CN108047466A - A kind of silk micropin and preparation method thereof - Google Patents
A kind of silk micropin and preparation method thereof Download PDFInfo
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- CN108047466A CN108047466A CN201711299062.7A CN201711299062A CN108047466A CN 108047466 A CN108047466 A CN 108047466A CN 201711299062 A CN201711299062 A CN 201711299062A CN 108047466 A CN108047466 A CN 108047466A
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- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08J—WORKING-UP; GENERAL PROCESSES OF COMPOUNDING; AFTER-TREATMENT NOT COVERED BY SUBCLASSES C08B, C08C, C08F, C08G or C08H
- C08J3/00—Processes of treating or compounding macromolecular substances
- C08J3/24—Crosslinking, e.g. vulcanising, of macromolecules
- C08J3/243—Two or more independent types of crosslinking for one or more polymers
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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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- B—PERFORMING OPERATIONS; TRANSPORTING
- B29—WORKING OF PLASTICS; WORKING OF SUBSTANCES IN A PLASTIC STATE IN GENERAL
- B29C—SHAPING OR JOINING OF PLASTICS; SHAPING OF MATERIAL IN A PLASTIC STATE, NOT OTHERWISE PROVIDED FOR; AFTER-TREATMENT OF THE SHAPED PRODUCTS, e.g. REPAIRING
- B29C39/00—Shaping by casting, i.e. introducing the moulding material into a mould or between confining surfaces without significant moulding pressure; Apparatus therefor
- B29C39/02—Shaping by casting, i.e. introducing the moulding material into a mould or between confining surfaces without significant moulding pressure; Apparatus therefor for making articles of definite length, i.e. discrete articles
- B29C39/026—Shaping by casting, i.e. introducing the moulding material into a mould or between confining surfaces without significant moulding pressure; Apparatus therefor for making articles of definite length, i.e. discrete articles characterised by the shape of the surface
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- C07K14/43563—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from invertebrates from insects
- C07K14/43586—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from invertebrates from insects from silkworms
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- 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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- 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
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- B—PERFORMING OPERATIONS; TRANSPORTING
- B29—WORKING OF PLASTICS; WORKING OF SUBSTANCES IN A PLASTIC STATE IN GENERAL
- B29L—INDEXING SCHEME ASSOCIATED WITH SUBCLASS B29C, RELATING TO PARTICULAR ARTICLES
- B29L2031/00—Other particular articles
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- B29L2031/7544—Injection needles, syringes
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- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08J—WORKING-UP; GENERAL PROCESSES OF COMPOUNDING; AFTER-TREATMENT NOT COVERED BY SUBCLASSES C08B, C08C, C08F, C08G or C08H
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Abstract
A kind of silk micropin and preparation method thereof, is related to micropin.Including silk cocoon is obtained silk solution through degumming, dissolving, dialysis;One of the aldehydes such as glutaraldehyde, vanillic aldehyde and diazols chemical cross-linking agent are doped to the silk solution obtained in silk solution through chemical crosslinking as chemical cross-linking agent;Solution is poured into template shaping and prepares micropin;Steam treatment is carried out after silk micropin is made up to high intensity silk micropin.The micropin of making can be pierced into skin very well, and can be mixed into high amount of drug, and preparation condition is mildly simple, at low cost.
Description
Technical field
The present invention relates to micropin, more particularly, to a kind of silk micropin and preparation method thereof.
Background technology
Micropin (microneedles) is usually a kind of pin height in 100 μm or more of micron order acicular texture array, material
Mainly metal, silicon, ceramics, polymer etc..Due to micropin realize percutaneous dosing relative injection reduce feeling of pain can be real
Existing painless percutaneous dosing, and Relative oral administration avoids the first pass effect of liver and digesting and assimilating for stomach and intestine, and micropin
Percutaneous dosing can greatly improve the percutaneous permeation of drug, and micropin is widely used to beauty, therapeutic administration and tissue detection
Wait biomedical sectors.Micropin is commonly used as drug delivery in biomedical sector, and it is strong that this needs micropin to possess good mechanics
Degree can be pierced into skin, and good toughness will not be broken in skin, and good biocompatibility also requires micropin to have more
Drugloading rate and load pharmacopoeia class.
