CN108478852A - A kind of pharmaceutical products, the carrier for loading pharmaceutical products, hydrogel and its method - Google Patents
A kind of pharmaceutical products, the carrier for loading pharmaceutical products, hydrogel and its method Download PDFInfo
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- CN108478852A CN108478852A CN201810308852.5A CN201810308852A CN108478852A CN 108478852 A CN108478852 A CN 108478852A CN 201810308852 A CN201810308852 A CN 201810308852A CN 108478852 A CN108478852 A CN 108478852A
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- fibroin
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- pharmaceutical products
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L26/00—Chemical aspects of, or use of materials for, wound dressings or bandages in liquid, gel or powder form
- A61L26/0009—Chemical aspects of, or use of materials for, wound dressings or bandages in liquid, gel or powder form containing macromolecular materials
- A61L26/0028—Polypeptides; Proteins; Degradation products thereof
- A61L26/0047—Specific proteins or polypeptides not covered by groups A61L26/0033 - A61L26/0042
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L26/00—Chemical aspects of, or use of materials for, wound dressings or bandages in liquid, gel or powder form
- A61L26/0009—Chemical aspects of, or use of materials for, wound dressings or bandages in liquid, gel or powder form containing macromolecular materials
- A61L26/0028—Polypeptides; Proteins; Degradation products thereof
- A61L26/0033—Collagen
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L26/00—Chemical aspects of, or use of materials for, wound dressings or bandages in liquid, gel or powder form
- A61L26/0009—Chemical aspects of, or use of materials for, wound dressings or bandages in liquid, gel or powder form containing macromolecular materials
- A61L26/0028—Polypeptides; Proteins; Degradation products thereof
- A61L26/0038—Gelatin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L26/00—Chemical aspects of, or use of materials for, wound dressings or bandages in liquid, gel or powder form
- A61L26/0061—Use of materials characterised by their function or physical properties
- A61L26/008—Hydrogels or hydrocolloids
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
- A61L27/14—Macromolecular materials
- A61L27/22—Polypeptides or derivatives thereof, e.g. degradation products
- A61L27/222—Gelatin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
- A61L27/14—Macromolecular materials
- A61L27/22—Polypeptides or derivatives thereof, e.g. degradation products
- A61L27/227—Other specific proteins or polypeptides not covered by A61L27/222, A61L27/225 or A61L27/24
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
- A61L27/14—Macromolecular materials
- A61L27/22—Polypeptides or derivatives thereof, e.g. degradation products
- A61L27/24—Collagen
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
- A61L27/50—Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
- A61L27/52—Hydrogels or hydrocolloids
-
- C—CHEMISTRY; METALLURGY
- 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
- C08J3/02—Making solutions, dispersions, lattices or gels by other methods than by solution, emulsion or suspension polymerisation techniques
- C08J3/03—Making solutions, dispersions, lattices or gels by other methods than by solution, emulsion or suspension polymerisation techniques in aqueous media
- C08J3/075—Macromolecular gels
-
- C—CHEMISTRY; METALLURGY
- 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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L2400/00—Materials characterised by their function or physical properties
- A61L2400/06—Flowable or injectable implant compositions
-
- C—CHEMISTRY; METALLURGY
- 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
- C08J2389/00—Characterised by the use of proteins; Derivatives thereof
-
- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08K—Use of inorganic or non-macromolecular organic substances as compounding ingredients
- C08K3/00—Use of inorganic substances as compounding ingredients
- C08K3/16—Halogen-containing compounds
- C08K2003/162—Calcium, strontium or barium halides, e.g. calcium, strontium or barium chloride
-
- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08K—Use of inorganic or non-macromolecular organic substances as compounding ingredients
- C08K3/00—Use of inorganic substances as compounding ingredients
- C08K3/16—Halogen-containing compounds
Abstract
A kind of pharmaceutical products, the carrier for loading pharmaceutical products, hydrogel and its method, belong to field of gel.Hydrogel is a kind of to carry out cross-linking reaction under the action of enzyme by protein and obtain a kind of transparent biomaterial that can be used in a manner of injection.Its elasticity having had, biocompatibility, have a extensive future.
Description
Technical field
The present invention relates to gel rubber material fields, in particular to a kind of hydrogel and its method.
