WO2020227895A1 - 一种平面金属微针阵列及其制备方法 - Google Patents

一种平面金属微针阵列及其制备方法 Download PDF

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Publication number
WO2020227895A1
WO2020227895A1 PCT/CN2019/086662 CN2019086662W WO2020227895A1 WO 2020227895 A1 WO2020227895 A1 WO 2020227895A1 CN 2019086662 W CN2019086662 W CN 2019086662W WO 2020227895 A1 WO2020227895 A1 WO 2020227895A1
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Prior art keywords
metal
microneedle
sheet
needle
micro
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English (en)
French (fr)
Inventor
马国军
吴承伟
牛玉婷
张伟
吕永涛
韩啸
马建立
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Dalian University of Technology
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Dalian University of Technology
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Priority to PCT/CN2019/086662 priority Critical patent/WO2020227895A1/zh
Priority to US16/960,169 priority patent/US11738185B2/en
Publication of WO2020227895A1 publication Critical patent/WO2020227895A1/zh
Anticipated expiration legal-status Critical
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Classifications

    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B21—MECHANICAL METAL-WORKING WITHOUT ESSENTIALLY REMOVING MATERIAL; PUNCHING METAL
    • B21G—MAKING NEEDLES, PINS OR NAILS OF METAL
    • B21G1/00—Making needles used for performing operations
    • B21G1/003—Needles for special purposes, e.g. knitting, crochet, hat-pins
    • 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
    • A61M2037/0046—Solid 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
    • 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
    • A61M2205/00—General characteristics of the apparatus
    • A61M2205/02—General characteristics of the apparatus characterised by a particular materials
    • A61M2205/0244—Micromachined materials, e.g. made from silicon wafers, microelectromechanical systems [MEMS] or comprising nanotechnology
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B23—MACHINE TOOLS; METAL-WORKING NOT OTHERWISE PROVIDED FOR
    • B23H—WORKING OF METAL BY THE ACTION OF A HIGH CONCENTRATION OF ELECTRIC CURRENT ON A WORKPIECE USING AN ELECTRODE WHICH TAKES THE PLACE OF A TOOL; SUCH WORKING COMBINED WITH OTHER FORMS OF WORKING OF METAL
    • B23H7/00—Processes or apparatus applicable to both electrical discharge machining and electrochemical machining
    • B23H7/02—Wire-cutting

