CN115227957A - Preparation method and product of hollow microneedle - Google Patents

Abstract

The invention relates to a preparation method of a hollow microneedle, which comprises the following steps: preparing a hollow microneedle male die; forming a metal layer on the microneedle male die; forming a microneedle needle point and a microneedle needle hole; and removing the male microneedle mould.

Description

Preparation method and product of hollow microneedle

technical field

The present invention generally relates to the field of microneedle technology. Specifically, the present invention relates to a preparation method of hollow microneedles and products thereof.

Background technique

Micro-needles are considered as possible because they can minimally invasively intervene in the surface layer of the skin, break through the barrier to drug absorption by the stratum corneum of the skin, and achieve high-efficiency transdermal drug delivery. One of the key technologies for the benefit of mankind is expected to become the representative of transdermal drug delivery technology.

Microneedles can be divided into two types: solid microneedles and hollow microneedles according to their structure. Among them, solid microneedle products are mainly used in the form of piercing holes and then applying drugs to achieve the effect of drug delivery. The use process is relatively cumbersome, and then gradually optimized soluble microneedles, swelling microneedles, porous microneedles and other load-bearing microneedles Solid microneedles with higher drug efficiency and easier use. However, solid microneedles still cannot drive enough liquid medicine into the human body through pressure like traditional injection, and the problems of long single use time and small dosage are more common. As another research direction of microneedle, hollow microneedle not only has the advantages of minimally invasive and painless drug delivery, but also basically has the potential of all the advantages of traditional injection, and related research has attracted much attention in the industry.

Chinese patent CN 108348292 A discloses a device for delivering fluid to biological tissue, including a single crystal silicon hollow microneedle device and a method for preparing the microneedle. The microneedle is prepared by using a single crystal silicon wafer, and the size change of the microneedle is relatively limited. Meanwhile, the mechanical properties of single crystal silicon make it easy to cause people to worry about the needle tip breaking during use when it is used as a microneedle preparation material.

Chinese patent CN 112245792 A discloses a hollow metal microneedle array and its preparation method, and a transdermal drug delivery patch. Part of the process of this method is difficult to control, such as how to ensure the complete and consistent shape of the needle tip during the cutting process, and at the same time prepare two-dimensional Microneedle arrays are difficult.

Chinese patent CN109078260A discloses a method for preparing hollow microneedle arrays in batches. In the method for preparing hollow microneedle arrays, a microneedle array negative template with holes is used to prepare a polymer microneedle array positive template, and then the needle bodies are electroplated, and finally polished or Laser drilling creates pinholes. This process uses a laser to prepare the negative mold of the microneedle. The final size of the microneedle needle is usually larger in various microneedle processes, and the needle tip is blunt and the consistency is not good. The experience of using the corresponding product is easy to worry.

SUMMARY OF THE INVENTION

In order to at least partially solve the above problems in the prior art, the present invention provides a method for preparing hollow microneedles, which includes: preparing a hollow microneedle male mold; forming a microneedle layer on the microneedle male mold; forming a microneedle tip and a microneedle. Needle pinholes; and removal of microneedle male molds.

The present invention also provides a hollow microneedle product, comprising: a sheet-like hollow microneedle, the sheet-like hollow microneedle comprises a base layer and at least one hollow needle body protruding from a first side of the base layer, the hollow needle The inner cavity opening of the body is located on the second side of the base layer, the hollow needle body is integrally formed with the base layer and is composed of the same material layer, and the hollow needle body includes a needle tip at the top and a needle hole penetrating the material layer; and A base, the base includes a base body and a first connection port and a second connection port arranged on the base body, the first connection port is connected with the second side of the sheet-shaped hollow microneedle, and the second connection port is connected with other components, using The delivery or extraction of fluid is accomplished through the sheet-like hollow microneedle and base at a specific time.

Description of drawings

In order to further clarify and other advantages and features of the various embodiments of the invention, a more specific description of the various embodiments of the invention will be presented with reference to the accompanying drawings. It is understood that these drawings depict only typical embodiments of the invention and are therefore not to be considered limiting of its scope. In the drawings, the same or corresponding parts will be denoted by the same or similar numerals for clarity.

FIG. 1 shows a flow chart of a method for preparing a sheet metal hollow microneedle array according to an embodiment of the present invention.

Figure 2 illustrates an exposed pattern reticle according to one embodiment of the present invention.

FIG. 3 shows a schematic view of exposure of a microneedle positive mold prepared from a positive photoresist according to an embodiment of the present invention.

4 shows a schematic diagram of a hollow microneedle positive mold prepared by positive photoresist lithography according to an embodiment of the present invention.

5 shows a schematic diagram of a microneedle metal female mold according to an embodiment of the present invention.

6 shows a schematic diagram of a hollow microneedle male mold prepared by hot embossing according to an embodiment of the present invention.

7 shows a schematic cross-sectional view of a microneedle positive mold metal layer formed according to an embodiment of the present invention.

FIG. 8 shows a schematic structural diagram of a film coated with a polymer coating after the deposition of the microneedle positive mold metal layer according to an embodiment of the present invention.

FIG. 9 shows a schematic diagram of a method for cutting and processing needle tips after depositing a metal layer in a positive microneedle mold according to an embodiment of the present invention.

FIG. 10 shows a schematic diagram of a method for dicing and processing needle tips after depositing a metal layer in a positive microneedle mold according to an embodiment of the present invention.

FIG. 11 shows a schematic diagram of a method for locating the needle tip in the positive cutting process after depositing the metal layer on the microneedle positive mold according to the present invention.

12 shows a schematic diagram of a sheet-like microneedle array after removal of the male mold according to an embodiment of the present invention.

Figure 13 shows an enlarged perspective schematic view of a single needle body.

FIG. 14 shows a schematic diagram of a method for processing the needle tip by bevel cutting after depositing a metal layer on a positive microneedle mold according to the present invention.

15 shows a schematic diagram of a sheet-like microneedle array after removal of the male mold according to an embodiment of the present invention.

Figure 16 shows an enlarged perspective schematic view of a single needle body.

FIG. 17 shows a schematic diagram of a method for laser drilling a needle tip after depositing a metal layer in a positive microneedle mold according to an embodiment of the present invention.

Figure 18 shows an enlarged perspective schematic view of a single needle body.

FIG. 19 shows a schematic three-dimensional assembly diagram of a hollow microneedle product according to an embodiment of the present invention.

FIG. 20 shows a schematic cross-sectional structure diagram of a base of a product according to an embodiment of the present invention.

FIG. 21 shows a schematic diagram of the appearance structure of a product after assembly according to an embodiment of the present invention.

FIG. 22 shows a schematic cross-sectional structure diagram of a product base according to an embodiment of the present invention.

FIG. 23 shows a schematic cross-sectional structure diagram of a base of a product according to an embodiment of the present invention.

