Microneedle chip and manufacturing method thereof

Abstract

A microneedle chip and manufacturing method. The method comprises injecting, into a female mold, a fluid needle liquid, wherein forming cavities matching the shapes of needles of a microneedle chip are provided at the female mold and form a cavity array, injection inlets are provided at a surface of one side of the female mold, and air ejection openings are provided at a surface of another side of the female mold to form an air ejection surface; covering the air ejection surface of the female mold using a breathable film, and during injection, passing a gas through the breathable film so as to retain the liquid inside the forming cavities; curing the fluid needle liquid to form the microneedle chip, and demolding to obtain the same. By employing the air ejection openings and the breathable film, a liquid is retained while ejecting a gas, providing a favorable micro-injection effect.

Claims

1. A method for manufacturing a microneedle chip, the method comprising: placing a female mold with a gas-permeable membrane on a supporting plate besprinkled with through-holes, wherein the female mold is provided with a plurality of mold cavities matched with a shape of a needle body of the microneedle chip, each of the plurality of mold cavities is provided with an injecting inlet and an exhaust port, the plurality of mold cavities are arranged in a same direction to form an array of mold cavities, wherein the injecting inlet is open at one side surface of the female mold and located at a needle base end of the plurality of mold cavities, the exhaust port is open at the other side surface of the female mold and located at a needle tip end of the plurality of mold cavities, and a surface of the female mold having a plurality of the exhaust ports forms an exhaust surface; the gas-permeable membrane covers the exhaust surface, wherein the gas-permeable membrane is waterproof and has a gas permeability in a range of 12,000 to 150,000 cm3/(cm2*h*MPa) under a positive pressure in a range of 0.001 MPa to 0.5 MPa, or under a negative pressure in a range of −0.5 MPa to −0.001 MPa; placing the female mold, the gas-permeable membrane and the supporting plate in a chamber enclosed by a vacuum system and a pressurizing system, wherein the vacuum system comprises a vacuum pump and a first frame body that is disposed along an edge of the supporting plate, a receiving chamber for receiving the female mold and the gas-permeable membrane is formed on one side of the supporting plate, and a sealed hollow chamber that is in communication with the vacuum pump is formed on the other side of the supporting plate; and the pressurizing system comprises a second frame body that is matched with the first frame body so as to seal the female mold and the gas-permeable membrane in the receiving chamber, and a liquid loading port for applying pressure and loading liquid is disposed on the second frame body; injecting a fluidized needle body liquid containing a bioactive component from the liquid loading port into the female mold; allowing gas to pass through the gas-permeable membrane and the fluidized needle body liquid to be retained within the plurality of mold cavities by applying a positive pressure at a injecting side of the female mold to promote the injection of the fluidized needle body liquid into the mold cavities; and/or by vacuumizing at an exhaust port side of the female mold to form a negative pressure to promote the injection of the fluidized needle body liquid into the mold cavities; and demolding after the fluidized needle body liquid is cured to form the microneedle chip.

2. The method of claim 1, wherein the positive pressure applied at the injecting side of the female mold has an intensity of pressure in the range of 0.001 MPa to 0.9 MPa, and the negative pressure formed by vacuumizing at the exhaust port side of the female mold has an intensity of pressure in the range of −0.9 MPa to −0.001 MPa.

3. The method of claim 1, wherein the fluidized needle body liquid has a viscosity in a range of 100 cps to 60,000 cps.

4. The method of claim 3, wherein the fluidized needle body liquid has a viscosity in the range of 2,000 cps to 40,000 cps.

5. The method of claim 1, wherein the female mold includes a main body portion and a base portion; wherein the main body portion is provided with the plurality of the mold cavities, the injecting inlet at one side surface and the exhaust port at the other side surface, and the exhaust surface is formed by a surface provided with the exhaust port; the base portion has an inner surface covering over the exhaust surface and is internally provided with an exhaust hole, the exhaust hole in communication with the exhaust port at an end and open at an outer surface of the base portion at the other end, and having the same maximum radial size as that of the exhaust port and a length greater than 0 μm but less than or equal to 500 μm; and wherein the gas-permeable membrane covers over the outer surface of the base portion.

