CN114939100A - High-density random curved surface polymer microneedle array and preparation method and application thereof - Google Patents
High-density random curved surface polymer microneedle array and preparation method and application thereof Download PDFInfo
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Abstract
The invention discloses a high-density random curved surface polymer microneedle array and a preparation method and application thereof. The invention prepares the high-density random curved surface polymer micro-needle array by adopting the principle of spontaneous tight assembly of the metal micro-needles under the action of a magnetic field; the preparation method does not depend on machining, etching or processing or assembling methods such as a hole die substrate mold and the like, so that the preparation method is simpler and more efficient, has higher expansibility and better flexibility and economy, and can meet the requirements of neural interfaces, drug delivery, subcutaneous injection and the like. The space between the high-density random curved surface polymer microneedle array needles prepared by the method is less than 100 micrometers, the number of the microneedles in each square millimeter reaches more than 40, the assembly density of the microneedles is remarkably improved, the shape of the needle point surface is easier to control, and the preparation of the microneedle array with both high density and random curved surface characteristics can be realized.
Description
Technical Field
The invention belongs to the technical field of biomedical engineering, and particularly relates to a high-density random curved surface polymer microneedle array, and a preparation method and application 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. In applications such as neural interfaces and drug delivery, the ideal microneedle should also have several characteristics. First, to achieve more efficient performance, a high density microneedle array would be preferred. For example, high density microneedle electrodes (e.g., high channel count) can better discriminate complex neural signals from dense neurons or nerve fibers. In addition, high density microneedles can improve drug delivery efficiency. Second, microneedles of different heights (or lengths) will allow for more comprehensive detection of neurons located at different depths in a complex three-dimensional nervous system (e.g., stratified cortical regions and peripheral nerves). In the case of electrical stimulation, such as stimulation of nerve fibers or the retina, microneedles of different heights may individually or simultaneously stimulate different levels of the three-dimensional space of the nervous system. Therefore, the preparation of the microneedle array with high-density microneedles and the needlepoint plane which can be any curved surface has important practical significance and application value.
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, and although the microneedles can be relatively completely inserted into a skin cuticle, the curved substrate is still prone to the problems of complex processing process and uneven stress during use, for example, when a microneedle patch is torn down, the microneedles on the side edge are 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.
Patent (CN103301092A) discloses a method for preparing polymer microneedles, wherein the length of the microneedles can be adjusted as required, and a microneedle array with an arbitrary curved surface can be formed by adjusting the length. The patent (CN103908740A) discloses a method for preparing a metal microneedle array, and specifically discloses that a substrate device mold which is poured with epoxy resin solution and has a hole mold placed on the upper surface is placed in a magnetic field generating device, and a uniform magnetic field is utilized to interact with metal microneedles in the holes of a hole film, so as to form a stable microneedle array structure. The patent (US2019022365a1) discloses a method for preparing a microneedle array with arbitrary curved surface, which is based on a hole die, can be assembled in rows, and the heights of needles can be adjusted according to the surface to which the microneedles are applied, so that the microneedles are the same (i.e. the needle tip surfaces are flat surfaces) or different (curved surfaces).
Although these methods have the capability of preparing microneedle arrays with arbitrary curved surfaces, the fabrication of the hole mold substrate device usually uses machining and other techniques, so that the pitch of the prepared microneedle array needles cannot be smaller than 100 micrometers, and the hole mold substrate device does not have the technical characteristics of high density, and cannot completely meet the dual requirements of high density and arbitrary curved surfaces in the practical application of the microneedle array, and therefore, there is a need for developing a method for preparing microneedle arrays with both high density and arbitrary curved surface characteristics.
Disclosure of Invention
In order to overcome the disadvantages and shortcomings of the prior art, the present invention is primarily directed to a method for preparing a high-density random-curved polymer microneedle array. The preparation method does not depend on machining, etching or processing or assembling methods such as a hole die substrate mold and the like, so that the preparation method is simpler and more efficient, has higher expansibility and better flexibility and economy, and can meet the requirements of neural interfaces, drug delivery, subcutaneous injection and the like.
The second purpose of the invention is to provide a high-density random curved surface polymer microneedle array prepared by the preparation method.
The third purpose of the invention is to provide the application of the high-density random curved surface polymer micro-needle array.
