CN107596438B - A kind of natural polysaccharide self-healing hydrogel of injectable and the preparation method and application thereof - Google Patents
A kind of natural polysaccharide self-healing hydrogel of injectable and the preparation method and application thereof Download PDFInfo
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Abstract
The invention discloses natural polysaccharide self-healing hydrogels of a kind of injectable and the preparation method and application thereof, include the following steps：1) polyethylene glycol reacts the polyethylene glycol for preparing two terminal modified benzaldehydes with 4 carboxyl benzaldehydes；2) by N, ethylenediamine is introduced into agarose skeleton by the mode of N ' carbonyl dimidazoles activation, prepares ethylene diamine-modified agarose skeleton；3) aqueous solution of the polyethylene glycol of two terminal modified benzaldehydes is mixed with the aqueous solution of ethylene diamine-modified agarose skeleton, the injectable natural polysaccharide macromolecule hydrogel based on reversible imine linkage is prepared.The hydrogel has injectable and self-healing characteristics, as wound dressing in use, can realize load medicine in situ and can fill irregular wound, while can greatly prolong the service life of dressing.
Description
Technical field
The invention belongs to technical field of polymer materials, more particularly to the natural polysaccharide self-healing hydrogel of a kind of injectable
And the preparation method and application thereof, specifically apply the polyethylene glycol key base of ethylene diamine-modified agarose and two terminal modified benzaldehydes
It is cross-linked to form injectable gel in imine linkage, and these reversible covalent bonds assign the good self-healing performance of hydrogel, and will
Gel application promotes the healing of skin wound in the technical field of wound dressing.
Background technology
The skin and mucous membrane of human body are to maintain human internal environment stable and prevent the barrier of microorganism invasion, due to ulcer,
Skin and mucosa injury caused by the reasons such as wound, burn and inflammation can cause a series of problem of body, such as bacterium sense
Dye, metabolism aggravation, moisture and protein be excessively lost in, endocrine and immune system dysfunction etc., serious to endanger
And life.Suitable dressing should be selected to be covered on wound when skin and mucosa injury, it can play keep wound moist environment,
The effect for absorbing secretion, relieving pain and controlling bleeding, to promote wound healing.
Ideal wound dressing, which needs to meet, to be made wound quick-make, promotes wound healing, reduces the requirements such as secondary insult,
The wound dressing of the multiple materials such as rubber, film, electrostatic spinning nano fiber and hydrogel is had been developed that so far.Tradition
Dressing mainly play isolation and bacteriostasis for wound, but frequently result in wound is dry, destroy the growth factor of health and
It is easy to stick on cambium, the secondary insult of wound can be caused when dressing removes, and be difficult to apply with larger
The filling etc. of depth or/and wound in irregular shape.
With the raising of people's living standard and medical level, more stringent requirements are proposed for dressing by people：(1) can
Control and exudate is absorbed, keeps wound moist and the environment without diffusate；(2) bacteria preventers are capable of providing, are built
The good environment of one suitable tissue growth promotes tissue growth；(3) the suitable transmitance with gas and vapor；(4) make
With conveniently, adhesion is suitable, does not cause secondary injury；(5) nontoxic, harmless, non-stimulated.Gel dressing is exactly that one kind disclosure satisfy that
The high-quality dressing of above 5 kinds of requirements, but if applied in the filling with larger depth or/and wound in irregular shape
When, then it is injectable gel dressing to require gel dressing.It needs to meet several passes applied to biomedical injection aquagel
Key requirement：(1) injection aquagel itself and its precursor solution should have good biocompatibility；(2) the injectable water
The precursor solution of gel needs to have in the cured ability of target site rapid shaping；(3) precursor solution is in target site
Plastic solidification after, also need to be rapidly reached certain mechanical strength, so as not to surrounding tissue squeeze or deformation and hydrogel is caused to damage
Wound.However, traditional injection aquagel is but difficult to meet three above requirement simultaneously so that existing gel dressing is also difficult to
It applies in the filling with larger depth or/and wound in irregular shape, moreover, existing gel dressing surrounding tissue squeezes
Or damage is be easy to cause under the action of ambient pressure, but self-healing is can not achieve, the service life of gel dressing is largely effected on,
And frequently more change dressings are unfavorable for the healing of wound, and then define the popularization and application of gel dressing.
