CN105169552B - The production method for the metal-polymer microneedle array that magnetic field stretches - Google Patents

The production method for the metal-polymer microneedle array that magnetic field stretches Download PDF

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CN105169552B
CN105169552B CN201510526870.7A CN201510526870A CN105169552B CN 105169552 B CN105169552 B CN 105169552B CN 201510526870 A CN201510526870 A CN 201510526870A CN 105169552 B CN105169552 B CN 105169552B
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microneedle array
metal
microneedles
magnetic field
substrate
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CN105169552A (en
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蒋乐伦
陈志鹏
徐洁雯
焦家铭
金典雯
陈珂云
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Sun Yat Sen University
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Sun Yat Sen University
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M37/00—Other apparatus for introducing media into the body; Percutany, i.e. introducing medicines into the body by diffusion through the skin
    • A61M37/0015—Other apparatus for introducing media into the body; Percutany, i.e. introducing medicines into the body by diffusion through the skin by using microneedles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M37/00—Other apparatus for introducing media into the body; Percutany, i.e. introducing medicines into the body by diffusion through the skin
    • A61M37/0015—Other apparatus for introducing media into the body; Percutany, i.e. introducing medicines into the body by diffusion through the skin by using microneedles
    • A61M2037/0053—Methods for producing microneedles

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  • Health & Medical Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Dermatology (AREA)
  • Medical Informatics (AREA)
  • Anesthesiology (AREA)
  • Biomedical Technology (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Hematology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Media Introduction/Drainage Providing Device (AREA)

Abstract

本发明涉及生物医学工程方法的技术领域，公开了磁场拉伸的金属‑聚合物微针阵列的制作方法，包括以下制作步骤：1)、制备铁磁性流体；2)、微针阵列模具的弹簧针蘸取铁磁性流体；磁场中放置基体；3)、下压弹簧针，使铁磁性流体液滴抵接在基体上，往上提微针阵列模具，在基体上形成底宽上尖状的微针；4)、对微针进行固化；5)、在固化后的微针表面溅镀金属层，形成金属‑聚合物微针阵列。弹簧针蘸取铁磁性流体，利用磁场的磁力作用，铁磁性流体液滴在基体上形成底宽上尖的微针，将微针固化后，表面溅镀金属层，形成金属‑聚合物微针阵列；该制作方法操作简单方便，制作周期短、效率高、降低生产成本，利于微针的推广，实现批量生产。

The invention relates to the technical field of biomedical engineering methods, and discloses a method for manufacturing a metal-polymer microneedle array stretched by a magnetic field. The needle is dipped into the ferromagnetic fluid; the substrate is placed in the magnetic field; 3), press down the pogo pin to make the ferromagnetic fluid droplets abut on the substrate, and lift the microneedle array mold upward to form a sharp bottom-width and top-shaped microneedle on the substrate. Microneedles; 4), curing the microneedles; 5), sputtering a metal layer on the surface of the cured microneedles to form a metal-polymer microneedle array. The pogo pin is dipped in ferromagnetic fluid. Using the magnetic force of the magnetic field, the ferromagnetic fluid droplets form microneedles with a wide bottom and a sharp top on the substrate. After curing the microneedles, a metal layer is sputtered on the surface to form metal-polymer microneedles. The manufacturing method has the advantages of simple and convenient operation, short manufacturing period, high efficiency, and reduced manufacturing cost, which is beneficial to the popularization of microneedles and realizes mass production.