The primary purpose of the invention is realized by the following technical scheme:
a preparation method of a high-density random curved surface polymer microneedle array comprises the following steps:
(1) preparation of a metal microneedle array prototype: vertically or obliquely placing two or more conical metal microneedles with the diameter range of 0.05-0.5 mm and the diameter range of 0.001-0.01 mm on a magnet, tightly arranging the metal microneedles under the action of a high-strength magnetic field, adding an arbitrary curved substrate between the metal microneedles and the magnet, and tightly contacting the metal microneedles with the substrate under the action of magnetic force to obtain a metal microneedle array prototype with the same spatial characteristics as the substrate;
(2) preparing a template: preparing a template by using the metal microneedle array prototype obtained in the step (1) and a template material;
(3) separating the metal micro-needle array prototype from the template to obtain a high-density metal micro-needle array template;
(4) pouring the polymer mixed solution into the high-density metal microneedle array template removed in the step (3);
(5) vacuumizing to ensure that the polymer mixed solution poured into the high-density metal microneedle array template completely fills 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) and (5) 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 high-density random curved surface polymer microneedle array.
Preferably, the metal microneedle in the step (1) is at least one of an acupuncture needle, a stylet, a painless needle head and a metal wire which are etched or not etched.
Preferably, the metallic microneedle body diameter is preferably 0.05, 0.1, 0.2, 0.3, 0.5 mm; the diameters of the metal microneedle tips are preferably 0.002, 0.005 and 0.01 mm.
Preferably, the arbitrary-curved-surface substrate in the step (1) is at least one of an arbitrary curved surface obtained by machining or three-dimensional printing.
Preferably, the magnetic field intensity of the magnet in the step (1) is 0.3T-0.5T.
Preferably, the template material in step (2) is at least one of polyethylene, polytetrafluoroethylene, polydimethylsiloxane and gypsum.
Preferably, when the template material in step (2) is polyethylene, polytetrafluoroethylene and plaster, a microneedle template is obtained by punching a sheet made of the material using a metal microneedle array prototype.
Preferably, when the template material in the step (2) is polydimethylsiloxane, the polydimethylsiloxane is poured into the prepared container, the metal microneedle array prototype is inserted until the mixed liquid slightly submerges the needle tip surface, the vacuum pumping is carried out for 15-30 minutes until no bubble exists in the container, and then the container is placed into a 70 ℃ oven for curing for 3-4 hours.
Preferably, in the step (4), the polymer mixed solution is at least one of polylactic acid, lactic acid/glycolic acid copolymer, polyvinylpyrrolidone and polyvinyl alcohol, and the mass percentage of the polymer in the polymer mixed solution is 10-80%.
The second purpose of the invention is realized by the following technical scheme:
a high-density random curved surface polymer microneedle array is disclosed, wherein the gap between microneedles is less than 100 micrometers, the number of the microneedles in each square millimeter reaches more than 40, the height of the microneedles reaches more than 900 micrometers, and the number and the size of the microneedles can be specifically adjusted according to needs.
Compared with commercial microneedles, the high-density random curved surface microneedles prepared by the invention have the remarkable characteristics of high density, large height and one-step molding.
The third purpose of the invention is realized by the following technical scheme:
an application of a high-density random curved surface polymer micro-needle array.
In particular to the application of the high-density random curved surface polymer microneedle array in the fields of drug delivery, medical cosmetology, tissue fluid extraction, biosensing and the like.
The invention has the beneficial effects that:
(1) the invention prepares the high-density random curved surface polymer micro-needle array by adopting the principle of spontaneous tight assembly of the metal micro-needles under the action of a magnetic field; the preparation method does not depend on machining, etching or processing or assembling methods such as a hole die substrate mold and the like, so that the preparation method is simpler and more efficient, has higher expansibility and better flexibility and economy, and can meet the requirements of neural interfaces, drug delivery, subcutaneous injection and the like.
(2) The invention breaks through the limitation of the existing machining or etching and other processing methods on the preparation of the high-density microneedle array, the space between the high-density polymer microneedle array needles with any curved surface obtained by the preparation method is less than 100 microns, the number of the microneedles in each square millimeter reaches more than 40, the assembly density of the microneedles is obviously improved, the shape of the needle point surface is easier to control, and the preparation of the microneedle array with both high density and any curved surface characteristics can be realized.
(3) The metal microneedle unit adopted by the invention can be combined with the processes of etching and the like to improve the sharpness, so as to further improve the transdermal capacity, the mechanical strength and other properties of the high-density random curved surface polymer microneedle array.