Invention content
In order to solve the above technical problems, it is an object of the present invention to provide a kind of natural polysaccharide self-healings of injectable
The preparation method of hydrogel.
Second object of the present invention is to provide the preparation method system of the natural polysaccharide self-healing hydrogel of above-mentioned injectable
Standby obtained natural polysaccharide self-healing hydrogel.The hydrogel has injectable and self-healing characteristics, is used as wound dressing
When, it can be achieved that in situ carry medicine and can fill irregular wound, while the service life of dressing can be greatly prolonged.
Third object of the present invention is to provide above-mentioned natural self-healing hydrogels as the application in wound dressing.
In order to solve the above technical problems, the technical scheme is that：
A kind of natural polysaccharide self-healing hydrogel of injectable, includes the polyethylene glycol and ethylenediamine of two terminal modified benzaldehydes
The agarose skeleton of modification, aldehyde radical in the polyethylene glycol of two terminal modified benzaldehydes on ethylene diamine-modified agarose skeleton
Amino reaction generates reversible imine linkage.
Amino on ethylene diamine-modified agarose skeleton passes through with the aldehyde radical in the polyethylene glycol of two terminal modified benzaldehydes
Schiff base reaction generates reversible imine linkage, maintains the property of covalent bond to a certain extent and can be stabilized, they are again
With invertibity, i.e., there are dynamic equilibrium for the fracture and generation of key.These dynamic chemical keys are distributed in entire hydrogel network,
Make the presence of uncrosslinked active group in network always, when hydrogel is crushed, these active groups can be cross-linked to form newly again
Reversible covalent bonds, broken hydrogel fragment can self-healing be combined into one block of complete hydrogel again in this way.Institute
With, when gel dressing is when surrounding tissue squeezes or deformation under the action of causes damage, can self-healing quickly, and then improve solidifying
The service life of glue dressing.And hydrogel have good biocompatibility, can in 10s very fast plastic, have certain machine
Tool intensity fully meets the requirement of injection aquagel so that it can apply with larger depth and wound in irregular shape
In mouth filling.
Preferably, the weight average molecular weight of the polyethylene glycol is 1500-3000.Preferably weight average molecular weight is 1700-
2500, most preferably 2000.
The preparation method of the natural polysaccharide self-healing hydrogel of above-mentioned injectable, includes the following steps：
1) polyethylene glycol reacts the polyethylene glycol for preparing two terminal modified benzaldehydes with 4- carboxyl benzaldehydes；
2) by N, ethylenediamine is introduced into agarose skeleton, prepares ethylenediamine and repair by the mode of N '-carbonyl dimidazoles activation
The agarose skeleton of decorations；
3) by the aqueous solution of the aqueous solution of the polyethylene glycol of two terminal modified benzaldehydes and ethylene diamine-modified agarose skeleton
Mixing, is prepared the injectable natural polysaccharide macromolecule hydrogel based on reversible imine linkage.
The present invention uses the natural polysaccharide material with good biocompatibility as hydrogel backbone, and building-up process is simple
Green, reaction condition are mild.
Preferably, in step 1), the weight average molecular weight of the polyethylene glycol is 1500-3000.Preferably weight average molecular weight
For 1700-2500, most preferably 2000.
Preferably, polyethylene glycol reacts the method for the polyethylene glycol for preparing two terminal modified benzaldehydes with 4- carboxyl benzaldehydes,
Include the following steps：
Polyethylene glycol, 4- carboxyl benzaldehydes and 4-dimethylaminopyridine are dissolved into tetrahydrofuran, then in protection gas
N is added into system under body protection, N '-dicyclohexylcarbodiimides obtain the polyethylene glycol of two terminal modified benzaldehydes after reaction.