Definitions

  • the invention belongs to the technical field of medical equipment and the field of mechanical processing, and relates to a planar metal microneedle array and a preparation method thereof.
  • Oral administration, injection administration and transdermal administration are currently the three most commonly used methods of administration, but oral administration needs to pass through tissues and organs such as the gastrointestinal tract and liver. Intestinal inactivation and liver "first pass" Some drugs are metabolized and the absorption efficiency is greatly reduced; on the other hand, some drugs can cause adverse gastrointestinal irritation and other side effects, which limits the application scope of oral administration, especially not suitable for protein, insulin, and DNA types. Drug delivery. Although injection drug delivery technology overcomes the above-mentioned shortcomings, penetrating a larger-sized ordinary needle into human tissues often brings pain that cannot be ignored to the patient.
  • transdermal administration refers to a drug delivery method in which the drug is directly applied to the surface of the skin and absorbed through the subcutaneous capillaries, then enters the human blood circulation and achieves an effective blood drug concentration to achieve disease treatment or defense.
  • transdermal administration has the following advantages: (1) It avoids the damaging effects of the liver and gastrointestinal tract on the drug, and improves the bioavailability of the drug; (2) It has a sustained release of the drug It can achieve long-acting and controllable administration; (3) The blood drug level is stable, which improves the efficacy of the drug; (4) It avoids the irritation of the gastrointestinal tract and reduces the toxic and side effects of the drug; (5) It can be achieved Painless, non-invasive or minimally invasive drug delivery; (6) Simple and convenient to use, no professional operation required. Because of these advantages, transdermal drug delivery technology has received extensive attention from researchers at home and abroad.
  • this drug delivery technology also has shortcomings such as small drug delivery doses, relatively low drug delivery efficiency, and limited drug delivery varieties.
  • the main reason is that the outermost layer of the skin has a stratum corneum composed of dead skin cells with a thickness of about 10-20 microns, which seriously hinders the penetration of drugs through the skin.
  • people continue to study the improved methods of transdermal drug delivery technology from the aspects of chemistry, physics and biology, such as the chemical method using various penetration enhancers and the use of ion Physical methods such as introduction, ultrasonic introduction, electroporation and supersonic jet of micro powder.
  • microneedles is receiving more and more attention.
  • Microneedle generally refers to a microneedle with a length of tens of microns to a few millimeters and a tip diameter of less than tens of microns.
  • the barrier function of the stratum corneum of the skin is a key issue that limits the transdermal drug delivery technology.
  • the use of microneedles will locally destroy the stratum corneum of the skin and temporarily form micron-sized drug delivery microchannels on the surface of the skin. An order of magnitude larger), which not only significantly improves the transdermal drug delivery efficiency, but also significantly increases the scope of application of transdermal drugs.
  • microneedle because the size of the microneedle is very small, it can only pierce the stratum corneum without nerves without touching the deep tissues of the skin rich in nerves and blood vessels. The pain and trauma caused by the piercing process are far less than traditional injections. Medicine, which can achieve painless, non-invasive or minimally invasive drug delivery. If combined with other microfluidic control systems, microneedles can also achieve long-term controlled drug delivery. After being specially designed and combined with the corresponding microfluidic control and analysis system, the microneedle can also be used for painless micro-biochemical analysis of the human body. Therefore, microneedle related research has become one of the hot research directions in the medical field.
  • microneedles at home and abroad mainly include silicon microneedles, glass microneedles, ceramic microneedles, metal microneedles, hydrogel microneedles, polymer microneedles, and sugars (such as maltose, lactose, etc.).
  • silicon is often used as a microneedle material because of its relatively mature processing technologies such as photolithography, dry etching, and wet etching, and its high hardness and easy penetration into the skin.
  • silicon microneedles have high requirements for environmental cleanliness, low processing efficiency, and high corresponding costs, so they cannot meet the requirements of mass production.
