CN219208698U

CN219208698U - Sheet hollow microneedle

Info

Publication number: CN219208698U
Application number: CN202221935629.1U
Authority: CN
Inventors: 陈新明; 林鹏
Original assignee: Air Core Micro Medical Technology Shanghai Co ltd
Current assignee: Air Core Micro Medical Technology Shanghai Co ltd
Priority date: 2022-07-26
Filing date: 2022-07-26
Publication date: 2023-06-20
Anticipated expiration: 2032-07-26

Abstract

The utility model relates to a sheet hollow microneedle, comprising: a base layer; and at least one hollow needle body protruding from the first side of the substrate layer, wherein an inner cavity opening of the hollow needle body is positioned on the second side of the substrate layer, the hollow needle body is integrally formed with the substrate layer and is composed of 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, so that the needle hole is communicated with a hollow part of the hollow needle body.

Description

Sheet hollow microneedle

Technical Field

The present utility model relates generally to the field of microneedle technology. In particular, the present utility model relates to a sheet-shaped hollow microneedle.

Background

The micro needle can minimally invasive intervene on the surface layer of the skin, breaks through the barrier of the skin stratum corneum to drug absorption, realizes efficient transdermal drug delivery, has no pain or little pain in the process, simultaneously facilitates accurate control of the intervention depth and the drug delivery rate, is considered as one of key technologies for benefiting mankind, and is expected to become a representative of transdermal drug delivery technologies.

Microneedles can be classified into solid microneedles and hollow microneedles according to structures. The solid microneedle product is mainly used in the mode of penetrating holes and then coating medicines to achieve the drug administration effect, the use process is relatively complicated, and then solid microneedles with higher drug carrying efficiency and more convenient use such as soluble microneedles, swelling microneedles, porous microneedles and the like are gradually optimized. However, the solid micro-needle still cannot drive enough liquid medicine into a human body through pressurization like the traditional injection, and the problems of long single use time and small application amount are common. As another research direction of the micro-needle, the hollow micro-needle has the advantages of minimally invasive painless or painless administration, and simultaneously has the potential of basically having all the advantages of the traditional injection, and related researches are attracting attention in the industry.

Chinese patent CN 108348292A discloses a device for delivering fluid to biological tissue, comprising a single crystal silicon hollow microneedle device and a method for preparing the microneedles thereof. The micro needle is prepared from a monocrystalline silicon wafer, the size change of the micro needle is relatively limited, and meanwhile, when the micro needle is used as a micro needle preparation material due to the mechanical property of the monocrystalline silicon, the worry that the needle tip is broken in the use process is easily caused.

Chinese patent CN 112245792A discloses a hollow metal microneedle array, a preparation method thereof, and a transdermal drug delivery patch, part of the process of the method is difficult to control, for example, how to ensure complete and consistent formation of the needlepoint in the cutting process, and meanwhile, the difficulty of preparing a two-dimensional microneedle array is high.

Chinese patent CN109078260a discloses a method for preparing hollow microneedle arrays in batches, which uses a microneedle array female template with holes to prepare a polymer microneedle array male template, electroplates the needle body, and finally polishes or laser drills to form pinholes. The process adopts laser to prepare the microneedle female die, the size of the final microneedle needle body is generally larger in various microneedle processes, meanwhile, the needle tip is blunt, the consistency is poor, and the use experience of corresponding products is easy to worry about.

Disclosure of Invention

To at least partially solve the above-described problems in the prior art, the present utility model provides a sheet-shaped hollow microneedle comprising: a base layer; and at least one hollow needle body protruding from the first side of the substrate layer, wherein an inner cavity opening of the hollow needle body is positioned on the second side of the substrate layer, the hollow needle body and the substrate layer are integrally formed and are composed of 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, so that the needle hole is communicated with a hollow part of the hollow needle body.

In one embodiment, there is a pinhole formed by partially removing the top material layer and a needle tip formed by the top remaining material on top of the hollow needle body by cutting with a cutting blade perpendicular to the base layer.

In one embodiment, the hollow needle body has a bevel on top thereof formed by cutting with a cutting blade at a specific angle inclined to the base layer, the bevel tip constituting the needle tip, the needle hole through the layer of material being in the bevel.

In one embodiment of the present utility model, in one embodiment, the material layer comprises gold, silver, cobalt, platinum, copper alloy, iron alloy, aluminum alloy, nickel alloy, titanium titanium alloy chromium, chromium alloy, tungsten, zinc alloy, tin, PLA, PP, PVC, PE, PTFE, POM, ABS, PA or a combination structure thereof.

In one embodiment, the substrate layer and the hollow microneedle needles have a polymer coating at least in part on the inner and outer surfaces.

In one embodiment, the substrate layer is flat sheet-shaped or has a certain concave-convex shape, and the outline of the substrate layer is of any shape and the thickness of the substrate layer is 1-1000 mu m.

In one embodiment, the hollow needle has a height of 100 to 2500 μm, a needle bottom side length or diameter of 10 to 1000 μm, and a needle hole diameter or longest diagonal of 1 to 200 μm.

In one embodiment of the present invention, in one embodiment, the hollow needle body is cone-shaped, pyramid-shaped, the pyramid is combined with the cylinder, the cone is combined with the cylinder, the pyramid is combined with the pyramid platform or the cone is combined with the truncated cone.

In one embodiment, the sheet-like hollow microneedle comprises a plurality of hollow needle bodies arranged in a specific array.

In one embodiment, the distribution density, shape, and/or size of the microneedles at different locations in the array are the same or different.

In one embodiment, the microneedle distribution density in the array is 1 to 100 needles per square centimeter.

In one embodiment, the pinhole is a pinhole formed by a laser beam through the material layer at a top location of one side of the needle body.

Drawings

To further clarify the advantages and features present in various embodiments of the present utility model, a more particular description of various embodiments of the present utility model will be rendered by reference to the appended drawings. It is appreciated that these drawings depict only typical embodiments of the utility model and are therefore not to be considered limiting of its scope. In the drawings, for clarity, the same or corresponding parts will be designated by the same or similar reference numerals.

Fig. 1 shows a flowchart of a method of manufacturing a sheet metal hollow microneedle array according to an embodiment of the present utility model.

Fig. 2 illustrates an exposure pattern reticle according to one embodiment of the utility model.

Fig. 3 shows a schematic exposure of a microneedle positive mold prepared with a positive-working photoresist according to one embodiment of the present utility model.

Fig. 4 shows a schematic diagram of a hollow microneedle positive die prepared by positive photoresist lithography according to an embodiment of the present utility model.

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

Fig. 6 shows a schematic diagram of a hollow microneedle male mold prepared by hot stamping according to an embodiment of the present utility model.

FIG. 7 shows a schematic cross-sectional view of a microneedle male mold metal layer formed according to an embodiment of the present utility model.