Background technology
Fibroin albumen abundance, of low cost, main constituent is amino acid, at the same it also have it is non-stimulated
Property, good dissolved oxygen permeability, controllable biological degradability.Fibroin albumen can support in vitro various cell adhesions, growth and
Differentiation；In vivo, fibroin albumen is likewise supplied with good organization's compatibility.Therefore, fibroin albumen organizational project, biomedicine,
Medicament slow release and optical image field have a wide range of applications.Recent, fibroin albumen can be used for clinical doctor by FDA approvals
It learns.However, untreated regenerated silk material is soluble easily in water due to containing a large amount of random coil structure, need to pass through object
Reason or the method for chemistry are modified processing could practical application.By physical modification (ethyl alcohol immersion, pH, high temperature and metal from
Son etc.) fibroin membrane brittleness it is larger, flexibility is poor, can not bending fold.And chemical treatments pass through in fibroin intramolecule
With the intermolecular reticular structure for forming Covalent bonding together, the stability and mechanical property of film can be effectively improved.However it is common
Chemical linking agent such as glutaraldehyde, diglycidyl ether can bring certain cytotoxicity, limit it in technical field of biological material
The application of aspect.
As function modified research of the biotechnology in high molecular material is increasingly deep, fibroin material is improved with enzymatic technique
Expect that the research report of performance is commonplace." a kind of enzyme process prepares fibroin/elastin laminin composite film material to Chinese invention patent
Method " (publication number CN 105218842A) applies beta-Tyrosinase to amino acid converting in fibroin, tyrosine in increase fibroin
The quantity of residue is then crosslinked with elastin laminin by tyrosinase catalysis oxidation fibroin, it is thin to be prepared for fibroin/elastin laminin
Film.But it is wherein amino acid converting to have used phenol, residual that influence the biocompatibility of material in the process.
Hydrogel is a kind of special material with Space network of polymer structure, can absorb a large amount of moisture, is swollen
Original structure can also be kept to be not dissolved simultaneously.Be now widely used for medicament slow release, tissue engineering material, artificial skin, can
Injection material etc..Currently, fibroin passes through physical method (ultrasound, change pH, surfactant induction etc.) and chemical method
(addition glutaraldehyde, diglycidyl ether etc.) can prepare fibroin hydrogel, however hydrogel prepared by physical method takes
Long, beta sheet structure increases, and ultimately forms milky hydrogel and elasticity is poor.The hydrogel elastic that the method for chemistry is formed
Preferably, but the chemical small molecule of bringing system into needs secondary removal, poor biocompatibility, it is difficult to internal as may be injected into
Biomaterial.
The information for being disclosed in the background technology part is merely intended to deepen the understanding to the general background technology of invention, without
It should be considered as recognizing or implying in any form that the information constitutes the prior art known to those skilled in the art.
Invention content
Based on the deficiencies of the prior art, the carrier the present invention provides a kind of pharmaceutical products, for loading pharmaceutical products, water
Gel and its method, partly or entirely to improve, even solve problem above.
The invention is realized in this way：
In a first aspect, the embodiment of the present invention provides a kind of hydrogel.
Hydrogel is a kind of biomaterial that can be used in a manner of injection, and hydrogel is by using composite crosslinking
Agent makes the protein cross being contained in raw material form, wherein protein contains tyrosine, and multiple crosslinking agent includes horseradish peroxide
Change enzyme (Peroxidase Horseradish, HRP) and hydrogen peroxide.
In second aspect, the embodiment of the present invention provides a kind of carrier for loading pharmaceutical products.
Carrier for loading pharmaceutical products is made by hydrogel, wherein pharmaceutical products include antimicrobial, anodyne
And it is one or more in growth factor.
In the third aspect, the embodiment of the present invention provides a kind of pharmaceutical products.
Pharmaceutical products are made by hydrogel, and wherein pharmaceutical products include dressing, internal injectable materials, in vivo filling
Object, tissue renovation material, isolated material.
In fourth aspect, an embodiment of the present invention provides a kind of methods preparing hydrogel.
Production method includes：Make to the addition horseradish peroxidase from the dispersion liquid of the protein obtained in raw material is dispersed with
Proteolytic adds hydrogen peroxide and carries out cross-linking reaction.