  • brittle material As a typical brittle material, silicon is prone to fracture and damage if the design is unreasonable, the processing is defective, or when it is subjected to greater stress during use. Moreover, due to the poor biocompatibility of silicon, it remains on the skin after fracture Fragments inside may cause adverse reactions. In severe cases, these tiny fragments may enter the blood vessels and heart, causing some worse consequences. Similar problems exist in brittle materials such as glass and ceramics. Polymers generally have better biocompatibility and toughness. On the one hand, they can reduce the rejection reaction of the body when used in the manufacture of microneedles. On the other hand, they can ensure that the microneedles penetrate into the skin without fracture and damage.
  • metal microneedles have good toughness and high strength, and the biological safety of metals such as stainless steel and titanium alloys has been verified for a long time, so they are considered to be one of the preferred materials for microneedles.
  • the processing methods of metal microneedles are quite abundant, including chemical etching, ultraviolet lithography, micro-milling, laser cutting, electroplating, etc., but these processing methods have the disadvantages of low processing accuracy, low processing efficiency and high cost, which are difficult to meet the batch requirements. Production requirements.
  • the present invention provides a sheet-like flat metal microneedle array and a new processing method thereof.
  • the flat microneedle array adopts sheet-like stainless steel with good biocompatibility, strength and toughness. Or titanium alloy material, prepared by traditional wire cutting technology.
  • the microneedle array is composed of a substrate 6 and a microneedle body 7 for subsequent clamping and assembly. The substrate and the needle body are integrated and are on the same plane. This type of microneedle array is easy to use, and the processing method can ensure accuracy and is suitable for high-efficiency and low-cost mass production.
  • a method for preparing a planar metal microneedle array includes the following steps:
  • the large-size metal foil is cut into small metal foils 5 that are convenient for clamping.
  • the small metal foil 5 has a thickness of 20 to 200 microns, a length of 30 to 50 mm, and a width of 10 to 30 mm.
  • the second step is to process special sheet clamping tooling
  • the tooling is composed of two identical upper and lower metal cover plates 2, and the overall thickness of each cover plate is 5-10 mm.
  • a groove 3 matching the size of the small metal sheet 5 is processed, that is, the length and width of the groove are consistent with the length and width of the metal sheet 5, which is used to place the metal sheet 5; 1 ⁇ 5mm; the peripheral edges of the upper and lower cover main body 2 are processed with through holes 1 for passing the fastening bolts 4.
  • the clamping tooling materials are metal materials such as stainless steel and 45# steel with good conductivity and high strength.
  • the third step is to place the small metal foil 5 in the groove 3 of any tooling metal cover for stacking.
  • the number of 5 metal foils placed at a time is adjusted according to the thickness of the foil and the depth of the groove; the other tooling metal cover is placed On the cover plate where the sheet metal has been placed, the grooves face the sheet metal and are aligned up and down; the upper and lower metal cover plates of the clamping tool are sealed by tightening bolts 4, and the metal sheet 5 is compacted to form a whole with the upper and lower cover plates.
  • the fourth step is to design the geometry and size of the chip microneedle array
  • the sheet-shaped microneedle array is composed of a substrate 6 and a microneedle body 7 for subsequent clamping parts, and is formed by integrally cutting the same metal sheet 5.
  • the number of microneedle bodies 7 on each substrate is 3-50, the distance between the microneedle bodies 7 is 0.25-10 mm, and the thickness is the thickness of the metal foil 5 itself.
  • Each microneedle body 7 is triangular or sword-shaped, with a height of 100 to 500 microns, a width of the root of the needle body of 50 to 300 microns, and a thickness of the metal foil 5 itself.
  • the fifth step is to clamp the metal foil 5 and tooling packaged in the third step to the wire cutting equipment.
  • the wire cutting equipment determines the wire path according to the microneedle geometry and size designed in the fourth step. Wire cutting is performed as a whole, and the metal sheet 5 is processed into a substrate 6 and a microneedle body 7. In the wire cutting process, the tip of the microneedle body 7 is cut using an "8"-shaped path to ensure the sharpness of the microneedle tip.
  • the substrate 6 is not completely cut, and 2 ⁇ 5 mm is reserved on both sides for cutting, ensuring that the tooling metal cover plate and the metal sheet 5 are still in the overall structure after cutting, which prevents the microneedles from being processed by the coolant. Washing away can ensure that the tooling after use still has sufficiently high structural rigidity, making the tooling reusable.
  • the sixth step is to remove the fastening bolts 4 on the tooling, take out the processed metal sheet 5 and clean it.