Chinese patent CN205948285U mentions a kind of preparation of metal micro-needle, is bored using concave rib is made on silicon substrate, it
Thick glue electroplated coating is made on recessed pyramid afterwards, metal conducting layer and electroplated layer obtain gold on vapor deposition on thick glue electroplated coating
Belong to micropin graph layer, silicon substrate is finally gone to handle to obtain metal micro-needle structure.Metal micro-needle generally has short-term biological tolerance,
Good mechanical property typically is provided with, but metal micro-needle generally can only be by the method for face coat when carrying medicine, this just makes
Metal micro-needle there are drugloading rate it is limited the shortcomings that.Chinese patent CN104117136A discloses the metal micro-needle battle array with drug slot
Row, microneedle transdermal delivery patch and device, first metal micro-needle of the invention with drug slot, then part excision metal tube, obtain this
Kind of micropin can increase drugloading rate and drug is prevented to be applied to surface and caused by come off in vitro.But this metal micro-needle makes
Difficulty increases.
The micropin of the marketization also has silicon micropin now, as Chinese patent CN106730309A has invented a kind of silicon micropin substrate
And preparation method thereof, after silicon substrate purification, silicon dioxide film is grown on the two sides of silicon substrate, is then hidden on silicon dioxide film
The mask plate with solid pattern is covered, the solid pattern on mask plate is transferred on silicon dioxide film by photoetching, exposure,
Recycle wet etching silicon substrate that needle point and needle body is made, it is micro- then to obtain silicon with the extra silicon dioxide film of BOE etching aways
Pin substrate.Although this preparation method is at low cost also simpler than dry etching, the biocompatibility of silicon micropin is unsatisfactory,
Silicon micropin does not possess biodegradability, and silicon micropin enbrittles since misoperation is likely to occur needle body fracture so as to cause mistake
It is quick.There is Chinese patent CN106581849A to propose a kind of hypo-allergenic monocrystalline silicon micropin, in nanometer needle tubing made from monocrystalline silicon
On be coated with layer gold, provide good anti-fracture and hypo-allergenic effect.Although the fracture for solving silicon micropin generally existing causes
The problem of allergy, but but also cost improves, preparation is more complicated.
Compared to silicon micropin, ceramic micropin has intensity height is not easily broken to puncture the good advantage of effect, and ceramic micropin also has
Good bio-compatibility.If Chinese patent CN106187126A has invented a kind of ceramic micropin chip and preparation method thereof, first
Process causes needle-shaped concave mother matrix with array distribution, by the wafer stock mixed coated in master surfaces, by original
Material mixture sintering is molded to obtain chip.The mechanical strength of obtained ceramic micropin is high, can pierce through skin very well, however dioxy
SiClx has fusing point high, and melting viscosity is big, there is the defects of fusing is difficult, and heat consumption is big.In addition, the Drug loading capacity of ceramic micropin
It is limited.