Description

The production method for the metal-polymer microneedle array that magnetic field stretches
Technical field
The metal-polymer stretched the present invention relates to the technical field of biomedical engineering method more particularly to magnetic field is micro- The production method of needle array.
Background technique
Traditional administration mode mainly has oral administration, drug administration by injection, sublingual administration, rectally and spraying sucking etc., These administration modes are respectively present more defect, as follows:
Although being administered orally, safe and simple, convenient and easy and expense is lower, and drug is easy by other drugs and food It influences, and makes the inefficiency of drug, be unable to reach pharmaceutically-active maximization, and some drugs will cause one to alimentary canal Fixed damage；Although drug administration by injection avoids the curative effect disadvantage of oral drugs, but more pain can be brought to patient, treatment effect Fruit can also be deteriorated；The administration modes such as sublingual administration, rectally and spraying sucking are then only used for individual several drugs, Wu Faman The demand that foot is administered now.In addition, there is also can not dilute completely drug above-mentioned convenient administration mode.
Currently, emerging administration mode mainly has cutaneous penetration and micropin administration.Cutaneous penetration is by coating agent form Drug is affixed on skin surface, drug delivery is carried out using the infiltration of skin, but due to the obstruction of skin, the transmission of drug is imitated Rate is low, speed is slow；And a kind of minimally invasive means as relative efficiency are administered in micropin, had both it is high-efficient, damage it is low, can be sustained, Speed waits four big advantages fastly, although micropin medicine-feeding technology has many advantages, such as, since micropin scaled fine is small, it is applicable in In the problem that the production of the micropin of administration is medical field, it is difficult to be processed with traditional handicraft.
The production of micropin mainly uses silicon materials, but unknown due to the brashness of silicon materials and biocompatibility, so that The micropin of silicon materials support is difficult to promote currently.On the contrary, polymer micro needle is good in the above performance but is difficult to, phase Over the ground, metal-polymer micropin shows well in mechanical performance, and the biocompatibility of some alloys is good, working process skill Art is mature, the production suitable for micropin.
In the prior art, the LIGA technology based on MEMS (MEMS technology) is metal-polymer microneedle array Production provides effective way, and still, costly and fabrication cycle is long due to synchronous X-ray, LIGA technology makes metal- The cost of polymer micro needle array is very high, and complex manufacturing process, is difficult to control, fabrication cycle is long, is not suitable for producing.
Summary of the invention
The purpose of the present invention is to provide the production methods for the metal-polymer microneedle array that magnetic field stretches, it is intended to solve It solves in the prior art, there are at high cost, fabrication cycle be long and complex manufacturing process for the production of metal-polymer microneedle array The problem of.
The invention is realized in this way the production method for the metal-polymer microneedle array that magnetic field stretches, including following system Make step:
1), preparation can be formed by curing the ferromagnetic fluids of micropin；
2) ferromagnetic fluids, are dipped using the spring needle of microneedle array mold, form the lower end of the spring needle There is ferromagnetic fluids drop；The microneedle array mold is placed in magnetic field, and is placed in magnetic field and has to ferromagnetic fluids The matrix of compatibility；
3), the spring needle is placed in above described matrix, the spring needle is pushed, makes the ferromagnetic of the spring needle lower end Property fluid drop abut on the matrix, then up mention the microneedle array mold, the ferromagnetic fluids drop is described Micropin pointed in bottom width is formed on matrix；
4), the micropin formed on the matrix is solidified；
5), the microneedle surface sputtered metal layer after the solidification forms metal-polymer microneedle array.
Compared with prior art, the production method for the metal-polymer microneedle array that magnetic field provided by the invention stretches, leads to It crosses and dips ferromagnetic fluids on the spring needle of microneedle array mold, form ferromagnetic fluids drop in the lower end of spring needle, it will Ferromagnetic fluids drop is connected on matrix, and using the magneticaction in magnetic field, ferromagnetic fluids drop forms bottom width on matrix The micropin of upper point, after micropin is solidified, surface sputtered metal layer forms metal-polymer microneedle array；Production method operation It is simple and convenient, fabrication cycle is short, it is high-efficient, can effectively reduce production cost, conducive to the popularization of micropin, it is raw to be easy to implement batch It produces, economic benefit and social benefit are significant.