6. The method of claim 5, wherein the female mold has a thickness from an injecting inlet side to an outer surface side of the base portion in the range of 50 μm to 3,000 μm.

7. The method of claim 1, wherein the exhaust port has a maximum radial size in the range of 0.1 μm to 100 μm.

8. The method of claim 1, wherein the gas-permeable membrane is made of a polytetrafluoroethylene film or an adhesive fiber membrane of polytetrafluoroethylene and polyester fiber.

9. The method of claim 1, wherein the female mold is made of polydimethylsiloxane.

10. The method of claim 1, wherein after the fluidized needle body liquid is injected into the plurality of mold cavities of the female mold, a needle base material is coated on a needle base portion of the microneedle chip via a coating, and the fluidized needle body liquid and the needle base material, after being cured, are demolded to give the microneedle chip.

11. The method of claim 10, wherein the needle base material is at least one of polyvinylpyrrolidone K30, copolymer Gantrez AN-139, copolymer Gantrez S97 BF, or hyaluronic acid.

Description

BRIEF DESCRIPTION OF THE DRAWINGS

(1) FIG. 1 is a cross-sectional schematic view of a female mold according to a specific embodiment;

(2) FIG. 2 is an enlarged schematic view of part A shown in FIG. 1;

(3) FIG. 3 is a top schematic view of a female mold according to a specific embodiment;

(4) FIG. 4 is a schematic view of a mold set used in a specific embodiment;

(5) FIG. 5 is a top schematic view of a supporting plate according to a specific embodiment;

(6) FIG. 6 is a schematic view of a male mold according to Example 1;

(7) FIG. 7 is a schematic view of an injection process according to Example 1;

(8) FIG. 8 is a schematic view of the fluidized needle body liquid fully injecting into the mold cavities of the female mold according to Example 1;

(9) FIG. 9 is a schematic view of coating with a needle base material according to Example 1;

(10) FIG. 10 is a schematic view of a demoulding process according to Example 1;

(11) wherein: 100. male mold; 200. female mold; 210. main body portion; 211. exhaust port; 212. injecting inlet; 220. base portion; 221. exhaust hole; 300. gas-permeable membrane; 410. supporting plate; 420. vacuum pump; 430. first frame body; 500. second frame body; 510. liquid loading port; 600. fluidized needle body liquid; 610. needle body; 700. needle base material; 710. needle base layer.

DETAILED DESCRIPTION OF EMBODIMENTS

(12) To facilitate the understanding of the present disclosure, the present disclosure will be described more fully hereinafter with reference to the accompanying drawings. The accompanying drawings show preferred embodiments of the present disclosure. However, the present disclosure may be embodied in many different forms and is not limited to the embodiments described herein. Rather, these embodiments are provided for a purpose of more thorough and full understanding of the present disclosure.

(13) It should be noted that when an element is considered as being “in communication with” another element, it can be communicated with an element directly or a mediating element may be also present.

(14) Unless otherwise specified, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which the present disclosure belongs. The terms used herein is for the purpose of describing specific example only and is not intended to limit the present disclosure. As used herein, the term “and/or” includes any and all combinations of one or more of the associated items listed.

(15) Each of the raw materials used in the following examples are as follows:

(16) Sylgard 184 silicone elastomer, model Sylgard® 184, purchased from Dow Corning Corporation (USA);

(17) SILASTIC MDX4-4210 silicone elastomer of biomedical grade, model Silastic MDX4-4210, purchased from Dow Corning Corporation (USA);

(18) adhesive film of polytetrafluoroethylene and polyester fiber, model PUW876, purchased from DONG GUAN PUW EPTFE MATERIAL CO., LTD.;

(19) expanded polytetrafluoroethylene film, model PUW576, purchased from DONG GUAN PUW EPTFE MATERIAL CO., LTD.;

(20) Polyvinylpyrrolidone (PVP) K30, model K30, purchased from BASF (Germany);

(21) Copolymer Gantrez AN-139, model Gantrez AN-139, purchased from Ashland (USA);

(22) Copolymer Gantrez S97 BF, model Gantrez S97 BF, purchased from Ashland (USA).