(4) The high-density random curved surface polymer microneedle array prepared by the method disclosed by the invention is attached to the skin, is more uniform in stress and is not easy to break; due to the characteristic of high density, the drug carrier has higher drug loading when being applied to drug delivery and medical cosmetology; when the device is used for tissue fluid extraction, a larger sample size can be extracted; while being able to detect more densely in a smaller area when used for biosensing.
Drawings
Fig. 1 is a schematic view of the preparation of a prototype of a high-density metal microneedle array according to example 1;
fig. 2 is a microscope image of a prototype of the high-density metallic microneedle array prepared in example 1;
FIG. 3 is a schematic view showing the preparation of a high-density random-curvature polymer microneedle array according to example 2;
FIG. 4 is a scanning electron microscope image of the high-density random curved polymer microneedle array in example 2;
fig. 5 is a schematic view of the preparation of a high-density random curved polymer microneedle array in example 3;
fig. 6 is a microscope image of the high-density arbitrary curved polymer microneedle array in example 3;
FIG. 7 is a schematic view of the structure of any curved microneedle in example 3;
FIG. 8 is a schematic view of the structure of any curved microneedle in example 3;
FIG. 9 is a schematic representation of a polyethylene template in example 6;
FIG. 10 is a scanning electron microscope image of a high-density random curved polymer microneedle array in example 6;
fig. 11 is a commercially available microneedle a image;
fig. 12 is a commercially available microneedle B image;
fig. 13 is a commercially available microneedle C image;
fig. 14 is a graph showing the needle height contrast of microneedles fabricated according to the present invention and commercially available microneedles;
fig. 15 is a graph comparing the distance between microneedles fabricated according to the present invention and commercially available microneedles;
wherein, the metal micro-needle-1, the magnet-2 and the curved substrate-3.
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
The embodiment provides a high-density planar polydimethylsiloxane microneedle array with a metal microneedle main body diameter of 0.05 mm, and a preparation method of the high-density planar polydimethylsiloxane microneedle array comprises the following steps:
fig. 1 and fig. 2 are schematic diagrams of the preparation of a high-density metal microneedle array prototype and a microscope image of the prepared high-density random curved surface polymer microneedle array prototype, respectively.
Weighing 3g of polydimethylsiloxane in a disposable cup, stirring the polydimethylsiloxane by using a fork for 10 minutes, uniformly mixing the polydimethylsiloxane and the fork, putting the mixture into a vacuum pump, and vacuumizing for 15 minutes to remove bubbles; fixing the prepared 36 metal wires with the diameter of 0.05 mm and the length of 40 mm by using a circular tube, and vertically erecting the metal wires on a magnet to enable all needle points to be on the same plane; all the needle points are in spontaneous close contact with the substrate under the action of a magnetic field; adding a small amount of polydimethylsiloxane into the tube, and curing the polydimethylsiloxane in a 70 ℃ oven for 1h 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 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 hours; and (3) separating the metal micro-needle array prototype from the polydimethylsiloxane template to obtain the planar 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, and then putting the template into a 70 ℃ oven to be cured for 1 hour; and (4) separating the microneedle array from the template to obtain the high-density planar polydimethylsiloxane microneedle array.
Example 2
The embodiment provides a high-density planar polydimethylsiloxane microneedle array with a microneedle main body diameter of 0.2 mm, and a preparation method of the high-density planar polydimethylsiloxane microneedle array, which comprises the following steps:
weighing 3g of polydimethylsiloxane in a disposable cup, stirring the polydimethylsiloxane by using a fork for 10 minutes, uniformly mixing the polydimethylsiloxane and the fork, putting the mixture into a vacuum pump, and vacuumizing for 15 minutes to remove bubbles; fixing 100 prepared stainless steel acupuncture needles with a diameter of 0.2 mm, a length of 40 mm and a needle point diameter of 0.002 mm by using a circular tube, and vertically making the needle point surfaces of the needles droop and stand on a magnet so that all the needle points are in the same plane; all the needle points are in spontaneous close contact with the substrate under the action of a magnetic field; adding a small amount of polydimethylsiloxane into the tube, and curing the polydimethylsiloxane in a 70 ℃ oven for 1h 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 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 hours; and (3) separating the metal micro-needle array prototype from the polydimethylsiloxane template to obtain the planar 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 until no bubbles exist, and then putting the template into a 70 ℃ oven for curing for 1 hour; and (4) separating the microneedle array from the template to obtain the high-density planar polydimethylsiloxane microneedle array.