FIG. 24 shows a schematic diagram of the appearance structure of a product after assembly according to an embodiment of the present invention.

FIG. 25 shows a schematic diagram of the appearance structure of a product after assembly according to an embodiment of the present invention.

FIG. 26 shows test results according to an embodiment of the present invention.

Figure 27 shows a schematic diagram of the results of a puncture test of an article according to an embodiment of the present invention.

Figure 28 shows a schematic diagram of the results of an article injection test according to an embodiment of the present invention.

Detailed ways

It should be noted that various components in the various figures may be shown exaggerated for illustration purposes and not necessarily to correct scale. In the various figures, identical or functionally identical components are provided with the same reference numerals.

In the present invention, unless otherwise specified, "arranged on," "arranged over," and "arranged over" do not exclude the case where there is an intermediate between the two. In addition, "arranged on or above" only means the relative positional relationship between two components, and in certain circumstances, such as after reversing the product direction, it can also be converted to "arranged under or below", and vice versa Of course.

In the present invention, each embodiment is only intended to illustrate the solution of the present invention, and should not be construed as limiting.

In the present invention, unless otherwise specified, the quantifiers "a" and "an" do not exclude the scenario of multiple elements.

It should also be pointed out here that, in the embodiments of the present invention, for the sake of clarity and simplicity, only a part of the components or assemblies may be shown, but those of ordinary skill in the art can understand that under the teaching of the present invention, according to specific The scene needs to add the required parts or components. Furthermore, unless stated otherwise, features in different embodiments of the invention may be combined with each other. For example, a certain feature in the second embodiment can be used to replace the corresponding or functionally identical or similar feature in the first embodiment, and the resulting embodiment also falls within the scope of disclosure or description of the present application.

It should also be pointed out that within the scope of the present invention, the terms "same", "equal" and "equal to" do not mean that the two values are absolutely equal, but allow a certain reasonable error, that is, the said The wording also covers "substantially the same", "substantially equal", "substantially equal". By analogy, in the present invention, the terms "perpendicular to", "parallel to" and the like in the table direction also cover the meanings of "substantially perpendicular to" and "substantially parallel to".

In addition, the numbering of the steps of each method of the present invention does not limit the execution order of the method steps. Unless otherwise indicated, the various method steps may be performed in a different order.

In the embodiments of the present invention, the present invention discloses a method for preparing hollow microneedles and products thereof. Specifically disclosed are sheet-shaped hollow microneedle arrays and preparation methods thereof, products comprising hollow microneedles and preparation methods thereof. The sheet-shaped hollow microneedle array disclosed in the present invention is prepared by using biosafety materials, with outstanding mechanical properties, convenient adjustment of microneedle size and array density, the sheet-shaped microneedle array can be arbitrarily cut according to the requirements of subsequent products, and has a wide range of applications; The preparation method of the hollow microneedle array combines micromachining, precision machining, precision injection molding and other technologies, the method is stable and reliable, the cost is economical, and it is suitable for mass production. The invention also discloses several kinds of hollow microneedle products, which can meet the requirements of implementing hollow microneedles in local points and small areas. The structure of the implementation surface of the products in contact with biological tissues can be further optimized, and can be used in combination with vacuum negative pressure. The use is convenient and reliable, and the application field is wide . The hollow microneedle product is prepared by precision injection molding and precision machining technology. The preparation method is mature and reliable, and the cost is economical. It is suitable for batch manufacturing and mass promotion.

FIG. 1 shows a flow chart of a method for preparing a sheet-shaped hollow microneedle array according to an embodiment of the present invention.

First, in step 110, a hollow microneedle male mold is prepared. In the present invention, the male mold refers to a raised structure.

In the embodiments of the present invention, the hollow microneedle male mold can be prepared by techniques such as micromachining, hot pressing, precision injection molding, 3D printing, and micromolding.

Specifically, in an embodiment of the present invention, a positive mold for hollow microneedles is prepared by positive photoresist photolithography, including the following steps:

First, a positive photoresist is coated on the front side of the transparent substrate. The positive photoresist may include, but is not limited to, thick photoresist, photosensitive polyimide, and the like. Transparent substrates include, but are not limited to, glass substrates, PMMA substrates, and the like. The transparent substrate can be cleaned with plasma water and then dried before applying the positive photoresist. The positive photoresist can be applied by rolling, spin coating, spray coating, printing, non-spin coating, hot pressing, vacuum pressing, soaking, pressure bonding and the like.

Next, the positive photoresist 320 is exposed obliquely from the back surface of the transparent substrate 310 using a mask of a predetermined shape. Specifically, FIG. 2 illustrates an exposure pattern reticle 210 in accordance with one embodiment of the present invention. According to the shape of the needle body of the microneedle male mold, select the corresponding exposure pattern mask for oblique exposure, as shown in Figure 3. The reticle 210 is placed horizontally, the light is perpendicular to the reticle 210, and the transparent substrate 310 is horizontally inclined at an angle β, where the inclination angle β is half the angle between the tips of the microneedle positive mold. Using the opaque square array pattern mask as shown in FIG. 2, the platform sequentially exposes the substrate along the four sides obliquely. In other embodiments of the present invention, the angle of the mask 210 and the transparent substrate 310 can be kept unchanged, and the incident light can be inclined to realize oblique exposure.

After exposure, use the corresponding developer to develop the positive photoresist, remove the excess photoresist, and complete the preparation of the microneedle positive mold. FIG. 4 shows a schematic diagram of a hollow microneedle male mold 410 prepared by positive photoresist lithography according to an embodiment of the present invention. As shown in FIG. 4 , the hollow microneedle male mold 410 is a quadrangular pyramid structure protruding from the transparent substrate. In other embodiments of the present invention, the hollow microneedle male mold can also be in the shape of a pyramid, a cone, a combination of a pyramid and a cylinder, a combination of a cone and a cylinder, and the like.

In another embodiment of the present invention, a hollow microneedle male mold is prepared by hot embossing, including the following steps:

The microneedle metal female mold is fixed between the upper and lower mold frames of the hot embossing equipment, and the polymer pellets or sheets are filled into the microneedle mold for later use. 5 shows a schematic diagram of a microneedle metal female mold according to an embodiment of the present invention.

Run the hot stamping equipment to complete the hot stamping process. Various parameters of the thermal embossing equipment are set according to the selected polymer properties. For example, the temperature can be set in the range of 90～250℃, the pressure can be set in the range of 15～45T, the vacuum degree can be set in the range of -60～-95Kpa, and the hot pressing time can be set in the range of 3～15min within the range.

After the hot pressing process, after the mold is cooled to a suitable temperature, the microneedle male mold is taken out and the above process is repeated to achieve continuous production. FIG. 6 shows a schematic diagram of a hollow microneedle male mold 610 prepared by hot embossing according to an embodiment of the present invention.

