CN101905856A - Method for preparing plane hollow microneedle for transdermal administration - Google Patents
Method for preparing plane hollow microneedle for transdermal administration Download PDFInfo
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- CN101905856A CN101905856A CN 201010204623 CN201010204623A CN101905856A CN 101905856 A CN101905856 A CN 101905856A CN 201010204623 CN201010204623 CN 201010204623 CN 201010204623 A CN201010204623 A CN 201010204623A CN 101905856 A CN101905856 A CN 101905856A
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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
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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
- A61M2037/003—Other apparatus for introducing media into the body; Percutany, i.e. introducing medicines into the body by diffusion through the skin by using microneedles having a lumen
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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
- A61M2037/0053—Methods for producing microneedles
Abstract
The invention discloses a method for preparing a plane hollow microneedle for transdermal administration, which comprises the following steps of: defining a microneedle flow channel pattern on one surface of a first metal substrate to form a trench, and defining a microneedle pattern on the other surface to form a cutting sign, wherein the central axis of the flow channel pattern is aligned with that of the microneedle pattern; bonding a second metal substrate with a trench surface of the first metal substrate; thinning a non-bonding surface of the second metal substrate, and allowing the cutting sign on the first metal substrate to align with and transfer to the non-bonding surface of the second metal substrate; and thinning a non-bonding surface of the first metal substrate, and cutting by aligning with the cutting sign on the second metal substrate to form the plane hollow microneedle. Based on the micromachining technology and by combining the conventional technology of machining and cutting at the same time, the method reduces the process difficulty, increases the using reliability of the microneedle, and is favorable for quantity production.
Description
Technical field
The present invention relates to micromachining technology, particularly be used for the preparation method of the plane hollow microneedle of cutaneous penetration.
Background technology
Main administering mode is oral and injection at present.Oral drugs are because the absorption in stomach and the first pass effect of liver have influenced the practical effect of medicine to site of action greatly.Injection not only can bring tangible pain to the patient, also needs the professional to operate simultaneously, even the local damage even the infection of skin can occur, and not being suitable for long-term reaching needs the accurately sustained-release administration of control.
Percutaneous dosing is a reasonable solution.Skin is divided into three layers from outside to inside: cuticula, epidermal area and skin corium.About 10～20 microns of cutin bed thickness is that one deck is extremely organized, and does not have blood vessel and nerve; Epidermal area is positioned at outer subcutaneous about 50～100 microns places, contains a small amount of living cells and nerve, does not contain blood vessel; More also have a large amount of living cells, nerve and blood vessel in the corium of depths.As seen, cuticula is the maximum barrier that medicine absorbs through skin.People have adopted the method for multiple physics, chemistry to promote absorbing through skin of medicine for this reason.Such as physical methods such as ion importing, ultrasonic importing, electroporation and hot piercings, remarkable through the skin assimilation effect, but most automatically controlled property equipment that needs dependence that energy source is arranged is bigger to the damage of skin, and medication person can't independently voluntarily use.Chemical penetrating agent is not obvious through the skin assimilation effect to macromolecular drug then, and generally have than strong and stimulating.
Comparatively speaking, microneedle cutaneous is a kind of administering mode between hypodermic injection and transdermal patch.Micropin also belongs to the short technology of oozing of physics, it is that the acicular texture of a kind of size of difformity that Micrometer-Nanometer Processing Technology makes and material in micron dimension arranged, handle by skin being carried out painless pore, produce the permeability that medicine is improved in small duct at keratoderma, thus improve greatly medicine especially macromolecular drug through the skin uptake; Because the needle point size is minimum, skin is not almost damaged simultaneously, and easy to use, do not need professional training, be fit to individual independent operation.