Most polymer possesses biocompatibility, and biodegradability and good toughness do not allow easy fracture, and
The making of some polymer micro needles only needs room temperature, it is possible to drug are mixed into starting material solution and prepare micropin, both increased
Drugloading rate will not influence pharmaceutical activity.As Chinese patent CN106902453A has invented that a kind of needle body is solvable and substrate can not
Molten microneedle preparation method prepares water-soluble polymers, and utilizes micropin mold at room temperature, forms soluble needle body layer, from
And improve micropin operational efficiency.But macromolecule or polymer micro needle also face a problem, are exactly compared to metal micro-needle
And silicon micropin, the fracture strength of polymer micro needle is low, is not easy to be pierced into skin when medical treatment or beauty are administered or is pierced into skin
In the presence of insertion than it is not high enough the problem of.So it needs to be pierced into than low to solve the skin of polymer micro needle by improving mechanical strength
The problem of, if referred to a kind of new polymers microneedle array and preparation method thereof in Chinese patent CN106619480A, utilize
Hyaluronic acid, collagen, chitosan lactate, polyvinylpyrrolidone, poloxamer, polyethylene glycol polyvinyl alcohol copolymer
At least two mixtures composition in object, chondroitin sulfate, by preparing starting material solution, pouring for original solution is heating and curing
And demoulding step, the preparation of new polymers micropin is completed, chondroitin sulfate has been participated in that patent and has usually improved mechanical strength
Convenient for being pierced into skin.But the preparation of polymer micro needle needs the cost of chondroitin sulfate higher, and be inserted into than cannot still protect
Card is very and its insertion depth still cannot be guaranteed.Chinese patent CN106474620A prepares drug control using template
Microneedle patch is sustained, which refers to cross-linked gelatin, used Geniposide or glutaraldehyde does chemical cross-linking agent, it can be found that handing over
Although the mechanical strength of the micropin after connection, which is improved, can ensure to be inserted into pigskin but there are the non-uniform problem of insertion depth,
And the use cost of gelatin is high.
Fibroin is as a kind of natural albumen, mechanical performance, good biocompatibility and the biology of silk uniqueness
Degradability gradually appears advantage.In recent years, in order to meet the application demand in the fields such as biology device and beauty, also have
Research makes micropin with fibroin.International monopoly WO2016155082A1, which is disclosed, a kind of prepares swellability fibroin albumen micropin
Delivery system and its preparation using PDMS negative templates, small molecule sweller are added in after fibroin albumen and pours into PDMS negative templates
Obtain swellable silk micropin.But fibroin micropin compares the mechanics of metal micro-needle or silicon micropin as macromolecule micropin
Intensity is low, be pierced into skin there are still problem, moreover the fibroin albumen in silk can by regulate and control the secondary structure of its albumen come
Improve its fracture strength.Konstantinos Tsioris etc. (Konstantinos Tsioris, Waseem K.Raja,
Eleanor M.Pritchard,et al.Fabrication of Silk Microneedles for Controlled-
Release Drug Delivery [J] .Adv.Funct.Mater, 2012,22:330-335) micro- template is utilized, by PDMS
The negative template that aluminium film plate prepares PDMS is poured into, the silk solution for being mixed with drug is poured into PDMS negative templates afterwards, obtains silk
Micropin recycles α spirals in steam treatment regulation and control fibroin to the transformation of β-pleated sheet and then realizes the control of silk micropin administration
Sustained release.And steam treatment therein also improves mechanical strength while β-pleated sheet is increased, but it is inserted into ratio and still needs to be carried
It is high.The methods of Chinese patent CN103260693A refers to vapor and anneals, methanol solution post-processes, and reaches control fibroin albumen
The content of middle β-pleated sheet structure, so that micropin realization medicament slow release not soluble in water.But the patent mention steam treatment when
Between it is long, add the production time and be not reaching to best mechanical strength.For another example using super in Chinese patent CN103800998A
Processing silk fibroin protein solution is swung in acoustic shock, promotes silk fibroin protein solution pre-crystallized, and this pre-crystallized silk fibroin protein solution is entering
After mold, Silk fibroin gel micropin can be formed in several minutes of inner gels, this gel micropin is slowly dried in vacuum drying chamber
Xerogel is formed, there is high intensity, be easily pierced into skin, the ultrasonic vibration which utilizes, treatment conditions are mild, are not required to
Chemical cross-linking agent is added, does not influence the biocompatibility of fibroin, the micropin strength and hardness after shaping can be kept.It is but ultrasonic
It needs at 20~50 DEG C, if this temperature when drug is mixed into through ultrasound before this temperature ultrasound may make enzymes activity
The species that may be limited and carry medicine is reduced, and that drug can be caused to mix is uneven for solution viscosity increase after ultrasound.