In the embodiment of the present invention, the polymer used in the positive polymer microneedle mold includes but is not limited to: positive photopolymer, negative photopolymer, polylactic acid (PLA), polyglycolic acid (PGA), polymethyl methacrylate Methyl acrylate (PMMA), ABS plastic, epoxy resin, polydimethylsiloxane, polypropylene, polyethylene, polycaprolactone, polyglycolic acid, polylactic-glycolic acid, polysulfone, polyoxymethylene, One or more of ethylene-vinyl acetate copolymer, phenolic plastic, polystyrene, polyamide, polyurethane, polycarbonate.

Those skilled in the art should understand that the two specific embodiments of the above-mentioned preparation method of the hollow microneedle male mold are only used to illustrate the present invention, rather than limit the present invention, and other preparation methods should also fall under the protection of the present invention scope.

Next, at step 120, a microneedle layer is formed on the microneedle male mold. In the embodiment of the present invention, the method for forming the microneedle layer includes, but is not limited to, PVD, CVD, evaporation, pulsed laser deposition, electroforming, electroless plating, and the like.

Microneedle layer materials may include, but are not limited to: gold, silver, cobalt, platinum, copper, copper alloys, iron, iron alloys, aluminum, aluminum alloys, nickel, nickel alloys, titanium, titanium alloys chromium, chromium alloys, tungsten, zinc, Zinc alloy, tin, PLA, PP, PVC, PE, PTFE, POM, ABS, PA and other polymers or their combined structures. The microneedle layer can be a single-layer structure or a multi-layer laminated structure.

For example, in a specific embodiment of the present invention, forming the microneedle layer on the microneedle male mold includes the following steps:

1. A conductive metal layer, such as gold, silver, titanium, etc., can be deposited on the positive mold of the microneedle by vapor deposition.

2. Immerse the metal male mold after depositing the conductive layer into the electroforming tank for electroforming. According to the required microneedle performance, the electroforming rate can be set in the range of 0.05-5 μm/min, the electroforming time can be set, or the final electroforming thickness can be set in the range of 0.8 μm-80 μm, and finally the microstructure of the deposited metal layer can be obtained. Needle mold. 7 shows a schematic cross-sectional view of a microneedle layer 710 formed on a male microneedle mold according to an embodiment of the present invention.

Next, at step 130, microneedle tips and microneedle holes are formed. In the embodiments of the present invention, techniques such as cutting, grinding, laser drilling, etching and the like may be used to form microneedle tips and microneedle holes. The pinhole runs through the metal layer of the microneedle. As one of the core parts of the microneedle structure, the structure and formation process of the pinhole must maintain the sharpness of the needle tip and cannot damage the strength of the needle tip. By preparing the microneedle pinhole on the metal layer of the microneedle male mold, the sharpness of the needle tip can be achieved and the strength of the needle tip can be maintained.

In a specific embodiment of the present invention, a cutting method is used to prepare the microneedle tip and the microneedle hole, including the following steps:

1. Coating a polymer coating 810 on the metal layer of the microneedle male mold, as shown in FIG. 8 .

2. Use the wafer cutting machine to cut the microneedle tip according to the preset trajectory and parameters, and simultaneously form the shape of the microneedle tip and the microneedle pinhole, as shown in Figure 9. The specific cutting methods can be subdivided into two types: tangent and oblique.

The tip tangent means that the cutting edge 910 is perpendicular to the cutting plane (ie, the plane where the substrate is located), as shown in FIG. 10 . When the needle body is in the shape of a quadrangular pyramid needle, it is preferable that the side of the cutting edge is parallel to the diagonal line of the bottom of the quadrangular pyramid microneedle needle body. Similar changes can be made to the above-mentioned method for other types of needle bodies. When the quadrangular pyramid needle body microneedle is being cut, the distance between the side of the cutting edge close to the microneedle tip and the microneedle axis on the same side is in the range of 0 to 20 μm, and the distance between the effective cutting outer contour of the cutting edge 910 and the microneedle tip is 10 μm. ~600 μm range, refer to FIG. 11 . 12 shows a schematic diagram of a sheet-like microneedle array after removal of the male mold according to an embodiment of the present invention. Figure 13 shows an enlarged perspective schematic view of a single needle body. As shown in Fig. 13, the metal on the top of the needle tip is partially removed, thereby forming a pinhole through the metal layer, and the remaining metal on the top constitutes the needle tip, thereby obtaining good sharpness.

Needle tip bevelling means that the side surface of the blade 910 forms a certain angle with the cutting plane, as shown in FIG. 14 . When the needle body is in the shape of a quadrangular pyramid needle, it is preferable that the side of the cutting edge is parallel to the diagonal line of the bottom of the quadrangular pyramid microneedle needle body. Similar changes can be made to the above-mentioned method for other types of needle bodies. When the quadrangular pyramid needle body microneedle is obliquely cut, the angle α between the cutting blade 910 and the cutting plane is in the range of 40-80°, and the height of the lowest position of the blade cutting needle body from the top of the needle tip is in the range of 30-600 μm. 15 shows a schematic diagram of a sheet-like microneedle array after removal of the male mold according to an embodiment of the present invention. Figure 16 shows an enlarged perspective schematic view of a single needle body. As shown in FIG. 16 , a bevel is formed on the top of the metal layer by chamfering, the top of the bevel constitutes a sharp needle tip, and the pinhole penetrating the metal layer is in the bevel.

In another specific embodiment of the present invention, using laser drilling technology to prepare microneedle tips and pinholes includes the following steps:

Place the substrate on which the metal layer of the microneedle positive mold is deposited horizontally on the processing platform to ensure that the laser beam 1710 is completely perpendicular to the plane of the microneedle array. Preferably, the light spot is focused on the center line of one side surface of the needle body, and the horizontal distance between the light spot and the axis of the microneedle is in the range of 0-50 μm, as shown in FIG. 17 . Figure 18 shows an enlarged perspective schematic view of a single needle body. As shown in FIG. 18 , the laser beam forms a pinhole through the metal layer at the top position of one side surface of the needle body, and the other side surfaces remain basically unchanged, thereby obtaining good sharpness.

Those skilled in the art should understand that the above two specific embodiments of the preparation method of the hollow microneedle tip and the pinhole are only used to illustrate the present invention, rather than limit the present invention, and other preparation methods should also fall into the present invention scope of protection.

Next, at step 140, the male microneedle mold is removed. In the embodiment of the present invention, the method for removing the microneedle male mold includes, but is not limited to, chemical solvent removal, heat treatment removal, mechanical removal, and the like.

For example, in a specific embodiment of the present invention, a chemical solvent is used to remove the microneedle polymer metal positive mold: the chemical solvent is preferably a polymer organic solvent, including but not limited to dichloromethane, chloroform, chloroform, ethanol, One or more mixtures of ether, xylene, benzene, methanol, N-N dimethyl sulfoxide, toluene, dimethylformamide, ethyl acetate, acetone, etc.