(23) The mold used in the following examples is as follows:

(24) A mold for manufacturing a microneedle chip comprises a female mold and a gas-permeable membrane.

(25) As shown in FIGS. 1-2, a female mold 200 is provided with a plurality of mold cavities matched with the shape of a needle body of the microneedle chip, each of the mold cavities is provided with an injecting inlet 212 and exhaust port 211, and the plurality of mold cavities are arranged in the same direction to form an array of mold cavities; the injecting inlet 212 is open at one side surface of the female mold and located at a needle base end of the mold cavities, the exhaust port 212 is open at the other side surface of the female mold and located at a needle tip end of the mold cavities, and a surface of the female mold having a plurality of the exhaust port 211 forms an exhaust surface.

(26) In some embodiments, as shown in FIG. 2, the female mold is divided into a main body portion 210 and a base portion 220. The main body portion 210 is provided with a plurality of the mold cavities; as shown in FIG. 3, the main body portion 210 is provided with the injecting inlet 212 at one side surface and the exhaust port 211 at the other side surface; and the exhaust surface is formed by a surface provided with the exhaust port 211. Due to differences between the methods for manufacturing the female mold, the female mold can be further provided with the base portion 220, the base portion having an inner surface covering over the exhaust surface and being internally provided with an exhaust hole 221. The exhaust hole 221 is in communication with the exhaust port 211 at an end and is open at an outer surface of the base portion 220 at the other end. The exhaust hole 221 has the same maximum radial size as that of the exhaust port 211, and a length greater than 0 μm but less than or equal to 500 μm. At this time, the gas-permeable membrane covers over the outer surface of the base portion to prevent the passage of liquid and allow the passage of gas. It can be understood that, if the female mold does not include the base portion, the gas-permeable membrane covers the exhaust surface for preventing the passage of liquid and allowing the passage of gas.

(27) In some embodiments, the exhaust port 211 has a maximum radial size in the range of 0.1 μm to 100 μm. If the exhaust port is round in shape, the diameter is the maximum radial size; if the exhaust port is square in shape, the diagonal line length is the maximum radial size. The injecting inlet 212 has a maximum radial size in the range of 50 μm to 500 μm. The injecting inlet is preferably regular polygon or round in shape, wherein regular polygon can be square, regular hexagon, and the like. The diagonal line length or diameter is the maximum radial size. The female mold has a thickness from the injecting inlet side to an exhaust port side of the base portion, i.e. the overall thickness of the female mold, in the range of 50 μm to 3,000 μm.

(28) In some embodiments, the gas-permeable membrane is made of a polytetrafluoroethylene film or an adhesive fiber membrane of polytetrafluoroethylene and polyester fiber, wherein the polytetrafluoroethylene film further includes an expanded polytetrafluoroethylene film. The gas-permeable membrane is preferably an adhesive film of expanded polytetrafluoroethylene and expanded polyester fiber. In order to achieve a better gas exhaust effect, the gas-permeable membrane has an effect of waterproofness and gas permeability of 120 to 1,500 cm.sup.3(cm.sup.2/h)@0.1 bar under a positive pressure in the range of 0.001 Mpa to 0.5 Mpa, or a negative pressure in the range of −0.5 Mpa to −0.001 Mpa. Generally, the gas-permeable membrane, which has a thickness in the range of 50-2,000 μm and a micropore having a pore size of 0.05 μm to 0.5 μm provided thereon, is selected.