Distinguish according to making material, micropin mainly contains three kinds on silicon, polymer and metal.Silicon materials have ripe micro fabrication technology, be easy to produce in batches, but its bio-compatibility is relatively poor, and easy fracture are stranded in the skin, and this is the key factor of its development of restriction.Polymer micro needle has good bio-compatibility and degradable, but its intensity is relatively poor, all has much room for improvement on new material excavation and processing technology.Metal micro-needle is cheap, technology is simple, is fit to mass production, and needle point is sharp-pointed, hardness is bigger, is easy to pierce through skin and easy fracture not.Such as metals such as the titanium with bio-compatibility, nickel, stainless steels, be the good material of making micropin.
Distinguish according to manufacture craft, micropin mainly contains from face and plane two kinds, and the former needle shaft is perpendicular to substrate surface, and the latter's axle then is parallel to substrate surface.From the face micropin, especially for large ratio of height to width from the face micropin, complex process is wayward, difficulty is more with high costs.Then technology is simple relatively for the plane micropin, and the convenient control of micropin pattern combines integrated fluid channel, sensor etc. easily and forms the microinjection control system with other technologies.
Distinguish according to internal structure, micropin mainly contains solid and hollow two kinds, and the former can produce skin physics through hole, and the mode of medicine with infiltration is transferred in the body; The latter then can be stored in medicine in the cavity, treats to be released in the body after needle point thrusts skin.As seen, empty micropin more is similar to conventional syringe, and cutaneous penetration is more efficient.
People such as Chen in 1997 utilize the anisotropy etch stop technology of silicon to make the silicon-base plane of fluid channel empty micropin is arranged (CHEN J, et al.A multichannel neural probe for selective chemical Delivery at the Cellular Level[J] .IEEE Transactions on Biomedical Engineering, 1997,44 (8): 760-769.).Lin in 1999 etc. utilize similar techniques made the silicon nitride micropin (LIN L, PISANO A P.Silicon-Processed Microneedles[J] .IEEE Journal of Microelectmmechanical Systems, 1999,8 (1): 78-84.).People such as Oka in 2002 utilize the corrosive liquid undercutting to make silicon form zigzag, in conjunction with silicon-silicon bond close, plasma etching and copolymerization pyrophosphate ion bundle bombardment lithographic technique made plane hollow silicon micropin (OKAK, et al.Fabrication of a microneedle for a trace blood test[J] .Sensors and Actuators A, 2002,97-98:478-485).People such as Paik in 2004 utilize dry etching and raceway groove to recharge technology and have made monocrystalline silicon plane hollow microneedle array (PAIK S J, et al.A novel microneedle array integrated with a PDMS biochip for microfluid systems[A] .The 12th International Conference on Solid State Sensors, Actuators and Microsystems[C] .Boston:2003.146-1449; PAIK S J, et al.In-plane single-crystal-silicon microneedles for minimally invasive microfluid systerns[J] .Sensors and Actuators A:Physical, 2004,114 (2-3): 276-284).Because the use of silica-base material, most of ripe silicon process technology all can use, but the silicon materials built-in problem can't be avoided simultaneously.Except the crisp easy fracture of silicon micropin matter, silicon face also can adsorbed proteins, makes white blood cell stick to the micropin surface, may produce stress reactions such as inflamed, so the silicon micropin is not suitable for being directly used in human body therapy.Even in subsequent technique, add gold thin film etc. and since surface film technology in conjunction with reliability a little less than, be difficult to from changing this problem in essence.