Fig. 3 is a schematic diagram illustrating the preparation of a high-density random curved polymer microneedle array according to the present embodiment, wherein the metal microneedle array prototype comprises metal microneedles 1 and magnets 2; fig. 4 shows a scanning electron microscope image of the high-density random curved polymer microneedle array of the present embodiment.
Example 3
The embodiment provides a high-density curved polydimethylsiloxane microneedle array with a microneedle diameter of 0.2 mm, and a preparation method of the high-density curved polydimethylsiloxane microneedle array comprises the following steps:
fig. 5 is a schematic diagram illustrating the preparation of a high-density random curved polymer microneedle array according to the present embodiment, wherein the metal microneedle array prototype comprises metal microneedles 1, magnets 2 and a curved substrate 3; fig. 6 is a microscope image showing the high-density arbitrarily curved polymer microneedle array of this example.
Weighing 3g of polydimethylsiloxane in a disposable cup, stirring the polydimethylsiloxane by using a fork for 10 minutes, uniformly mixing the polydimethylsiloxane and the fork, putting the mixture into a vacuum pump, and vacuumizing for 15 minutes to remove bubbles; fixing 100 prepared stainless steel needles with the diameter of 0.2 mm and the length of 40 mm by using a circular tube, vertically arranging the needle points on a curved substrate which is obtained by machining or three-dimensional printing and has a downward needle point surface on a magnet, and enabling all the needle points to spontaneously and tightly contact the substrate under the action of a magnetic field; adding a small amount of polydimethylsiloxane into the tube, and curing the polydimethylsiloxane in a 70 ℃ oven for 1h to tightly connect and fix the needle and the circular tube; and drying to obtain a curved 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 hours; and (3) separating the metal micro-needle array prototype from the polydimethylsiloxane template to obtain the curved 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, and then putting the template into a 70 ℃ oven to be cured for 1 hour; and (4) separating the micro-needle array from the template to obtain the high-density curved polydimethylsiloxane micro-needle array.
Similarly, the high-density polymer microneedle structure with a curved substrate capable of being changed into any curved surface is schematically shown in fig. 7 and 8.
Example 4
The present embodiment provides a high-density lactic acid/glycolic acid copolymer microneedle array, and the preparation method thereof includes the following steps:
the microneedle material was changed to lactic acid/glycolic acid copolymer as in example 2 or 3. The specific method comprises the following steps:
0.2g of lactic acid/glycolic acid copolymer and 0.8g of diethylene glycol dimethyl ether were weighed and dissolved in diethylene glycol dimethyl ether to obtain a 20% lactic acid/glycolic acid copolymer solution. Pouring a lactic acid/glycollic acid copolymer solution into the template, vacuumizing for 15 minutes till no bubbles exist, and then drying at room temperature for 24 hours; and (3) separating the microneedle array from the template to obtain the high-density curved-surface lactic acid/glycolic acid copolymer microneedle array.
Example 5
The embodiment provides a high-density polyvinyl alcohol microneedle array, and a preparation method thereof comprises the following steps:
as in example 2 or 3, the microneedle material was changed to polyvinyl alcohol. The specific method comprises the following steps:
4.5g of polyvinyl alcohol was weighed out and dissolved in 30ml of water to give a 15% polyvinyl alcohol solution. Pouring polyvinyl alcohol solution into the template, vacuumizing for 15 minutes till no bubbles exist, and then drying at room temperature for 48 hours; and (4) separating the micro-needle array from the template to obtain the high-density polyvinyl alcohol micro-needle array.
Example 6
The embodiment provides a high-density microneedle array polyethylene plate template, and a preparation method thereof comprises the following steps:
like example 2 or 3, the template material polydimethylsiloxane was changed to a polyethylene plate (fig. 9 and 10). The specific method comprises the following steps:
and (3) placing the polyethylene plate on a heating plate, heating to 50 ℃ to slightly soften, pressing the polyethylene plate on the heating plate by using a metal microneedle array prototype, cooling and shaping to obtain the high-density polyethylene template.
FIG. 9 is a schematic diagram of a polyethylene template in this example; fig. 10 is a scanning electron microscope image of the high-density random curved polymer microneedle array in this example.
Example 7
This example provides a comparison of the effect of the high density microneedle arrays prepared in examples 1-5 with commercial microneedle products.
