CN109078217A - A kind of wound healing material and preparation method thereof - Google Patents
A kind of wound healing material and preparation method thereof Download PDFInfo
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- CN109078217A CN109078217A CN201811011103.2A CN201811011103A CN109078217A CN 109078217 A CN109078217 A CN 109078217A CN 201811011103 A CN201811011103 A CN 201811011103A CN 109078217 A CN109078217 A CN 109078217A
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- growth factor
- wound healing
- healing material
- heparin
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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
- A61L26/0019—Chemical aspects of, or use of materials for, wound dressings or bandages in liquid, gel or powder form containing macromolecular materials obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds
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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
- A61L26/0023—Polysaccharides
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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
- A61L26/0061—Use of materials characterised by their function or physical properties
-
- 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
- A61L26/0066—Medicaments; Biocides
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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
- A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
- A61L2300/40—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices characterised by a specific therapeutic activity or mode of action
- A61L2300/41—Anti-inflammatory agents, e.g. NSAIDs
-
- 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
- A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
- A61L2300/40—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices characterised by a specific therapeutic activity or mode of action
- A61L2300/412—Tissue-regenerating or healing or proliferative agents
- A61L2300/414—Growth factors
-
- 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
- A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
- A61L2300/60—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices characterised by a special physical form
- A61L2300/602—Type of release, e.g. controlled, sustained, slow
- A61L2300/604—Biodegradation
Abstract
The present invention relates to a kind of wound healing materials and preparation method thereof, are related to biomedical materials field.The preparation method of the wound healing material includes: the freeze-drying of dialysing after condensation reaction by the buffer of heparinate and dopamine mixed with polymers, obtains heparin-DOPA amine polymer, and the heparinate is the heparinate after activated carboxylic.Heparin-the dopamine is polymer-modified on magnetic nanoparticle, obtain initial reaction product.Growth factor is grafted into the initial reaction product, up to the wound healing material, preparation method operation is controllable, and preparation process is relatively simple, wound healing material obtained, the stability of growth factor can be improved, it realizes that growth factor discharges for a long time, has no toxic side effect, while adequately participating in treating wound the process of healing, reduce inflammation, wound healing.
Description
Technical field
The present invention relates to biomedical materials fields, and in particular to a kind of wound healing material and preparation method thereof.
Background technique
Growth factor is a kind of signaling molecule secreted by cell, similar to hormone, and majority is peptide matters, has and adjusts
The effect of ganglion cell growth and differentiation, can promote the proliferation of cell, the hyperplasia of collagen, the generation of granulation tissue, the differentiation of tissue.
But since growth factor is degradable, half-life short, be easy inactivation, can not long duration of action in wound site generate life
The performance of object effect, bioactivity has dose dependent, it is therefore desirable to which large dosage uses repeatedly, expensive, and utilizes
Rate is low.Therefore improving the stability of growth factor and utilization rate by building slow-releasing system is particularly important.
Summary of the invention
The purpose of the present invention is to provide a kind of wound healing materials, and the stability and sustained release effect of growth factor can be improved
Fruit has no toxic and side effect to human body, while inflammation is effectively reduced, wound healing, effectively improves the efficiency and effect of healing.
Another object of the present invention is to provide a kind of preparation methods of wound healing material, and operation is controllable, preparation process
Relatively simple, the slow release effect and trauma care effect of wound healing material obtained are good.
The present invention solves its technical problem and adopts the following technical solutions to realize.
The present invention proposes a kind of preparation method of wound healing material comprising:
By the buffer of heparinate and dopamine mixed with polymers, it is poly- to obtain heparin-dopamine for freeze-drying of dialysing after condensation reaction
Object is closed, heparinate is the heparinate after activated carboxylic.
Magnetic nanoparticle is complexed to heparin-DOPA amine polymer, initial reaction product is obtained.
Growth factor is grafted into initial reaction product to get wound healing material.
The present invention proposes a kind of wound healing material, is made by above-mentioned preparation method.
The present invention proposes a kind of wound healing material comprising carrier and the growth factor for grafting on carrier, carrier packet
It includes heparin-DOPA amine polymer and has modified heparin-DOPA amine polymer magnetic nanoparticle.
A kind of beneficial effect of wound healing material of the embodiment of the present invention and preparation method thereof is:
The present invention magnetic nanoparticle polymer-modified by building heparin-dopamine, passes through the specificity parent of heparin
And effect, the graft growth factor can form the slow-released system of growth factor, improve the stability of growth factor, realize for a long time
Release, adequately participate in treating wound the process of healing, wound healing.Secondly dopamine has very strong inoxidizability,
It can reduce the ROS in wound healing period, to promote the polarization of macrophage, and by the intervention of magnetic nanoparticle,
It is not given only heparin-DOPA amine polymer-stable carrier structure of growth factor system one, moreover it is possible to pass through its distinctive magnetic
Property, external magnetic field energy is introduced, the synergistic effect with dopamine can effectively facilitate the polarization of macrophage during wound repair,
Promote the generation of blood vessel, the reduction of the deposition and inflammation of collagen, so that healing speed greatly increases.Meanwhile it is obtained
Wound healing material non-toxic side effect, securely and reliably.