People such as last century Mo Frazier adopt surperficial micro fabrication to process the hollow palladium micropin in isoplanar (Paputsky in conjunction with cryogenic conditions, et a l.A low temperature IC compatable process for fabricating surfacemicromachined metallic microchannels.IEEE J Microelectromech Sys, 1998,7 (2): 267-273; J.Brazzle, et al.Fluid-coupled metallic micromachined needle arrays.20thinter.ConeIEEE.Med﹠amp; Bio Society, Hong Kong, 1998.1837-1840; J.Brazzle, et al.Hollow metallic micromachined needle arrays.J.Micro Biomed Devices, 2000,2:197-205.).Its colleague Chandrasekaran etc. has also processed similar micropin (S.Chandrasekaran, et al.Surface micromachined metallic microneedles, J Microelectromech Sys, 2003, (12): 281-288.).Above-mentioned micropin preparation technology designs low temperature process, and its technology difficulty expends high more greatly, and architectural characteristic and quality control also are difficult for guaranteeing.2006, people such as Parker utilize deep erosion and golden gold bonding to produce titanium base micropin (E.R.Parker, et al.Bulk Titanium Microneedles with Embedded Microfluidic Networks for Transdermal Drug Delivery.IEEEMEMS 2006, Istanbul, Turkey, 22-26January 2006:498-501.).This is all having bigger improvement and raising aspect material and the processing technology.But since golden gold bonding bond strength a little less than, wait test as the micropin security reliability of inserting device.Simultaneously, too much use the deep etching technique of titanium, very high to technical process requirement itself, difficulty is bigger, and the also corresponding raising of cost is many.Be exactly its little machining process that adopts in addition, or not be not suitable for volume production with traditional silicon disk processing technology coupling.2009, people such as Xiao Yan Xiao of Shanghai Communications University utilize electroplating technology to prepare the thick nickel plane micropin of 50 μ m, afterwards again deposit 2 microns polymer proliferation compatibility (YAN Xiao-xiao, et al.MEMS In-Plane Metallic Microneedle for Drug Delivery.Nanotechnology and Precision Engineering, Sep.2009, Vol.7No.5:419-422).Its micropin of electroplating preparation and substrate caking power a little less than, the polymer of while deposit also more easily comes off, global reliability and ease for use all have much room for improvement.
Summary of the invention
The purpose of this invention is to provide a kind of preparation method who is used for the plane hollow microneedle of cutaneous penetration, this method simultaneously in conjunction with traditional machining and cutting technique, strengthens the dependability of micropin based on micromachining technology, reduce technology difficulty, and realize producing in batches.
Technical scheme of the present invention is as follows:
A kind of preparation method of plane hollow microneedle may further comprise the steps:
1) at the one side definition micropin runner figure of first metal substrate, forms raceway groove, aim at raceway groove location definition micropin figure at another side then, form cut mark; Perhaps, at the one side definition micropin figure of first metal substrate, form cut mark earlier, aim at micropin graphical definition micropin runner figure at another side then, form raceway groove;
2) get one second metal substrate, the raceway groove face of itself and first metal substrate is bonded together;
3) the nonbonding face of attenuate second metal substrate, and the cut mark on first metal substrate aimed at transfer on the nonbonding face of second metal substrate;
4) the nonbonding face of attenuate first metal substrate is aimed at the cut mark cutting on second metal substrate then, forms plane hollow microneedle.
Above-mentioned steps 1) formation of raceway groove and cut mark is adjustable in proper order in, as long as micropin figure and runner figure are aimed at mutually, and the central axial alignment of ordinary circumstance lower flow channel figure and micropin figure.The mode of definition figure can be photoetching, laser marking, serigraphy etc., the mode that forms raceway groove and cut mark can be that substrate is carried out wet etching or dry etching etc., and wherein the mode of wet etching comprises again and is soaked in corrosion and spray corrosion in the corrosive liquid.
Preferably use following method to form raceway groove for step 1): at a resist coating of first metal substrate, lithographic definition goes out micropin inner flow passage figure, is that mask etching first metal substrate forms raceway groove then with the photoresist.The photoresist that uses in etching process as mask, the negative photoresist of anti-etchings such as preferred SU8; Dry etching is generally adopted in the formation of raceway groove, for example adopts reactive ion etching (RIE) technology, and etching depth depends on the size design of raceway groove and micropin.
For the preferred following method of the formation of cut mark in the step 1): at the another side resist coating of first metal substrate, lithographic definition goes out that the expose portion of wet etching first metal substrate forms cut mark behind the micropin figure, removes photoresist again.The photoresist that uses can be the eurymeric photoresist; Wet etching forms cut mark, and the corrosive liquid that is adopted is decided according to the material of substrate.Etching time is very short, and general 1-2min is so even if form raceway groove earlier, corrosion process is also little to the influence of raceway groove.Be the protection raceway groove, also can form the back it is protected (as coating protection glue), form cut mark again at raceway groove.