(29) In some embodiments, in order to facilitate the operation, as shown in FIG. 4, the mold further comprises a supporting plate 410, a vacuum system, and a pressurizing system; as shown in FIG. 5, the supporting plate 410 is besprinkled with through-holes and arranged below the gas-permeable membrane 300 so as to support the female mold 200 and the gas-permeable membrane 300. The vacuum system comprises a vacuum pump 420 and a first frame body 430. The first frame body 430 is disposed along an edge of the supporting plate 410. Meanwhile, a receiving chamber for receiving the female mold 200 and the gas-permeable membrane 300 is formed on one side of the supporting plate 410, and a sealed hollow chamber is formed on the other side of the supporting plate 410. The sealed hollow chamber is in communication with the vacuum pump 420. The pressurizing system comprises a second frame body 500. The second frame body 500 is matched with the first frame body 430, so that the female mold 200 and the gas-permeable membrane 300 are sealed in the receiving chamber, and a liquid loading port 510 for increasing a pressure and loading a liquid is provided on the second frame body 500.

Example 1

(30) A method for manufacturing a microneedle chip comprises the following steps:

1. Manufacture of the Male Mold

(31) By using MEMS (Micro-Electro-Mechanical System) technology, a male mold with a conical needle body model on the surface was formed by processing brass as raw material.

(32) In addition to brass, the male mold was also made of at least one of stainless steel, aluminum, a titanium alloy, nickel, palladium, silicon, and silicon dioxide. It was only necessary to select a female mold that is made of hard material and can cooperate with the female mold liquid solution to make mold cavities with good shape.

(33) The male mold can also be made by methods, such as ion etching, laser cutting, chemical etching, X-ray lithography micro-electro-mechanical systems, or UV lithography micro-electro-mechanical systems, and the like. It was only necessary to make a positive model with a precise shape.

(34) As shown in FIG. 6, the male mold was provided with an array of microneedle chip needle body model with 10×10 rows (100 pieces) and a height of 550 μm. In the array of microneedle chip needle body model, the needle body model has a bottom diameter of 150 μm and a needle spacing of 150 μm.

2. Manufacture of the Female Mold

(35) The pre-mixed and degassed Sylgard 184 silicone elastomer was taken as a female mold liquid solution and injected into the above male mold. The male mold was placed on a horizontal plane so that the needle tip of the male mold was pierced through a liquid surface of the female mold liquid solution. The male mold was left at 100° C. for 20 mins, and the female mold liquid solution was cured and demoulded to form a female mold of 5.0 cm×5.0 cm. The female mold was besprinkled with mold cavities that were sieve-like in shape and matched with the shape of the needle bodies of the microneedle chip. Meanwhile, due to the needle tip of the male mold being pierced through the liquid surface, the mold cavity of the female mold had an exhaust port at the needle tip end and in communication with the outer surface of the female mold. The exhaust port was round in shape and had a pore size of 15 μm.

3. Microinjection

(1). Preparation of Solution

(36) Dextran 40000, bovine serum albumin (BSA), carboxymethyl cellulose (CMC), and water for injection were mixed in a mass fraction ratio of 0.8:0.2:0.2:4.0, swelled until no significant precipitate left and used as the fluidized needle body liquid.

(37) The fluidized needle body liquid had a viscosity of 3765 cP.

(2). Injection

(38) A mold set as shown in FIG. 4 was used. The mold set further comprised a supporting plate 410, a vacuum system, and a pressurizing system. As shown in FIG. 5, the supporting plate 410 was besprinkled with through-holes and arranged below the gas-permeable membrane 300 so as to support the female mold 200 and the gas-permeable membrane 300. The vacuum system comprised a vacuum pump 420 and a first frame body 430. The first frame body 430 was disposed along an edge of the supporting plate 410. Meanwhile, a receiving chamber for receiving the female mold 200 and the gas-permeable membrane 300 was formed on one side of the supporting plate 410, and a sealed hollow chamber was formed on the other side of the supporting plate 410. The sealed hollow chamber was in communication with the vacuum pump 420. The pressurizing system comprised a second frame body 500. The second frame body 500 was matched with the first frame body 430, so that the female mold 200 and the gas-permeable membrane 300 were sealed in the receiving chamber, and a liquid loading port 510 for increasing a pressure and loading a liquid was provided on the second frame body 500.