  • the seventh step is to cut the material in the reserved areas on both sides of the substrate 6 on the metal foil 5 described in the sixth step, so that the sheet-shaped microneedle array is peeled from the metal foil 5 to obtain a sheet with multiple microneedle bodies.
  • the planar metal microneedle array can be further assembled into three-dimensional microneedle arrays with different layout specifications by using the planar microneedle array for design use.
  • the sheet-shaped microneedle array is composed of a substrate 6 and a needle body 7.
  • the substrate 6 and the needle body 7 are integrally cut from the same metal sheet, and the substrate 6 and the needle body 7 are in the same plane and
  • the needle body 7 is located above the substrate 6, and the number, shape and size of the needle body 7 are adjusted as required.
  • the metal flake materials include medical stainless steel or titanium alloy materials; the height of the microneedle body 7 is 100-500 microns, the root width is 50-300 microns, and the thickness is the thickness of the metal flake 5; the number of microneedles on each substrate is 3 ⁇ 50 pieces, spacing 0.25 ⁇ 10mm, the shape of the microneedle body is triangle or sword.
  • the sheet-like flat microneedle design is conducive to simplifying the processing procedure, and it is flexible to use. Through simple assembly, three-dimensional microneedle arrays of different specifications can be made. Metal microneedle arrays can be processed in batches at one time, and the ideal total cutting thickness for wire cutting is 2 cm. For example, the overall wall thickness of the upper and lower parts of the tooling is 5 mm, the groove depth is 2 mm, and the thickness of each sheet of metal is 100 microns. The number of microneedles that can be cut at one time is 140, which is greatly improved in efficiency compared with other microneedle processing methods. In addition to the relatively low cost of wire cutting processing technology, the microneedle array processing method provided by the present invention has low cost.
  • the clamping tooling compacts the sheet into a whole, which can prevent the deviation of the processing size due to the lateral force during cutting. If the metal sheet is cut in a single piece, because the thickness is very thin, a small lateral force will be It is difficult to ensure the machining accuracy by deforming the microneedle; when the microneedle tip is cut, the "8"-shaped processing path is adopted, which can effectively avoid the tip passivation caused by directly changing the direction at the tip, thereby ensuring the machining accuracy of the microneedle tip.
  • Figure 1 is a front view of a sheet clamping tool
  • Figure 2 is a top view of the sheet clamping tool
  • Figure 3 is a side view of the sheet clamping tool
  • Figure 4 is a schematic diagram of the metal substrate after being put into the tooling and connected and compacted by bolts;
  • Figure 5 is a schematic diagram of the wire cutting processing path
  • Figure 6 is a schematic diagram (top view) of the sheet clamping tool after the cutting is completed without disassembly
  • FIG. 7 is an overall schematic diagram of the microneedle array and the substrate after the sheet clamping tool is disassembled after cutting, but the metal sheet is not cut;
  • Fig. 8 is a schematic diagram of a sheet-shaped planar microneedle array with a sword-shaped needle body after the final cutting is completed.
  • the microneedle material is a medical 304 stainless steel sheet material with good biocompatibility, strength and toughness.
  • the size of the sheet shown is 1000 mm in length, 100 mm in width, and 80 microns in thickness.
  • the large-sized stainless steel sheet is cut into small metal sheets 5 of suitable size and convenient for clamping.
  • the metal sheets 5 are 50 mm long, 25 mm wide, and 80 microns thick, but are not limited to this size.
  • the tooling structure is shown in Figure 1, Figure 2, and Figure 3.
  • the clamping tooling material is stainless steel, which has good electrical conductivity and high strength.
  • the tooling consists of two identical upper and lower metal cover plates 2. Each cover plate has a thickness of 6 mm, a cover plate length of 80 mm, and a width of 55 mm.
  • the inner walls of the upper and lower cover plates are provided with grooves 3 matching the size of the small sheet.
  • the groove 3 has a length of 50 mm and a width of 25 mm, and the depth of the upper and lower cover grooves is 3 mm.
  • Both sides of the tooling are processed to pass through the through holes 1 of the fastening bolts 4. In this embodiment, the diameter of the through holes 1 is 6 mm.
  • the microneedle array is composed of a substrate 6 and a microneedle body 7, which are formed by cutting the same metal sheet 5 as a whole.
  • the height of the microneedle body is 300 microns
  • the width of the root of the needle body is 150 microns.
  • the thickness is the thickness of the metal foil itself of 80 microns, and the shape of the needle body is sword-shaped; the number of microneedles on a single substrate is 7 and the pitch is 3.5 mm.
  • a CAD model of the planar microneedle is constructed.