Fig. 8 shows a schematic structural diagram of a platelet-applied polymer coating after deposition of a microneedle male mold metal layer, according to an embodiment of the present utility model.

Fig. 9 shows a schematic diagram of a cutting treatment tip method after a metal layer is deposited on a microneedle positive mould according to an embodiment of the present utility model.

Fig. 10 shows a schematic diagram of a method of positive cutting a needle tip after deposition of a metal layer by a microneedle positive mold in accordance with an embodiment of the present utility model.

Fig. 11 shows a schematic diagram of a method for positioning a tip of a tangent process after a metal layer is deposited on a microneedle positive mold according to the present utility model.

Fig. 12 shows a schematic view of a sheet-like microneedle array after removal of a male mold according to an embodiment of the present utility model.

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

Fig. 14 shows a schematic diagram of a bevel cut processing tip method after deposition of a metal layer by a microneedle positive die in accordance with the utility model.

Fig. 15 shows a schematic view of a sheet-like microneedle array after removal of a male mold according to an embodiment of the present utility model.

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

Fig. 17 shows a schematic diagram of a laser drilling processing tip method after a metal layer is deposited by a microneedle positive die, according to an embodiment of the utility model.

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

Fig. 19 shows a schematic perspective assembly of a hollow microneedle article according to one embodiment of the present utility model.

FIG. 20 shows a schematic cross-sectional view of an article chassis according to one embodiment of the present utility model.

Fig. 21 shows a schematic view of the external appearance structure of an article after assembly according to an embodiment of the present utility model.

FIG. 22 shows a schematic cross-sectional view of an article chassis according to one embodiment of the present utility model.

FIG. 23 shows a schematic cross-sectional structure of an article chassis according to one embodiment of the present utility model.

Fig. 24 shows a schematic view of the appearance structure of an article after assembly according to one embodiment of the present utility model.

Fig. 25 shows a schematic view of the external appearance structure of an article after assembly according to an embodiment of the present utility model.

Fig. 26 shows test results according to an embodiment of the present utility model.

FIG. 27 shows a schematic representation of the results of an article puncture test according to an embodiment of the present utility model.

Fig. 28 shows a schematic of the results of an injection test of an article according to an embodiment of the utility model.

Detailed Description

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

In the present utility model, unless specifically indicated otherwise, "disposed on …", "disposed over …" and "disposed over …" do not preclude the presence of an intermediate therebetween. Furthermore, "disposed on or above" … merely indicates the relative positional relationship between the two components, but may also be converted to "disposed under or below" …, and vice versa, under certain circumstances, such as after reversing the product direction.

In the present utility model, the embodiments are merely intended to illustrate the scheme of the present utility model, and should not be construed as limiting.

In the present utility model, the adjectives "a" and "an" do not exclude a scenario of a plurality of elements, unless specifically indicated.

It should also be noted herein that in embodiments of the present utility model, only a portion of the components or assemblies may be shown for clarity and simplicity, but those of ordinary skill in the art will appreciate that the components or assemblies may be added as needed for a particular scenario under the teachings of the present utility model. In addition, features of different embodiments of the utility model may be combined with each other, unless otherwise specified. For example, a feature of the second embodiment may be substituted for a corresponding feature of the first embodiment, or may have the same or similar function, and the resulting embodiment would fall within the disclosure or scope of the disclosure.

It should also be noted herein that, within the scope of the present utility model, the terms "identical", "equal" and the like do not mean that the two values are absolutely equal, but rather allow for some reasonable error, that is, the terms also encompass "substantially identical", "substantially equal". By analogy, in the present utility model, the term "perpendicular", "parallel" and the like in the table direction also covers the meaning of "substantially perpendicular", "substantially parallel".

The numbers of the steps of the respective methods of the present utility model are not limited to the order of execution of the steps of the methods. The method steps may be performed in a different order unless otherwise indicated.

In embodiments of the present utility model, methods of making hollow microneedles and articles thereof are disclosed. Specifically disclosed are a sheet-like hollow microneedle array and a method for preparing the same, and a product comprising the hollow microneedle array and a method for preparing the same. The flaky hollow microneedle array disclosed by the utility model is prepared from a biological safety material, has outstanding mechanical properties, is convenient to adjust the size and the array density of the microneedles, can be cut at will according to the requirements of subsequent products, and has a wide application range; the preparation method of the flaky hollow microneedle array combines the technologies of micromachining, precise machining, precise injection molding and the like, is stable and reliable, has low cost and is suitable for mass production and manufacture. The utility model also discloses a plurality of hollow microneedle products, which can meet the requirement of implementing hollow microneedles at local points and small areas, can further optimize the structure of the implementation surface of the products contacting biological tissues, can be used in combination with vacuum negative pressure, is convenient and reliable to use and has wide application field. The hollow microneedle product is prepared by adopting precise injection molding and precise machining technologies, the preparation method is mature and reliable, the cost is economical, and the hollow microneedle product is suitable for batch manufacturing and is widely popularized.

Fig. 1 shows a flowchart of a method of manufacturing a sheet-shaped hollow microneedle array according to an embodiment of the present utility model.

First, at step 110, a hollow microneedle male mold is prepared. In the present utility model, the male mold refers to a convex structure.

In embodiments of the present utility model, hollow microneedle positive molds may be prepared using techniques such as micromachining, hot briquetting, precision injection moulding, 3D printing, micro-moulding, and the like.

Specifically, in one embodiment of the present utility model, a hollow microneedle positive mold is prepared by positive photoresist lithography, comprising the steps of:

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

Next, the positive photoresist 320 is obliquely exposed from the back surface of the transparent substrate 310 using a mask of a predetermined shape. Specifically, FIG. 2 illustrates an exposure graphics reticle 210 according to one embodiment of the utility model. And selecting a mask plate corresponding to the exposure pattern to perform oblique exposure according to the shape of the pin body of the micro-pin male die, as shown in fig. 3. The mask 210 is horizontally placed, the light is perpendicular to the mask 210, and the transparent substrate 310 is horizontally inclined by an angle beta, wherein the inclination angle beta is one half of the included angle of the tip of the male microneedle mould. The substrate is sequentially exposed in a four-side inclined manner by using the opaque square array pattern mask plate shown in fig. 2. In other embodiments of the present utility model, the angle of reticle 210 and transparent substrate 310 may be maintained constant, and the incident light may be tilted to achieve oblique exposure.

And developing the positive photoresist by using a corresponding developer after exposure, removing the redundant photoresist, and completing the preparation of the microneedle male die. Fig. 4 shows a schematic diagram of a hollow microneedle positive mold 410 prepared by positive photoresist lithography according to an embodiment of the present utility model. As shown in fig. 4, the hollow microneedle male mold 410 is a rectangular pyramid structure protruding from a transparent substrate. In other embodiments of the present utility model, the hollow microneedle male mold may also be in the shape of a pyramid, a cone, a pyramid-cylinder combination, a cone-cylinder combination, or the like.

