 5 shows a polymer microneedle array of the present embodiment. The polymer microneedle array comprises a substrate body 1, wherein a substrate thin layer 2, and microneedles 3 and a microneedle body 4 which are erected on the substrate thin layer and are used for penetrating into a skin epidermal layer are connected to the substrate body 1.
The tip surface was changed to a curved surface as in example 1. The specific method comprises the following steps:
preparing a thin-wall semicircular pipeline with an arc-shaped cross section, and placing the pipeline on a magnet with an upward opening; the needle point of a stainless steel needle fixed by a round tube is placed on the arc semi-round tube with the surface facing downwards, so that all the needle points are in contact with the tube wall. Adding a small amount of polydimethylsiloxane into the tube, putting the tube into an oven at 70 ℃ for 1-2 h, and tightly connecting and fixing the needle and the circular tube; and drying to obtain the outward convex cambered surface metal microneedle array prototype.
Pouring polydimethylsiloxane into the prepared container, inserting the metal microneedle array prototype until the mixed liquid slightly submerges the needle point, vacuumizing for 15-30 minutes until no bubbles exist, and then putting the metal microneedle array prototype into a 70 ℃ oven for curing for 3-4 hours; and (3) separating the metal micro-needle array prototype from the polydimethylsiloxane template to obtain the polydimethylsiloxane template. And (3) treating the template for 5-10 minutes by using a plasma cleaner, and dropwise adding a small amount of 1H,1H,2H, 2H-perfluorooctyl trichlorosilane beside the template into a chemical fume hood overnight to uniformly deposit the trichlorosilane on the surface of the template.
Pouring polydimethylsiloxane into the template, vacuumizing for 30 minutes till no bubbles exist, covering the substrate glass slide which is treated by a plasma cleaning machine on the template, and putting the substrate glass slide into a 70 ℃ oven for curing for 1 hour; and (3) separating the microneedle array from the template to obtain the polydimethylsiloxane microneedle array shown in the figure 5.
Example 4
Fig. 6 shows a polymer microneedle array of the present embodiment, and fig. 7 shows a polymer microneedle array structure of the present embodiment. The polymer microneedle array comprises a substrate body 1, wherein a substrate thin layer 2, and microneedles 3 and a microneedle body 4 which are erected on the substrate thin layer and are used for penetrating into a skin epidermal layer are connected to the substrate body 1.
The tip face was changed to an arbitrary slope as in example 2. The specific method comprises the following steps:
preparing an inclined plane with an arbitrary cross section, and placing the inclined plane on the magnet with an opening facing upwards; the tip of a stainless steel needle fixed by a round tube is placed on the inclined plane in a downward mode, and all the tips of the stainless steel needle are in contact with the wall of the tube. Adding a small amount of polydimethylsiloxane into the tube, placing the tube into an oven at 70 ℃, and curing for 1-2 hours to tightly connect and fix the needle and the circular tube; and drying to obtain the metal microneedle array prototype with any inclined plane structure.
Pouring polydimethylsiloxane into the prepared container, inserting the metal microneedle array prototype until the mixed liquid slightly submerges the needle point, vacuumizing for 15-30 minutes until no bubbles exist, and then putting the metal microneedle array prototype into a 70 ℃ oven for curing for 3-4 hours; and (3) separating the metal micro-needle array prototype from the polydimethylsiloxane template to obtain the polydimethylsiloxane template. And (3) treating the template for 5-10 minutes by using a plasma cleaner, and dropwise adding a small amount of 1H,1H,2H, 2H-perfluorooctyl trichlorosilane beside the template into a chemical fume hood overnight to uniformly deposit the trichlorosilane on the surface of the template.
Pouring polydimethylsiloxane into the template, vacuumizing for 30 minutes till no bubbles exist, covering the substrate glass slide which is treated by a plasma cleaning machine on the template, and putting the substrate glass slide into a 70 ℃ oven for curing for 1 hour; and (3) releasing the microneedle array from the template to obtain the polydimethylsiloxane microneedle array shown in the figure 6.
Example 5
Fig. 8 shows a polymer microneedle array of the present embodiment, and fig. 9 shows a polymer microneedle array structure of the present embodiment. The polymer microneedle array comprises a substrate body 1, wherein a substrate thin layer 2, and microneedles 3 and a microneedle body 4 which are erected on the substrate thin layer and are used for penetrating into a skin epidermal layer are connected to the substrate body 1.
The tip surface was changed to an arbitrary curved surface as in example 3. The specific method comprises the following steps:
preparing a curved surface with an arbitrary cross section, and placing the curved surface on the magnet with an opening facing upwards; the tip of a stainless steel needle fixed by a round tube is placed on the curved surface in a downward facing manner, so that all the tips contact the wall of the tube. Adding a small amount of polydimethylsiloxane into the tube, putting the tube into an oven at 70 ℃ for 1-2 h, and tightly connecting and fixing the needle and the circular tube; and drying to obtain the outward convex cambered surface metal microneedle array prototype.