(39) The above female mold was placed on a gas-permeable membrane made of a 4.0 cm×4.0 cm adhesive film of expanded polytetrafluoroethylene and polyester fiber, and the female mold and the gas-permeable membrane were placed as a whole on the supporting plate.

(40) Firstly, an appropriate amount of the above fluidized needle body liquid was sucked up and covered over a surface of the female mold to ensure that all the micropores of the mold cavities in the female mold were covered. As shown in FIG. 7, the female mold was covered and sealed with the second frame body; a pressure of 0.04 Mpa was applied from the liquid loading port in the upper portion, so that the fluidized needle body liquid was injected into the mold cavities matched with the shape of the needle bodies of the microneedle chip, as shown in FIG. 8.

4. Coating the Needle Base

(1). Preparation of Solution

(41) Polyvinylpyrrolidone (PVP) K30, copolymer Gantrez AN-139, glycerol, and ethanol solution having a volume percent of 50% were mixed in a mass fraction ratio of 1:3:0.5:10, uniformly swelled and used as a needle base material.

(2). Coating

(42) Excess needle body liquid was scraped away, and a solution of the above needle base material was coated by means of coating on the surface of the female mold that had been injected with the needle body liquid, as shown in FIG. 9.

5. Curing and Demoulding

(43) The above fluidized needle body liquid and the solution of the needle base material solution, after being cured and dried, was demoulded to give a blank microneedle chip without a drug, as shown in FIG. 10. The microneedle chip comprised a needle base layer 710 and a needle body 610. The microneedle chip obtained in this example, due to a good microinjection effect and no air embolism formation during the microinjection, was less prone to phenomenon of needle breakage or deficiency, and has a better uniformity and quality than those manufactured by conventional methods.

Example 2

(44) A method for manufacturing a microneedle chip comprises the following steps:

1. Manufacture of the Male Mold

(45) By using MEMS (Micro-Electro-Mechanical System) technology, a male mold with a conical needle body model on the surface was formed by processing brass as raw material. The male mold was provided with an array of microneedle chip needle body model with 10×10 rows (100 pieces) and a height of 950 μm. In the array of microneedle chip needle body model, the needle body model has a bottom diameter of 200 μm and a needle spacing of 300 μm.

2. Manufacture of the Female Mold

(46) The pre-mixed and degassed Sylgard 184 silicone elastomer was taken as a female mold liquid solution and injected into the above male mold. The male mold was placed on a horizontal plane so that the height, at which the needle tip of the male mold was submerged in the female mold liquid solution, is 200 μm. The male mold was left at 60° C. for 4 hours, and the female mold liquid solution was cured and demoulded to form a female mold of 5.0 cm×5.0 cm. Then an exhaust hole was made by perforating at a position corresponding to the needle hole at the other side of the female mold with a UV laser. Furthermore, the exhaust hole penetrated into the mold cavity and formed an exhaust port in the mold cavity matched with the shape of the needle body. The exhaust port was round in shape, and had a pore size of 30 μm. Finally, a female mold having a thick of 1150 μm was obtained. The female mold was besprinkled with mold cavities that were sieve-like in shape and matched with the shape of the needle bodies of the microneedle chip. The exhaust port was round in shape and had a pore size of 30 μm, and the exhaust hole had a length of 200 μm.

3. Microinjection

(1). Preparation of Solution

(47) Dextran 40000, bovine serum albumin (BSA), polyethylene glycol (PEG) 6000, salmon calcitonin (sCT), and water for injection were mixed in a mass fraction ratio of 1.0:0.3:0.4:0.1:4.0, swelled until no significant precipitate left and used as the fluidized needle body liquid.

(48) The fluidized needle body liquid had a viscosity of 4872 cP.