The specific operation includes immersing the sheet-like microneedle array after the microneedle tip processing is completed in a chemical solvent. During the process, it is preferable to synchronize heating and ultrasound to speed up the removal of the male mold. After removing the male mold, a sheet metal hollow microneedle array was obtained.

Existing research has found that the preparation method of hollow microneedles and the shape and distribution of the prepared microneedles play an important role in the product form, use and use method of subsequent related products. The inventors realized that the sheet metal hollow microneedle array is convenient to adjust the shape, size, array mode and density of the needle body, and can be further cut according to subsequent uses, which is easy to integrate into end products in various fields, and realizes the application advantages of hollow microneedles. The sheet metal hollow microneedle array prepared by the preparation method of the present invention has simple structure and high stability.

The sheet metal hollow microneedle array disclosed in the present invention is composed of a base layer and a metal hollow microneedle body, and the two are connected as a whole, the metal hollow microneedles are located on one side of the base layer, and the inner cavity opening of the metal hollow microneedles is at the base layer. The other side. The base layer is usually flat and flake-like, and it can also have certain concavities and convexities as required. The size difference between the unevenness and the convexity may be in the range of 0 to 10 mm, but is not limited thereto. The outer contour of the base layer is usually rectangular, circular or oval, and its thickness is usually 1-1000 μm, preferably 20-100 μm. The base layer can be composed of a single metal and alloy materials, including but not limited to gold, silver, cobalt, platinum, copper, copper alloys, iron, iron alloys, aluminum, aluminum alloys, nickel, nickel alloys, titanium, titanium alloys, chromium, chromium alloys , tungsten, zinc, tin or their combination, can also be composed of the above-mentioned material composite layer structure. The base layer can also be composed of PLA, PP, PVC, PE, PTFE, POM, ABS, PA and other polymers. Further, the surfaces of both sides of the base layer can be re-coated with polymer coatings, which can lubricate, insulate, conduct electricity, improve biological safety, and decorate. The polymer coating can also be patterned, that is, the polymer layer is coated according to a specific pattern rule, and the rest area is hollowed out to leak the metal layer, so that different areas have different electrical properties.

The metal hollow micro-needle body is located on one side of the base layer, and further extends along this side in a different plane direction. Usually, the needle body is distributed in a uniform array, and it can also be arranged in a specific pattern according to the requirements of subsequent products. The metal hollow microneedle body can be composed of a single metal and alloy material, including but not limited to gold, silver, cobalt, platinum, copper, copper alloy, iron, iron alloy, aluminum, aluminum alloy, nickel, nickel alloy, titanium, titanium alloy, Chromium, chromium alloy, tungsten, zinc, tin or their combination can also be composed of the above-mentioned material composite layer structure. Furthermore, the inner and outer surfaces of the metal hollow microneedle can be coated with a polymer coating again to achieve lubrication, insulation, Conductive electricity, enhance biological safety and decoration. The shape of the metal hollow microneedle needle body is usually a pyramid, a cone, or a combination of a pyramid and a cylinder, a combination of a cone and a cylinder, and the like. The height of the needle body is usually 100-2500 μm, preferably 200-1500 μm, and the length or diameter of the bottom of the needle body is 10-1000 μm, preferably 50-400 μm. Microneedles of different shapes and sizes can be placed at different positions in the same array. For example, the shape or size of the microneedles in the center of the array is different from the shape or size of the microneedles at the edges. The metal hollow microneedle pinholes have different shapes according to different preparation methods, and the diameter or longest diagonal of the pinholes is usually 1-200 μm, preferably 20-80 μm. The metal hollow microneedles are distributed in an array on one side of the base layer, which can be distributed in a uniform array, or the distribution density can be specifically set as required. For example, the density of microneedles in the center of the array is different from the density of microneedles at the edges, typically 1 to 100 needles per square centimeter, preferably 1 to 36 needles per square centimeter.

In the embodiments of the present invention, the diameter of the needle tip of the microneedle body is less than 60 μm, and the aspect ratio of the needle body is in the range of 1 to 6. The term “needle body aspect ratio” refers to the height of the needle body and the length of the bottom of the needle body or The ratio of diameters; when the vertical downward pressure displacement at the tip of a single microneedle is greater than 30μm, the force feedback is more than 0.5N.

In some embodiments of the present invention, hollow microneedle products can be manufactured based on the sheet metal hollow microneedle array prepared by the preparation method of the present invention.

Hollow microneedles are often prepared in the form of arrays, and then they often need to be further integrated into various structures to become the final product or its components.

The hollow microneedle product provided by the present invention generally includes a sheet-shaped hollow microneedle and a base, the sheet-shaped hollow microneedle includes at least one or more hollow microneedles, and the main part of the microneedle base usually includes a base body and at least two connection ports, Distributed on different surfaces of the microneedle base body, the interior of the microneedle base body contains channels connected to at least two connecting ports, and the shape of the base is usually cylindrical or sheet-like, and can be a cylinder, a square column, a circular sheet, a square sheet or other Special-shaped structure, the outer surface of the base can be a smooth surface except for the connection port, and further the outer surface can be designed with a connection and fixing structure. When the microneedle base only includes two connection ports, the first port is used to integrate sheet-shaped hollow microneedles, the second port can be a Luer interface or a threaded interface with through holes and various types of quick-release bayonet, the second port It is convenient to connect other components after the sheet-shaped hollow microneedle is integrated with the base, and can realize the delivery or extraction of fluid through the hollow microneedle needle hole, the base and the second port through hole at a specific time. Further, when the microneedle base includes three connection ports, the first port is used to integrate sheet-shaped hollow microneedles, the second port can be a Luer interface or a threaded interface with a through hole and various types of quick-release bayonet, the second The port is convenient to connect other components after the sheet-shaped hollow microneedle is integrated with the base. The base body has a first channel connecting the first port and the second port, and can realize the passage of the hollow microneedle needle hole, the base and the second port at a specific time. The through hole completes the delivery or extraction of fluid. The third port can be a Luer interface or a threaded interface with a through hole and various types of quick-release bayonet. The inside has a second channel connecting the first port and the third port, and can realize that the outer surface area of the sheet-shaped hollow microneedle completes the delivery or extraction of fluid through the base and the through hole of the third port at a specific time, and the fluid can be gas or liquid . The first channel and the second channel may directly communicate with each other, or may be isolated from each other.

Those skilled in the art should understand that the internal structure of the base body and the number of interfaces can be designed and adjusted according to actual needs. For example, four or more interfaces can be set on the base, and each interface can communicate with other specific interfaces through internal channels. One or more interfaces communicate, and each channel may communicate or partially communicate with other channels, or each channel may not communicate with each other.