Above-mentioned steps 2) material of second metal substrate is identical with first metal substrate usually, and selectable metal material includes but not limited to titanium, stainless steel, nickel or their alloy, is preferably titanium.The all metal substrates of the present invention are all selected smooth thin slice usually, and thickness is generally 50～2000 μ m.Most preferred, described first metal substrate and second metal substrate all use four cun titanium basic circle sheets.First metal substrate is twin polishing, second metal substrate can be the single or double polishing, the bonding face of second metal substrate and first metal substrate is a burnishing surface, and the bonding mode can adopt surperficial Direct Bonding (for example diffusion welding (DW) bonding), also can adopt intermediate layer bonding etc.The diffusion welding (DW) bonding is normally 1 * 10
-4Under the vacuum environment of Pa, temperature is about 1000～1200 ℃, and pressurization kept 1～2 hour, wherein, and pressure and the time relation of being inversely proportional to.
Above-mentioned steps 3) method of transfer cut mark figure can be to aim at photoetching, laser marking, serigraphy etc., and wet etching or dry etching second metal substrate obtain cut mark at its nonbonding face then.Preferred resist coating at attenuate and after polishing the nonbonding face of second metal substrate, and the cut mark of aiming on first metal substrate carries out photoetching, by wet etching second metal substrate cut mark is transferred on second metal substrate from first metal substrate then, removed photoresist again.Employed photoresist generally is the eurymeric photoresist, and wet etching shifts cut mark, and the corrosive liquid that is adopted is decided on the material of metal substrate.
Above-mentioned steps 3) and can use methods such as wet etching (comprise spray corrosion) or chemically mechanical polishing that metal substrate is carried out attenuate in the step 4).The thickness of the plane micropin of Xing Chenging depends on bonding pad thickness and thickness thinning at last.
Above-mentioned steps 4) cutting mode can be laser cutting, line cutting, ion beam cutting, the cutting of water cutter etc. in, can adopt method cleaning micropin surface and cut edge residues such as pickling processes after the cutting, the general use carried out as the mixed liquor of hydrofluoric acid, nitric acid and sulfuric acid or the mixed diluting solution of hydrogen peroxide and water.
The plane hollow microneedle structure of the present invention's preparation is made of the needle body array of front end and the supporting mass and the reservoir one of rear end usually, and described needle body is parallel with the substrate direction, and pattern is determined by layout design.
Plane hollow microneedle of the present invention can be widely used in the cutaneous penetration device, and micropin produces physics hole enhancing operational efficiency by piercing through keratoderma, particularly at macromolecular drug, is the painless cutaneous penetration mode of a kind of safety.Owing to have fluid channel, micropin of the present invention can extract with partly integrated painless microinjection and the body fluid that is applied to accurately control of syringe; By the adjustable reservoir of capacity, can combine the purpose that reaches medicament slow release simultaneously, thereby realize more efficient, accurate, the long-term conveying of medicine with patch or heeling-in.
The present invention combines multiple technologies such as micromachined, traditional machining and cutting, has reduced technology difficulty with respect to prior art, has strengthened the dependability of micropin, and can realize producing in batches.Concrete advantage is for example: 1. introduce Pervasion Weld Technology and make two substrate fusion bondings, strengthened joint dynamics and sealing between two tracts of runners, improved the reliability that micropin uses; 2. adopt cutting formation pin types such as laser, reduced process complexity preferably, also saved costs such as preparation reticle simultaneously with respect to dry etching; 3. preferably adopt hardness, toughness and the bio-compatibility of titanium base material, and adopt body titanium processing technology, avoided micropin and the caducous shortcoming of substrate adhesiveness difference with the assurance micropin; 4. introduce four cun titanium basic circle sheets, making traditional machining combine with the MEMS process technology becomes possibility, has expanded preparation means greatly.
Description of drawings
Fig. 1 a～1k is the process chart that the embodiment of the invention prepares titanium base plane empty micropin.