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Abstract

一种平面金属微针阵列及其制备方法，属于医疗器械技术领域与机械加工领域。将大尺寸金属薄片裁剪为小型金属薄片；加工由上下两块金属盖板组成的夹持工装，工装上下盖板内侧设有与小型金属薄片尺寸匹配的凹槽，且盖板四周边缘处设有通孔；将金属薄片放置于凹槽内，并通过螺栓紧固；设计片状微针阵列的几何形状和尺寸，构建平面微针CAD模型；按照CAD模型切割走丝路径，微针尖端加工时采用"8"字形路径保证针尖尖锐程度，微针阵列基片两侧留少许材料不切割；加工完成后拆卸工装清洗基片，并裁切微针基片两侧未加工部分，得到具有多个微针针体的平面金属微针阵列。本发明通过简单组装可大批量制成微针阵列，成本低效率高，且能够保证微针尖端加工精度。

Description

一种平面金属微针阵列及其制备方法 技术领域
本发明属于医疗器械技术领域与机械加工领域，涉及一种平面金属微针阵列及其制备方法。
 背景技术
口服给药、注射给药和经皮给药是目前最为常用的三种给药方式，但口服给药需经过胃肠道及肝脏等组织器官，肠道灭活及肝脏“首过效应”会使部分药物被代谢掉，吸收效率大为降低；另一方面，部分药物会对肠胃产生不良刺激等副作用，从而限制了口服给药的应用范围，尤其不适合用于蛋白质、胰岛素以及DNA等类型的药物输送。注射给药技术虽然克服了上述缺点，但将尺寸较大的普通针头刺入人体组织，往往会给患者带来不可忽视的疼痛，在婴幼儿输药过程中，这种疼痛甚至会导致输药无法顺利进行，而且较大尺寸的针头会使人体受到创伤较大，处理不当容易引起皮肤感染等不良后果，因此需要专业人员操作；此外，普通注射给药是在短时间内将药物注入人体，使得局部药物浓度过高，之后药物浓度又快速下降，不利于药物长时间连续稳定释放。经皮给药技术可以克服口服给药和注射给药的上述缺点。所谓经皮给药，是指将药物直接贴敷在皮肤表面并通过皮下毛细血管吸收后进入人体血液循环并达到有效血药浓度、实现疾病治疗或防御的一种输药方法。
相比口服给药与注射给药，经皮给药具有以下优点：(1) 避免了肝脏与胃肠道对药物的破坏作用，提高了药物的生物利用度；(2) 对药物具有缓释作用，可实现长效可控给药；(3) 血药水平稳定，提高了药物的疗效；(4) 避免了对胃肠道的刺激作用，降低了药物的毒副作用；(5) 可实现无痛、无创或微创给药；(6) 使用简单方便，无需专业人员操作。因为具有这些优点，经皮给药技术受到国内外研究人员的广泛关注，但这种给药技术也存在输药剂量较小、输药效率相对较低以及输药品种有限等缺点。究其原因，主要是因为皮肤最外层有厚度约为10~20 微米，由死亡皮肤细胞构成的角质层，严重阻碍药物经皮渗透。为了改善经皮输药效率并扩充经皮输药的种类，人们不断从化学、物理以及生物学等方面研究经皮输药技术的改进方法，如使用各种促透剂的化学法，采用离子导入、超声导入、电致孔法以及微粉超音速喷射等物理方法。近年来，随着现代微纳米加工技术的飞速发展，一种被称之为微针的新型经皮给药促进方法正受到人们越来越多的关注。
微针(Microneedle, MN)一般是指长度在几十微米到几毫米，尖端直径在几十微米以下的微型针头。如前所述，皮肤角质层的屏障作用是限制经皮给药技术的关键问题，利用微针将皮肤角质层局部破坏，在皮肤表层短暂形成微米级的药物输送微通道(比一般药物分子尺寸大一个数量级)，不仅使经皮给药的输药效率显著提高，而且可以显著增加经皮给药的药物适用范围。此外，因为微针尺寸非常微小，可以只刺破不含神经的皮肤角质层而基本不触及富含神经和血管的皮肤深层组织，刺入过程产生的疼痛感和创伤都远远小于传统注射给药，从而可实现无痛、无创或微创给药。若再结合其它微流体控制系统，微针还可以实现长效可控给药。经过特殊设计后结合相应的微流体控制和分析系统，微针还可以用于人体无痛微量生化采用分析。因此，微针相关研究已成为医疗领域的热门研究方向之一。