Fig. 11, 12 and 13 show sem images of various commercial microneedle A, B, C products; as can be seen from fig. 14 and 15, the microneedle array prepared in examples 1 to 5 according to the present invention has a pitch of the needles of a diameter of a single needle, a height of 950 μm, and a number of needles per square millimeter of 40 or more. The distance between the needles of the commercial micro-needle is more than 250 microns, the height of the micro-needle is less than 400 microns, and the number of the needles in each square millimeter is less than 25. It can be seen that the microneedle arrays prepared in examples 1 to 5 of the present invention have smaller pitches and higher heights than those of the microneedle A, B, C products.
Example 8
The embodiment provides a comparison of drug loading of the high-density microneedle array prepared by the invention and a commercial microneedle product, and the method specifically comprises the following steps:
the drug carried by the microneedle is insulin (nordherin, 300IU/3 mL).
The insulin solution is diluted to 5IU, and one high-density microneedle patch is soaked in every 200 microliters of the insulin solution for 30 minutes. After 30 minutes, the high-density microneedle patch was removed, and the concentration of insulin in the soaked solution was measured by high performance liquid chromatography. The insulin solution soaked with the commercial microneedle patch and the insulin solution not soaked with the microneedle patch were tested in the same manner. Through detection, the content of insulin in the solution soaking the high-density microneedle patch is smaller than the content of insulin in the solution soaking the commercial microneedle patch is smaller than the content of insulin in the non-soaked microneedle patch, namely the drug-loading rate of the high-density microneedle prepared by the method is larger than the drug-loading rate of the commercial microneedle.
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 (9)
1. A preparation method of a high-density random curved surface polymer microneedle array is characterized by comprising the following steps:
(1) preparation of a metal microneedle array prototype: vertically or obliquely placing two or more conical metal microneedles with the diameter range of 0.05-0.5 mm and the diameter range of 0.001-0.01 mm on a magnet, tightly arranging the metal microneedles under the action of a high-strength magnetic field, adding an arbitrary curved substrate between the metal microneedles and the magnet, and tightly contacting the metal microneedles with the substrate under the action of magnetic force to obtain a metal microneedle array prototype with the same spatial characteristics as the substrate;
(2) preparing a template: preparing a template by using the metal micro-needle array prototype obtained in the step (1) and a template material;
(3) separating the metal microneedle array prototype from the template to obtain a high-density metal microneedle array template;
(4) pouring the polymer mixed solution into the high-density metal microneedle array template removed in the step (3);
(5) vacuumizing to ensure that the polymer mixed solution poured into the high-density metal microneedle array template completely fills 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) and (4) 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 high-density random curved surface polymer microneedle array.
2. The method for preparing a high-density random curved polymer microneedle array according to claim 1, wherein the metal microneedles in step (1) are at least one of an acupuncture needle, a painless needle, and a wire, which may or may not be etched.
3. The method for preparing a high-density curved-surface polymer microneedle array according to claim 1, wherein the diameter of the metallic microneedle main body is 0.05, 0.1, 0.2, 0.3, 0.5 mm; the diameters of the metal microneedle tips are 0.002, 0.005 and 0.01 mm.
4. The method for preparing a high-density curved polymer microneedle array according to claim 1, wherein the curved substrate in the step (1) is at least one of a machined or three-dimensionally printed curved surface.
5. The method for preparing a high-density curved polymer microneedle array according to claim 1, wherein the magnetic field strength of the magnet in the step (1) is 0.3T to 0.5T.
6. The method of preparing a high-density random-curvature polymer microneedle array according to claim 1, wherein the template material in the step (2) is at least one of polyethylene, polytetrafluoroethylene, polydimethylsiloxane and gypsum.
7. The method of claim 1, wherein in the step (4), the polymer mixture is at least one of polylactic acid, lactic acid/glycolic acid copolymer, polyvinylpyrrolidone and polyvinyl alcohol, and the polymer is present in the polymer mixture in an amount of 10 to 80% by mass.
8. The high-density random curved surface polymer microneedle array is characterized in that a gap between every two microneedles of the high-density random curved surface polymer microneedle array is smaller than 100 micrometers, the number of the microneedles in each square millimeter reaches more than 40, the height of each microneedle reaches more than 900 micrometers, and the number and the size of the microneedles can be specifically adjusted according to needs.
9. The use of the high-density freeform polymer microneedle array according to claim 9 in the fields of drug delivery, medical cosmetology, tissue fluid extraction and biosensing.
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