The content of the invention
In view of the above-mentioned deficiencies in the prior art, it is an object of the present invention to provide the mechanical strength that can improve silk micropin, use
Be chemically crosslinked and be physical crosslinking the method for dual synergistic effect, preparation process is simply mild, at low cost, can loading gage medicine greatly, system
The intensity for the fibroin micropin made is high, is easy to puncture skin, be inserted into than superelevation, not easy to break with toughness, and with very
Good biocompatibility and a kind of silk micropin of biodegradability and preparation method thereof.
The silk micropin includes chemical cross-linking agent and silk solution, and the chemical cross-linking agent is glutaraldehyde, vanillic aldehyde etc.
Aldehydes or diazols, chemical cross-linking agent are added in silk solution, and steam treatment is carried out after silk micropin is made.
The composition of the silk micropin includes fibroin albumen, and the fibroin albumen may include in domestic silkworm silk, tussah silk etc.
One kind.
The fracture strength of the silk micropin single needle up to 5 times or more of unprocessed micropin, the silk micropin
Pin height can be 100~500 μm.
The silk micropin is 0.24~0.35N compared to the fracture strength of the single needle of untreated pure silk micropin,
The fracture strength of single needle reaches 1.71~2.45N, improves 5 times or more.
The preparation method of the silk micropin comprises the following steps:
1) silk cocoon is obtained into silk solution, mass concentration is 5%~12% by degumming, dissolving, dialysis or the anti-dialysis of warp;
2) by chemical cross-linking agent, it is 1% to be diluted with water to mass percentage concentration, obtains 1% chemical crosslinking agent solution;
3) PDMS is poured into the microneedles template being ready for, PDMS negative templates are prepared using micro- template;
4) the silk solution that step 1) obtains and the chemical cross-linking agent class solution that step 2) obtains are mixed, utilizes micro- template
Method pours into the PDMS negative templates that step 3) obtains, and crosslinked silk micropin is made;
5) the crosslinked silk micropin for obtaining step 4) carries out steam treatment to get silk micropin.
In step 2), the aldehyde radical of the aldehydes such as glutaraldehyde, vanillic aldehyde can be used in the chemical cross-linking agent, by with fibroin egg
White amino occurs the aldehydes chemical cross-linking agent of polycondensation reaction and coupling occurs instead with the aromatic rings in fibroin albumen tyrosine
The chemical cross-linking agent that at least one of diazol answered can be chemically crosslinked with fibroin albumen.
In step 3), micro- template is first to pour into ready aluminum alloy pattern plate, Stainless Molding Board, titanium template with PDMS
Wait at least one of metals class microneedles template or silicon microneedles template, at least one micropin mould of high 100~500 μm of template pin
Plate prepares negative template, and the silk solution for mixing glutaraldehyde is poured into negative template afterwards prepares silk micropin.
In step 5), the temperature of the steam treatment can be 94~97 DEG C, time of steam treatment can be 100~
120min。
The present invention is using can be with crosslinked diazols of phenyl ring in fibroin albumen tyrosine and can be with fibroin albumen
Anti- chemical cross-linking agent of the biochemical crosslinked aldehyde material as fibroin albumen of amino, steams by preparing silk micropin, and with water
Gas disposal, so as to obtain high intensity silk micropin.Silk solution prepares silk micropin after chemical crosslinking using micro- template
It is physical crosslinking again with steam treatment.
Compared with prior art, the present invention has silk micropin intensity higher obtained, and good toughness, stability is good, makes
Process is simple, at low cost, the strong advantage of plasticity, and by silk cocoon by degumming, dissolving, dialysis or the anti-dialysis of warp, it is molten to obtain silk
Liquid, mass concentration are 5%~12%;It has a wide range of applications in biologic medical and beauty treatment fields.
Description of the drawings
Fig. 1 is the compression verification figure of the high intensity silk micropin of embodiment 1.
Fig. 2 is the compression verification figure of the untreated pure silk micropin of embodiment 1.
Fig. 3 is the scanning electron microscope diagram of the high intensity silk micropin of embodiment 1.