It is further preferred that the temperature of reaction is 18-22 DEG C, the time of reaction is 15-20h.If temperature is excessively high, N, N '-
Dicyclohexylcarbodiimide is also easy to produce isomers to which side reaction occur.
It is further preferred that polyethylene glycol, 4- carboxyl benzaldehydes, 4-dimethylaminopyridine and N, N '-dicyclohexyl carbon two
The mass ratio of imines is 1.63:0.49:0.025:0.84.
It is further preferred that further including the steps that the product that will be prepared recrystallizes.To remove impurity.
Still more preferably, the recrystallization is specially：After reaction, white solid is obtained by filtration, white is solid
Body be dissolved in after tetrahydrofuran again thereto be added ether recrystallized.Recrystallization process repeats three times, preferably to remove
Impurity.
Preferably, in step 2), the preparation method of ethylene diamine-modified agarose skeleton includes the following steps：
It is dissolved 1. agarose is added in dimethyl sulfoxide (DMSO)；
2. by N, N '-carbonyl dimidazoles are dissolved in dimethyl sulfoxide (DMSO)；
3. by step 2. in solution obtained be added dropwise to step 1. in obtained solution, after stirring setting time,
Ethylenediamine is instilled dropwise, reacts setting time；
4. by step 3. in reaction after solution use retain molecule for the dialysis membrane of 8000-14000 in distilled water into
Row dialysis, the solution dialysed is lyophilized, ethylene diamine-modified agarose is obtained.
Freeze-drying refer to containing a large amount of moisture substance in advance carry out cooling be frozen into solid, then under vacuum
Water vapour is set directly to distil removing, in the left ice shelf when freezing of substance itself.So the original structure after dry is constant, profit
In subsequent reaction, be conducive to the performance for improving hydrogel.By step, 2. the middle N prepared, N '-carbonyl dimidazoles solution add dropwise
It is for the hydroxyl on activated agarose skeleton to enter into step agarose solution 1..After activated hydroxyl groups, due to ethylenediamine
Solubility is slower in step 2. solution obtained, to ensure ethylenediamine dissolving completely and accelerating reaction process, so adding dropwise
Enter ethylenediamine.
Preferably, step 3. in, by step 2. in solution obtained be added dropwise to step 1. in be in obtained solution
It is carried out at 20-35 DEG C.
Preferably, step 3. in, in order to ensure N, the hydroxyl on the complete activated agarose of N '-carbonyl dimidazoles, stirring
Time is 1.5-2.5h.
Preferably, step 3. in, the temperature of reaction is 20-35 DEG C, and time of reaction is 20-30h, preferably 20-25h,
Most preferably for 24 hours.
Preferably, step 4. in, time of dialysis is 3.5-4.5 days, and the distilled water is distilled water three times.
Above-mentioned natural self-healing hydrogel is as the application in wound dressing.
A kind of wound dressing, including above-mentioned natural polysaccharide self-healing hydrogel and it is carried on the natural polysaccharide self-healing Heshui
It is one or more in drug, cell factor or growth factor in gel.
Beneficial effects of the present invention are：
1, preparation process of the invention is simply ripe, environmentally protective, is not necessarily to organic solvent, and plastic speed is fast (within 10s),
And the dynamic characteristic of imine linkage makes hydrogel in the characteristic macroscopically to external environment with pH responses, and different pH may be implemented
Drug controlled release under environment.And gel structure is destroyed rear nothing and can quickly heal by external force condition, makes the solidifying of preparation
Glue dressing can be applied in the filling with larger depth or/and wound in irregular shape.
2, the preparation of hydrogel can regulate and control the mechanical performance of hydrogel, method letter by the rate of charge of feed change
It is single, it is easy to spread.
Description of the drawings
The accompanying drawings which form a part of this application are used for providing further understanding of the present application, and the application's shows
Meaning property embodiment and its explanation do not constitute the improper restriction to the application for explaining the application.
Fig. 1 is the polyethylene glycol of two terminal modified benzaldehydes1H nmr spectrums.
Fig. 2 is the infrared absorption spectrum of the polyethylene glycol of polyethylene glycol and two terminal modified benzaldehydes.