Advantageous effect：
Hydrogel provided in an embodiment of the present invention is a kind of enzyme crosslinking hydrogel, with certain transparency, and is had
There are syringeability, good elasticity and good cell compatibility.Hydrogel is used directly for the surface of all kinds of wounds (such as
Burn, ulcer, bedsore etc.), play the role of wound healing and insulation blocking.In addition, hydrogel is also used as drug
Carrier, loads all kinds of antimicrobials, anodyne and growth factor, and slow releasing function is played to drug, and the surface of a wound, which can be played, to be prevented
Infection, analgesic and the effect for promoting healing.For making in the material of hydrogel, matrix (raw material containing protein) and enzymatic
Crosslinked ingredient can and preferably natural biological sources, so as to so as to obtain hydrogel safe and reliable, facilitate sterilizing.And
And medical dressing is thus can be used as, internal injectable materials can be filled object and for fields such as tissue repairs, have in vivo
Good application prospect.
Description of the drawings
In order to more clearly explain the embodiment of the invention or the technical proposal in the existing technology, to embodiment or will show below
There is attached drawing needed in technology description to be briefly described.
Fig. 1 is the pictorial diagram of the fibroin hydrogel of the embodiment of the present invention 1~5；
Fig. 2 is the gel time figure of the hydrogel material in the embodiment of the present invention 1~3；
Fig. 3 is the light transmittance figure of the hydrogel under different conditions in the embodiment of the present invention 2.
Specific implementation mode
Embodiment of the present invention is described in detail below in conjunction with embodiment, but those skilled in the art will
Understand, the following example is merely to illustrate the present invention, and is not construed as limiting the scope of the invention.It is not specified in embodiment specific
Condition person carries out according to conventional conditions or manufacturer's recommended conditions.Reagents or instruments used without specified manufacturer is
The conventional products that can be obtained by commercially available purchase.
Below for the pharmaceutical products of the embodiment of the present invention, the carrier for loading pharmaceutical products, hydrogel and its method
It is specifically described：
Hydrogel provided in an embodiment of the present invention is a kind of biomaterial that can be used in a manner of injection.Hydrogel
It is so that the protein cross being contained in raw material is formed by using multiple crosslinking agent, wherein protein contains tyrosine, compound
Crosslinking agent includes horseradish peroxidase and hydrogen peroxide.
In the making raw material of hydrogel, horseradish peroxidase can be catalyzed silk under the booster action of micro hydrogen peroxide
Tyrosine residue in element generates Phenoxy radical, causes the crosslinking between fibroin molecule, in a short time, reaction system can shape
At gel.
Raw material therein can be various biomaterials, for example, silk, can derive from the differences such as silkworm, tussah, giant silkworm
The silkworm of type.Raw material can also be the product after being processed by silk, example in addition to that can be the silk as original material
Such as, one or more in fibroin, collagen, gelatin.
As aforementioned, before hydrogel provided in an embodiment of the present invention has wide application in the fields such as medicine and pharmacy
Scape.
For example, in some instances, hydrogel is used as a kind of carrier, by will obtain hydrogel it is directly moulding or
Person is made as the carrier for the form for having certain by adding other pharmaceutically acceptable auxiliary materials.By the way that pharmaceutical products are loaded
On carrier, the medication efficiency for improving pharmaceutical products and safety can be reached.Pharmaceutical products therein include antimicrobial, analgesic
It is one or more in medicine and growth factor.Above-mentioned pharmaceutical products are supported on carrier can be directly by pharmaceutical products
(forms such as powder, tablet, spraying) dispersion (modes such as coating, sprinkling) is on the surface or inside of hydrogel.
In addition, other than using hydrogel as such as above-mentioned carrier, hydrogel can also be directly as one
Kind pharmaceutical products use.I.e. pharmaceutical products are made by hydrogel.Wherein, pharmaceutical products include dressing, internal injectable material
Material, internal filler, tissue renovation material, isolated material.
A kind of production method of hydrogel is additionally provided in embodiments of the present invention.The production method includes：To point
Dissipate have from the dispersion liquid of the protein obtained in raw material be added horseradish peroxidase make proteolytic, add hydrogen peroxide into
Row cross-linking reaction.
In some instances, aforementioned dispersion liquid is silk fibroin aqueous solution, and raw material is silk, and protein is fibroin.Particularly,
Silk fibroin aqueous solution can make by the following method：The silk after degumming is set to be dissolved in water.
When the raw material for making hydrogel uses silk, the method that the silk after degumming is dissolved in water is set to include：By silkworm
It obtains fibroin fiber after degumming of silk to be dissolved in solvent, wherein solvent is lithium bromide water solution or ternary aqueous solution.