Detailed description of the invention
In order to illustrate the technical solution of the embodiments of the present invention more clearly, below will be to needed in the embodiment attached
Figure is briefly described, it should be understood that the following drawings illustrates only certain embodiments of the present invention, therefore is not construed as pair
The restriction of range for those of ordinary skill in the art without creative efforts, can also be according to this
A little attached drawings obtain other relevant attached drawings.
Fig. 1 is the first phenogram of wound healing material provided by the invention；
Fig. 2 is the second phenogram of wound healing material provided by the invention；
Fig. 3 A is the survival rate schematic diagram for the group of cells that 2 cell toxicity test of test example of the present invention provides；
Fig. 3 B is the survival rate schematic diagram that 2 cell survival rate of test example of the present invention influences the group of cells that test provides；
Fig. 4 is that 2 macrophage fluorescence of test example of the present invention expresses schematic diagram；
Fig. 5 is that test example 2 of the present invention expresses albumin A rg-1 to macrophage M2 type and M1 type expresses the fluorescence of albumen iNOS
Express ration statistics；
Fig. 6 is that the cell protein that test example 2 of the present invention provides the influence test to cell protein and gene level is horizontal
Express schematic diagram；
Fig. 7 is that the gene level expression that test example 2 of the present invention provides the influence test of cell protein and gene level is shown
It is intended to；
Fig. 8 is the bFGF degradation curve schematic diagram that test example 3bFGF Degrading experiment of the present invention provides；
Fig. 9 is the bFGF release profiles schematic diagram that test example 3bFGF release test of the present invention provides.
Specific embodiment
It in order to make the object, technical scheme and advantages of the embodiment of the invention clearer, below will be in the embodiment of the present invention
Technical solution be clearly and completely described.The person that is not specified actual conditions in embodiment, according to normal conditions or manufacturer builds
The condition of view carries out.Reagents or instruments used without specified manufacturer is the conventional production that can be obtained by commercially available purchase
Product.
The preparation method of the wound healing material of the embodiment of the present invention is specifically described below.
The embodiment of the present invention provides a kind of preparation method of wound healing material comprising:
S1. by the buffer of heparinate and dopamine mixed with polymers, freeze-drying of dialysing after condensation reaction obtains heparin-DOPA
Amine polymer.
It that is to say the strong anti-oxidation by dopamine, can reduce the ROS in wound healing period, to promote macrophage thin
The polarization of born of the same parents is condensed by heparin and dopamine, can effectively improve the speed of wound healing.
In order to which the combination for keeping the amino of carboxyl and dopamine in heparin more stable forms amido bond, potency is higher, this
In invention preferred embodiment, preferably heparinate is the heparinate after activated carboxylic.
Since dopamine antioxygenic property is extremely strong, easily by the dioxygen oxidation in air, so that polymer can not play it
Anti-oxidation characteristics, therefore, in preferred embodiments of the present invention, the step of carboxyl of activated heparin salt, includes:
Under inert gas, such as the protection of nitrogen, argon gas, the buffer of heparinate is mixed with carboxyl activator, instead
It answers in 25-40min, such as 26min, 28min, 29min, 30min, 31min, 34min, 36min, 37min, 38min or 40min
Any point value or in which any two point value between interval value, carboxyl activator includes 1- (3- dimethylamino-propyl) -3-
Ethyl carbodiimide (EDC) and n-hydroxysuccinimide (NHS).Using the carboxyl of EDC and NHS combination activated heparin, and
In reaction process the amino of the carboxyl of continuous activation heparin and dopamine generate amidation, promote polymer condensation reactions into
Row.
Further, in preferred embodiments of the present invention, 1- (3- dimethylamino-propyl) -3- ethyl carbodiimide and N- hydroxyl
The molar ratio of base succinimide is 1:1；The two collaboration cooperation, the carboxyl of common activated heparin salt.
Further, in preferred embodiments of the present invention, the molar ratio of heparin and carboxyl activator in heparinate is
1-10:1, such as the molar ratio of heparin and carboxyl activator is 2:1,3:1,4.5:1,5.5:1,6:1,7:1,8.1:1 or 9:1
Deng, prevent that carboxyl activator is very few to cause activation efficiency low, be also prevented from carboxyl activator it is excessive caused by waste.
In order to polymerize the heparin in buffer sufficiently with DOPA amine polymer, in preferred embodiments of the present invention,
In the step of heparinate and dopamine mixed with polymers, the molar ratio of heparin and DOPA amine polymer in heparinate is 1-
10:10-1, such as 1:1,1:2,1:3,1:5,1:8,1:10,2:1,2:4,2:5,2:9,3:1,3:4,3:7,3:10,4:2:, 4:
3,4:5,4:7,5:3,5:7,6:1,6:5,6:7,7:1,7:3,7:8,8:1,8:3,8:7,9:1,9:4,9:7 or 9:10 etc..