Fig. 3 is the thermal gravimetric analysis results of the polyethylene glycol of polyethylene glycol and two terminal modified benzaldehydes.
Fig. 4 is the infrared absorption spectrum of agarose and ethylene diamine-modified agarose.
Fig. 5 is the thermal gravimetric analysis results of agarose and ethylene diamine-modified agarose.
Fig. 6 is the infrared absorption light of ethylene diamine-modified agarose, the polyethylene glycol of two terminal modified benzaldehydes and xerogel
Spectrum.
Fig. 7 is the thermogravimetric analysis knot of ethylene diamine-modified agarose, the polyethylene glycol of two terminal modified benzaldehydes and xerogel
Fruit.
Fig. 8 is the scanning electron microscope characterization result of xerogel.
Fig. 9 is the X-ray diffraction characterization result of xerogel.
Figure 10 is the mechanical strength result for the gel with different rate of charges estimated by rheometer test.
Figure 11 is that macroscopical self-healing of gel is tested.
Figure 12 is the continuous one-step strain testing result by rheometer test.
Figure 13 is that macroscopical injectable of gel is tested.
Figure 14 is that the pH responses of gel are tested.
Figure 15 is the toxicity test of the HUVEC cells of gel.
Figure 16 is new zealand rabbit liver lacerated wound model schematic.
Figure 17 is gel, antiseptic gauze and the amount of bleeding assessment for not handling wound.
Figure 18 is gel, antiseptic gauze and the bleeding time assessment for not handling wound.
Specific implementation mode
It is noted that following detailed description is all illustrative, it is intended to provide further instruction to the application.Unless another
It indicates, all technical and scientific terms used herein has usual with the application person of an ordinary skill in the technical field
The identical meanings of understanding.
It should be noted that term used herein above is merely to describe specific implementation mode, and be not intended to restricted root
According to the illustrative embodiments of the application.As used herein, unless the context clearly indicates otherwise, otherwise singulative
It is also intended to include plural form, additionally, it should be understood that, when in the present specification using term "comprising" and/or " packet
Include " when, indicate existing characteristics, step, operation, device, component and/or combination thereof.
Agarose, is linear polymer, and basic structure is in the β-D- galactolipins of 1,3 connections and 3,6- of Isosorbide-5-Nitrae connection
The long-chain that ether-L- galactolipins alternately connect.
Embodiment 1
By PEG2000(1.63g, 0.815mmol), 4- carboxyl benzaldehydes (0.49g, 3.26mmol), 4-dimethylaminopyridine
(0.025g) is dissolved into the dry tetrahydrofuran of 50ml, and N, N '-dicyclohexyls is added into system under nitrogen protection later
Carbodiimide (0.84g, 4.075mmol).It reacts at 20 DEG C and stirs 18h.After reaction, white solid is obtained by filtration, it will
Diethyl ether recrystallization is added to remove impurity after being dissolved in tetrahydrofuran in white solid, this process repeats three times.After drying, obtain
The polyethylene glycol of the two terminal modified benzaldehydes of 1.42g (yield 77%).Its1H nuclear magnetic resoance spectrums are illustrated in shown in Fig. 1, infrared suction
Spectrum is received as shown in Fig. 2, thermal gravimetric analysis results are as shown in Figure 3.
The agarose of 100mg is added in the dimethyl sulfoxide (DMSO) of 60mL, 80 DEG C is heated to and makes it dissolve.The system of waiting for is cooled to
After room temperature, by 6.36g N, N '-carbonyl dimidazoles are dissolved in 40mL dimethyl sulfoxide (DMSO)s and are added dropwise in system.In room temperature
After stirring two hours, 10mL ethylenediamines are added dropwise, are stirred at room temperature for 24 hours.Later, with dialysis membrane, (molecular cut off is
8000-14000, Shanghai Blue Season Technology Development Co., Ltd) it dialyses 4 days in distilled water three times.The solution dialysed is lyophilized,
Obtain ethylene diamine-modified agarose.Its infrared absorption spectrum is as shown in figure 4, thermal gravimetric analysis results are as shown in Figure 5.