In another embodiment of the present utility model, a hollow microneedle male mold is prepared by hot stamping, comprising the steps of:

and fixing the microneedle metal female die between an upper die frame and a lower die frame of the hot stamping equipment, and filling polymer granules or sheets into the microneedle die for standby. Fig. 5 shows a schematic diagram of a microneedle metal female mold according to an embodiment of the present utility model.

And (5) operating the hot embossing equipment to finish the hot embossing process. And setting various parameters of the hot embossing equipment according to the characteristics of the selected polymer. For example, the temperature may be set in the range of 90 to 250 ℃, the pressure in the range of 15 to 45T, the vacuum degree in the range of-60 to-95 Kpa, and the hot pressing time in the range of 3 to 15 min.

After the hot pressing process is finished, the mould is cooled to a proper temperature, and the continuous production can be realized by repeating the processes after the microneedle male mould is taken out. Fig. 6 shows a schematic diagram of a hollow microneedle male mold 610 produced by hot stamping, according to an embodiment of the present utility model.

In embodiments of the present utility model, polymers employed by the polymeric microneedle positive mold include, but are not limited to: positive photopolymers, negative photopolymers, polylactic acid (PLA), polyglycolic acid (PGA), polymethyl methacrylate (PMMA), ABS plastic, epoxy resin, polydimethylsiloxane, polypropylene, polyethylene, polycaprolactone, polyglycolic acid, polylactic-glycolic acid, polysulfone, polyoxymethylene, ethylene-vinyl acetate copolymer, phenolic plastic, polystyrene, polyamide, polyurethane, polycarbonate.

It will be appreciated by those skilled in the art that the two specific examples of the method of preparing a hollow microneedle male mold described above are provided for illustrative purposes only and are not intended to limit the present utility model, as other methods of preparation are intended to fall within the scope of the present utility model.

Next, at step 120, a microneedle layer is formed on the microneedle male mold. In an embodiment of the present utility model, methods of forming a microneedle layer include, but are 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 alloy, iron iron alloy, aluminum alloy, nickel alloy, titanium titanium alloy chromium, chromium alloy, tungsten, zinc alloy, tin, PLA, PP, PVC, PE, PTFE, POM, ABS, PA and the like or a combination thereof. The microneedle layer may have a single-layer structure or a multilayer laminated structure.

For example, in one embodiment of the present utility model, forming a microneedle layer on a microneedle male mold comprises the steps of:

1. an electrically conductive metal layer, such as gold, silver, titanium, etc., may be deposited on the microneedle positive mold using an evaporation process.

2. Immersing the metal male die after depositing the conductive layer into an electroforming tank for electroforming. 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 0.8-80 μm according to the required microneedle performance, and finally the microneedle male die for depositing the metal layer can be obtained. Fig. 7 shows a schematic cross-sectional view of a microneedle layer 710 formed on a microneedle male mold according to an embodiment of the present utility model.

Next, at step 130, microneedle tips and microneedle pinholes are formed. In embodiments of the present utility model, techniques such as cutting, grinding, laser drilling, etching, and the like may be used to form the microneedle tips and microneedle pinholes. The pinholes penetrate the microneedle metal layer as one of the core parts of the microneedle structure, the structure and formation process thereof are to maintain the sharpness of the needle tip, and the strength of the needle tip cannot be damaged. The sharpness of the needle tip and the strength of the needle tip can be maintained by preparing the needle hole of the micro needle on the metal layer of the micro needle male die.

In one embodiment of the present utility model, the microneedle tips and microneedle pinholes are prepared by cutting, comprising the steps of:

1. a polymeric coating 810 is applied over the microneedle male die metal layer, as shown in fig. 8.

2. Cutting the microneedle tips according to preset tracks and parameters by using a wafer cutting machine to synchronously form the shapes of the microneedle tips and the microneedle pinholes, as shown in fig. 9. The specific cutting modes can be subdivided into two types: tangent and beveling.

The tangent of the tip refers to the cutting edge 910 being perpendicular to the cutting plane (i.e., the plane in which the substrate lies), as shown in fig. 10. When the needle body is in the shape of a rectangular pyramid, the side surface of the cutting blade is preferably parallel to the diagonal line of the bottom surface of the rectangular pyramid microneedle body, and other types of needle bodies can be similarly changed with reference to the above method. When the rectangular pyramid needle body microneedle is cutting, the distance between the side surface of the cutting blade close to the tip of the microneedle and the axis of the same side microneedle is in the range of 0-20 μm, and the distance between the effective cutting outline of the cutting blade 910 and the tip of the microneedle is in the range of 10-600 μm, as shown in fig. 11. Fig. 12 shows a schematic view of a sheet-like microneedle array after removal of a male mold according to an embodiment of the present utility model. Fig. 13 shows an enlarged schematic perspective view of a single needle. As shown in fig. 13, the metal at the top of the tip is partially removed, forming pinholes through the metal layer, and the remaining metal at the top constitutes the tip, resulting in good sharpness.

Tip beveling refers to the side of the blade 910 being at an angle to the cutting plane, as shown in fig. 14. When the needle body is in the shape of a rectangular pyramid, the side surface of the cutting blade is preferably parallel to the diagonal line of the bottom surface of the rectangular pyramid microneedle body, and other types of needle bodies can be similarly changed with reference to the above method. When the rectangular pyramid needle body is obliquely cut, the included angle alpha between the cutting blade 910 and the cutting plane is 40-80 deg, and the height between the lowest position of the blade cutting needle body and the tip of the needle tip is 30-600 microns. Fig. 15 shows a schematic view of a sheet-like microneedle array after removal of a male mold according to an embodiment of the present utility model. Fig. 16 shows an enlarged schematic perspective view of a single needle. As shown in fig. 16, a bevel is formed on top of the metal layer by beveling, the tip of the bevel constitutes a sharp needle tip, and a needle hole penetrating through the metal layer is in the bevel.

In another embodiment of the present utility model, the laser drilling technique is used to prepare microneedle tips and pinholes comprising the steps of:

the substrate after deposition of the metal layer on the male microneedle mould is placed horizontally on a processing platform to ensure that the laser beam 1710 is perfectly perpendicular to the plane of the microneedle array. Preferably, the light spot is focused on the central 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. Fig. 18 shows an enlarged schematic perspective view of a single needle. As shown in fig. 18, the laser beam forms a pinhole penetrating the metal layer at the top position of one side of the needle body, and the remaining sides remain substantially unchanged, thereby obtaining good sharpness.

It should be understood by those skilled in the art that the two specific examples of the preparation methods of hollow microneedle tips and pinholes described above are merely illustrative of the present utility model, not limiting the present utility model, and other preparation methods should fall within the scope of the present utility model.