In a specific embodiment of the present invention, a connecting piece can be added between the sheet-shaped hollow microneedle and the base, as shown in FIG. 19 . FIG. 19 shows a schematic three-dimensional assembly diagram of a hollow microneedle product according to an embodiment of the present invention. The hollow microneedle product includes a base 1910 , a connector 1920 , a sheet-shaped hollow microneedle 1930 , and a sealing structural adhesive 1940 . The connector 1920 has array through holes and fixed pins, the center distance of the array through holes is the same as the axial center distance of the chip hollow microneedles, and the pins are perpendicular to the plane where the connector through holes are located. On the side of the base 1910 where the sheet-shaped hollow microneedle port is integrated, mesh connection channels are distributed to correspond to the positions of the through holes of the connector, and the port also has a socket structure corresponding to the pins of the connector in a one-to-one manner. After the corresponding hollow microneedle product is assembled, the base and the sheet-like hollow microneedle integrate one side port, from bottom to top are the base 1910, the connecting piece 1920, the sheet-like hollow microneedle 1930, and the sealing structural glue 1940.

The preparation method of hollow microneedle product includes:

1. The sheet metal hollow microneedles are prepared by the preparation method of sheet metal hollow microneedles; the polymer base with specific structure is prepared by precision injection molding or hot pressing technology. The polymer materials include: PP, PVC, PLA, ABS, PMMA, resin and other materials ; Using precision machining, laser processing, etching to prepare specific structural connectors, the material of the connector can be metal or polymer, including but not limited to PP, PVC, PLA, ABS, PMMA, resin, gold, silver, cobalt, Platinum, copper, copper alloys, iron, iron alloys, stainless steel, aluminum, aluminum alloys, nickel, nickel alloys, titanium, titanium alloys, chromium, chromium alloys, tungsten, zinc, tin or combinations thereof, preferably metal materials.

2. Connect the sheet-shaped hollow microneedle with the connector. The connection method can use various glues and welding processes.

3. After connecting the sheet-shaped hollow microneedle with the connector, insert the pin of the connector into the end face tube seat structure of the base, and fix it with glue.

4. After connecting and fixing all the components included in the third step, apply a sealing structural adhesive around the edge of the sheet-shaped hollow microneedle in contact with the base, and complete the preparation of the microneedle product after curing.

The beneficial effects of the present invention are as follows: the sheet metal hollow microneedle array disclosed in the present invention not only has the advantages of minimally invasive painless or mildly painful administration, but also has the characteristics of traditional injection of actively driving medicinal liquid, which is convenient and safe. Usually, the final application products do not require professional operation, and the drug delivery is accurate. At the same time, the mechanical properties of the microneedle itself are outstanding, and the size and array density of the microneedle are easily adjusted. ; The preparation method of sheet metal hollow microneedle array combines micromachining, precision machining, precision injection molding and other technologies, the method is stable and reliable, the cost is economical, and it is suitable for mass production. The invention also discloses several kinds of hollow microneedle products. The sheet metal hollow microneedles can be assembled firmly and accurately. Combined with the characteristics of easy cutting of the sheet hollow microneedle array, they can be conveniently assembled into different specifications and types, respectively satisfying The hollow microneedle is implemented in local points and small areas, and the structure of the surface of the product contacting biological tissue can be further optimized. It can be used in combination with vacuum negative pressure to achieve simultaneous delivery or extraction of fluid and gas through the hollow microneedle needle hole and base at a specific time. The product can be integrated as a separate product or other product components, which is convenient and reliable to use, and has a wide range of applications; hollow microneedle products are prepared by precision injection molding and precision machining technology. The preparation method is mature and reliable, and the cost is economical, suitable for batch manufacturing and mass promotion.

The method for preparing the sheet metal hollow microneedles and the products thereof of the present invention are further described below with reference to specific examples.

Example 1

In Example 1, the sheet metal hollow microneedle array was prepared using a microfabrication process. Quartz glass with a thickness of 2 mm was selected as the transparent substrate, washed with plasma water and dried, and a hexamethyldisilazane (HMDS) film coating was deposited by a vacuum vapor deposition (CVD) process. After drying and curing, spin-coating positive photosensitive Polyimide glue, and heat-bake curing again, and spin-coating can be repeated many times, so that the thickness of the glue layer reaches 550μm. The glued substrate is placed on an exposure platform of ultraviolet exposure equipment. The microneedle needle body prepared in this example is a quadrangular pyramid, and a corresponding mask is selected for exposure, as shown in FIG. 2 . The exposure method is oblique exposure. As shown in Figure 3, the horizontal inclination angle β of the transparent substrate is one-half of the angle between the needle tips of the microneedle male mold. In this embodiment, the inclination angle β is 10°, and the hollow microneedle adopts a quadrangular pyramid. The needle body has a base length of 200 μm and a needle height of 550 μm. The needle bodies are evenly arranged in an array, and the distance between the axes of the needle bodies is 1000 μm. The exposure is completed in four times. The exposure platform tilts and exposes the substrate along the four sides of the mask in turn. After exposure, the entire substrate is immersed in the corresponding solvent for development. The process can be accompanied by slight vibration or ultrasonic waves. Needle mold.

The conductive metal layer silver was deposited on the same side of the microneedle positive mold and the substrate by an evaporation process, and a nickel-cobalt alloy layer was electroformed by using a high-frequency pulse current, and the thickness of the metal deposition layer was 15 μm. Continue to coat the surface of the metal deposition layer with a polyimide coating with a thickness of 600 μm, and after heat-baking and curing, use a wafer cutting machine to cut the microneedle tips. In this example, the needle tip tangential method is adopted for cutting. When cutting, the side of the cutting blade is flush with the diagonal line of the bottom of the quadrangular pyramid microneedle needle body and perpendicular to the cutting plane. As shown in Figure 10, the side of the blade close to the microneedle tip is the same The distance between the axis of the side microneedle is 0, and the distance between the effective cutting edge of the cutting edge and the tip of the microneedle is 65 μm, as shown in Figure 11. The microneedle array and substrate after the microneedle tip processing was completed were immersed in the special polyimide degumming solution. During the process, the solution was heated simultaneously, and the solution temperature was maintained at 40 °C. The mold is removed, and the sheet-like microneedle array after removing the male mold is shown in Figure 12, and the single needle body is enlarged as shown in Figure 13.

Example 2

In Example 2, a sheet metal hollow microneedle array was prepared by using a micromachining process combined with precision laser processing. This embodiment is the same as Embodiment 1. The positive mold of the sheet metal hollow microneedle array and the deposition method of the metal layer are the same.