目前国内外的微针主要有硅微针、玻璃微针、陶瓷微针、金属微针、水凝胶微针、聚合物微针以及糖等(如麦芽糖、乳糖等)。在这些微针当中，硅因为相应的光刻、干法刻蚀、湿法刻蚀等加工技术已较为成熟，而且材料硬度较高，易于刺入皮肤，所以常被用作微针材料。然而，硅微针加工时对环境洁净程度要求高，加工效率较低，相应的费用也较高，所以还无法满足批量生产的要求。此外，硅作为一种典型的脆性材料，若设计不合理、加工有缺陷或使用过程中受到较大应力时都容易发生断裂破坏，而且由于硅的生物相容性不好，断裂后残留在皮肤内的碎片可能引起不良反应，严重时这些微小碎片还有可能进入血管和心脏，引起一些更恶劣的后果，像玻璃、陶瓷等脆性材料也存在类似问题。聚合物通常具有更好的生物相容性和韧性，用于制造微针一方面可以减少机体的排异反应，另一方面能够确保微针刺入皮肤不发生断裂破坏，但由于聚合物材料的硬度和刚度通常较低，刺入皮肤或人体组织的过程中针尖容易发生屈曲破坏，导致无法刺破皮肤，所以应用也受到一定限制。金属微针相比较而言，韧性好、强度高，而且像不锈钢、钛合金等金属的生物安全性已经过长期验证，所以被认为是微针的首选材料之一。目前金属微针的加工手段颇为丰富，有化学刻蚀、紫外光刻、微铣削、激光切割、电镀等，但这些加工方法都存在加工精度低、加工效率低而成本高等缺点，难以满足批量生产要求。
 技术问题
针对微针现有制造技术中存在的问题，本发明提供一种片状平面金属微针阵列及其加工新方法，平面微针阵列采用生物相容性良好、强度和韧性俱佳的片状不锈钢或钛合金材料，通过传统线切割加工技术制备，微针阵列由用于后续夹持组装的基片6和微针针体7组成，基片与针体为一整体，且处于同一平面。该类型微针阵列易于使用，该加工方法既能保证精度，又适合高效率、低成本批量生产。
 技术解决方案
一种平面金属微针阵列的制备方法，包括以下步骤：
    第一步，将大尺寸金属薄片裁剪为方便夹持的小型金属薄片5，小型金属薄片5厚度为20~200微米，长为30~50毫米，宽为10~30毫米。
    第二步，加工专用的薄片夹持工装
工装由上下两块完全相同的金属盖板2组成，每块盖板总体厚度为5~10毫米。在工装上下盖板内壁加工与所述小型金属薄片5尺寸相匹配的凹槽3，即凹槽长宽与金属薄片5长宽一致，用于放置金属薄片5；上下盖板凹槽的深度均为1~5毫米；上下盖板主体2四周边缘处均加工用于通过紧固螺栓4的通孔1。所述夹持工装材料为导电性能良好、强度高的不锈钢、45#钢等金属材料。
第三步，将小型金属薄片5放置在任一工装金属盖板的凹槽3内进行堆叠，一次放置的金属薄片5片数根据薄片厚度和凹槽深度进行调整；将另一工装金属盖板放置在已放置金属薄片的盖板之上，凹槽朝向金属薄片，上下对齐；通过紧固螺栓4将夹持工装上下金属盖板封装，压实金属薄片5，与上下盖板成为一整体。
第四步，设计片状微针阵列的几何形状和尺寸
片状微针阵列由用于后续夹持部分的基片6和微针针体7组成，由同一金属薄片5整体切割而成。每片基片上微针针体7的个数为3~50根，微针针体7之间的间距0.25~10毫米，厚度为金属薄片5自身厚度。每个微针针体7形状为三角形或剑形，其高度为100~500微米、针体根部宽度为50~300微米、厚度为金属薄片5自身厚度。
第五步，将第三步封装好的金属薄片5和工装装夹到线切割设备上，线切割设备根据第四步设计的微针几何形状和尺寸确定走丝路径，对工装和金属薄片5作为整体进行线切割，金属薄片5加工出基片6和微针针体7。线切割过程中，对微针针体7的尖端加工采用 “8”字形路径切割，确保微针针尖尖锐程度。加工过程中，基片6不完全切割，两侧预留2~5毫米不进行切割，确保工装金属盖板、金属薄片5在切割后仍为整体结构，既防止所加工时微针被冷却液冲走，又能保证使用后的工装仍具有足够高结构刚度，使得工装可重复使用。
第六步，卸下工装上的紧固螺栓4，取出加工好的金属薄片5并进行清洗。
第七步，对第六步所述的金属薄片5上，基片6两侧预留区域材料进行裁剪，使片状微针阵列从金属薄片5剥离，得到具有多个微针针体的片状平面金属微针阵列，利用该平面微针阵列，可以进一步组装成不同排布规格的三维微针阵列，供设计使用。
一种平面金属微针阵列，片状微针阵列由基片6和针体7构成，基片6与针体7由同一金属薄片整体切割而成，基片6与针体7处于同一平面且针体7位于基片6上方，针体7的数量、形状及尺寸根据需要调整。所述的金属薄片材料包括医用不锈钢或钛合金材料；微针针体7高度为100~500微米，根部宽度为50~300微米，厚度为金属薄片5厚度；每片基片上微针个数为3~50根，间距0.25~10毫米，微针针体形状为三角形或剑形。
 有益效果