(2). Injection

(49) Injection was carried out by using the mold set of the Example 1.

(50) The above female mold was placed on a gas-permeable membrane made of a 4.0 cm×4.0 cm adhesive film of polytetrafluoroethylene and polyester fiber, and the female mold and the gas-permeable membrane were placed as a whole on the supporting plate.

(51) Firstly, an appropriate amount of the above fluidized needle body liquid was sucked up and covered over a surface of the female mold to ensure that all the micropores of the mold cavities in the female mold were covered. The female mold was covered and sealed with the second frame body; a pressure of 0.02 Mpa was applied from the liquid loading port in the upper portion, so that the fluidized needle body liquid was injected into the mold cavities matched with the shape of the needle bodies of the microneedle chip.

4. Coating the Needle Base

(1). Preparation of Solution

(52) Polyvinylpyrrolidone (PVP) K30, copolymer Gantrez AN-139, and ethanol solution having a volume percent of 50% were mixed in a mass fraction ratio of 1:3:10, uniformly swelled and used as a needle base material.

(2). Coating

(53) Excess needle body liquid was scraped away, and a solution of the above needle base material was coated by means of coating on the surface of the female mold that had been injected with the needle body liquid.

5. Curing and Demoulding

(54) The above fluidized needle body liquid and the solution of the needle base material solution, after being cured and dried, was demoulded to give a microneedle chip containing salmon calcitonin. The microneedle chip was less prone to phenomenon of needle breakage or deficiency, and has a better uniformity and quality.

Example 3

(55) A method for manufacturing a microneedle chip comprises the following steps:

1. Manufacturing of the Male Mold

(56) By using MEMS (Micro-Electro-Mechanical System) technology, a male mold with a conical needle body model on the surface was formed by processing brass as raw material. The male mold was provided with an array of microneedle chip needle body model with 10×20 rows (100 pieces) and a height of 250 μm. In the array of microneedle chip needle body model, the needle body model has a bottom diameter of 100 μm and a needle spacing of 100 μm.

2. Manufacturing of the Female Mold

(57) The pre-mixed and degassed SILASTIC MDX4-4210 silicone elastomer was taken as a female mold liquid solution and injected into the above male mold. The male mold was placed on a horizontal plane so that the needle tip of the male mold was pierced through a liquid surface of the female mold liquid solution. The male mold was left at room temperature for 24 hours, and the female mold liquid solution was cured and demoulded to form a female mold of 5.0 cm×5.0 cm. The female mold was besprinkled with mold cavities that were sieve-like in shape and matched with the shape of the needle bodies of the microneedle chip. Meanwhile, since the needle tip of the male mold was pierced through the liquid surface, the mold cavities of the female mold had an exhaust port at the needle tip end and in communication with an outer surface of the female mold. The exhaust port was round in shape and had a pore size of 25 μm.

3. Microinjection

(1). Manufacturing of Solution

(58) Dextran 40000, bovine serum albumin (BSA), polyethylene glycol (PEG) 4000, salmon calcitonin (sCT), and water for injection were mixed in a mass fraction ratio of 0.8:0.2:0.4:0.1:3.5, swelled uniformly and used as the fluidized needle body liquid.

(59) The fluidized needle body liquid had a viscosity of 4069 cP.

2. Injection

(60) Injection was carried out by using the mold set of the Example 1.

(61) The above female mold was placed on a gas-permeable membrane made of 4.0 cm×4.0 cm polytetrafluoroethylene film, and the female mold and the gas-permeable membrane were placed as a whole on the supporting plate.

(62) Firstly, an appropriate amount of the above fluidized needle body liquid was sucked up and covered over a surface of the female mold to ensure that all the micropores of the mold cavities in the female mold were covered. The female mold was covered and sealed with the second frame body. A negative pressure of −0.03 Mpa was made by vacuumizing from the lower portion, so that the fluidized needle body liquid was injected into the mold cavities matched with the shape of the needle bodies of the microneedle chip.