Fig. 2 is the runner figure and the micropin pattern schematic diagram of plane hollow microneedle of the present invention.
The micropin pattern photo that Fig. 3 obtains for laser cutting, wherein B is the enlarged drawing of a needle body shown in the A.
The specific embodiment
Bottom in conjunction with the accompanying drawings, further the present invention is described in detail by embodiment, but the scope that does not limit the present invention in any way.
By machining, utilize the mode of line cutting to prepare four cun titanium basic circle sheets to chemical pure titanium material.Carry out cryogenic vacuum annealing and chemically mechanical polishing, obtain the titanium basic circle sheet of thick four cun two-sided or single-sided polishings of 200 μ m.Utilize and should prepare plane hollow microneedle according to following step by middle titanium basic circle sheet:
1, forms the micropin runner
The titanium basic circle sheet of getting a slice twin polishing is as the first titanium substrate 1, and the thick SU83010 photoresist 2 of spin coating 15 μ m left standstill 24 hours on one side burnishing surface.(stopped 2 minutes through baking before the hot plate from 45 ℃ of per 10 degree, stopped 10 minutes to 95 ℃, naturally be cooled to room temperature then), be printed on four cun chromium plate exposure 28s of micropin runner figure, baking (stopped 1 minute from 45 ℃ of per 10 degree after carrying out hot plate then, to 95 ℃ of stops 5 minutes, be cooled to room temperature then naturally).Use the special-purpose developer solution of SU8 that it is carried out developing in 8 minutes to the reticle figure at last and occur fully, as shown in Figure 1a.Utilize the ICP/RIE dry etching technology, adopt chlorine-based gas, the etching 30 μ m degree of depth.Etching parameters is: coil power 300-500W, and dull and stereotyped power 50W-200W, gas flow 30-70sccm forms raceway groove 3, shown in Fig. 1 b.
2, form cut mark
At the even eurymeric photoresist 4 that is coated with of the opposite side burnishing surface of the first titanium substrate, thickness is 1 μ m, be printed on the runner figure one by one four cun reticle of corresponding cutting pattern aim at the exposure 4s, carried out 120 ℃ of hot plate post bakes then 1 minute, developing to figure occurs fully, shown in Fig. 1 c.Immerse HF: HNO
3: H
2O=1: in the solution of 1: 30 (volume ratio) 1～2 minute, erode away cut mark 5, shown in Fig. 1 d.Immerse afterwards and remove photoresist in the acetone soln, see Fig. 1 e.
3, diffusion welding (DW) bonding
Get another sheet list and throw (or two throwing) titanium basic circle sheet, shown in Fig. 1 f, make the runner face of its burnishing surface and the first titanium substrate 1 carry out the diffusion welding (DW) bonding as the second titanium substrate 6.Diffusion welding (DW) is 1 * 10
-4Under the vacuum environment of Pa, temperature is about 1000～1200 ℃, and pressurization kept 1～2 hour.Wherein, pressure and the time relation of being inversely proportional to.Bonding pressure can reach more than the 18.18MPa.
4, attenuate and transfer cut mark
Nonbonding face to the second titanium substrate 6 carries out attenuate CMP polishing, makes it to reduce 150 μ m thickness, shown in Fig. 1 g.The even thereon afterwards eurymeric photoresist 7 that is coated with uses the existing cut mark in the cutting pattern domain and the back side to aim at exposure imaging (seeing Fig. 1 h).Then photoetching face is carried out wet etching, reach the purpose of metastatic marker.Concrete processing step erodes away cut mark 8 on the nonbonding face of the second titanium substrate 6, shown in Fig. 1 i with above-mentioned step 2.The first titanium substrate, 1 nonbonding face is carried out CMP polishing attenuate, make whole bonding pad thickness reach 100～150 μ m, see Fig. 1 j.