（1）片状的平面微针设计有利于简化加工程序，而且使用灵活，通过简单组装便可制成不同规格的三维微针阵列。可一次性成批量加工金属微针阵列，以线切割较理想的总切割厚度2厘米计算，例如工装上下整体壁厚5毫米，凹槽深度2毫米，每片金属薄片的厚度为100微米，则一次可切割的微针数量为140片，与其它微针加工方法相比效率大幅提高，再加上线切割加工技术相对较低的成本，所以本发明所提供的微针阵列加工方法成本低廉。
（2）夹持工装使用过后除了切割丝所经路径处的材料被切割掉外，其它部分仍保持完整，这一方面能保整工装有足够高的刚度供后续重复夹持使用，另一方面由于加工路径处工装材料已被切除，后续再使用时只需切割金属薄片本身，从而进一步增加一次可加工的金属微针的片数，提高效率并降低成本。
（3）夹持工装将薄片压实为一整体，可以防止切割时因侧向力导致加工尺寸偏差，而如果对金属薄片进行单片切割，由于厚度很薄，很小的侧向力就会使微针变形，难以保证加工精度；微针尖端切割时采用“8”字型加工路径，可以有效避免直接在尖端进行变向而导致的尖端钝化，从而保证微针尖端加工精度。
 附图说明
图1为薄片夹持工装的主视图；
图2为薄片夹持工装的俯视图；
图3为薄片夹持工装的侧视图；
图4为金属基片放入工装并经螺栓连接压实后的示意图；
图5为线切割加工路径示意图；
图6为切割完成后薄片夹持工装未拆卸时的示意图（俯视图）；
图7为切割完成薄片夹持工装拆卸后，但金属薄片未裁剪时的微针阵列与基片的整体示意图；
图8为最终裁剪完成后的具有剑形针体的片状平面微针阵列示意图。
图中：1通孔，2金属盖板，3凹槽，4紧固螺栓，5金属薄片，6基片，7针体。
 本发明的实施方式
以下结合附图详细描述本发明的技术方案。本发明实施例仅用于说明并解释本发明的技术方案而非限制，尽管参照较佳实施例对本发明进行了详细说明，本领域的普通技术人员应当理解，可以对发明的技术方案进行修改或者等同替换而不脱离本发明技术方案的精神和范围，其均应涵盖在本发明的权利要求范围中。
S1：微针材料采用生物相容性好、强度和韧性俱佳的的医用304不锈钢薄片材料，所示薄片尺寸长为1000毫米，宽100毫米，厚度80微米。将大尺寸不锈钢薄片裁剪为大小合适且方便夹持的小型金属薄片5，金属薄片5长50毫米，宽25毫米，厚度80微米，但不限于该尺寸。
S2：加工专用的薄片夹持工装
工装结构如图1、图2、图3所示，夹持工装材料为不锈钢，其导电性能良好、强度高。工装由完全相同的上下两块金属盖板2组成，每块盖板厚度6毫米，盖板长度80毫米，宽度55毫米，上下盖板内壁设置与所述小型薄片尺寸相匹配的凹槽3，凹槽3长度50毫米，宽度25毫米，上下盖板凹槽深度均为3毫米。工装两侧加工用于通过紧固螺栓4的通孔1，本实施例中通孔1直径为6毫米。
S3：将100片小型金属薄片5（薄片堆叠厚度8毫米）放置在下金属盖板2的凹槽3内，将上金属盖板2放置到已放置好金属薄片的盖板之上，凹槽朝向金属薄片，上下对齐，通过紧固螺栓4将上下盖板封装，压实金属薄片5。封装好的金属薄片和工装如图4所示。
S4：根据需要设计微针阵列的几何形状、尺寸、根数、间距以及高度等参数。微针阵列由基片6和微针针体7组成，由同一金属薄片5整体切割而成。本实施例中微针针体高度300微米，针体根部宽度150微米，厚度即为金属薄片自身厚度80微米，针体形状为剑形；单片基体上的微针根数为7根，间距3.5毫米。根据设计的微针阵列的几何形状和尺寸，构建平面微针的CAD模型。
S5：将如图4所示封装好的金属薄片和工装作为整体，装夹到线切割设备上；根据步骤S4所设计的微针几何形状和尺寸，按照如图5所示的走丝路径进行切割加工，针尖加工采用图6所示的“8”字形路径切割，确保微针针尖尖锐程度，得到如图6所示的切割后的工装与基片。此外，加工时，基片不完全切割，两侧留3毫米不进行切割，确保工装和金属薄片5在加工后仍为一整体。切割完成后的金属薄片和工装未拆卸时的示意图如图6所示（俯视图）。
S6：将工装上的紧固螺栓4卸下，从工装内取出加工好的金属薄片5，将金属薄片5放入75%乙醇溶液中，在超声清洗仪中震荡清洗15分钟，然后在干燥箱内120℃烘烤2小时，最后得到如图7所示的未裁剪的金属薄片5。
S7：对加工时，基片6两侧预留的3毫米区域进行裁剪，使片状微针阵列从金属薄片5剥离，得到如图8所示的具有多个微针针体的片状平面金属微针阵列，利用该平面微针阵列，可以进一步组装成不同排布规格的三维微针阵列，供设计使用。
 