Hold above-mentioned, heparin and dopamine polymer condensation reactions are carried out by following equation:
Obtained heparin-DOPA amine polymer characterization is as shown in Figure 1 and Figure 2.
Wherein, in preferred embodiments of the present invention, heparinate for example can be heparin sodium, calciparine, heparin lithium, clarin
Etc. water-soluble heparinate, preferably heparin sodium, effect is more preferable.
In order to remove the salt ion after condensation reaction in reaction solution, and then obtain heparin-dopamine of pure macromolecular
In preferred embodiments of the present invention, the reaction solution after condensation reaction is dialysed for polymer, and specifically, the time of dialysis is 36-
During which 60h, such as 38d, 40d, 45d, 48d or 50d carry out changing water at interval of 6-12h.
S2. heparin-dopamine is polymer-modified on magnetic nanoparticle, obtain initial reaction product.
Wherein, by the addition of magnetic nanoparticle, magnetic field and magnetic Nano can be utilized under the action of externally-applied magnetic field
The synergistic effect of grain, can be used for regulating and controlling polarization of the wound site macrophage to M2 type, plays the role of wound healing.
Specifically, in preferred embodiments of the present invention, magnetic nanoparticle is selected from Fe3O4Nano particle, Fe2O3Nanometer
Grain and Co3O4At least one of nano particle, such as magnetic nanoparticle are Fe3O4Nano particle, Fe2O3Nano particle and
Co3O4The mixture or Fe of nano particle2O3Nano particle.
Due to Fe3O4The good biocompatibility of nano particle, size are easy to regulate and control, and magnetic saturation intensity is higher, therefore preferably
Ground, in preferred embodiments of the present invention, magnetic nanoparticle Fe3O4Nano particle.Wherein, Fe3O4Nano particle can be bought
In market, can also voluntarily prepare.
The present invention is preferably in embodiment, Fe3O4When nano particle is voluntarily prepared, following several method preparation can be used:
The first production method: ferric acetyl acetonade being dissolved among the mixed solution of benzyl ether and oleyl amine, is divided after heating
From gained, specifically, such as: by the ferric acetyl acetonade of 0.71g be dissolved in 10ml benzyl ether and 10ml oleyl amine mixed solution it
In, oil bath pan is heated to 110 DEG C and is dehydrated one hour, is then poured into Ci Zhou and is put among atmosphere furnace, its ladder speed heating is arranged
To 300 DEG C, this temperature 2h is kept, is taken out after its cooling, 50ml dehydrated alcohol is added after being cooled to room temperature, collects sediment
It is centrifuged 10 minutes under 8000rpm-10000rpm revolving speed, ethyl alcohol cleans 3 times to obtain Fe3O4Nano particle.Fe in order to prevent simultaneously3O4
Nano particle is assembled, and optionally, takes the Fe of 150mg3O4Nano particle is dispersed among 10ml n-hexane, and 0.25ml is added
Oleic acid stablizes Fe3O4Nano particle.
Second of production method: hydro-thermal method is made, and passes through Fe2 ++2Fe3 ++8OH?=Fe3O4↓+4H2O specifically will
FeCl2·4H2O and FeCl3·6H2The ratio mixing that O is 1: 2 in the mass ratio of the material is put into flask, and 200mL distilled water is added,
Temperature is controlled in (30 ± 1) DEG C, stirs and be slowly added dropwise the NH of 0.4mol/L strongly3·H2O to pH=9, by solution high temperature constant temperature
Water-bath crystallization certain time.Reaction terminates, Fe3O4Crystal grain is precipitated, is centrifugated, and repeatedly washed with deionized water to
PH value of solution=7 are to get while obtained Fe3O4Nano particle is mainly spherical shape, and average grain diameter is in 10nm or so.
The third production method: first by FeCl3(0.65g, 4.0mmol) and trisodium citrate (0.20g, 0.68mmol) are molten
Solution is then added with stirring NaAc (1.20g) in 300rpm in ethylene glycol (20mL).Mixture is vigorously stirred 30 minutes,
Then it is sealed in stainless steel autoclave (50mL capacity), autoclave is heated to 200 DEG C and is kept for 10 hours, is subsequently cooled to
Room temperature will finally obtain black product and be washed for several times with ethyl alcohol and deionized water.
Since magnetic nanoparticle activity is high, in order to allow to more uniformly be scattered in solution, it is convenient for abundant network
It is bonded to heparin-DOPA amine polymer, it is therefore, in preferred embodiments of the present invention, heparin-dopamine is polymer-modified to magnetism
It further include that magnetic nanoparticle is handled using cationic surfactant before nano particle, so as to can fine dispersion in water
For modifying heparin-dopamine polymeric layer.