Fig. 4 is the scanning electron microscope diagram of the high intensity silk micropin of embodiment 2.
Specific embodiment
Below by embodiment and attached drawing, the present invention is described in further detail.
Embodiment 1
A, the dilution of glutaraldehyde solution
25%wt glutaraldehyde solutions are diluted to the glutaraldehyde solution of 1%wt, as chemical cross-linking agent.
B, the preparation of silk solution
Degumming:15g silk cocoons are taken, first steep 30min with warm water, repeat bubble 3 times, by the silk cocoon steeped through warm water, 16g bicarbonates
Sodium and 3L deionized waters, are heated to seething with excitement, maintain 35min, 3 times repeatedly.It is then placed in immersion, magnetic agitation in 4.5L distilled water
30min, 3 times repeatedly.By the silk after degumming, 60 DEG C of oven for drying are positioned over.
Dissolving:The silk after 5g degummings is taken, lithium-bromide solution is added in the ratio of 1 ︰ 6, is positioned over 4h in 60 DEG C of baking ovens and fills
Divide dissolving.
Dialysis:Dissolved silk solution is placed in bag filter and (is spaced 2h with deionized water dialysis 48h and changes a water),
Obtain the silk solution that concentration is 6.3%.
C, the crosslinking of silk solution
The two is mixed and is crosslinked by the glutaraldehyde solution for taking the 215 above-mentioned dilutions of μ L good, the silk solution of 10mL.
D, the preparation of silk micropin
The silicon microneedles template that PDMS is poured into a height of 100 μm of the original pin of micropin obtains PDMS negative templates afterwards, then will
Crosslinked silk solution pours into PDMS negative templates and dries to obtain silk micropin.
E, by above-mentioned 95 DEG C of processing 100min of silk micropin vapor, high intensity silk micropin is obtained.
Testing result is shown in Table 1.
Table 1
Detection project | Embodiment 1 | Embodiment 2 |
The fracture strength (N) of single needle | 2.45 | 1.71 |
Embodiment 2
A, the dilution of glutaraldehyde solution
25%wt glutaraldehyde solutions are diluted to the glutaraldehyde solution of 1%wt, as chemical cross-linking agent.
B, the preparation of silk solution
Degumming:Take 10g silk cocoons, 10g sodium acid carbonates and 2L deionized waters, be heated to seething with excitement, maintain 40min, 3 times repeatedly.
Then with several times of distilled water flushing, be put into 4.5L distilled water impregnate, magnetic agitation 40min, 2 times repeatedly.By the silkworm after degumming
Silk, is positioned over 60 DEG C of oven for drying.
Dissolving:The silk after 5g degummings is taken, lithium-bromide solution is added in the ratio of 1 ︰ 6, is positioned over 4h in 60 DEG C of baking ovens and fills
Divide dissolving.
Dialysis:Dissolved silk solution is placed in bag filter and (is spaced 2h with deionized water dialysis 48h and changes a water),
Obtain the silk solution that concentration is 7.7%.
C, the crosslinking of silk solution
The two is mixed and is crosslinked by the glutaraldehyde solution for taking the 215 above-mentioned dilutions of μ L good, the silk solution of 10mL.
D, the preparation of silk micropin
The silicon microneedles template that PDMS is poured into a height of 200 μm of the original pin of micropin obtains PDMS negative templates afterwards, then will
Crosslinked silk solution pours into PDMS negative templates and dries to obtain silk micropin.
E, by above-mentioned 96 DEG C of processing 110min of silk micropin vapor, high intensity silk micropin is obtained.
Testing result is shown in Table 1.
Referring to Fig. 1 and 2, as can be seen from the figure after prepared chemical crosslinking steam treatment high intensity silk micropin
Compared with pure silk micropin, there is fracture strength height, the mechanical property of good toughness.
Referring to Fig. 3 and 4, as can be seen from the figure after prepared chemical crosslinking the silk micropin of steam treatment size
Substantially can be realized by Control architecture size, pin height can be between 100~500 μm.