Next, at step 140, the microneedle positive mold is removed. In embodiments of the present utility model, methods of removing the microneedle positive mold include, but are not limited to, chemical solvent removal, heat treatment removal, mechanical removal, and the like.

For example, in one embodiment of the utility model, 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, one or more of methylene chloride, chloroform, ethanol, diethyl ether, xylene, benzene, methanol, N-N dimethyl sulfoxide, toluene, dimethylformamide, ethyl acetate, acetone, and the like.

The specific operation comprises immersing the sheet-shaped microneedle array which completes the processing of the microneedle tips in a chemical solvent, and preferably synchronously matching heating and ultrasonic in the process to accelerate the removal speed of the male mold. And removing the male die to obtain the sheet metal hollow microneedle array.

The prior researches find that the preparation method of the hollow microneedle and the shape and distribution of the prepared microneedle have important effects on the shape, the application and the using method of the product of the subsequent related products. The inventor realizes that the sheet metal hollow microneedle array has convenient needle body appearance, size, array mode and density adjustment, can further cut according to subsequent use, is convenient for integrating in the terminal product in each field, realizes hollow microneedle application advantage. The sheet metal hollow microneedle array prepared by the preparation method has the advantages of simple structure and high stability.

The utility model discloses a sheet metal hollow microneedle array, which consists of a basal layer and a metal hollow microneedle body, wherein the basal layer and the metal hollow microneedle body are connected into a whole, the metal hollow microneedle is positioned at one side of the basal layer, and an inner cavity opening of the metal hollow microneedle is positioned at the other side of the basal layer. The basal layer is usually in a flat sheet shape and can also be in a certain concave-convex shape according to the requirement. The height of the irregularities may be in the range of 0 to 10mm, but is not limited thereto. The outer contour of the substrate layer is generally rectangular, circular, oval or the like, and its thickness is usually 1 to 1000 μm, preferably 20 to 100 μm. The base layer may be composed of a single metal and alloy material, including but not limited to gold, silver, cobalt, platinum, copper alloys, iron alloys, aluminum alloys nickel, nickel alloys, titanium alloys, chromium alloys, tungsten, zinc, tin, or combinations thereof, and can also be formed by the composite layer structure of the materials. The base layer may also be composed of a polymer such as PLA, PP, PVC, PE, PTFE, POM, ABS, PA. Furthermore, the polymer coating can be coated on the two side surfaces of the basal layer again, so that the effects of lubrication, insulation, conductivity, biological safety improvement, decoration and the like are achieved. The polymer coating can be patterned, namely, the polymer coating is coated according to a specific pattern rule, and the metal layer is leaked from the rest area in a hollowed-out manner, so that different areas have different electrical characteristics and the like.

The metal hollow microneedle bodies are positioned on one side of the basal layer and extend further along the different plane directions of the side surface, and are generally distributed in a uniform array, and can be arranged according to specific patterns according to the requirements of subsequent products. The metal hollow microneedle body can be made of single metal and alloy materials, including but not limited to gold, silver, cobalt, platinum, copper alloys, iron alloys, aluminum alloys nickel, nickel alloys, titanium alloys, chromium alloys, tungsten, zinc, tin, or combinations thereof, the composite material layer structure can also be used for forming the composite material layer structure, and further the inner surface and the outer surface of the metal hollow microneedle can be coated with a polymer coating again, so that the effects of lubrication, insulation, conductivity, biological safety improvement, decoration and the like are achieved. The outer shape of the metal hollow microneedle body is usually pyramid and cone, and can also be pyramid and cylinder combination, cone and cylinder combination and other shapes. The needle height is generally from 100 to 2500. Mu.m, preferably from 200 to 1500. Mu.m, the needle bottom side length or diameter is from 10 to 1000. Mu.m, preferably from 50 to 400. Mu.m. Different locations in the same array may be provided with different shapes and different sizes of microneedles. For example, the microneedle profile or size at the center of the array is different from the microneedle profile or size at the edge. The metallic hollow microneedle pinholes are of different shapes according to different preparation methods, and the pinhole diameter or longest diagonal is usually 1 to 200 μm, preferably 20 to 80 μm. The metal hollow micro-needles are distributed in an array on one side of the basal layer, can be uniformly distributed in an array, and can be specifically set according to the requirement. For example, the microneedle density in the center of the array is different from the microneedle density at the edges, typically 1 to 100 pins per square centimeter, preferably 1 to 36 pins per square centimeter.

In embodiments of the present utility model, the microneedle needle tip diameter is less than 60 μm and the needle aspect ratio is in the range of 1 to 6, the term "needle aspect ratio" referring to the ratio of the height of the needle to the length or diameter of the needle bottom; when the vertical downward displacement of the needle point of the single microneedle is larger than 30 mu m, the force feedback is more than 0.5N.

In some embodiments of the present utility model, hollow microneedle articles may be fabricated based on sheet metal hollow microneedle arrays prepared by the methods of the present utility model.

Hollow microneedles are often prepared in an array arrangement, and thereafter often require further integration into a variety of different structures, either as the final article or as a component thereof.

The hollow microneedle product provided by the utility model generally comprises a sheet-shaped hollow microneedle and a base, wherein the sheet-shaped hollow microneedle at least comprises one or more hollow microneedles, the main body part of the microneedle base generally comprises a base body and at least two connecting ports, the connecting ports are distributed on different surfaces of the microneedle base body, the interior of the microneedle base body comprises a channel connected with at least two connecting ports, the shape of the base is generally columnar or sheet-shaped, the shape of the base can be a column, a square column, a wafer, a square sheet or other special-shaped structures, the outer surface of the base except the connecting ports can be a smooth surface, and the outer surface can be further provided with a connecting and fixing structure. When the microneedle base only comprises two connecting ports, the first port is used for integrating the sheet hollow microneedle, the second port can be a luer interface or a threaded interface with a through hole and various quick-clamping bayonets, the second port is convenient for connecting other components after the sheet hollow microneedle and the base are integrated, and the delivery or extraction of fluid can be completed through the hollow microneedle needle hole, the base and the through hole of the second port at a specific time. Further, when the microneedle base includes three connection ports, the first port is used for integrating the sheet hollow microneedle, the second port can be a luer or a threaded interface with a through hole and various quick-card bayonets, the second port is convenient for connecting other components after the sheet hollow microneedle is integrated with the base, the base body is internally provided with a first channel for connecting the first port and the second port, delivery or extraction of fluid can be completed through the hollow microneedle needle hole, the base and the second port through hole at a specific time, the third port can be a luer or a threaded interface with a through hole and various quick-card bayonets, the third port is convenient for connecting other components after the sheet hollow microneedle is integrated with the base, the base body is internally provided with a second channel for connecting the first port and the third port, and the delivery or extraction of fluid can be completed through the base and the third port through hole at a specific time in the outer surface area of the sheet hollow microneedle, and the fluid can be gas or liquid.