Further, in preferred embodiments of the present invention, cationic surfactant is selected from octadecyl trimethyl chlorination
Ammonium (CTAB), cation guar gum, cationic panthenol, cation-modified silicone oil and dodecyldimethylamine oxide are right
The surface modification effect of magnetic nanoparticle is good.
Further, in preferred embodiments of the present invention, cationic surfactant is octadecyl trimethyl chlorination
Ammonium, good to the surface modification effect of magnetic nanoparticle, the magnetic nanoparticle after can enabling modification is molten into water, thus
The modification of dopamine-heparin is carried out, while there is certain bactericidal effect, prevents from introducing bacterium, makes heparin-DOPA amine polymer
After modifying magnetic nanoparticle processing, have no adverse effects to during the initial reaction product graft growth factor.
In order to modify magnetic nanoparticle adequately by cationic active agent, while preventing of the invention preferable
Embodiment in, using cationic surfactant handle magnetic nanoparticle the step of include:
Organic solvent containing magnetic nanoparticle is added dropwise in the aqueous solution of cationic surfactant, 25- is stirred
35min then removes organic solvent and extra cationic surfactant, prevents extra cationic surfactant pair
Have an impact in subsequent reactions.
In preferred embodiments of the present invention, organic solvent is chloroform, on the one hand, magnetic nanoparticle is readily dispersed in it
In, while without reaction, while its is volatile, subsequent need to heat and can remove, and effectively save the time.
It that is to say, S1 and step S2 is made in wound healing material and carries required for growth factor through the above steps
Body.
S3. growth factor is grafted into initial reaction product to get wound healing material.
In preferred embodiments of the present invention, growth factor is thin selected from human body Basic Fibroblast Growth Factor (bFGF), angling
The intracellular growth factor (KGF), epithelical cell growth factor (EGF), nerve growth factor (NGF), corium growth factor (AFGF), blood
Endothelial tube growth factor (VEGF), human fibroblast growth factor-21 (FGF-21) and human fibroblastic growth factor -9
At least one of (FGF-9), for example, growth factor be bFGF, AFGF, FGF-21, EGF and AFGF mixture or VEGF,
The mixture etc. of KGF and EGF.
In preferred embodiments of the present invention, growth factor is human body Basic Fibroblast Growth Factor, is a kind of with rush
The peptide material of the bioactivity such as the vascularization into cell proliferation and differentiation and wound plays important regulation to wound repair and makees
With having a wide range of application.
Based on the above method, the present invention also provides a kind of wound healing materials, by the preparation of above-mentioned wound healing material
Method is made.
In addition to wound healing material made from the preparation method as above-mentioned wound healing material, the present invention also provides a kind of wounds
Heal material in face, does not limit preparation method herein, it is only necessary to which it meets and the preparation method of above-mentioned wound healing material is made
The identical property of wound healing material and effect.
It should be noted that wound healing material or other methods system is made by the preparation method of above-mentioned wound healing material
The wound healing material obtained, includes carrier and the growth factor for grafting on carrier, and carrier includes heparin-dopamine polymerization
Object and it is complexed to heparin-DOPA amine polymer magnetic nanoparticle.
It that is to say, for wound healing material using magnetic nanoparticle as carrier, dopamine increases its biocompatibility, and more
Bar amine has very strong inoxidizability, can reduce the ROS in wound healing period, to promote the polarization of macrophage, with magnetic field
Synergistic effect after effect it is more obvious.A small amount of magnetic nanoparticle is used simultaneously, and (magnetic nanoparticle can't be to human body
Cause damages) cell survival rate height.The characteristic of heparin and biotic factor chemical bonds simultaneously, by biotic factor slow release,
Effect of the forming material as the slow-released system of drug, participates in the prolonged healing process in wound, and experiment shows in this material
After modification, biotic factor such as bFGF etc., release time reaches 12 days or more, and fractional release has reached 40%, can
It is obviously promoted the regeneration of the proliferation and tissue of cell, good effect, and synthesis side are played during treating wound
Method is relatively simple.Above-mentioned wound healing material has no toxic and side effect to human body simultaneously, safe and reliable.
In preferred embodiments of the present invention, content of the growth factor in wound healing material is 2%-20%；Such as it is raw
Content of the long factor in wound healing material be 2%, 2.2%, 2.5%, 3.1%, 3.5%, 3.7%, 4%, 7%, 8%,
12%, the interval value between any one point value or any two point value in 15%, 16% or 20%.
In preferred embodiments of the present invention, growth factor is thin selected from human body Basic Fibroblast Growth Factor (bFGF), angling
The intracellular growth factor (KGF), epithelical cell growth factor (EGF), nerve growth factor (NGF), corium growth factor (AFGF), blood
Endothelial tube growth factor (VEGF), human fibroblast growth factor-21 (FGF-21) and human fibroblastic growth factor -9
At least one of (FGF-9), for example, growth factor be bFGF, AFGF, FGF-21, EGF and AFGF mixture or VEGF,
The mixture etc. of KGF and EGF.