Claims (4)

  1. 一种平面金属微针阵列的制备方法，其特征在于，包括以下步骤：
        第一步，将大尺寸金属薄片裁剪为小型金属薄片(5)，小型金属薄片(5)厚度为20~200微米，长为30~50毫米，宽为10~30毫米；
        第二步，加工专用的薄片夹持工装
    工装由上下两块完全相同的金属盖板(2)组成，每块盖板总体厚度为5~10毫米；在工装上下盖板内壁加工与金属薄片(5)尺寸相匹配的凹槽(3)，用于放置金属薄片(5)；上下盖板凹槽的深度均为1~5毫米；上下金属盖板(2)四周边缘处均加工用于通过紧固螺栓(4)的通孔(1)；
    第三步，将金属薄片(5)放置在任一金属盖板的凹槽(3)内进行堆叠，一次放置的金属薄片(5)片数根据薄片厚度和凹槽深度进行调整，并将另一金属盖板(2)放置在其上方，凹槽朝向金属薄片(5)，上下对齐；通过紧固螺栓(4)将夹持工装上下金属盖板(2)封装，压实金属薄片(5)，与上下金属盖板(2)成为一个整体；
    第四步，设计片状微针阵列的几何形状和尺寸
    片状微针阵列由基片(6)和微针针体(7)组成，基片(6)与微针针体(7)由同一金属薄片整体切割而成，针体(7)的数量、形状及尺寸根据需要调整；
    第五步，将第三步封装好的金属薄片(5)和夹持工装装夹到线切割设备上，线切割设备根据第四步设计的微针几何形状、尺寸确定走丝路径，对工装和金属薄片(5)作为整体进行线切割，金属薄片(5)加工出基片(6)和微针针体(7)；线切割过程中，对微针针体(7)的尖端加工采用 “8”字形路径切割，确保微针针尖尖锐程度；此外，线切割过程中，基片(6)两侧预留2~5mm不进行切割，确保工装和金属薄片(5)在切割后仍为一整体；
    第六步，卸下工装上的紧固螺栓(4)，取出加工好的金属薄片(5)并进行清洗；
    第七步，对第六步所述的金属薄片(5)上，基片(6)两侧预留区域的材料进行裁剪，使片状微针阵列从金属薄片(5)剥离，得到具有多个微针针体的片状平面金属微针阵列。
  2. 根据权利要求1所述的一种平面金属微针阵列的制备方法，其特征在于，所述的夹持工装材料为不锈钢、45#钢金属材料。
  3. 根据权利要求1所述的一种平面金属微针阵列的制备方法，其特征在于，所述的金属薄片(5)材料为医用不锈钢或钛合金材料。
  4. 权利要求1-3任一所述的方法制备得到的平面金属微针阵列，其特征在于，所述的微针阵列由基片(6)和微针针体(7)构成，基片(6)与针体(7)处于同一平面；每个微针针体(7)高度为100~500微米、针体根部宽度为50~300微米、厚度为金属薄片(5)自身厚度；每片基片上微针针体(7)的个数为3~30根，微针针体(7)之间的间距0.25~10毫米，微针针体形状为三角形或剑形。
     
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KR100682534B1 (ko) * 2005-10-10 2007-02-15 한국과학기술원 미세바늘 어레이 제작방법
CN106512199A (zh) * 2014-06-16 2017-03-22 游学秋 异平面微针阵列及其制作方法

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WO2005044364A1 (en) * 2003-11-10 2005-05-19 Agency For Science, Technology And Research Microneedles and microneedle fabrication

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KR100682534B1 (ko) * 2005-10-10 2007-02-15 한국과학기술원 미세바늘 어레이 제작방법
CN106512199A (zh) * 2014-06-16 2017-03-22 游学秋 异平面微针阵列及其制作方法

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