The surface of the metal deposition layer is coated with a polyimide coating with a thickness of 600 μm. After thermal curing, laser drilling is used to process the tips of the microneedles. Here, the polyimide coating before laser drilling can also be omitted. , preferably retained, can properly protect the microneedle body in the subsequent processing process. During processing, place the film on which the metal layer of the microneedle positive mold is deposited horizontally on the processing platform to ensure that the laser beam is completely perpendicular to the plane of the microneedle array, the light spot is focused on the centerline of the side surface of the needle body, and the horizontal distance between the light spot and the axis of the microneedle is 5 μm. . The microneedle array and substrate after the microneedle tip processing was completed were immersed in the special polyimide degumming solution. During the process, the solution was heated simultaneously to maintain the solution temperature at 40 °C, and high-frequency The needle male mold was removed to obtain a sheet metal hollow microneedle array.

Example 3

In Example 3, a sheet metal hollow microneedle array was prepared using hot embossing combined with precision machining. The specific method is to use a specific microneedle metal female mold and combine with hot embossing technology to prepare a sheet metal hollow microneedle array male mold. In this embodiment, the female microneedle metal mold is made of stainless steel. The surface of one side of the female microneedle metal mold has a rectangular concave area. The size and shape correspond to the base of the male microneedle mold. The thickness of the base of the needle male mold is 1.5mm, and the size of the concave area here can also be adjusted according to the size specification of the sheet metal hollow microneedle array. A fence is formed around the rectangular concave area of the microneedle metal female mold. There is a hot-pressed material overflow groove in the middle area of the four-sided fence. The overflow groove is designed with a narrow door and a two-way wide overflow channel outside the door to improve the excess material during the hot-pressing process. While improving the overflow capacity, ensure that the molding area has sufficient molding pressure, and the specific overflow groove can also be reasonably changed with reference to a similar mechanism. The microneedle needle body concave holes are distributed in an array on the bottom surface of the rectangular concave area of the microneedle metal female mold. In this embodiment, the concave holes are inverted quadrangular pyramids, and the corresponding microneedle male mold needle body is a quadrangular pyramid. The length of the bottom side of the needle body is 280 μm, and the needle height 850μm, needle body axis distance 2000μm.

During preparation, the microneedle metal female mold (as shown in Figure 5) was fixed between the upper and lower mold frames of the hot embossing equipment, and polylactic acid (PLA) pellets were filled into the microneedle mold, and the operating temperature of the equipment was set to 170 °C, The pressure is 30T, the vacuum degree is -85Kpa, and the hot pressing time is set to 8min. After the hot pressing process is over, after the mold is cooled down to a suitable temperature, the male microneedle mold is taken out.

The conductive metal layer silver was deposited on the same side of the microneedle positive mold and the substrate by PVD process, and the nickel-cobalt alloy layer was electroformed by high-frequency pulse current, and the thickness of the metal deposition layer was 20 μm. The surface of the metal deposition layer is coated with a polyimide coating with a thickness of 900 μm, and after heat-baking and curing, the micro-needle tips are cut by a wafer cutting machine. In this example, the needle tip tangential method is used for cutting. When cutting, the side of the cutting blade is flush with the diagonal line of the bottom of the quadrangular pyramid microneedle needle body, and is perpendicular to the cutting plane. The distance is 0, and the effective cutting edge of the cutting edge is 160 μm away from the microneedle tip. The microneedle array and the substrate after the processing of the microneedle tips were immersed in a chloroform solution, and the solution was simultaneously subjected to high-frequency ultrasound during the process until the microneedle metal male mold was removed.

Example 4

In Example 4, the positive mold of the sheet metal hollow microneedle array and the deposition method of the metal layer were the same as those in Example 3. The surface of the metal deposition layer was coated with a polyimide coating with a thickness of 900 μm. The wafer cutting machine is used for cutting processing. The specific cutting method is oblique cutting. When cutting, the side of the cutting blade is flush with the corner of the bottom of the quadrangular pyramid microneedle needle body, and the side of the blade and the cutting plane are at a certain angle, as shown in Figure 14 shown. In this embodiment, the included angle α is 70°, and the minimum position of the needle body cut by the blade is 400 μm from the height of the needle tip. The finished sheet-like microneedle array is shown in Figure 15, and the single needle body is enlarged as shown in Figure 16.

The microneedle array and the substrate after the processing of the microneedle tips were immersed in a chloroform solution, and the solution was simultaneously subjected to high-frequency ultrasound during the process until the microneedle metal male mold was removed.

Example 5

In Example 5, the positive mold of the sheet metal hollow microneedle array and the deposition method of the metal layer were the same as those in Example 3. The surface of the metal deposition layer was coated with a polyimide coating with a thickness of 900 μm. The microneedle tip is treated with the hole, and the polyimide coating before the laser drilling can also be omitted here, and it is preferable to keep it, so that the microneedle body can be properly protected in the subsequent processing process. During processing, place the sheet on which the metal layer of the microneedle positive mold is deposited horizontally on the processing platform to ensure that the laser beam is completely perpendicular to the plane of the microneedle array, the light spot is focused on the centerline of the side surface of the needle body, and the horizontal distance between the light spot and the axis of the microneedle is 10 μm. . Immerse the microneedle array and substrate after the microneedle tip processing is completed in a chloroform solution, and perform high-frequency ultrasound on the solution simultaneously during the process until the microneedle metal male mold is removed, and the drilled needle body is shown in Figure 18.

Example 6: Preparation of sheet metal hollow microneedle array products

Hollow microneedles are often prepared in the form of arrays, and then they often need to be further integrated into various structures to become the final product or its components. This Example 6 uses the sheet metal hollow microneedle array prepared in Example 5, and further divides it into 4*4 microneedle array sheets. The microneedle array sheet and the connector are assembled with a base with two connection ports, and finally sealed and fixed with a sealing structural adhesive (as shown in Figure 19). The base of this embodiment is made of medical-grade PVC material, and is made of precision injection molding. The shape is a cylindrical structure, with a diameter of 14 mm and a height of 12 mm. The base is integrated with one side of the sheet-shaped hollow micro-needle port, and there are mesh connection channels corresponding to the positions of the through holes of the connector. , the port also has a one-to-one correspondence with the connector pins. The port on the other side of the base is a threaded structure, as shown in Figure 20, this structure is convenient for connection with other components. The base has one or more channels connected to the ports on both sides. The connector is made of medical grade 304 stainless steel, prepared by laser processing, with a thickness of 0.1mm. The connector has an array of through holes and fixed pins. The center distance of the array through holes is the same as the axial distance of the chip hollow microneedle, and the pins are perpendicular to the connection. the plane where the through hole is located.

When assembling, use adhesive to bond the microneedle array sheet to the connector first. During bonding, the axis of the microneedle corresponds to the center of the through hole of the connector array one by one. After the bonding is fixed, the pin of the connector is used to insert the end face tube of the base. seat structure and fix it again with glue. Finally, around the edge of the sheet-shaped hollow microneedle in contact with the base, a sealing structural adhesive is applied, and the preparation of the microneedle product is completed after curing, as shown in Figure 21.