The ethylene diamine-modified agaroses of 10mg are added to 800 μ L three times in distilled water, about 70 DEG C is heated to and makes it dissolve
Obtain ethylene diamine-modified agarose solution.The polyethylene glycol of the two of 30mg terminal modified benzaldehydes is added to 200 μ L to distill three times
It in water, is added dropwise in ethylene diamine-modified agarose solution, in vortex 10s, obtains a concentration of 1wt% ethylenediamines of 1mL and repair
The hydrogel of the polyethylene glycol of the two terminal modified benzaldehydes of agarose 3wt% of decorations.The infrared absorption spectrum of xerogel such as Fig. 6 institutes
Show, thermal gravimetric analysis results are as shown in Figure 7.
By the water-setting of the polyethylene glycol of two terminal modified benzaldehydes of agarose 3wt% ethylene diamine-modified a concentration of 1wt% of 1mL
Xerogel is obtained after jelly is dry.The scanning electron microscope characterization result of xerogel shows that gel has porous structure, aperture equal
In the micron-scale not, the results are shown in Figure 8.
By the water-setting of the polyethylene glycol of two terminal modified benzaldehydes of agarose 3wt% ethylene diamine-modified a concentration of 1wt% of 1mL
Xerogel is obtained after jelly is dry.The X-ray diffraction characterization of xerogel proves that gel is undefined structure, and the results are shown in Figure 9.
Mechanical strength test
By the characterization of the stress scans of rheometer test, the mechanical strength of sample, fixed ethylene diamine-modified fine jade have been estimated
Lipolysaccharide concentration, increases the Polyethylene glycol of two terminal modified benzaldehydes, and gel mechanical strength increases, thus it is speculated that is due to macromolecular chain
Both increase, wind even closer between strand, fix two kinds of material rates, while increasing concentration, gel mechanical strength increases
Greatly, thus it is speculated that be since schiff bases number of crosslinks increases, and macromolecular chain number increases, and forms more firm gel structure, as a result
As shown in Figure 10.
Self-healing performance test
Gel with self-healing performance can greatly prolong the service life of dressing as wound dressing, in order to prove gel from
Healing properties, from macroscopic view experiments have shown that the self-healing performance of gel：By the ethylene diamine-modified agaroses of a concentration of 1wt% of preparation
The self-healing gel of the polyethylene glycol of two terminal modified benzaldehydes of 3wt% makes it contact with each other again after being cut into two sections, quiet at room temperature
After setting 1 minute, it is found that gel recovery can be at an entirety, by the soak after healing in the PBS buffer solution that pH is 7.4
5 hours find that gel does not disperse, and own wt can be born by being picked up with tweezers, this is proved at the plane of disruption of gel, aldehyde radical
It reacts with amido, forms dynamic schiff bases crosslinking, and simple adherency occurs between non-ruptured gel, gel has good
Good self-healing performance, as a result as shown in figure 11.
Macroscopical injectable performance test
The self-healing gel of preparation has syringeability simultaneously, by syringe needle that a concentration of 1wt% of 1mL is ethylene diamine-modified
After the hydrogel injection of the polyethylene glycol of two terminal modified benzaldehydes of agarose 3wt%, gel can still keep its intact form, with glass
Glass is carrier, and a whole gel thread can be injected by syringe needle.Pass through the natural polysaccharide that two pieces are prepared with syringe
Self-healing hydrogel injects in small beaker, and mixing compacting, after 1 minute, the gel pieces in small beaker heal again becomes one piece
Complete hydrogel is whole, and has certain mechanical strength, it was demonstrated that this kind of hydrogel has good self-healing performance, knot
Fruit is as shown in figure 13.