Detailed description of the invention
Fig. 1 is the master of the making step one for the metal-polymer microneedle array that magnetic field provided in an embodiment of the present invention stretches Depending on schematic diagram；
Fig. 2 is the master of the making step two for the metal-polymer microneedle array that magnetic field provided in an embodiment of the present invention stretches Depending on schematic diagram；
Fig. 3 is the master of the making step three for the metal-polymer microneedle array that magnetic field provided in an embodiment of the present invention stretches Depending on schematic diagram；
Fig. 4 is the cut-away illustration for the metal-polymer microneedle array that magnetic field provided in an embodiment of the present invention stretches；
Fig. 5 is the solid of the micropin mold for the metal-polymer microneedle array that the magnetic field that stupid inventive embodiments provide stretches Schematic diagram.
Specific embodiment
In order to make the objectives, technical solutions, and advantages of the present invention clearer, with reference to the accompanying drawings and embodiments, right The present invention is further elaborated.It should be appreciated that the specific embodiments described herein are merely illustrative of the present invention, and It is not used in the restriction present invention.
Realization of the invention is described in detail below in conjunction with specific embodiment.
The same or similar label correspond to the same or similar components in the attached drawing of the embodiment of the present invention；It is retouched in of the invention In stating, it is to be understood that if the orientation or positional relationship for having the instructions such as term " on ", "lower", "left", "right" is based on attached drawing Shown in orientation or positional relationship, be merely for convenience of description of the present invention and simplification of the description, rather than indication or suggestion is signified Device or element must have a particular orientation, be constructed and operated in a specific orientation, therefore positional relationship is described in attached drawing Term only for illustration, should not be understood as the limitation to this patent, for the ordinary skill in the art, can To understand the concrete meaning of above-mentioned term as the case may be.
It is preferred embodiment provided by the invention shown in referring to Fig.1~5.
The production method of the metal-polymer microneedle array that magnetic field provided in this embodiment stretches the following steps are included:
1) ferromagnetic fluids for constituting micropin 14, are prepared, which can solidify solidification；
2) ferromagnetic fluids, are dipped using the spring needle 121 of microneedle array mold 12, so that 121 lower end of spring needle is formed There is ferromagnetic fluids drop 13, and microneedle array mold 12 is placed in magnetic field, matrix 11 is placed in magnetic field, the matrix 11 Or attractability affinity to ferromagnetic fluids；
3) spring needle 121 of microneedle array mold 12, is placed in 11 top of matrix, spring needle 121 is pushed, so that spring needle The ferromagnetic fluids drop 13 of 121 lower ends is connected to matrix 11, then up lifts mold 12, under the influence of a magnetic field, ferromagnetism Fluid drop 13 forms needle-shaped, that is, shape sharp in bottom width on matrix 11, forms micropin 14；
4) and to the micropin 14 being formed on matrix 11 solidify, multiple micropins 14 form micro- on matrix 11 Needle array；
5), one layer of metal layer of sputter on the surface of the micropin 14 on matrix 11, so that microneedle array forms metal-polymerization Object microneedle array.
In the production method of the metal-polymer microneedle array of above-mentioned offer, pass through the spring in microneedle array mold 12 Ferromagnetic fluids are dipped on needle 121, ferromagnetic fluids drop 13 are formed in the lower end of spring needle 121, by ferromagnetic fluids drop 13 are connected on matrix 11, and using the magneticaction in magnetic field, ferromagnetic fluids drop 13 forms sharp in bottom width on matrix 11 Micropin 14, after micropin 14 is solidified, surface sputtered metal layer forms metal-polymer microneedle array；Production method operation letter Folk prescription just, fabrication cycle is short, it is high-efficient, can effectively reduce production cost, conducive to the popularization of micropin 14, it is raw to be easy to implement batch It produces, economic benefit and social benefit are significant.
In the present embodiment, in step 4) and 5) between, after the micropin 14 on matrix 11 solidifies, smeared on matrix 11 PDMS solution is also convenient for sputtered metal layer so that matrix 11 obtains good substrate mechanical property and surface property, also, The surface of micropin 14 plates one layer of metal, conveniently dips drug on micropin 14 and is administered.