Example 7

This example uses the sheet metal hollow microneedle array prepared in Example 3, and further divides it into 5*5 microneedle array sheets. The base of this embodiment is made of medical-grade PVC material, and is made of precision injection molding. The shape is a cylindrical structure, with a diameter of 16mm and a height of 16mm. The base is integrated with one side of the sheet-shaped hollow microneedle port, and there are mesh connection channels corresponding to the positions of the through holes of the connecting piece. , the port also has a one-to-one correspondence with the connector pins. The base has one or more channels connected to the ports on both sides. The port on the other side of the base is a Luer interface, as shown in Figure 22, this structure is convenient for connection with other components. This embodiment uses medical grade 304 stainless steel connectors, which are prepared by precision machining, with a thickness of 0.2 mm. The connectors have array through holes and fixed pins. The center distance of the array through holes is the same as the axial center distance of the sheet hollow microneedles. The feet are perpendicular to the plane where the through holes of the connector are located.

When assembling, use adhesive to bond the microneedle array sheet to the connector first. During bonding, the axis of the microneedle corresponds to the center of the through hole of the connector array one by one. After the bonding is fixed, the pin of the connector is used to insert the end face tube of the base. seat structure and fix it again with glue. Finally, the sealing structure adhesive is applied around the edge of the sheet-shaped hollow microneedle in contact with the base, and the preparation of the microneedle product is completed after curing.

Example 8

In Example 8, the sheet metal hollow microneedle array prepared in Example 3 was used, and it was further divided into 4*4 microneedle array sheets. The base of this embodiment is made of medical-grade PP material, and adopts precision injection molding. The shape of the main body is a cylindrical structure, with a diameter of 14mm and a height of 16mm. The base includes three connection ports, as shown in Figure 23. The first port 2310 is used to integrate sheet-shaped hollow microneedles, the second port 2320 is a threaded interface, and the third port 2330 is located on the cylindrical surface and is a Luer interface. The base has one or more channels in it connecting the first port and the second port. The base also has one or more channels connected to the first port and the third port. The first port 2310 is distributed with mesh connection channels corresponding to the positions of the through holes of the connector. The port also has a socket structure corresponding to the pins of the connector one-to-one and a ring structure 2340 higher than the integration plane of the sheet-shaped hollow microneedles. For example, the height of the ring structure relative to the integration plane of the sheet-like hollow microneedles can be set as a ring structure of 0.9 mm, and the thickness of the ring can be set as 0.6 mm. The second port 2320 facilitates connection of other components after the sheet-shaped hollow microneedle is integrated with the base, and can realize the delivery or extraction of fluid through the hollow microneedle needle hole, the base and the through hole of the second port at a specific time. The third port 2330 is convenient for connecting the sheet-shaped hollow microneedle with the base and other components after integration. Combined with the annular structure of the first port higher than the sheet-shaped hollow microneedle integration plane, the outer surface area of the sheet-shaped hollow microneedle can pass through at a specific time. The base and the through hole of the third port complete the delivery or extraction of gas, and provide functions such as vacuum negative pressure or vacuum breaking.

There is a connector between the sheet metal microneedle and the base. The connector is made of medical grade 304 stainless steel, prepared by precision machining, with a thickness of 0.1mm. The connector has an array of through holes and fixed pins. The distance between the axes of the hollow microneedles is the same, and the pins are perpendicular to the plane where the through holes of the connector are located. When assembling, use adhesive to bond the microneedle array sheet to the connector first. During bonding, the axis of the microneedle corresponds to the center of the through hole of the connector array one by one. After the bonding is fixed, the pin of the connector is used to insert the end face tube of the base. seat structure and fix it again with glue. Finally, around the edge of the sheet-shaped hollow microneedle in contact with the base, a sealing structural adhesive is applied, and the preparation of the microneedle product is completed after curing, as shown in FIG. 24 .

Example 9

In Example 9, the sheet metal hollow microneedle array prepared in Example 2 was used, and it was further cut into 1*3 microneedle array sheets. The base is made of medical-grade PVC and is precision injection-molded. The main body has a wedge-shaped structure and a height of 12mm. The base includes two connection ports, which are distributed on both sides of the base. The base has one or more channels in it connecting the first port and the second port. The first port is used to integrate the sheet-shaped hollow microneedle, and the second port is a Luer interface, which is convenient for the integration of the sheet-shaped hollow microneedle with the base to connect other components. Port through holes complete the delivery or extraction of fluids.

When assembling, first align the microneedle array sheet with the mesh connection channel of the base, and use adhesive to fix it. Subsequently, the edge of the sheet-shaped hollow microneedle in contact with the base is coated with a sealing structural adhesive, and the preparation of the microneedle product is completed after curing, as shown in FIG. 25 .

The mechanical properties of microneedles play a very important role in the smooth implementation of microneedle products. Among the mechanical test indicators, the axial force data of microneedle needles can be relatively well used to measure the mechanical properties of microneedle penetration into the tissue. The microneedle axial force test method usually uses a force measuring instrument to press the needle body vertically. During the pressing process, the displacement and load force are collected synchronously, and the load-displacement curve is generated.

In some embodiments of the present invention, the test is performed using a push-pull force meter (RHESCA PTR-1101, Japan Co., Ltd.). During the test, the sheet metal hollow microneedle array is horizontally bonded to the test fixture, and then the fixture is fixed on the equipment test platform. The horizontal condition is observed during the process to avoid the tilt of the sheet metal hollow microneedle array. Set the parameters of the device to ensure that the device pressing the probe and the axis of the microneedle body to be measured are coincident. FIG. 26 shows test results according to an embodiment of the present invention. It can be seen from Figure 26 that no obvious numerical mutation was observed in the test curve, and the curve continuity was good. Combined with the optical images of the needle body before and after the test, it was confirmed that the metal hollow microneedle needle body did not break during the test. The typical force associated with penetrating human skin for the size of microneedle used in the test is well below 1N. Combined with the shape, structure and size of the microneedle, the axial force at the moment when the removal pressure is displaced by 10 μm represents the withstand force value of the microneedle in the process of penetrating the needle tip. It can be seen from the test data that the microneedle in this embodiment can effectively penetrate the human skin without breaking or bending. fold.

Further, the microneedles prepared in Examples 2, 3, and 4 were tested according to the above method, and the axial force of the respective microneedles was tested. The test results are as follows:

Table 1: Microneedle axial force test data of different embodiments

In the test data, the axial force of the microneedle in Example 4 is relatively the best, the RSD value is the smallest, and there is no significant difference in the data of each example. Combined with the above analysis, the microneedle of each example can effectively penetrate the human skin without breaking or bending. discount requirements.

Next, the puncture test is performed on the sheet metal hollow microneedle array product.

The puncture test was performed using the sheet metal hollow microneedle array product prepared in Example 7. Combined with the current research results, it is generally believed that pigskin skin is closer to the structure of human skin. In this test, pigskin skin is used to simulate the process and results of microneedle puncturing of human skin.