PH response performances are tested
The formation of known imine linkage is a homeostasis process, and some environmental stimulis can be made by interference balancing
Solation occurs for gel.Imine linkage is easily decomposes in acidic environment, and stablizes relatively in alkaline environment, therefore contains imines
The self-healing hydrogel of key can degrade in acid condition, and the gelation once again in alkaline environment.In order to prove this
It is ethylene diamine-modified to be added to a concentration of 1wt% of 1mL by the pH responses of hydrogel for the aqueous solution of the concentrated hydrochloric acid of 20 microlitres of 3mol/L
Two terminal modified benzaldehydes of agarose 3wt% polyethylene glycol hydrogel in, it is observed that gel is complete in two minutes
It is complete to decompose.The gel being decomposed backward in be added equivalent sodium hydrate aqueous solution, colloidal sol 1 minute can gelation once again, knot
Fruit is as shown in figure 14, it is seen then that the hydrogel has different responses in different pH environments.
The toxicity of cell is tested
1) cell culture
By Human umbilical vein endothelial cells HUVEC cell culture in the DMEM fluid nutrient mediums containing 10% fetal calf serum,
It is placed in 37 DEG C, cultivates in the incubator of 5% carbon dioxide.
2) cell extract configures：By gel be immersed in 10% fetal calf serum DMEM fluid nutrient mediums distinguish 12 hours and
In 24 hours, as sample.
3) cell viability measures
With 2000 cells/well density, by cell inoculation in 96 orifice plates.It is adherent for 24 hours after, be added cell culture fluid sample make
Its concentration is respectively 80% and 100%.After processing for 24 hours, MTT solution (the MTT cell experiments of 20 μ L, 5mg/mL are added per hole
Dyestuff used), after being incubated 4h in the incubator, absorbance value at 570nm is measured in microplate reader.Every group of absorbance value deducts empty
After white solution absorbance value, per hole respective value divided by the absorbance value of control group is as cell viability.Every group of setting 6 is parallel
Hole.As a result as shown in figure 15, it is small that 20 grams of prepared self-healing hydrogels are immersed in 12-24 in 20mL cell culture fluids respectively
Shi Hou extracts gel leaching liquid, HUVEC is cultivated 24-48 hours in gel leaching liquid, finds cell survival rate 80%
More than, it was demonstrated that hydrogel prepared by the present invention does not have toxicity, can be safe to use..
Animal Efficacy experiments
Laboratory sample is the aerogel dressing sample prepared according to the embodiment, and control sample is common medical saline
Gauze.
Abdomen of this experiment using operation method in new zealand rabbit (2Kg) is dissected, and the wound that length is 1cm is made in liver
Scars model is as shown in figure 16.Pad of cotion is used for absorbing wound bleeding under wound location, by the weight for weighing gauze
To estimate the amount of bleeding of wound.
1, modeling
By being injected intravenously barbital, that anaesthetizes rabbit, and after the abdomen cropping of new zealand rabbit, 4% vulcanized sodium is de-
Hair, warm water cleaning are dried, and dissection leaks out liver, the wound for being 1 centimetre with scalpel Cutting Length on lobe of the liver.As a result as schemed
Shown in 15.
2, stop blooding
The dry gauze for weighing up weight is padded under wound and is used for absorbing wound bleeding, by gel sample and antiseptic gauze point
It is not placed in wound hemostasis.The gauze weight after sucking blood is weighed to estimate amount of bleeding, stopwatch is used in combination to record the bleeding time.As a result
As shown in Figure 17 and Figure 18, stop blooding compared to normal gauze, after applying self-healing hydrogel, bleeding amount of wound greatly reduces,
0.19 ± 0.03g is down to by 0.71 ± 0.09g, and the bleeding time is down to by 72 ± 11s within 10s, it was demonstrated that gel effectively stops
Blood effect.
Embodiment 2
By PEG2000(3.26g, 1.63mmol), 4- carboxyl benzaldehydes (0.98g, 6.52mmol), 4-dimethylaminopyridine
(0.05g) is dissolved into the dry tetrahydrofuran of 100ml, and N, N '-dicyclohexyls is added into system under nitrogen protection later
Carbodiimide (1.68g, 8.15mmol).It reacts at 22 DEG C and stirs 20h.After reaction, white solid is obtained by filtration, it will be white
Diethyl ether recrystallization is added to remove impurity after being dissolved in tetrahydrofuran in color solid, this process repeats three times.After drying, obtain
The polyethylene glycol of the two terminal modified benzaldehydes of 2.6g (yield 70%).