In preferred embodiments of the present invention, growth factor is human body Basic Fibroblast Growth Factor, is a kind of with rush
The peptide material of the bioactivity such as the vascularization into cell proliferation and differentiation and wound plays important regulation to wound repair and makees
With having a wide range of application.
In preferred embodiments of the present invention, content of the magnetic nanoparticle in wound healing material is 55%-70%, example
As content of the magnetic nanoparticle in wound healing material be 55.5%, 58%, 60%, 64%, 65%, 67%, 68%,
The interval value between any one point value or any two point value in 69% or 70%.
Specifically, in preferred embodiments of the present invention, magnetic nanoparticle is selected from Fe3O4Nano particle, Fe2O3Nanometer
Grain and Co3O4At least one of nano particle, such as magnetic nanoparticle are Fe3O4Nano particle, Fe2O3Nano particle and
Co3O4The mixture or Fe of nano particle2O3Nano particle.
Due to Fe3O4The good biocompatibility of nano particle, size are easy to regulate and control, and magnetic saturation intensity is higher, therefore preferably
Ground, in preferred embodiments of the present invention, magnetic nanoparticle Fe3O4Nano particle.Wherein, Fe3O4Nano particle can be bought
In market, can also voluntarily prepare.
It should be noted that growth factor apply the amount in the surface of a wound be it is micro, generally with each site of injury using growth because
Son is preferred in 1 μ g-1.6 μ g, specifically, can refer to existing technology.Therefore, the amount of the magnetic nanoparticle of site of injury very
It is small, it will not do harm to huamn body.
Feature and performance of the invention are described in further detail with reference to embodiments.
Embodiment 1
Heparin-DOPA amine polymer is made by following methods:
50mg heparin sodium is dissolved in the PBS of 20ml, be added EDC 3.13mg and NHS2.15mg (so that heparin, EDC and
NHS three's molar ratio is 1:1:1), it is sufficiently stirred after half an hour under nitrogen protection, the dopamine of 32.13mg is added,
Stirrer is stirred to react 2 hours, is then extracted reaction solution and is fitted into bag filter, is dialysed 2 days, needs to change every 6-12 hours primary
Water.It takes dialyzate freeze dryer to be lyophilized, obtains heparin-DOPA amine polymer.
Embodiment 2
Initial reaction product is made by following methods:
The CTAB of 40mg is dissolved among the pure water of 1ml, the Fe of 0.5mg is taken3O4Nano particle be dissolved in 0.1ml chloroform it
In, it is then added dropwise in the CTAB solution of 1ml, stirrer, which is stirred to react, to be stablized 30 minutes.Then 70 DEG C in oil bath pan
Middle heating 10 minutes, removal chloroform make its clarification.Obtained liquid is in charge of centrifugation, adds water to clean the solid obtained after centrifugation
Extra CTAB is removed three times, is obtained through CTAB treated Fe3O4Magnetic nanoparticle.
By the Fe of obtained 0.5mg3O4It is water-soluble that magnetic nanoparticle is added to heparin-dopamine that 1ml concentration is 5mg/ml
In liquid, 2h is reacted, subsequent 12000rpm high speed centrifugation obtains initial reaction product, wherein heparin-dopamine is mentioned by embodiment 1
The method of confession is made.
Embodiment 3
Wound healing material is made by following methods:
In the PBS buffer solution for the initial reaction product obtained by embodiment 2 that 400 μ l concentration are 30 μ g/ml, it is added 32
μ l concentration is the PBS buffer solution of the bFGF of 1mg/ml, is then reacted in 40 DEG C of biochemical cultivation case for 24 hours, high speed centrifugation
Obtain wound healing material.
Wherein, embodiment 3 is repeated, wound healing material obtained includes carrier and the growth factor for grafting on carrier,
Carrier includes heparin-DOPA amine polymer and is complexed to heparin-DOPA amine polymer magnetic nanoparticle.Wherein grow because
Content of the son in wound healing material is (4+1) %；Content of the magnetic nanoparticle in wound healing material is (58+
0.5) %.
Embodiment 4
Heparin-DOPA amine polymer is made by following methods:
200mg calciparine is dissolved in the PBS of 20ml, EDC3.13mg and NHS2.15mg is added, fills under nitrogen protection
Divide after stirring 40min, the dopamine of 32.13mg is added, stirrer is stirred to react 2 hours, then extracts reaction solution loading dialysis
In bag, dialyses 2 days, needed to change a water every 8-10 hours.It takes dialyzate freeze dryer to be lyophilized, obtains heparin-dopamine polymerization
Object.