The above-mentioned microneedle products were fixed on the push-pull force meter (RHESCA PTR-1101, Japan Co., Ltd.) to test the motion module, and the isolated pig skin was flatly fixed on the test platform, and the instrument pushed the microneedle products vertically to the pig with a thrust of 20N. The skin surface was restored after the puncture was completed, and the puncture site was dyed with a cotton swab dipped in 0.005% methylene blue solution. The dyeing results are shown in Figure 27.

In the test picture, 25 dyeing points can be clearly observed, corresponding to the 5*5 metal hollow microneedle array mounted on the product of this example, which confirms the effectiveness of the microneedle needle body puncture.

Further, the surface of the microneedles of the product in this example was treated, coated with methylene blue solution and dried, and the above pigskin puncture experiment was repeated, and then the distribution of methylene blue in the pigskin was scanned using a German Leica confocal microscope (TCS SP8 STED). In order to analyze the depth of microneedle penetration into the skin, the test results are as follows:

Table 2: Puncture Depth of Pig Skin with Microneedle Products

Pig skin piercing Testing frequency 5 Average penetration depth μm 480 Standard Deviation μm 102 RSD(%) 21.5

The puncture experiment was repeated 5 times, and the confocal microscope randomly selected 5 pinholes from the pinholes generated by the puncture each time to measure and scan, a total of 25 measurement data, and the average penetration depth of the test was 480 μm. It was found that the microneedle body had any breakage and bending.

Next, the injection test of the sheet metal hollow microneedle array product was carried out.

This injection test uses the sheet metal hollow microneedle array product prepared in Example 9 for injection test. The solution injection was carried out after puncturing human skin with simulated microneedles using isolated suckling pig skin. The microneedle product was connected to the test pipeline, and the injection in the pipeline was replaced by 0.005% methylene blue solution. During the test, the microneedle was vertically pierced into the simulated skin and maintained, and then the pipeline applied 15psi back pressure, and the time required for the injection of 100μL injection was counted. The test structure is as follows:

Table 3: Pigskin Injection of Microneedle Products

The injection experiment was repeated 5 times, and the average injection time was 35s. During and after the test, the microneedle body was not found to be broken or bent. After the test, the microneedle product was removed, and a small amount of solution overflow was observed from the skin surface, as shown in Figure 28. Simultaneously, it could be observed that centered on the injection point, methylene blue had diffused under the skin to form color spots.

While various embodiments of the present invention have been described above, it should be understood that they have been presented by way of example only, and not limitation. It will be apparent to those skilled in the relevant art that various combinations, modifications and changes can be made therein without departing from the spirit and scope of the present invention. Therefore, the breadth and scope of the invention disclosed herein should not be limited by the above-disclosed exemplary embodiments, but should be defined only in accordance with the appended claims and their equivalents.

Claims (13)

1. A method of preparing hollow microneedles, comprising:

preparing a hollow microneedle male die;

forming a microneedle layer on the microneedle male die;

forming a microneedle point and a microneedle pinhole; and

and removing the microneedle male mould.

2. The method for preparing hollow microneedles in claim 1, wherein the male hollow microneedle mold is prepared by micro-machining, hot-press molding, precision injection molding, 3D printing and micro-molding.

3. A method of preparing hollow microneedles in claim 1, wherein preparing a positive hollow microneedle mold comprises:

coating positive photosensitive glue on the front surface of the transparent substrate;

performing four-side inclined exposure on the positive photosensitive resist from the back of the transparent substrate by using a mask plate with a preset shape;

and developing the positive photosensitive resist by using a corresponding developer, removing redundant photosensitive resist, and completing the preparation of the microneedle male mold.

4. A method of preparing a hollow microneedle according to claim 1, wherein preparing a positive hollow microneedle mold comprises:

fixing the microneedle metal female die between an upper die frame and a lower die frame of hot-stamping equipment, and filling polymer granules or sheets into the microneedle die;

operating hot-pressing equipment to finish the hot-pressing process;

and after the hot pressing process is finished, taking out the microneedle male die after the temperature of the die is reduced to a proper temperature.

5. The method of manufacturing a hollow microneedle according to claim 1, wherein the microneedle tip and the microneedle pinhole are formed by cutting, grinding, laser drilling, and etching.

6. A method of preparing a hollow microneedle according to claim 1, wherein forming a microneedle needle tip and a microneedle needle hole comprises:

applying a polymer coating on the microneedle layer;

and cutting the microneedle needle point by using a wafer cutting machine according to the preset track and the preset parameters to synchronously form the outline of the microneedle needle point and the microneedle needle hole.

7. A method for preparing hollow microneedles in claim 6, wherein the cutting blade of the wafer cutter is perpendicular to the cutting plane, after the cutting process, the material on the top of the microneedle layer is partially removed, so that pinholes penetrating through the microneedle layer are formed, and the residual material on the top forms needle points.

8. The method for preparing hollow microneedles of claim 6, wherein an angle α between a cutting blade of the wafer cutter and a cutting plane is in a range of 40-80 °, a distance between a lowest position of the blade cutting needle body and a top end of the needle tip is in a range of 30-600 μm, after the cutting process, a bevel is formed at the top of the microneedle layer, a tip of the bevel forms the needle tip, and a pinhole penetrating through the microneedle layer is in the bevel.

9. The method for preparing a hollow microneedle according to claim 1, wherein the diameter of the tip of the microneedle body is less than 60 μm, the aspect ratio of the microneedle body is in the range of 1 to 6, and the force feedback is greater than or equal to 0.5N when the vertical pressing displacement at the tip of a single microneedle is greater than 30 μm.

10. A hollow microneedle article comprising:

the sheet-shaped hollow microneedle comprises a substrate layer and at least one hollow needle body protruding from a first side of the substrate layer, an inner cavity opening of the hollow needle body is positioned at a second side of the substrate layer, the hollow needle body and the substrate layer are integrally formed and are formed by the same material layer, and the hollow needle body comprises a needle point positioned at the top and a needle hole penetrating through the material layer; and

and the base comprises a base body, and a first connecting port and a second connecting port which are arranged on the base body, the first connecting port is connected with the second side of the sheet-shaped hollow microneedle, and the second connecting port is connected with other components and used for completing delivery or extraction of fluid through the sheet-shaped hollow microneedle and the base at a specific time.

11. The hollow microneedle article of claim 10, wherein the hollow needles of the sheet-like hollow microneedles are arranged in a specific array.

12. A hollow microneedle article according to claim 10, wherein the metal at the top of the material layer is partially removed, thereby forming pinholes through the material layer, the remaining metal at the top constituting a needle tip.

13. A hollow microneedle article according to claim 10, wherein the top of the material layer has a bevel, the tip of the bevel defining a needle tip, and the needle hole through the material layer is in the bevel.

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