The agarose of 100mg is added in the dimethyl sulfoxide (DMSO) of 70mL, 90 DEG C is heated to and makes it dissolve.The system of waiting for is cooled to
After room temperature, by 7.63g N, N '-carbonyl dimidazoles are dissolved in 50mL dimethyl sulfoxide (DMSO)s and are added dropwise in system.In room temperature
After stirring two hours, 12mL ethylenediamines are added dropwise, 36h is stirred at room temperature.Later, with dialysis membrane, (molecular cut off is
8000-14000, Shanghai Blue Season Technology Development Co., Ltd) it dialyses 5 days in distilled water three times.The solution dialysed is lyophilized,
Obtain ethylene diamine-modified agarose.
The ethylene diamine-modified agaroses of 8mg are added to 800 μ L three times in distilled water, about 80 DEG C is heated to and makes it dissolve
To ethylene diamine-modified agarose solution.The polyethylene glycol of the two of 24mg terminal modified benzaldehydes is added to 200 μ L distilled water three times
In, it is added dropwise in ethylene diamine-modified agarose solution, in vortex 8s, it is ethylene diamine-modified to obtain a concentration of 0.8wt% of 1mL
Two terminal modified benzaldehydes of agarose 2.4wt% polyethylene glycol hydrogel.
Embodiment 3
By PEG2000(0.815g, 0.408mmol), 4- carboxyl benzaldehydes (0.25g, 1.63mmol), 4- dimethylamino pyrroles
Pyridine (0.0125g) is dissolved into the dry tetrahydrofuran of 25ml, and N ,-two hexamethylenes of N ' is added into system under nitrogen protection later
Base carbodiimide (0.42g, 2.038mmol).It reacts at 25 DEG C and stirs 16h.After reaction, white solid is obtained by filtration,
White solid is dissolved in after tetrahydrofuran, Diethyl ether recrystallization is added to remove impurity, this process repeats three times.After drying, obtain
To the polyethylene glycol of the two terminal modified benzaldehydes of 0.74g (yield 80%).
The agarose of 100mg is added in the dimethyl sulfoxide (DMSO) of 80mL, 80 DEG C is heated to and makes it dissolve.The system of waiting for is cooled to
After room temperature, by 9.54g N, N '-carbonyl dimidazoles are dissolved in 50mL dimethyl sulfoxide (DMSO)s and are added dropwise in system.In room temperature
After stirring two hours, 15mL ethylenediamines are added dropwise, 48h is stirred at room temperature.Later, with dialysis membrane, (molecular cut off is
8000-14000, Shanghai Blue Season Technology Development Co., Ltd) it dialyses 6 days in distilled water three times.The solution dialysed is lyophilized,
Obtain ethylene diamine-modified agarose.
The ethylene diamine-modified agaroses of 12mg are added to 800L three times in distilled water, about 80 DEG C is heated to and makes it dissolve
To ethylene diamine-modified agarose solution.The polyethylene glycol of the two of 36mg terminal modified benzaldehydes is added to 200L distilled water three times
In, it is added dropwise in ethylene diamine-modified agarose solution, in vortex 6s, it is ethylene diamine-modified to obtain a concentration of 1.2wt% of 1mL
Two terminal modified benzaldehydes of agarose 3.6wt% polyethylene glycol hydrogel.
The foregoing is merely the preferred embodiments of the application, are not intended to limit this application, for the skill of this field
For art personnel, the application can have various modifications and variations.Within the spirit and principles of this application, any made by repair
Change, equivalent replacement, improvement etc., should be included within the protection domain of the application.