Test example 1
Wounds in animals model
(1) 42 health C57BL/6 mouse (20-22g) is taken to establish mouse skin full-thickness excisional wound model.Every first
C57BL/6 mouse 4% chloraldurate (0.01ml/g) intraperitoneal injection of anesthesia, mouse four limbs is fixed on cystosepiment, shaving
Machine removes mouse back hair and is removed completely with depilatory cream, is carried out disinfection using alcohol to its skin of back.
(2) it is 8mm by internal diameter, outer diameter 16mm, with a thickness of the ring apron of 0.5mm is fixed on every with 6-0 nylon wire
On position at two lateral extent ear 2.5cm of C57BL/6 dorsal midline, suture is tensed, cushion rubber perfection is made to be fitted in mouse back
Portion, to prevent skin from healing because of shrinkage.Then use round skin puncher the alignment of its back two sides do two diameters for
The skin wound of 6mm.
(3) 42 health C57BL/6 mouse are randomly divided into six groups, every group 7.
First group is given the wound healing material that embodiment 3 provides, while externally-applied magnetic field acts on, as bFGF Fe3O4@H-
D NPs+ group；Second group is given only the wound healing material that embodiment 3 provides, as bFGF Fe3O4@H-D NPs group；Third group
It is given only bFGF, as bFGF group；4th group is given only initial reaction product made from embodiment 2, as Fe3O4@H-D NPs
Group；5th group is the control group for being given only PBS, as Control group；6th group be externally-applied magnetic field after giving PBS magnetic field pair
According to group, as Control+ group.
To guarantee that consistency is administered, first group to the 4th group, every group of bFGF content is 80 μ g/ml, 20 μ of administered volume
L guarantees the bFGF containing 1.6 μ g in the solution of 20 μ l.5th group and the 6th group PBS for then giving 20 μ l.To protect wound
It prevents from infecting, be covered on disk with 3M transparent dressing.
(4) using sterile Elastic bandage around mouse body one week, immobilizing bandage and by bandage together with skin closure,
Mouse is prevented to sting bad internal cushion rubber.
(5) it was shot at the 17th day and counts surface of a wound area.Wound healing rate is calculated, while observing each group wound, as a result such as
Shown in table 1.
1 each group wound healing result of table
According to table 1, wound healing material provided by the invention can effectively facilitate wound healing, especially when its with
Externally-applied magnetic field collective effect, curative effect highest.It is compared simultaneously by bFGF Fe3O4@H-D NPs group and bFGF group, it can
With discovery, the curative effect of wound healing material provided by the invention is substantially better than the effect of individual bFGF.
Test example 2
It cultivates mouse embryonic fibroblasts (NIH 3T3), with 10% fetal calf serum (FBS) and 1% penicillin/strepto-
The high glucose medium culture of plain (p/s).The cell pancreatin of 0.25%EDTA is digested, 1000rpm 3min is centrifuged later
Make cell precipitation, remove supernatant, add 1ml complete medium, piping and druming uniformly, then carries out cell count, with every hole 5000 number
Amount is laid on 96 orifice plates, if every group of 6 secondary orifices.
1. cell toxicity test
It is divided into following 4 groups:
Normal high glucose medium (Control group), bFGF group, Fe3O4@H-D NPs group, Fe3O4@H-D bFGF NPs group,
Wherein Fe3O4@H-D bFGF NPs and bFGF Fe3O4@H-D NPs indicates wound healing material provided by the present invention.
Every group of administration for 24 hours, then sucks culture medium, and after PBS cleaning is primary, basal medium, which is added, makes cell starvation 2-
Then 4h sucks culture medium, after PBS is cleaned 1 time, be added and contain 1%Cell Counting kit-8 (2- (2- methoxyl group -4-
Nitrobenzophenone) -3- (4- nitrobenzophenone) -5- (2,4- disulfonic acid benzene) -2H- tetrazolium monosodium salt) solution complete training in, about one is small
When or so, after solution becomes yellow, absorbance is surveyed under microplate reader 450nm wavelength, calculates cell survival rate.As a result such as Fig. 3 A
It is shown.P < 0.01 wherein * P < 0.05 compared with BFGF group, * *.
It can be obtained by Fig. 3 A, Fe3O4The cell of@H-D bFGF NPs group (that is to say wound healing material provided by the invention)
Survival rate highest, while Fe3O4The cell survival rate of@H-D bFGF NPs group is significantly higher than the cell survival rate of BFGF group, says
It is bright, Fe3O4@H-D bFGF NPs group can be used safely, to cytotoxic side effect.
2. cell survival rate influences test
Respectively by the product Fe of the present invention of same concentrations3O4@H-D bFGF NPs (wound healing material) is divided into 6 groups, and first
Group room temperature, second group in 4 DEG C of placement 16h, third group in 55 DEG C of placement 30min, the 4th group be scattered in pH4.7 solution it
In, fifth component dissipates in 1% trypsin solution, the 6th group of externally-applied magnetic field effect.The same concentrations of room temperature are selected when logical
BFGF group and Fe3O4@H-D NPs, and normal high glucose medium (Control group), 8 samples are administered for 24 hours respectively, are carried out
Cck-8 experiment, surveys cell survival rate.As a result as shown in Figure 3B.