Claims (8)
1. a kind of silk micropin, it is characterised in that including chemical cross-linking agent and silk solution, the chemical cross-linking agent for glutaraldehyde,
Vanillic aldehyde aldehydes or diazols, chemical cross-linking agent are added in silk solution, and steam treatment is carried out after silk micropin is made.
2. a kind of silk micropin as described in claim 1, it is characterised in that the composition of the silk micropin includes fibroin albumen,
The fibroin albumen includes one kind in domestic silkworm silk, tussah silk.
3. a kind of silk micropin as described in claim 1, it is characterised in that the fracture strength of the silk micropin single needle is not up to
Through handling 5 times or more of micropin, a height of 100~500 μm of the pin of the silk micropin.
4. a kind of silk micropin as described in claim 1, it is characterised in that the silk micropin compares untreated pure silk
The fracture strength of the single needle of micropin is 0.24~0.35N, and the fracture strength of single needle reaches 1.71~2.45N.
5. a kind of preparation method of silk micropin as described in Claims 1 to 4, it is characterised in that comprise the following steps:
1) silk cocoon is obtained into silk solution by degumming, dissolving, dialysis or the anti-dialysis of warp;
2) by chemical cross-linking agent, it is 1% to be diluted with water to mass percentage concentration, obtains 1% chemical crosslinking agent solution;
3) PDMS is poured into the microneedles template being ready for, PDMS negative templates are prepared using micro- template;
4) the silk solution that step 1) obtains and the chemical cross-linking agent class solution that step 2) obtains are mixed, is fallen using micro- template
Enter the PDMS negative templates that step 3) obtains, crosslinked silk micropin is made;
5) the crosslinked silk micropin for obtaining step 4) carries out steam treatment to get silk micropin.
6. a kind of preparation method of silk micropin as claimed in claim 5, it is characterised in that in step 2), the chemical crosslinking
Agent is chemically crosslinked using glutaraldehyde, the aldehyde radical of vanillic aldehyde aldehydes by the aldehydes that polycondensation reaction occurs with the amino of fibroin albumen
Agent and at least one of the diazol of coupling reaction occurs with the aromatic rings in fibroin albumen tyrosine and fibroin albumen is sent out
Biochemical crosslinked chemical cross-linking agent.
7. a kind of preparation method of silk micropin as claimed in claim 5, it is characterised in that in step 3), micro- template
First to be poured into PDMS in ready aluminum alloy pattern plate, Stainless Molding Board, titanium templated metal class microneedles template or silicon microneedles template
At least one, at least one microneedles template of high 100~500 μm of template pin, prepares negative template, will mix glutaraldehyde afterwards
Silk solution pours into negative template and prepares silk micropin.
8. a kind of preparation method of silk micropin as claimed in claim 5, it is characterised in that in step 5), at the vapor
The temperature of reason is 94~97 DEG C, and the time of steam treatment is 100~120min.
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CN114557953A (en) * | 2022-02-22 | 2022-05-31 | 烟台毓璜顶医院 | Preparation method of autofluorescent serum albumin microneedle |
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CN102580232A (en) * | 2012-02-23 | 2012-07-18 | 游学秋 | Silk fibroin micro-needle system, silk fibroin nanometer particle and preparation method thereof |
CN105030657A (en) * | 2015-09-08 | 2015-11-11 | 中国科学院上海微系统与信息技术研究所 | Implantable multifunctional compound type fibroin micro needle array and preparation method thereof |
CN105251052A (en) * | 2015-10-15 | 2016-01-20 | 天津市天津医院 | Cartilage extracellular matrix and silk fibroin composite orientation cartilage support and preparation method thereof |
CN106474620A (en) * | 2016-09-22 | 2017-03-08 | 北京化工大学 | A kind of polymer micro needle of medicine controlled release, preparation method and microneedle patch |
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CN114557953A (en) * | 2022-02-22 | 2022-05-31 | 烟台毓璜顶医院 | Preparation method of autofluorescent serum albumin microneedle |
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