Alternatively, the flexible substrates of PDMS solution formation are formed on matrix 11, in this way, micropin battle array as other embodiments Ferromagnetic fluids drop 13 on the spring needle 121 of column mold 12 directly abuts on a flexible substrate, micro- after micropin 14 solidifies Needle array then can directly be distinguished with flexible substrates, then can sputter in the vacuum between without coating PDMS solution again Metal layer forms metal-polymer microneedle array.
Specifically, matrix 11 generally uses filter paper, it is of course also possible to use other materials, consequently facilitating spring needle 121 Ferromagnetic fluids drop 13 is stretched on the surface of matrix 11, forms micropin 14, and manufacture is suitable for the metal-polymer of different field Microneedle array.
In addition, when in order to avoid stretching, matrix 11 is difficult to solid when spring needle 121 is when stretching ferromagnetic fluids drop 13 It is fixed, it is equipped with bottom glass piece in the lower section of matrix 11, and be respectively equipped with pressed glass piece in the two sides of the top of matrix 11, utilized Pressed glass piece is pressing against matrix 11, so that stretching of the ferromagnetic fluids drop 13 in magnetic field is gone on smoothly.
In the present embodiment, by when micropin 14 is solidified on the matrix 11 of formation, heat using the method for heating solid Change, heating film is set in the lower section of bottom glass, using heating film by the thermally conductive of bottom glass, on the matrix 11 of formation Micropin 14 is heating and curing.Also, in order to preferably control the heating temperature of heating film, connect between heating film and generator It is connected to controller, the heating of heating film is controlled using controller.Specifically, heating film can use PI heating film.
As other embodiments, the heat distributed after being powered using coil adds the micropin 14 on matrix 11 Heat.
Under normal circumstances, the temperature being heating and curing to micropin 14 is controlled using controller at 80 DEG C or less；Alternatively, Using other conditions of cure, micropin 14 can also be solidified using light (such as infrared light), to 1-2 hours Afterwards, the solidification of micropin 14 is completed, and microneedle array is obtained.
In the present embodiment, the coil used the power on generates magnetic field, also, in order to shorten metal-polymer microneedle array Multiple coils can be stacked together by fabrication cycle, increasing magnetic field, form the bigger magnetic field of intensity.
Specifically, using the metal frame in doorframe shape and alterable height, coil is placed in the lower section of metal frame, the coil is logical After electricity, then magnetic field is formed, above-mentioned matrix 11 and the mold 12 for dipping ferromagnetic fluids drop 13 are then placed in coil generation Magnetic field in.
Specifically, matrix 11 is arranged in magnetic field, and in order to guarantee the maximization of magnetic field strength, matrix 11 is placed on coil Center, also, in order to guarantee stretch micropin 14 structure it is more uniform, each spring needle of microneedle array mold 12 The amount of the ferromagnetic fluids drop 13 dipped on 121 is roughly equal.
In the present embodiment, the structure of microneedle array mold 12 is as follows: sequentially stacking placement with multiple magnet, it is flat to form multilayer Platform is placed with the copper sheet with pin hole on each magnet, and the upper end of spring needle 121 is plugged in the pin hole of copper sheet, and makes The syringe needle of multiple 121 lower ends of spring needle is in same plane arrangement.
Specifically, under normal circumstances, platform is built using 2~3 layers of magnet, places copper on the platform that each magnet is formed Piece.
In above-mentioned steps 4) in, after spring needle 121 dips ferromagnetic fluids drop 13, ferromagnetic fluids drop 13 is in base It being stretched on body 11 after forming micropin 14, the syringe needle for needing to dip the spring needle 121 of ferromagnetic fluids drop 13 steeps in alcohol, When the residual ferromagnetic fluids on 121 syringe needle of spring needle are dissolved in alcohol, wiped clean and after air-drying, 121 ability of spring needle It continues to use.
In the present embodiment, stretchable ferromagnetic fluids include micron order or nano-scale particle and high molecular material, according to According to performance requirement, according to suitable ratio, micron order or nano-scale particle are mixed with high molecular material, preferably the mixing of the two Ratio is 1:1；Also, as a preferred embodiment, high molecular material is epoxy resin.
The foregoing is merely illustrative of the preferred embodiments of the present invention, is not intended to limit the invention, all in essence of the invention Made any modifications, equivalent replacements, and improvements etc., should all be included in the protection scope of the present invention within mind and principle.