4. Coating the Needle Base

(1). Manufacturing of Solution

(63) Polyvinylpyrrolidone (PVP) K90, hyaluronic acid, copolymer Gantrez S97 BF and ethanol solution having a volume percent of 50% were mixed in a mass fraction ratio of 2:2:1:9, uniformly swelled and used as a needle base material.

(2). Coating

(64) Excess needle body liquid was scraped away, and a solution of the above needle base material was coated by means of coating on the surface of the female mold that had been injected with the needle body liquid.

5. Curing and Demoulding

(65) The above fluidized needle body liquid and the solution of the needle base material solution, after being cured and dried, was demoulded to give a microneedle chip containing salmon calcitonin. The microneedle chip was less prone to phenomenon of needle breakage or deficiency, and has a better uniformity and quality.

Example 4

(66) A method for manufacturing a microneedle chip comprises the following steps:

1. Manufacturing of the Male Mold

(67) By using MEMS (Micro-Electro-Mechanical System) technology, a male mold with a conical needle body model on the surface was formed by processing brass as raw material. The male mold was provided with an array of microneedle chip needle body model with 10×15 rows (150 pieces) and a height of 750 μm. In the array of microneedle chip needle body model, the needle body model has a bottom diameter of 200 μm and a needle spacing of 200 μm.

2. Manufacturing of the Female Mold

(68) The pre-mixed and degassed Sylgard 184 silicone elastomer was taken as a female mold liquid solution and injected into the above male mold. The male mold was placed on a horizontal plane so that the needle tip of the male mold was pierced through a liquid surface of the female mold liquid solution. The male mold was left at 120° C. for 15 mins, and the female mold liquid solution was cured and demoulded to form a female mold of 5.0 cm×5.0 cm. The female mold was besprinkled with mold cavities that were sieve-like in shape and matched with the shape of the needle bodies of the microneedle chip. Meanwhile, since the needle tip of the male mold was pierced through the liquid surface, the mold cavities of the female mold had an exhaust port at the needle tip end and in communication with an outer surface of the female mold. The exhaust port was round in shape and had a pore size of 15 μm.

3. Microinjection

(1). Manufacturing of Solution

(69) Dextran 60000, hyaluronic acid, Thymopentin (Tp5), and water for injection were mixed in a mass fraction ratio of 0.8:0.4:0.01:3.5, swelled until no significant precipitate left and used as the fluidized needle body liquid.

(70) The fluidized needle body liquid had a viscosity of 2193 cP.

2. Injection

(71) Injection was carried out by using the mold set of the Example 1.

(72) The above female mold was placed on a gas-permeable membrane made of a 4.0 cm×4.0 cm adhesive film of polytetrafluoroethylene and polyester fiber, and the female mold and the gas-permeable membrane were placed as a whole on the supporting plate.

(73) Firstly, an appropriate amount of the above fluidized needle body liquid was sucked up and covered over a surface of the female mold to ensure that all the micropores of the mold cavities in the female mold were covered. The female mold was covered and sealed with the second frame body. Two approaches was combined, including increasing a pressure of 0.1 Mpa from the upper portion and making a negative pressure of −0.1 Mpa by vacuumizing from the lower portion, so that the fluidized needle body liquid was injected into the mold cavities matched with the shape of the needle bodies of the microneedle chip.

4. Coating the Needle Base

(1). Manufacturing of Solution

(74) Polyvinylpyrrolidone (PVP) K90, glycerol, and anhydrous ethanol were mixed in a mass fraction ratio of 1:0.1:2.5, uniformly swelled and used as a needle base material.

(2). Coating

(75) Excess needle body liquid was scraped away, and a solution of the above needle base material was coated by means of coating on the surface of the female mold that had been injected with the needle body liquid.

5. Curing and Demoulding

(76) The above fluidized needle body liquid and the solution of the needle base material solution, after being cured and dried, was demoulded to give a microneedle chip containing thymopentin. The microneedle chip was less prone to phenomenon of needle breakage or deficiency, and has a better uniformity and quality.