The first and second channels may be in direct communication with each other or may be isolated from each other.

It will be understood by those skilled in the art that the internal structure of the base body and the number of interfaces may be designed and adapted according to actual needs, for example, four or more interfaces may be provided on the base, each of which may communicate with other specific interface or interfaces through internal channels, each of which may communicate or partially communicate with other channels, or each of which may not communicate with each other.

In one embodiment of the present utility model, a connector may be added between the sheet-like hollow microneedle and the base, as shown in fig. 19. Fig. 19 shows a schematic perspective assembly of a hollow microneedle article according to one embodiment of the present utility model. The hollow microneedle article comprises a base 1910, a connector 1920, a sheet-like hollow microneedle 1930, and a seal 1940. The connecting piece 1920 is provided with an array through hole and a fixed pin, the center distance of the array through hole is the same as the axle center distance of the sheet hollow micro-needle, and the pin is perpendicular to the plane where the connecting piece through hole is located. One side of the integrated sheet hollow microneedle port of the base 1910 is distributed with netlike connecting channels corresponding to the positions of the through holes of the connecting piece, and the port is provided with a tube seat structure corresponding to the pins of the connecting piece one by one. After the corresponding hollow microneedle product is assembled, the base and the sheet hollow microneedle are integrated into one side port, and the base 1910, the connecting piece 1920, the sheet hollow microneedle 1930 and the sealing structure glue 1940 are respectively arranged from bottom to top.

The preparation method of the hollow microneedle product comprises the following steps:

1. preparing a sheet-shaped hollow microneedle by adopting a sheet-shaped metal hollow microneedle preparation method; the polymer base with a specific structure is prepared by adopting a precise injection molding or hot pressing technology, and the polymer materials comprise: PP, PVC, PLA, ABS, PMMA, resin, etc.; adopting precision machining, laser machining and etching to prepare the connecting piece with a specific structure, wherein the connecting piece can be made of metal or polymer, including but not limited to PP, PVC, PLA, ABS, PMMA, resin, gold, silver, cobalt, platinum, copper alloy, iron alloy, stainless steel, aluminum, copper alloy, iron alloy, copper alloy, iron alloy, copper alloy, iron, stainless steel, copper alloy, iron aluminum alloy, nickel alloy, titanium alloy, chromium alloy, tungsten, zinc, tin, or combinations thereof, preferably a metallic material.

2. The flaky hollow micro-needle is connected with the connecting piece in a connecting mode by adopting various glues and welding processes.

3. After the flaky hollow micro-needle is connected with the connecting piece, the pin of the connecting piece is inserted into the base end face tube seat structure and fixed by glue.

4. And 3, after all the components are connected and fixed, coating sealing structural adhesive around the edge of the sheet hollow microneedle contacted with the base, and after curing, completing the preparation of the microneedle product.

The beneficial effects of the utility model are as follows: the flaky metal hollow microneedle array disclosed by the utility model has the advantages of minimally invasive painless or minimally painful drug delivery, has the characteristic of active driving of liquid medicine by traditional injection, is convenient and safe, does not need professional operation for products which are usually applied finally, is accurate in drug delivery, has outstanding mechanical properties, is convenient to adjust the size and the array density of the microneedles, can be cut at will according to the requirements of subsequent products, and has a wide application range; the preparation method of the sheet metal hollow microneedle array combines the technologies of micromachining, precise machining, precise injection molding and the like, is stable and reliable, has low cost and is suitable for mass production and manufacture. The utility model discloses several hollow microneedle products at the same time, the sheet metal hollow microneedle can be assembled firmly and accurately, the characteristics of easy cutting of the sheet metal hollow microneedle array are combined, the sheet metal hollow microneedle can be assembled into different specification types conveniently, the hollow microneedle can be implemented by meeting the requirements of local points and small areas respectively, the structure of the product contact biological tissue implementation surface can be further optimized, the vacuum negative pressure can be combined for use, the delivery or extraction of fluid and gas can be simultaneously completed through the hollow microneedle pinholes and the base at a specific time, the product can be integrated as an independent product or other product components, the use is convenient and reliable, and the application field is wide; the hollow microneedle product is prepared by adopting precise injection molding and precise machining technologies, the preparation method is mature and reliable, the cost is economical, and the hollow microneedle product is suitable for batch manufacturing and is widely popularized.

The method of preparing the sheet metal hollow microneedle and its product according to the present utility model are further described below with reference to specific examples.

Example 1

In example 1, a sheet metal hollow microneedle array was prepared using a micromachining process. Selecting quartz glass with the thickness of 2mm as a transparent substrate, cleaning and drying by using plasma water, depositing a Hexamethyldisilazane (HMDS) film coating by adopting a vacuum vapor deposition (CVD) process, spin-coating positive photosensitive polyimide glue after drying and curing, and performing heat curing again, wherein the spin-coating can be repeated for a plurality of times, so that the thickness of the glue coating layer reaches 550 mu m. The substrate after being glued is placed on an exposure platform of an ultraviolet exposure device, the microneedle body prepared by the embodiment is in a quadrangular pyramid shape, and the corresponding mask plate is selected for exposure, as shown in fig. 2. The exposure mode is oblique exposure, as shown in fig. 3, the horizontal inclination angle beta of the transparent substrate is one half of the included angle of the tip of the male mould of the micro needle, in this embodiment, the inclination angle beta is 10 degrees, the hollow micro needle adopts a rectangular pyramid needle body, the bottom edge length is 200 μm, the needle height is 550 μm, the needle bodies are uniformly arranged in an array, and the axle center distance of the needle body is 1000 μm. The exposure is completed in four times, the exposure platform sequentially and obliquely exposes the substrate along the four sides of the mask, the whole substrate is immersed in a corresponding solvent for development after exposure, slight vibration or ultrasound can be carried out in a matched mode in the process, and after development and drying, the microneedle male die is obtained.

And depositing silver on the conductive metal layer on the same side of the microneedle male die and the substrate by adopting an evaporation process, and electroforming a nickel-cobalt alloy layer by adopting high-frequency pulse current, wherein the thickness of the metal deposition layer is 15 mu m. And continuously coating polyimide coating on the surface of the metal deposition layer, wherein the thickness is 600 mu m, and cutting the microneedle tips by a wafer cutting machine after heat drying and curing. In the embodiment, the cutting is performed in an arc tangent mode, the side face of the cutting edge is flush with the diagonal line of the bottom face of the rectangular pyramid microneedle body during cutting, the distance between the side face of the edge, close to the tip of the microneedle, and the axis of the microneedle on the same side is 0, and the distance between the effective cutting outline of the cutting edge and the tip of the microneedle is 65 mu m, as shown in fig. 11. And immersing the microneedle array and the substrate which finish the processing of the microneedle tips in a photoresist removing solution special for polyimide, heating the solution synchronously in the process, maintaining the temperature of the solution at 40 ℃, and intermittently performing high-frequency ultrasonic to accelerate the removal of the male die, wherein the sheet-shaped microneedle array is shown in fig. 12 after the removal of the male die, and the enlargement of a single needle body is shown in fig. 13.