It can be obtained according to Fig. 3 B, the cell survival rate of Fe3O4@H-D bFGF NPs provided by the invention is high, is higher than individual
BFGF group and Fe3O4@H-D NPs group in other words illustrates that bFGF is being grafted on Fe by cell activity variation3O4@H-D
After NPs is upper, effectively change its stability, at the same 4 DEG C of placement 16h, 55 DEG C of placement 30min, be scattered in pH4.7 solution it
In, and the degree of stability height being scattered under the extreme condition of 1% trypsin solution.
3. the influence to cell protein and gene level is tested
Raw264.7 cell line is circle M1 type macrophage, with 10% fetal calf serum (FBS) and 1% penicillin/chain
The high glucose medium culture of mycin (p/s).Cell is laid in six orifice plates in the method that test example 2 provides, every hole paving 100,000 is thin
Born of the same parents, culture cell is for 24 hours.
Then normal high glucose medium (Control group), bFGF group, Fe are given respectively3O4@H-D NPs group, Fe3O4@H-D
BFGF NPs group, Fe3O4@H-D bFGF NPs+ carries out administration in 12 hours, then replaces culture medium, giving 6h concentration is
The LPS of 200nM is stimulated, and the other magnetic stimulation of applying portion group, is then carried out fluorescent staining and scraping albumen to cell, is led to
The variation for crossing Western Blot detection protein level, the change of its gene level is detected finally by PCR.As a result such as Fig. 4, figure
5, shown in Fig. 6 and Fig. 7.
Complex chart 4 can be obtained to Fig. 7, give Fe3O4@H-D bFGF NPs, and apply magnetic field, cell is more advantageous to M2
Type macrophage differentiation, the M2 type macrophage marker such as protein level CD206, IL10 is improved, and INOS, CD86 etc.
Then there is a degree of decline, gene level is also led to the same conclusion, it was demonstrated that wound healing material provided by the invention is in magnetic
The process that M1 macrophage can be activated to convert to M2 type under field action.
Test example 3
Stability test
1. bFGF Degrading experiment
By the bFGF Fe of bFGF (as the Free bFGF group) and 200ul of 200ul3O4@H-D NPs solution is placed respectively
Among 37 DEG C of constant incubators, the bFGF stoste of 2ul then is taken in 0h, 12h, 1d, 2d, 4d, 6d, 8d, 10d, 12d respectively
The bFGF Fe of (not add-back) and 100ul3O4The supernatant of@H-D NPs, while the PBS of add-back 100ul.Utilize ELISA
BFGF kit surveys bFGF concentration, bFGF palliating degradation degree is calculated, as a result as shown in table 2 and Fig. 8.
2 bFGF of table is averaged palliating degradation degree
In table 2, abscissa refers to the bFGF concentration that ELISA bFGF kit measures.As shown in table 2 and Fig. 8, bFGF
Fe3O4The degradation speed of bFGF in@H-D NPs is significantly less than the degradation efficiency of individual bFGF, that is to say that it can be improved
The stability of growth factor.
2. bFGF release test
By the bFGF Fe of 200 μ l3O4@H-D NPs solution is placed among 37 DEG C of constant incubators, respectively at 0h, 3h,
6h, 12h, for 24 hours, 48h, 72h, 120h, 168h, 192h, 216h, 240h and 264h take the centrifugate of 100 μ l (wherein 0h take
It is bFGF stoste), it is added back into the pbs buffer of 100 μ l and disperses bFGF Fe again3O4@H-D NPs, will be last resulting
Its concentration is detected with bFGF ELISA kit after 10 times of liquid diluting, it is calculated and discharges percentage, as a result such as table 3 and Fig. 9
It is shown.
The average discharge rate of 3 bFGF of table
According to table 3 and Fig. 9, the slow release effect of wound healing material produced by the present invention is good, can be under the conditions of 4 degree
It is kept for 2 weeks or more.
It has been investigated that the method provided using embodiment 3, is distinguished using the mixture of FGF-9, EGF, aFGF and bFGF
BFGF is replaced, grafting culture is carried out, as a result, it has been found that the compatibility of initial reaction product and three that embodiment 2 provides is preferable,
Simultaneously for can achieve the effect of wound healing after the surface of a wound.Pass through Fe2O3Nano particle, Co3O4Nano particle, with
And Co3O4Nano particle and Fe3O4The mixture of nano particle replaces Fe respectively3O4Nano particle, progress are mentioned with embodiment 1 and 4
The heparin of confession-DOPA amine polymer is complexed, as a result, it has been found that the initial reaction product after complexing is between growth factor
Compatibility is preferable, while can promote the healing of the surface of a wound under the action of external magnetic field.