5, cutting forms needle point
Utilize ultraviolet nanosecond or psec green (light) laser to aim at bonding pad cut mark 8 and carry out the micropin cutting, form needle body and medicine storage pool, the plane hollow microneedle that obtains designing.The preferred power of laser is 3～50w.The gained micropin is immersed HF: HNO
3: H
2O=1: pickling is 1～2 minute in the solution of 1: 30 (volume ratio), removes the laser cutting residue, improves its surfacing fineness.
In the such scheme, the runner figure of prepared plane hollow microneedle and micropin pattern are as shown in Figure 2.The length of needle body is 200～800 microns, and width is 20～80 microns, and thickness is 100～300 microns, and the needle point angle is less than 30 °.Wherein, 30 microns of the inner flow passage degree of depth, width is 10～40 microns; Reservoir is the square of the length of side 1～5mm.
The employed metal substrate material of present embodiment is 99.99% chemical pure titanium, and micropin is parallel with titanium substrate base direction, forms single microneedle array (as shown in Figure 3), and the pin type can be adjusted domain according to needs and set up on their own.
The titanium material is having irreplaceable advantage as a kind of bio-compatibility good metal aspect the making micropin.At first, titanium has enough hardness to make needle point can pierce through skin, also has good toughness simultaneously, and instant bending also is unlikely to fracture and stays skin.Secondly, the titanium pin thrust the too drastic property reaction that should not cause skin, reduce phenomenons such as the issuable inflammation allergy of administered area.But as the extremely strong metal material of a kind of corrosion resistance, the processing technology difficulty of titanium is big, cost is high also is to limit the biggest obstacle that it is applied always.In order to produce the titanium base micropin that reliability is higher, practicality is stronger, we have comprehensively used micromachined and multiple process technology such as traditional machining and laser cutting, prepared a kind of titanium base plane empty micropin that is used for cutaneous penetration, the preparation of wafer level has effectively improved the possibility of volume production, Pervasion Weld Technology has significantly strengthened the reliability of bonding, and the laser scribing method has increased the flexibility of microneedle configuration.
Claims (10)
1. the preparation method of a plane hollow microneedle may further comprise the steps:
1) at the one side definition micropin runner figure of first metal substrate, forms raceway groove, aim at raceway groove location definition micropin figure at another side then, form cut mark; Perhaps, at the one side definition micropin figure of first metal substrate, form cut mark earlier, aim at micropin graphical definition micropin runner figure at another side then, form raceway groove;
2) get one second metal substrate, the raceway groove face of itself and first metal substrate is bonded together;
3) the nonbonding face of attenuate second metal substrate, and the cut mark on first metal substrate aimed at transfer on the nonbonding face of second metal substrate;
4) the nonbonding face of attenuate first metal substrate is aimed at the cut mark cutting on second metal substrate then, forms plane hollow microneedle.
2. preparation method as claimed in claim 1 is characterized in that: the mode of definition figure is photoetching, laser marking or serigraphy in the step 1), and the mode that forms raceway groove and cut mark is that first metal substrate is carried out wet etching or dry etching.
3. preparation method as claimed in claim 2 is characterized in that: adopt reactive ion etching technology to form raceway groove in the step 1), adopt wet etching to form cut mark.
4. preparation method as claimed in claim 1 is characterized in that: first metal substrate is identical with the material of second metal substrate, is titanium, stainless steel, nickel or their alloy.
5. preparation method as claimed in claim 1 is characterized in that: the thickness of first metal substrate and second metal substrate is 50～2000 μ m.
6. preparation method as claimed in claim 1 is characterized in that: step 2) the bonding mode be surperficial Direct Bonding or intermediate layer bonding.
7. preparation method as claimed in claim 6 is characterized in that: step 2) employing diffusion welding (DW) bonding.
8. preparation method as claimed in claim 1 is characterized in that: use the method for wet etching or chemically mechanical polishing that metal substrate is carried out attenuate in step 3) and the step 4).
9. preparation method as claimed in claim 1 is characterized in that: step 3) shifts the figure of cut mark by the method for aiming at photoetching, laser marking or serigraphy, and by wet etching or be dry-etched on second metal substrate and form cut mark.