Example 2

In example 2, a sheet metal hollow microneedle array was prepared using a micromachining process in combination with precision laser machining. The male die of the sheet metal hollow microneedle array and the metal layer deposition method of this embodiment are the same as those of embodiment 1.

The polyimide coating is coated on the surface of the metal deposition layer, the thickness is 600 mu m, after heat drying and curing, the microneedle tips are treated by adopting laser drilling, the polyimide coating coated before laser drilling can be omitted, preferably reserved, and the microneedle bodies can be properly protected in the subsequent processing process. During processing, the wafer subjected to the metal layer deposition of the microneedle male die is horizontally placed on a processing platform, so that the laser beams are ensured to be completely perpendicular to the plane of the microneedle array, light spots are focused on the central line of the side face of the needle body, and the horizontal distance between the light spots and the axis of the microneedle is 5 mu m. Immersing the microneedle array and the substrate which finish the processing of the microneedle tips in a photoresist removing solution special for polyimide, heating the solution synchronously in the process, maintaining the temperature of the solution at 40 ℃, and intermittently performing high-frequency ultrasonic until the microneedle male die is removed, so as to obtain the sheet metal hollow microneedle array.

Example 3

In example 3, a sheet metal hollow microneedle array was prepared using hot stamping in combination with precision machining. The method specifically comprises the steps of adopting a specific microneedle metal female die and combining a hot stamping technology to prepare a sheet metal hollow microneedle array male die, wherein the microneedle male die comprises a needle body and a substrate, and is prepared by integral molding during hot stamping. The microneedle metal female die of the embodiment is made of stainless steel, a rectangular concave area is formed in one side surface of the microneedle metal female die, the size and the shape of the microneedle metal female die correspond to those of a microneedle male die substrate, the length and the width of the microneedle metal female die are respectively 10cm or 10cm, the concave depth is equal to the thickness of the microneedle male die substrate and is 1.5mm, and the size of the concave area can be adjusted according to the size specification of the sheet metal hollow microneedle array. The rectangular concave area of the microneedle metal female die is correspondingly surrounded to form a fence, a hot-pressing material overflow groove is arranged in the middle area of the four-edge fence, the overflow groove adopts a narrow gate and a two-way wide overflow channel structural design outside the gate, the overflow capacity of redundant materials in the hot-pressing process is improved, meanwhile, the forming area is ensured to have enough forming pressure, and the concrete overflow groove can be reasonably changed by referring to a similar mechanism. The bottom surface of the rectangular concave area of the microneedle metal female die is provided with microneedle needle concave holes in an array mode, the concave holes are inverted quadrangular pyramid, the corresponding microneedle male die needle is quadrangular pyramid, the bottom edge of the microneedle is 280 mu m long, the needle height is 850 mu m, and the axial center distance of the microneedle is 2000 mu m.

During preparation, a microneedle metal female die (shown in fig. 5) is fixed between an upper die frame and a lower die frame of a hot stamping device, polylactic acid (PLA) granules are filled into the microneedle die, the running temperature of the device is set to 170 ℃, the pressure is 30T, the vacuum degree is-85 Kpa, and the hot stamping time is set to 8 min. And after the hot pressing process is finished, taking out the microneedle male die after the die is cooled to a proper temperature.

And (3) depositing silver on the conductive metal layer on the same side of the microneedle male die and the substrate by adopting a PVD process, and electroforming a nickel-cobalt alloy layer by adopting high-frequency pulse current, wherein the thickness of the metal deposition layer is 20 mu m. And (3) coating a polyimide coating on the surface of the metal deposition layer, wherein the thickness is 900 mu m, and cutting the microneedle tips by a wafer cutting machine after heat drying and curing. In the embodiment, the cutting is performed in a needle point tangent mode, the side face of the cutting edge is flush with the diagonal line of the bottom face of the rectangular pyramid microneedle body during cutting and is perpendicular to the cutting plane, the distance between the side face of the edge, which is close to the tip of the microneedle, and the axis of the microneedle on the same side is 0, and the distance between the effective cutting outline of the cutting edge and the tip of the microneedle is 160 mu m. And immersing the microneedle array and the substrate which finish the processing of the microneedle tips in chloroform solution, and synchronously carrying out high-frequency ultrasonic on the solution in the process until the microneedle metal male die is removed.

Example 4

In example 4, the method for depositing the male die and the metal layer of the sheet metal hollow microneedle array is the same as that in example 3, a polyimide coating is coated on the surface of the metal deposition layer, the thickness is 900 μm, after the heat drying and curing, the microneedle tips are cut by a wafer cutting machine, the specific cutting mode is beveling, the side face of the cutting edge is flush with the diagonal line of the bottom face of the quadrangular pyramid microneedle body during cutting, and the side face of the cutting edge and the cutting plane form a certain angle, as shown in fig. 14. The included angle alpha of the embodiment is 70 degrees, and the lowest position of the cutting needle body of the cutting edge is 400 mu m away from the needle point. The finished sheet-like microneedle array is shown in fig. 15, and the individual needles are enlarged as in fig. 16.

And immersing the microneedle array and the substrate which finish the processing of the microneedle tips in chloroform solution, and synchronously carrying out high-frequency ultrasonic on the solution in the process until the microneedle metal male die is removed.

Example 5

In example 5, the male die of the sheet metal hollow microneedle array and the metal layer deposition method are the same as those in example 3, a polyimide coating is coated on the surface of the metal deposition layer, the thickness is 900 μm, after heat drying and curing, the microneedle tips are treated by laser drilling, the polyimide coating coated before laser drilling can be omitted, and the polyimide coating is preferably reserved, so that the microneedle bodies can be properly protected in the subsequent processing process. During processing, the wafer subjected to the metal layer deposition of the microneedle male die is horizontally placed on a processing platform, so that the laser beams are ensured to be completely perpendicular to the plane of the microneedle array, light spots are focused on the central line of the side face of the needle body, and the horizontal distance between the light spots and the axis of the microneedle is 10 mu m. And immersing the microneedle array and the substrate which finish the processing of the microneedle tips in chloroform solution, and synchronously carrying out high-frequency ultrasonic on the solution in the process until the microneedle metal male die is removed, and drilling to finish the needle body is shown in figure 18.