In a kind of alternative example, ternary aqueous solution is made of calcium chloride, ethyl alcohol and water.Preferably, ternary water
Solution is by calcium chloride, ethyl alcohol and water according to 1:2:8 molar ratio forms.The concentration of lithium bromide water solution can be chosen
It is selected as 9.3mol/L.
In addition, in order to promote the dissolving of fibroin fiber, in a kind of optional example, fibroin fiber is the condition in heating
Under be dissolved in solvent, wherein the temperature of heating be 50~80 DEG C, further preferably 50~70 DEG C, be most preferably 70~75
℃。
Cross-linking reaction above-mentioned is preferably by being performed under heating conditions.Preferably, it is heated after hydrogen peroxide being added
Reaction, and the condition for heating reaction is：10~50 DEG C of temperature, fibroin be a concentration of 1~8%, 5~20U/mL of horseradish peroxidase,
0.05~10mg/mL of hydrogen peroxide, 10~120min of time.
More preferably, after hydrogen peroxide is added, carry out catalytic crosslinking reaction before, production method further include by dispersion liquid,
The co-mixing system of horseradish peroxidase and hydrogen peroxide is handled by vacuum defoamation.
It should be noted that in the manufacturing process of hydrogel, the transparency and elasticity modulus of hydrogel can be according to fibroins
Concentration is adjusted.Meanwhile the cross-linking reaction time in manufacturing process can pass through horseradish peroxidase concentration, hydrogen peroxide concentration
And operative temperature is controlled.
As a kind of example, hydrogel is made using silk.
Include the following steps：(a) degumming is carried out to natural silk, with the silkworm after lithium bromide or ternary solution dissolving degumming
Silk, using dialysis, filtering, concentration, obtains silk fibroin aqueous solution (stoste)；(b) it is prepared with ultra-pure water and (is diluted stoste) and is certain dense
The silk fibroin aqueous solution of degree, sequentially adds horseradish peroxidase and aqueous hydrogen peroxide solution, is uniformly mixed；(c) by co-mixing system vacuum
After deaeration, it is placed under certain temperature condition and can be obtained fibroin hydrogel.
Wherein, the preparation method of silk fibroin aqueous solution is specially in step (a)：Fibroin fiber after degumming is placed in CaCl2-
In alcohol-water ternary solution or 9.3mol/L lithium-bromide solutions, heating makes the temperature of solution control between 50~80 DEG C, stirs
It mixes to dissolving, it is air-dried to be concentrated to give silk fibroin aqueous solution by filtering, centrifuging removal of impurities then with 36~72h of deionized water dialysis,
The CaCl2CaCl in alcohol-water ternary solution2, ethyl alcohol, water three the ratio between amount of substance be 1:2:8.
According to said program, fibroin mass concentration is 1~8% in step (b), 5~20U/ml of horseradish peroxidase, dioxygen
2~20mg/ml of water.
According to said program, uniformly rear vacuum defoamation, mixed solution inject in mold stir thoroughly at room temperature in step (c)
Afterwards, 10~50 DEG C of temperature ranges, 10~120min of time, you can obtain molding fibroin hydrogel.
According to inspection, inventor firmly believes, it includes but not limited to below each that hydrogel provided in an embodiment of the present invention, which has,
Kind advantage：
(1) using the high molecular material fibroin of natural reproducible as raw material, material source is extensive and is natural degradable high score
Son, catabolite have good biocompatibility and low immunogenicity.
(2) enzymatic crosslinking method is used, the Phenoxy radical generated by tyrosine residue shape between fibroin macromolecular
At the covalent crosslink stablized, the quick formation of fibroin hydrogel is promoted, stability is good, extends it in biomaterial
Application range.
(3) the fibroin hydrogel that finally prepares of the present invention is by controlled release preparation condition, can be obtained it is flexible it is transparent can
Inject hydrogel.
(4) preparation is simple for injection aquagel provided by the invention, and condition is easily controllable, can be gone out by filtering
Bacterium has preferable application prospect.
With reference to embodiments to pharmaceutical products, the carrier for loading pharmaceutical products, hydrogel and its side of the present invention
Method is described in further detail.
Embodiment 1
A kind of fibroin hydrogel material, is prepared by following preparation methods.