It holds above-mentioned, using the characteristic that heparin-bioagent specificity combines, is based on magnetic nanoparticle and dopamine conduct
Biotic factor is grafted on the surface of a wound for obtaining the invention offer above, is applied to skin wound by medium, can be effective
Biotic factor stability is improved, the activity of biotic factor is protected, so that it is discharged generation effect for a long time, thus wound healing.
This product can be kept 2 weeks or more under the conditions of 4 degree.
To sum up, wound healing material provided by the invention, can effectively improve biotic factor stability, protection biology because
The activity of son makes it discharge generation effect for a long time, thus wound healing, while it has no toxic and side effect to human body, and uses peace
It is complete reliable.The preparation method of the wound healing material is simple, is produced on a large scale, and production cost is effectively reduced.
Embodiments described above is a part of the embodiment of the present invention, instead of all the embodiments.Reality of the invention
The detailed description for applying example is not intended to limit the range of claimed invention, but is merely representative of selected implementation of the invention
Example.Based on the embodiments of the present invention, obtained by those of ordinary skill in the art without making creative efforts
Every other embodiment, shall fall within the protection scope of the present invention.
Claims (10)
1. a kind of preparation method of wound healing material, characterized in that it comprises:
By the buffer of heparinate and dopamine mixed with polymers, freeze-drying of dialysing after condensation reaction obtains heparin-dopamine polymerization
Object, the preferably described heparinate are the heparinate after activated carboxylic；
Heparin-the dopamine is polymer-modified to magnetic nanoparticle, obtain initial reaction product；
Growth factor is grafted into the initial reaction product to get the wound healing material.
2. preparation method according to claim 1, which is characterized in that the step of activating the carboxyl of the heparinate include:
Under the protection of inert gas, the buffer of heparinate is mixed with carboxyl activator, reacts 25-40min, wherein institute
Stating carboxyl activator includes 1- (3- dimethylamino-propyl) -3- ethyl carbodiimide and n-hydroxysuccinimide；
Preferably, mole of 1- (3- the dimethylamino-propyl) -3- ethyl carbodiimide and the n-hydroxysuccinimide
Than for 1:1；
It is highly preferred that the molar ratio of heparin and the carboxyl activator in the heparinate is 1-10:1.
3. preparation method according to claim 1, which is characterized in that the buffer of the heparinate to polymerize with dopamine
In the step of object mixes, the molar ratio of heparin and the DOPA amine polymer in the heparinate is 1-10:10-1.
4. preparation method according to claim 1, which is characterized in that the growth factor is grafted to the initial reaction
The step of product includes:
The initial reaction product is mixed in buffer with the growth factor, and in 3.5-4.5 DEG C of biochemical cultivation case
Middle culture 23-25h.
5. preparation method according to claim 1, which is characterized in that the heparin-dopamine is polymer-modified to magnetic
Property nano particle before, further include that the magnetic nanoparticle is handled using cationic surfactant；
Preferably, it is general to be selected from octadecyltrimethylammonium chloride, cation guar gum, cation for the cationic surfactant
Alcohol and cation-modified silicone oil；
It is highly preferred that the cationic surfactant is octadecyltrimethylammonium chloride.
6. preparation method according to claim 5, which is characterized in that using described in cationic surfactant processing
The step of magnetic nanoparticle includes:
Organic solvent containing the magnetic nanoparticle is added dropwise in the aqueous solution of cationic surfactant, 25- is stirred
35min then removes the organic solvent and extra cationic surfactant；
Preferably, the organic solvent is chloroform.
7. a kind of wound healing material, which is characterized in that it is made by preparation method as claimed in any one of claims 1 to 6；
Preferably, mass percentage of the growth factor in the wound healing material is 2%-20%；
It is highly preferred that mass percentage of the magnetic nanoparticle in the wound healing material is 55%-70%.
8. wound healing material according to claim 7, which is characterized in that the growth factor is selected from human body alkalinity into fibre
Tie up growth factor, keratinocyte growth factor, superficial cell growth factor, nerve growth factor, corium growth factor, intravascular
At least one of skin growth factor, human fibroblast growth factor-21 and human fibroblastic growth factor -9；
Preferably, the growth factor is human body Basic Fibroblast Growth Factor.
9. wound healing material according to claim 7, which is characterized in that the magnetic nanoparticle is selected from Fe3O4Nanometer
Particle, Fe2O3Nano particle and Co3O4At least one of nano particle；
Preferably, the magnetic nanoparticle is Fe3O4Nano particle.
10. a kind of wound healing material, which is characterized in that it includes carrier and the growth factor for grafting on the carrier, institute
Carrier is stated to include heparin-DOPA amine polymer and modified the heparin-DOPA amine polymer magnetic nanoparticle, it is described
Mass percentage of the growth factor in the wound healing material is 2%-20%, and the magnetic nanoparticle is in the wound
Mass percentage in face healing material is 55%-70%.
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