10. preparation method as claimed in claim 1 is characterized in that: the cutting mode in the step 4) is laser cutting, line cutting, ion beam cutting or the cutting of water cutter.
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Cited By (10)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103263727A (en) * | 2013-05-22 | 2013-08-28 | 清华大学 | Metal microneedle array, percutaneous medicine feeding paster, Dermaroller and microneedle electrode array |
| CN104056346A (en) * | 2014-06-16 | 2014-09-24 | 游学秋 | Isoplanar microneedle array and manufacturing method thereof |
| CN104057564A (en) * | 2014-06-06 | 2014-09-24 | 游学秋 | Micro-needle making method based on inclined casting mould |
| CN104326433A (en) * | 2014-10-31 | 2015-02-04 | 中国科学院光电技术研究所 | Nanofluidic channel preparation method based on template-induced cracking effect |
| CN104874098A (en) * | 2015-04-08 | 2015-09-02 | 上海交通大学 | Hollow metal micro-needle and method for manufacturing same on large scale |
| WO2016078452A1 (en) * | 2014-11-18 | 2016-05-26 | 无锡华润上华半导体有限公司 | Positioning method in microprocessing process of bulk silicon |
| CN106390277A (en) * | 2016-09-28 | 2017-02-15 | 成都市亿泰科技有限公司 | Pressure-controlled flexible microneedle drug delivery system |
| CN108704218A (en) * | 2018-05-02 | 2018-10-26 | 上海大学 | A kind of painless dosing paster of skin |
| CN110153651A (en) * | 2019-05-13 | 2019-08-23 | 大连理工大学 | Big L/D ratio planar metal microneedle array, preparation method and its clamping are pierced into auxiliary device |
| CN111659000A (en) * | 2020-06-30 | 2020-09-15 | 华东师范大学 | Hollow metal microneedle, hollow metal microneedle array and preparation method thereof |
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| CN103263727A (en) * | 2013-05-22 | 2013-08-28 | 清华大学 | Metal microneedle array, percutaneous medicine feeding paster, Dermaroller and microneedle electrode array |
| CN103263727B (en) * | 2013-05-22 | 2015-09-30 | 清华大学 | Metal micro-needle array, percutaneous dosing paster, micropin roller and microneedle electrodes array |
| CN104057564A (en) * | 2014-06-06 | 2014-09-24 | 游学秋 | Micro-needle making method based on inclined casting mould |
| CN104057564B (en) * | 2014-06-06 | 2016-08-03 | 游学秋 | Based on the micropin manufacture method tilting mold |
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| CN104326433A (en) * | 2014-10-31 | 2015-02-04 | 中国科学院光电技术研究所 | Nanofluidic channel preparation method based on template-induced cracking effect |
| WO2016078452A1 (en) * | 2014-11-18 | 2016-05-26 | 无锡华润上华半导体有限公司 | Positioning method in microprocessing process of bulk silicon |
| US9902613B2 (en) | 2014-11-18 | 2018-02-27 | Csmc Technologies Fab1 Co., Ltd. | Positioning method in microprocessing process of bulk silicon |
| CN104874098A (en) * | 2015-04-08 | 2015-09-02 | 上海交通大学 | Hollow metal micro-needle and method for manufacturing same on large scale |
| CN104874098B (en) * | 2015-04-08 | 2018-04-10 | 上海交通大学 | A kind of hollow metal micropin and its batch preparation |
| CN106390277A (en) * | 2016-09-28 | 2017-02-15 | 成都市亿泰科技有限公司 | Pressure-controlled flexible microneedle drug delivery system |
| CN108704218A (en) * | 2018-05-02 | 2018-10-26 | 上海大学 | A kind of painless dosing paster of skin |
| CN110153651A (en) * | 2019-05-13 | 2019-08-23 | 大连理工大学 | Big L/D ratio planar metal microneedle array, preparation method and its clamping are pierced into auxiliary device |
| CN111659000A (en) * | 2020-06-30 | 2020-09-15 | 华东师范大学 | Hollow metal microneedle, hollow metal microneedle array and preparation method thereof |
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