Natural silk is passed through to degumming successively first, dissolving, dialysis, filters and be concentrated to give the silk that mass fraction is 4%
Plain water dissolution.Wherein, course of dissolution is the fibroin fiber and CaCl that will be obtained after degumming2The ternary solution of alcohol-water composition is mixed
It closes, 0.5h is kept the temperature under 75 DEG C of temperature condition；In ternary solution, CaCl2, second alcohol and water substance amount ratio be 1:2:8.
Secondly, it is 1% silk fibroin solution to take mass fraction, and horseradish peroxide is sequentially added thereto in the case that mixing slowly
Change enzyme and hydrogen peroxide, a concentration of 10U/ml of final horseradish peroxidase wherein in blend solution, hydrogen peroxide it is a concentration of
0.6mg/ml。
Again, blend solution rapid vacuum deaeration is placed on 37 DEG C of water-baths.Fibroin is can be obtained after a period of time
Hydrogel.
Embodiment 2
A kind of fibroin hydrogel material, is prepared by following preparation methods.
Natural silk is passed through to degumming successively first, dissolving, dialysis, filters and be concentrated to give the silk that mass fraction is 4%
Plain water dissolution.Wherein, course of dissolution is the fibroin fiber and CaCl that will be obtained after degumming2The ternary solution of alcohol-water composition is mixed
It closes, 0.5h is kept the temperature under 75 DEG C of temperature condition；In ternary solution, CaCl2, second alcohol and water substance amount ratio be 1:2:8.
Secondly, it is 2% silk fibroin solution to take mass fraction, and horseradish peroxide is sequentially added thereto in the case that mixing slowly
Change enzyme and hydrogen peroxide, a concentration of 10U/ml of final horseradish peroxidase wherein in blend solution, hydrogen peroxide it is a concentration of
0.6mg/ml。
Again, blend solution rapid vacuum deaeration is placed on 37 DEG C of water-baths.Fibroin is can be obtained after a period of time
Hydrogel.
Embodiment 3
A kind of fibroin hydrogel material, is prepared by following preparation methods.
Natural silk is passed through to degumming successively first, dissolving, dialysis, filters and be concentrated to give the silk that mass fraction is 4%
Plain water dissolution.Wherein, course of dissolution is that the ternary solution that the fibroin fiber that will be obtained after degumming is formed with CaCl2- alcohol-waters mixes
It closes, 0.5h is kept the temperature under 75 DEG C of temperature condition；In ternary solution, CaCl2, second alcohol and water substance amount ratio be 1:2:8.
Secondly, it is 3% silk fibroin solution to take mass fraction, and horseradish peroxide is sequentially added thereto in the case that mixing slowly
Change enzyme and hydrogen peroxide, a concentration of 10U/ml of final horseradish peroxidase wherein in blend solution, hydrogen peroxide it is a concentration of
0.6mg/ml。
Again, blend solution rapid vacuum deaeration is placed on 37 DEG C of water-baths.Fibroin is can be obtained after a period of time
Hydrogel.
Comparative example 1
A kind of hydrogel, production process is with embodiment 3, the difference is that not adding hydrogen peroxide.
Comparative example 2
A kind of hydrogel, production process is with embodiment 3, the difference is that not adding horseradish peroxidase and dioxygen
Water.
Test example 1
Using the macro morphology of hydrogel is obtained in conventional method testing example 1-3 and comparative example 1-2, figure is as a result seen
1.As shown in the figure, the fibroin hydrogel transparency that embodiment 1-3 is obtained is high, and comparative example 1 and 2 fibroin hydrogels are in milky white
Color.By artificially measuring, the thickness of hydrogel is about 5mm.
Three width of part shows the transparent effect of obtained hydrogel in preferable example of the invention on Fig. 1.
In five figures of Fig. 1 lower parts, 1-1%SF indicates that the silk fibroin solution in embodiment 1 using 1% mass fraction makes
Hydrogel；2-2%SF indicates that the silk fibroin solution in embodiment 2 using 2% mass fraction makes hydrogel；3-1%SF indicates real
It applies the silk fibroin solution in example 3 using 3% mass fraction and makes hydrogel；4-3%SF is indicated in comparative example 1 using 3% mass point
Several silk fibroin solutions makes hydrogel；5-3%SF indicates that the silk fibroin solution in comparative example 2 using 3% mass fraction makes water-setting
Glue.3D indicates that SF indicates fibroin albumen 3 days.