Pouring polydimethylsiloxane into the prepared container, inserting the metal microneedle array prototype until the mixed liquid slightly submerges the needle point, vacuumizing for 15-30 minutes until no bubbles exist, and then putting the metal microneedle array prototype into a 70 ℃ oven for curing for 3-4 hours; and (3) separating the metal micro-needle array prototype from the polydimethylsiloxane template to obtain the polydimethylsiloxane template. And (3) treating the template for 5-10 minutes by using a plasma cleaner, and dropwise adding a small amount of 1H,1H,2H, 2H-perfluorooctyl trichlorosilane beside the template into a chemical fume hood overnight to uniformly deposit the trichlorosilane on the surface of the template.
Pouring polydimethylsiloxane into the template, vacuumizing for 30 minutes till no bubbles exist, covering the substrate glass slide which is treated by a plasma cleaning machine on the template, and putting the substrate glass slide into a 70 ℃ oven for curing for 1 hour; and (3) separating the microneedle array from the template to obtain the polydimethylsiloxane microneedle array shown in the figure 8.
The above embodiments are preferred embodiments of the present invention, but the present invention is not limited to the above embodiments, and any other changes, modifications, substitutions, combinations, and simplifications which do not depart from the spirit and principle of the present invention should be construed as equivalents thereof, and all such changes, modifications, substitutions, combinations, and simplifications are intended to be included in the scope of the present invention.
Claims (10)
1. The polymer microneedle array with the arbitrary curved surface is characterized by comprising a microneedle array and a substrate perpendicular to the microneedle array, wherein the microneedles are erected on the substrate and arranged on the substrate, and the substrate comprises a substrate thin layer and a substrate main body.
2. The randomly curved polymer microneedle array according to claim 1, wherein the microneedles are made of at least one of polydimethylsiloxane, polylactic acid, lactic acid/glycolic acid copolymer, polyvinylpyrrolidone and polyacrylamide polymers; the substrate thin layer is made of the same material as the microneedle material, and the substrate main body is made of at least one of glass, metal, polyethylene, rubber, latex and polydimethylsiloxane.
3. A preparation method of a polymer microneedle array with an arbitrary curved surface is characterized by comprising the following steps:
1) preparation of a metal microneedle array prototype: two or more conical stainless steel needles with the diameter of 0.2 mm or 0.1 mm or 0.3 mm or 0.4 mm are tightly fixed together on a magnet to obtain a metal microneedle array prototype with the same spatial characteristics as the target polymer microneedle array;
2) preparing a template: preparing a template by using the metal microneedle array prototype obtained in the step 1) and a template material;
3) removing the metal micro-needle array prototype from the template;
4) pouring the polymer mixed solution into the template of the metal microneedle array prototype removed in the step 3);
5) vacuumizing to make the polymer mixed liquid poured into the template completely fill the pores without leaving bubbles;
6) drying to solidify and mold the polymer mixed liquid material poured into the template to obtain the microneedle array part and the substrate thin layer part of the polymer microneedle array;
7) connecting the microneedle array part of the microneedle array prepared in the step 6) with the substrate thin layer and the substrate main body material together to obtain the polymer microneedle array with any curved surface.
4. The method for preparing an arbitrarily curved polymer microneedle array according to claim 3, wherein the tip surface of the metal microneedle array prototype in step 1) may be any one of a plane, an inclined surface, an arc surface and an arbitrarily curved surface.
5. The method for preparing an arbitrarily curved polymer microneedle array according to claim 3, wherein the template material in step 2) is at least one of polyethylene, polytetrafluoroethylene, polydimethylsiloxane and gypsum.
6. The method for preparing an arbitrarily curved polymer microneedle array according to claim 5, wherein when the template material in step 2) is polyethylene, polytetrafluoroethylene, or gypsum, the metal microneedle array prototype in step 1) is used to press-punch holes in a sheet made of the material.
7. The method for preparing a polymer microneedle array with an arbitrary curved surface according to claim 5, wherein when the template material in step 2) is polydimethylsiloxane, the polydimethylsiloxane is poured into the prepared container, the metal microneedle array prototype is inserted until the mixed solution slightly submerges the needle tip surface, the container is vacuumized for 15-30 minutes until no air bubbles exist in the container, and then the container is placed into a 70 ℃ oven for curing for 3-4 hours.
8. The method for preparing a polymer microneedle array having an arbitrary curved surface according to claim 3, wherein the polymer mixture is at least one of polydimethylsiloxane, polylactic acid, lactic acid/glycolic acid copolymer, polyvinylpyrrolidone, and polyacrylamide-based polymer.
9. The method for preparing a polymer microneedle array having an arbitrary curved surface according to claim 3, wherein when the polymer mixture in the step 4) is polydimethylsiloxane, the polydimethylsiloxane is prepared from a polymer and a crosslinking agent in a mass ratio of 10: 1.
10. The method for preparing a polymer microneedle array having an arbitrary curved surface according to claim 3, wherein when the polymer mixture in the step 4) is at least one of polylactic acid, lactic acid/glycolic acid copolymer, polyvinylpyrrolidone and polyacrylamide-based polymer, the mass percentage of the polymer in the polymer mixture is 20% to 80%.
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