Example 6: preparation of sheet metal hollow microneedle array product

Hollow microneedles are often prepared in an array arrangement, and thereafter often require further integration into a variety of different structures, either as the final article or as a component thereof. This example 6 uses the sheet metal hollow microneedle array prepared in example 5, which was further slit into 4*4 microneedle array sheets. The microneedle array sheet, together with the connector, is assembled with a base having two connection ports, and finally sealed and fixed with a sealing adhesive (as shown in fig. 19). The base of the embodiment adopts medical grade PVC material, adopts precise injection molding, has a cylindrical structure, has a diameter of 14mm and a height of 12mm, is arranged on one side of an integrated sheet-shaped hollow microneedle port of the base, is provided with netlike connecting channels corresponding to the positions of through holes of the connecting pieces, and is provided with a tube seat structure corresponding to the pins of the connecting pieces one by one. The other side of the base has a threaded configuration, as shown in fig. 20, which facilitates connection with other components. The base has one or more channels therein connecting the ports on both sides. The connecting piece adopts medical grade 304 stainless steel material, prepares through laser processing, and thickness 0.1mm, connecting piece area array through-hole and fixed pin, array through-hole centre-to-centre spacing is the same with the hollow microneedle axle center distance of slice, the pin is perpendicular to connecting piece through-hole place plane.

During assembly, the microneedle array sheet is adhered to the connecting piece by using an adhesive, the axes of the microneedles correspond to the centers of the through holes of the connecting piece array one by one during adhesion, and after the bonding and fixing, the pins of the connecting piece are inserted into the tube seat structure of the end face of the base, and the pins are fixed again by using glue. Finally, the periphery of the edge of the sheet hollow microneedle contacted with the base is coated with sealing structural adhesive, and the preparation of the microneedle product is completed after the sealing structural adhesive is cured, as shown in fig. 21.

Example 7

This example used the sheet metal hollow microneedle array prepared in example 3, which was further slit into 5*5 microneedle array sheets. The base of the embodiment adopts medical grade PVC material, adopts precise injection molding, has a cylindrical structure, has a diameter of 16mm and a height of 16mm, is arranged on one side of an integrated sheet-shaped hollow microneedle port of the base, is provided with netlike connecting channels corresponding to the positions of through holes of the connecting pieces, and is provided with a tube seat structure corresponding to the pins of the connecting pieces one by one. The base has one or more channels therein connecting the ports on both sides. The other side port of the base is a luer, as shown in fig. 22, which facilitates connection with other components. The embodiment adopts a medical grade 304 stainless steel connecting piece, the thickness is 0.2mm, the connecting piece is provided with an array through hole and a fixed pin, the center distance of the array through hole is the same as the axle center distance of the sheet hollow micro-needle, and the pin is perpendicular to the plane where the connecting piece through hole is located.

During assembly, the microneedle array sheet is adhered to the connecting piece by using an adhesive, the axes of the microneedles correspond to the centers of the through holes of the connecting piece array one by one during adhesion, and after the bonding and fixing, the pins of the connecting piece are inserted into the tube seat structure of the end face of the base, and the pins are fixed again by using glue. And finally, coating sealing structural adhesive around the edge of the sheet hollow microneedle contacted with the base, and preparing the microneedle product after curing.

Example 8

In example 8, the sheet metal hollow microneedle array prepared in example 3 was used, and further cut into 4*4 microneedle array sheets. The base of this embodiment is medical grade PP material, adopts accurate injection moulding, and the main part appearance is cylindrical structure, diameter 14mm, high 16mm, and the base includes three connection port, as shown in FIG. 23. The first port 2310 is used for integrating the sheet-shaped hollow micro needle, the second port 2320 is a threaded interface, and the third port 2330 is positioned on the cylindrical surface and is a luer interface. The base has one or more channels therein connecting the first port and the second port. The base also has one or more channels therein connecting the first port and the third port. The first ports 2310 are distributed with net-shaped connection channels corresponding to the positions of the through holes of the connecting pieces, and the ports are simultaneously provided with tube seat structures corresponding to the pins of the connecting pieces one by one and circular ring structures 2340 higher than the integration plane of the flaky hollow micro-needles. For example, the height of the annular structure with respect to the integration plane of the sheet-shaped hollow microneedle can be set to an annular structure of 0.9mm, and the annular thickness can be set to 0.6mm. The second port 2320 facilitates the integration of the sheet-like hollow microneedle with the base and the connection of other components and enables the delivery or extraction of fluid through the hollow microneedle needle aperture, the base and the second port throughbore at a specific time. The third port 2330 is convenient for the sheet hollow microneedle to be connected with other parts after being integrated with the base, and the circular ring structure that the first port is higher than the integrated plane of the sheet hollow microneedle is combined, so that the delivery or the gas extraction of the outer surface area of the sheet hollow microneedle can be completed through the base and the third port through hole at a specific time, and the functions of vacuum negative pressure or vacuum breaking and the like are provided.

The connecting piece is made of medical grade 304 stainless steel and is made of a precise machining method, the thickness of the connecting piece is 0.1mm, the connecting piece is provided with an array through hole and fixed pins, the center distance of the array through hole is the same as the axle center distance of the sheet hollow micro-needle, and the pins are perpendicular to the plane where the through holes of the connecting piece are located. During assembly, the microneedle array sheet is adhered to the connecting piece by using an adhesive, the axes of the microneedles correspond to the centers of the through holes of the connecting piece array one by one during adhesion, and after the bonding and fixing, the pins of the connecting piece are inserted into the tube seat structure of the end face of the base, and the pins are fixed again by using glue. Finally, the sealing structural adhesive is coated around the edge of the sheet hollow microneedle contacted with the base, and the microneedle product is prepared 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 further cut into 1*3 microneedle array sheets. The base is medical grade PVC material, adopts accurate injection moulding, and the main part appearance is wedge structure, and high 12mm, the base includes two connection ports, distributes the base both sides face. The base has one or more channels therein connecting the first port and the second port. The first port is used for integrating the flaky hollow micro-needle, the second port is a luer interface, other components are connected after the flaky hollow micro-needle and the base are integrated, and the delivery or extraction of fluid can be completed through the hollow micro-needle hole, the base and the through hole of the second port at a specific time.

When assembling, aligning the microneedle array sheet with the net-shaped connecting channel of the base, and bonding and fixing by using an adhesive. And then coating sealing structural adhesive around the edge of the sheet hollow microneedle contacted with the base, and preparing the microneedle product after curing, as shown in fig. 25.

The mechanical property of the micro-needle plays a very important role in smoothly implementing the micro-needle product, and in the mechanical test index, the axial force data of the micro-needle body can be relatively better used for measuring the mechanical property in the process of implementing the micro-needle penetration into the tissue. In the method for testing the axial force of the microneedle, a force measuring instrument is generally adopted to vertically downwards press the needle body, and displacement and load force conditions are synchronously collected in the pressing process, and a load displacement curve is generated.