Test example 2
Using the gel time of anastrophe record embodiment 1-3, the results are shown in Figure 2, and when the gel of comparative example 1 and 2
Between (37 DEG C) be respectively 40h and 42h (being not included in figure).It can be seen that enzyme-catalyzed change cross-linking reaction has been obviously shortened fibroin
Gel time improves the syringeability of silk fibroin material.
Test example 3
Embodiment 2 is measured using T9CS ultraviolet-visibles spectrophotometer (Beijing Puxi General Instrument Co., Ltd)
Visible light all band light transmittance under different conditions.Wherein deionized water is as a control group.From spectrogram as it can be seen that in visible light
In range, the light transmittance of fibroin hydrogel is higher, and range is in 50~80%.
Result of study shows to be obviously shortened using the fibroin hydrogel gel time that enzyme-catalyzed change cross-linking method is prepared, institute
The transparency of the hydrogel of formation is high.This kind of transparent fibroin hydrogel material prepared by the present invention extends fibroin bio-medical
The application range of material, can be used as medical dressing, and object can be filled and for necks such as tissue repairs in internal injectable materials in vivo
Domain has a good application prospect.
Although illustrate and describing the present invention with specific embodiment, it will be appreciated that without departing substantially from the present invention's
Many other change and modification can be made in the case of spirit and scope.It is, therefore, intended that in the following claims
Including belonging to all such changes and modifications in the scope of the invention.
Claims (10)
1. a kind of hydrogel, which is characterized in that the hydrogel is a kind of biomaterial that can be used in a manner of injection,
The hydrogel is so that the protein cross being contained in raw material is formed by using multiple crosslinking agent, wherein the protein
Containing tyrosine, the multiple crosslinking agent includes horseradish peroxidase and hydrogen peroxide.
2. hydrogel according to claim 1, which is characterized in that the raw material includes silk.
3. hydrogel according to claim 1, which is characterized in that the protein includes in fibroin, collagen and gelatin
It is one or more.
4. a kind of for loading the carriers of pharmaceutical products, which is characterized in that the pharmaceutical products include antimicrobial, anodyne and
It is one or more in growth factor, the carrier by as described in any one of claims 1 to 3 hydrogel make and
At.
5. a kind of pharmaceutical products, which is characterized in that the pharmaceutical products are by the water as described in any one of claims 1 to 3
Gel is made, and the pharmaceutical products include dressing, internal injectable materials, internal filler, tissue renovation material, isolation
Material.
6. a kind of production method of hydrogel as described in any one of claims 1 to 3, which is characterized in that the making
Method includes：To be dispersed be added from the dispersion liquid of the protein obtained in the raw material horseradish peroxidase make it is described
Proteolytic adds hydrogen peroxide and carries out cross-linking reaction.
7. the production method of hydrogel according to claim 6, which is characterized in that the dispersion liquid is silk fibroin aqueous solution,
The raw material is silk, and the protein is fibroin, and the silk fibroin aqueous solution makes by the following method：Make described after degumming
Silk is dissolved in water；
Preferably, the method that the silk after degumming is dissolved in water is made to include：It is fine by fibroin is obtained after the natural silk degumming
Dimension is dissolved in solvent, and the solvent is lithium bromide water solution or ternary aqueous solution, and the ternary aqueous solution is by calcium chloride, ethyl alcohol
And water composition, it is highly preferred that the fibroin fiber is to be dissolved in the solvent under heating conditions, wherein heating
Temperature is 50~80 DEG C, further preferably 50~70 DEG C, most preferably 70~75 DEG C.
8. the production method of hydrogel according to claim 7, which is characterized in that the ternary aqueous solution is by chlorination
Calcium, ethyl alcohol and water are according to 1:2:8 molar ratio forms, a concentration of 9.3mol/L of the lithium bromide water solution.
9. the production method of hydrogel according to claim 7, which is characterized in that carry out cross-linking reaction after hydrogen peroxide is added
It is to carry out under heating conditions, and the condition for heating reaction is：
10~50 DEG C of temperature, fibroin be a concentration of 1~8%, 5~20U/mL of horseradish peroxidase, 0.05~10mg/mL of hydrogen peroxide,
10~120min of time.
10. the production method of hydrogel according to claim 9, which is characterized in that after hydrogen peroxide is added, urged
Before changing cross-linking reaction, the production method further includes by the dispersion liquid, the horseradish peroxidase and the hydrogen peroxide
Co-mixing system handled by vacuum defoamation.
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