Example 5

(77) A method for manufacturing a microneedle chip comprises the following steps:

1. Manufacturing of the Male Mold

(78) By using chemical etching technology, a male mold with a conical needle body model on the surface was formed by processing silicon oxide as raw material. The male mold was provided with an array of microneedle chip needle body model with 10×20 rows (200 pieces) and a height of 550 μm. In the array of microneedle chip needle body model, the needle body model has a bottom diameter of 180 μm and a needle spacing of 100 μm.

2. Manufacturing of the Female Mold

(79) The pre-mixed and degassed Sylgard 184 silicone elastomer was taken as a female mold liquid solution and injected into the above male mold. The male mold was placed on a horizontal plane so that the needle tip of the male mold was pierced through a liquid surface of the female mold liquid solution. The male mold was left at 120° C. for 20 mins, and the female mold liquid solution was cured and demoulded to form a female mold of 5.0 cm×5.0 cm. The female mold was besprinkled with mold cavities that were sieve-like in shape and matched with the shape of the needle bodies of the microneedle chip. Meanwhile, since the needle tip of the male mold was pierced through the liquid surface, the mold cavities of the female mold had an exhaust port at the needle tip end and in communication with an outer surface of the female mold. The exhaust port was round in shape and had a pore size of 20 μm.

3. Microinjection

(1). Manufacturing of Solution

(80) Dextran 40000, polyethylene glycol (PEG) 4000, chondroitin sulfate, salmon calcitonin, and water for injection were mixed in a mass fraction ratio of 1.0:0.5:0.2:0.1:4.0, swelled until no significant precipitate left and used as the fluidized needle body liquid.

(81) The fluidized needle body liquid had a viscosity of 8178 cP.

2. Injection

(82) Injection was carried out by using the mold set of the Example 1.

(83) The above female mold was placed on a gas-permeable membrane made of a 4.0 cm×4.0 cm adhesive film of polytetrafluoroethylene and polyester fiber, and the female mold and the gas-permeable membrane were placed as a whole on the supporting plate.

(84) Firstly, an appropriate amount of the above fluidized needle body liquid was sucked up and covered over a surface of the female mold to ensure that all the micropores of the mold cavities in the female mold were covered. The female mold was covered and sealed with the second frame body. Two approaches was combined, including increasing a pressure of 0.01 Mpa from the upper portion and making a negative pressure of −0.05 Mpa by vacuumizing from the lower portion, so that the fluidized needle body liquid was injected into the mold cavities matched with the shape of the needle bodies of the microneedle chip.

4. Coating the Needle Base

(1). Manufacturing of Solution

(85) Polyvinylpyrrolidone (PVP) K30, glycerol, and ethanol aqueous solution having a volume percent of 60% were mixed in a mass fraction ratio of 5:0.5:8, uniformly swelled and used as a needle base material.

(2). Coating

(86) Excess needle body liquid was scraped away, and a solution of the above needle base material was coated by means of coating on the surface of the female mold that had been injected with the needle body liquid.

5. Curing and Demoulding

(87) The above fluidized needle body liquid and the solution of the needle base material solution, after being cured and dried, was demoulded to give a microneedle chip containing salmon calcitonin. The microneedle chip was less prone to phenomenon of needle breakage or deficiency, and has a better uniformity and quality.

(88) The technical features in the above-described embodiments may be combined arbitrarily. For clarity of description, not all the possible combinations of the technical features in the above embodiments are described. However, as long as no contradiction exists between the combination of these technical features, it should be considered as being within the scope recorded in this Specification.

(89) The above-mentioned examples merely represent several embodiments of the present disclosure, and are described in a specific and detailed way, but it should not be construed as limiting the scope of the present disclosure. It should be noted that, for those skilled in the art, several variations and improvements may be made without departing from the concept of the present disclosure, and these are all within the protection scope of the present disclosure. Therefore, the scope of protection of the present disclosure shall be subject to the appended claims.