Claims (9)
1. a kind of natural polysaccharide self-healing hydrogel of injectable, including the polyethylene glycol of two terminal modified benzaldehydes are repaiied with ethylenediamine
The agarose skeleton of decorations, the aldehyde radical in the polyethylene glycol of two terminal modified benzaldehydes and the ammonia on ethylene diamine-modified agarose skeleton
Base reaction generates reversible imine linkage；
The weight average molecular weight of the polyethylene glycol is 2000；
The preparation method of the natural polysaccharide self-healing hydrogel of the injectable, includes the following steps：
1) polyethylene glycol reacts the polyethylene glycol for preparing two terminal modified benzaldehydes with 4- carboxyl benzaldehydes；
2) by N, ethylenediamine is introduced into agarose skeleton, prepares ethylene diamine-modified by the mode of N '-carbonyl dimidazoles activation
Agarose skeleton；
3) aqueous solution of the polyethylene glycol of two terminal modified benzaldehydes is mixed with the aqueous solution of ethylene diamine-modified agarose skeleton,
The injectable natural polysaccharide macromolecule hydrogel based on reversible imine linkage is prepared；
In step 1), the method that polyethylene glycol reacts the polyethylene glycol for preparing two terminal modified benzaldehydes with 4- carboxyl benzaldehydes, packet
Include following steps：
Polyethylene glycol, 4- carboxyl benzaldehydes and 4-dimethylaminopyridine are dissolved into tetrahydrofuran, then protected in protective gas
N is added under shield into system, N '-dicyclohexylcarbodiimides obtain the polyethylene glycol of two terminal modified benzaldehydes after reaction；
The temperature of reaction is 18-22 DEG C, and the time of reaction is 15-20h；
Polyethylene glycol, 4- carboxyl benzaldehydes, 4-dimethylaminopyridine and N, N '-dicyclohexylcarbodiimide mass ratio be
1.63:0.49:0.025:0.84；
In step 2), the preparation method of ethylene diamine-modified agarose skeleton includes the following steps：
It is dissolved 1. agarose is added in dimethyl sulfoxide (DMSO)；
2. by N, N '-carbonyl dimidazoles are dissolved in dimethyl sulfoxide (DMSO)；
3. by step 2. in solution obtained be added dropwise to step 1. in obtained solution, after stirring setting time, dropwise
Ethylenediamine is instilled, setting time is reacted；
It is carried out thoroughly in distilled water for the dialysis membrane of 8000-14000 4. the solution after step 3. middle reaction is used and retains molecule
The solution dialysed is lyophilized, obtains ethylene diamine-modified agarose by analysis；
Wherein, step 3. in, by step 2. in solution obtained be added dropwise to step 1. in be in 20-35 in obtained solution
It is carried out at DEG C.
2. natural polysaccharide self-healing hydrogel according to claim 1, it is characterised in that：Further include that will be prepared in step 3)
The step of obtained injectable natural polysaccharide macromolecule hydrogel is recrystallized.
3. natural polysaccharide self-healing hydrogel according to claim 2, it is characterised in that：The recrystallization is specially：Instead
After answering, white solid is obtained by filtration, by white solid be dissolved in after tetrahydrofuran again thereto be added ether tied again
It is brilliant.
4. natural polysaccharide self-healing hydrogel according to claim 1, it is characterised in that：
Step 3. in, time of stirring is 1.5-2.5h；
Step 3. in, the temperature of reaction is 20-35 DEG C, and the time of reaction is 20-30h.
5. natural polysaccharide self-healing hydrogel according to claim 4, it is characterised in that：
Step 3. in, time of reaction is 20-25h.
6. natural polysaccharide self-healing hydrogel according to claim 5, it is characterised in that：
The time of reaction is for 24 hours.
7. natural polysaccharide self-healing hydrogel according to claim 1, it is characterised in that：Step 4. in, the time of dialysis
It it is 3.5-4.5 days, the distilled water is distilled water three times.
8. natural polysaccharide self-healing hydrogel is as the application in wound dressing described in claim 1.
9. a kind of wound dressing, it is characterised in that：Including natural polysaccharide self-healing hydrogel described in claim 1 and it is carried on institute
It states one or more in drug, cell factor or the growth factor in natural polysaccharide self-healing hydrogel.
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