In some embodiments of the present utility model, the test was performed using a push-pull tester (Japanese company, force, chemicals RHESCA PTR-1101). During testing, the sheet metal hollow microneedle array is horizontally adhered to the test fixing piece, the fixing piece is fixed on the equipment test platform, the horizontal condition is observed in the process, and the inclined condition of the sheet metal hollow microneedle array is avoided. And setting equipment parameters to ensure that the equipment pressing probe coincides with the axis of the measured microneedle body. Fig. 26 shows test results according to an embodiment of the present utility model. From fig. 26, it can be seen that no obvious numerical mutation is observed in the test curve, the continuity of the curve is better, and the optical images of the needle body before and after the test are synchronously combined, so that the fact that the metal hollow microneedle body is broken in the test process is confirmed. Typical forces associated with the penetration of microneedles of the dimensions used in the test into human skin are well below 1N. By combining the appearance structure and the size of the micro-needle, the axial force at the moment of taking down the displacement of 10 mu m represents the bearable force value of the micro-needle tip in the process of puncturing, and test data show that the micro-needle can effectively puncture human skin without breaking and bending.

Still further, the microneedles prepared in examples 2, 3, and 4 were tested for axial force as described above, and the test results are shown in the following table:

table 1: microneedle axial force test data for different embodiments

In the test data, the microneedle axial force of the example 4 is relatively optimal, the RSD value is minimum, no obvious difference is found in the data of each example, and the microneedle of each example meets the requirements of effectively penetrating into human skin without breaking and bending in combination with the analysis.

Next, a puncture test was performed on the sheet metal hollow microneedle array article.

Puncture testing was performed using the sheet metal hollow microneedle array article prepared in example 7. In combination with the current research results, the pigskin skin is generally considered to be relatively close to the human skin structure, and the pigskin skin is adopted to simulate the process and the result of the micro needle penetrating the human skin.

The microneedle product is fixed on a push-pull force instrument (RHESCA PTR-1101 of Japanese company, inc.) test motion module, the isolated pigskin is flatly paved and fixed on a test platform, the instrument pushes the microneedle product vertically to the surface of the pigskin with 20N thrust, after penetration, the microneedle product is reset, a cotton swab dips in 0.005% methylene blue solution to dye the penetrated part, and the dyeing result is shown in figure 27.

The test picture can clearly observe 25 dyeing points, and corresponds to the 5*5 metal hollow microneedle array carried by the product of the embodiment, and the effectiveness of the puncture of the microneedle body is verified.

Further, the microneedle surface of the product of this example was treated, coated with a methylene blue solution and dried, and the above-mentioned pig skin penetration test was repeated, and then the distribution of methylene blue in the pig skin was scanned using a german lycra confocal microscope (TCS SP8 STED), so that the penetration depth of the microneedle was analyzed, and the test results were as follows:

table 2: micro-needle product pigskin penetration depth

	Pigskin puncture
		Number of tests	5
Average penetration depth μm	480
		Standard deviation μm	102
RSD(％)	21.5

The puncture experiment is repeatedly carried out for 5 times, 5 confocal microscopes randomly select 5 needle holes generated by the puncture implementation for measurement scanning each time, 25 measurement data are obtained, the average puncture depth is 480 mu m, and no fracture and bending condition of the microneedle needle body are found in and after the test experiment.

Next, sheet metal hollow microneedle array article injection testing was performed.

This injection test was performed using the sheet metal hollow microneedle array product prepared in example 9. The solution injection is carried out after the micro needle is simulated to puncture the skin of the human body by adopting the in-vitro suckling pig skin. The microneedle article was connected to a test line where the injectate was replaced with 0.005% methylene blue solution. The test was performed by first penetrating the microneedle vertically into the simulated skin and maintaining it, then applying 15psi back pressure to the tubing, counting the time required for 100 μl of injectate to be injected, and the test structure is as follows:

Table 3: microneedle product pigskin injection

	Pigskin injection
		Number of tests	5
Injection back pressure psi	15
		Injection volume [ mu ] L	100
Average injection time s	35
		Standard deviation s	4.4
RSD(％)	12.6

The injection experiment was repeated 5 times with an average injection duration of 35s. During and after the test, no fracture or bending of the microneedle body is found. After testing, the microneedle article was removed and a small amount of solution was observed to spill from the skin surface, as shown in fig. 28, and methylene blue was simultaneously observed to have diffused in subcutaneous scattering to form a color spot centered on the injection site.

While various embodiments of the present utility model 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 variations can be made therein without departing from the spirit and scope of the utility model. Thus, the breadth and scope of the present utility model as disclosed herein should not be limited by any of the above-described exemplary embodiments, but should be defined only in accordance with the following claims and their equivalents.

Claims

1. A sheet-like hollow microneedle, comprising:

a base layer; and

the hollow needle body is integrally formed with the substrate layer and is composed of the same material layer, and the hollow needle body comprises a needle point at the top and a needle hole penetrating through the material layer, so that the needle hole is communicated with a hollow part of the hollow needle body.

2. The sheet-like hollow microneedle according to claim 1, wherein a needle hole formed by partially removing a top material layer and a needle tip formed by top surplus material are provided on top of the hollow needle body by cutting perpendicularly to the base layer by a cutting blade.

3. The sheet-shaped hollow microneedle according to claim 1, wherein a bevel formed by cutting a cutting blade along an inclination with respect to the base layer is provided at the top of the hollow needle body, the tip of the bevel constituting a needle tip, and a needle hole penetrating through the material layer is provided in the bevel.

4. The sheet-shaped hollow microneedle according to claim 1, wherein the substrate layer is flat sheet-shaped or has a certain concave-convex shape, and the outline of the substrate layer is of any shape and has a thickness of 1-1000 μm.

5. The sheet-like hollow microneedle according to claim 1, characterized in that,

the height of the hollow needle body is 100-2500 mu m, the side length or diameter of the bottom of the needle body is 10-1000 mu m, and the diameter or longest diagonal of the needle hole is 1-200 mu m.

6. The sheet-like hollow microneedle according to claim 1, wherein the hollow needle body is cone-shaped, pyramid-combined with a cylinder, cone-combined with a cylinder, pyramid-combined with a pyramid-and-a-table, or cone-combined with a table.

7. The sheet-like hollow microneedle of claim 1, wherein said sheet-like hollow microneedle comprises a plurality of hollow needle bodies arranged in an array.

8. The sheet-like hollow microneedle of claim 7, wherein the distribution density, shape, and/or size of the microneedle at different locations in the array is the same or different.

9. The sheet-like hollow microneedle of claim 7, wherein the microneedle distribution density in said array is 1 to 100 needles per square centimeter.

10. The sheet-shaped hollow microneedle according to claim 1, wherein the pinhole is a pinhole penetrating a material layer formed by a laser beam at a top position of one side surface of the needle body.

11. The sheet-shaped hollow microneedle according to claim 1, wherein the diameter of the tip of the microneedle body is smaller than 60 μm, the aspect ratio of the needle body is in the range of 1 to 6, and the force feedback is greater than or equal to 0.5N when the vertical downward displacement at the tip of a single microneedle is greater than 30 μm.