Claims (8)

1.磁场拉伸的金属-聚合物微针阵列的制作方法，其特征在于，包括以下制作步骤：1. the manufacture method of the metal-polymer microneedle array of magnetic field stretching, is characterized in that, comprises the following manufacture steps: 1)、制备可以固化形成微针的铁磁性流体；1), prepare a ferromagnetic fluid that can be solidified to form microneedles; 2)、利用微针阵列模具的弹簧针蘸取所述铁磁性流体，使所述弹簧针的下端形成有铁磁性流体液滴；将所述微针阵列模具置于磁场中，且磁场中放置有对铁磁性流体具有亲和性的基体；2), use the pogo pin of the microneedle array mold to dip the ferromagnetic fluid, so that the lower end of the pogo pin is formed with ferromagnetic fluid droplets; place the microneedle array mold in a magnetic field, and place in the magnetic field There is a matrix with affinity for ferrofluid; 3)、将所述弹簧针置于所述基体上方，下压所述弹簧针，使所述弹簧针下端的铁磁性流体液滴抵接在所述基体上，再往上提所述微针阵列模具，所述铁磁性流体液滴在所述基体上形成底宽上尖状的微针；3) Place the pogo pin above the base, press down the pogo pin, make the ferromagnetic fluid droplet at the lower end of the pogo pin abut on the base, and then lift the microneedle up an array mold, wherein the ferromagnetic fluid droplets form microneedles with a bottom width and a pointed top on the substrate; 4)、对形成在所述基体上的微针进行固化，采用线圈通电后对所述基体上的微针加热固化，且控制加热温度在80℃以下，将多个所述线圈叠放在一起，形成强度更大的磁场；4) Curing the microneedles formed on the substrate, heating and curing the microneedles on the substrate after the coil is energized, and controlling the heating temperature to be below 80°C, and stacking a plurality of the coils together , forming a stronger magnetic field; 5)、在所述固化后的微针表面溅镀金属层，形成金属-聚合物微针阵列。5), sputtering a metal layer on the surface of the cured microneedles to form a metal-polymer microneedle array. 2.如权利要求1所述的磁场拉伸的金属-聚合物微针阵列的制作方法，其特征在于，在所述步骤4)与步骤5)之间，当所述基体上的微针固化后，在所述基体上涂抹PDMS溶液。2. The method for producing a magnetic-field stretched metal-polymer microneedle array according to claim 1, wherein between the step 4) and the step 5), when the microneedles on the substrate are cured Then, apply PDMS solution on the substrate. 3.如权利要求1所述的磁场拉伸的金属-聚合物微针阵列的制作方法，其特征在于，放置在所述磁场内的基体上形成有PDMS溶液形成的柔性基底。3 . The method for fabricating a metal-polymer microneedle array stretched by a magnetic field according to claim 1 , wherein a flexible substrate formed of a PDMS solution is formed on the substrate placed in the magnetic field. 4 . 4.如权利要求1至3任一项所述的磁场拉伸的金属-聚合物微针阵列的制作方法，其特征在于，在所述步骤3)中，所述基体的下方设有底部玻璃片，且在所述基体上方的两侧分别设有压紧玻璃片。4. The method for producing a magnetic-field stretched metal-polymer microneedle array according to any one of claims 1 to 3, wherein in the step 3), a bottom glass is provided below the substrate The two sides above the base are respectively provided with pressed glass sheets. 5.如权利要求4所述的磁场拉伸的金属-聚合物微针阵列的制作方法，其特征在于，在所述步骤4)中，在所述底部玻璃片设置加热膜，通过所述加热膜加热固化所述基体上的微针。5. The method for producing a magnetic-field stretched metal-polymer microneedle array according to claim 4, wherein in the step 4), a heating film is arranged on the bottom glass sheet, and the heating The film heat cures the microneedles on the substrate. 6.如权利要求5所述的磁场拉伸的金属-聚合物微针阵列的制作方法，其特征在于，所述加热膜与发电机之间设有控制器，利用所述控制器控制加热膜的加热温度。6 . The method for manufacturing a magnetic-field stretched metal-polymer microneedle array according to claim 5 , wherein a controller is provided between the heating film and the generator, and the heating film is controlled by the controller. 7 . heating temperature. 7.如权利要求1至3任一项所述的磁场拉伸的金属-聚合物微针阵列的制作方法，其特征在于，采用高度可变的金属架，在所述金属架下方放置线圈，所述线圈通电后形成磁场，所述基体放置在所述线圈的中心位置。7. The method for producing a magnetic-field stretched metal-polymer microneedle array according to any one of claims 1 to 3, wherein a metal frame with a variable height is used, and a coil is placed under the metal frame, After the coil is energized, a magnetic field is formed, and the base body is placed at the center of the coil. 8.如权利要求1至3任一项所述的磁场拉伸的金属-聚合物微针阵列的制作方法，其特征在于，所述微针阵列模具包括多个依序堆叠放置的磁铁，各个所述磁铁上设有带针孔的铜片，所述弹簧针的上端插设在所述铜片的针孔中，且所述弹簧针下端的针头处于同一平面位置。8. The method for making a magnetic-field stretched metal-polymer microneedle array according to any one of claims 1 to 3, wherein the microneedle array mold comprises a plurality of magnets stacked in sequence, each The magnet is provided with a copper sheet with pin holes, the upper end of the pogo pin is inserted into the pin hole of the copper sheet, and the needles of the lower end of the pogo pin are in the same plane position.
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CN103908739A (en) * 2014-03-05 2014-07-09 中山大学 Method for manufacturing metal microneedle array
CN104307097A (en) * 2014-10-28 2015-01-28 中山大学 Method for manufacturing flexible-substrate metal microneedle array
CN104707240A (en) * 2015-03-06 2015-06-17 中山大学 Method for manufacturing magnetic guiding nanometer connection porous microneedle array

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