CN107596438A - A kind of natural polysaccharide self-healing hydrogel of injectable and preparation method and application - Google Patents
A kind of natural polysaccharide self-healing hydrogel of injectable and preparation method and application Download PDFInfo
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Abstract
The invention discloses natural polysaccharide self-healing hydrogel of a kind of injectable and preparation method and application, comprise the following steps：1) polyethylene glycol and the reaction of 4 carboxyl benzaldehydes prepare the polyethylene glycol of two terminal modified benzaldehydes；2) ethylenediamine is introduced into agarose skeleton by N, 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, the natural polysaccharide self-healing hydrogel of more particularly to a kind of injectable
And preparation method and application, specifically using ethylene diamine-modified agarose and the polyethylene glycol key base of two terminal modified benzaldehydes
Injectable gel is cross-linked to form in imine linkage, and these reversible covalent bonds assign hydrogel good self-healing performance, 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, a series of problem of body, such as bacterium sense can be caused
Dye, metabolism aggravation, moisture and protein are excessively lost in, endocrine and immune system dysfunction etc., serious possibility danger
And life.When skin and mucosa injury suitable dressing should be selected to be covered on wound, it can play keep wound moist environment,
Secretion, pain of alleviation and the effect for controlling bleeding are absorbed, so as to promote wound healing.
Preferable wound dressing needs satisfaction to make wound quick-make, promote wound healing, reduce the requirement 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
Easily stick on cambium, the secondary insult of wound can be caused when dressing removes, and be difficult to apply with larger
Filling of depth or/and wound in irregular shape etc..
With the raising of people's living standard and medical level, people propose higher requirement for dressing：(1) can
Control and exudate is absorbed, keep wound moist and the environment without diffusate；(2) bacteria preventers can be provided, built
The good environment of one suitable tissue growth, promotion organization growth；(3) there is the suitable transmitance of gas and vapor；(4) make
With conveniently, adhesion is suitable, does not cause secondary injury；(5) it is nontoxic, harmless, non-stimulated.Gel dressing is exactly that one kind disclosure satisfy that
The high-quality dressing of 5 kinds of requirements of the above, 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.Injection aquagel applied to biomedicine needs to meet several passes
Key requirement：(1) injection aquagel is in itself and its precursor solution should have good biocompatibility；(2) the injectable water
The precursor solution of gel is needed with the ability in the solidification 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 extruding 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
Apply in the filling with larger depth or/and wound in irregular shape, moreover, existing gel dressing surrounding tissue extrudes
Or damage is easily caused in the presence of ambient pressure, but self-healing can not be realized, the service life of gel dressing is largely effected on,
And frequently more change dressings is unfavorable for the healing of wound, and then define the popularization and application of gel dressing.
The content of the invention
In order to solve the above technical problems, it is an object of the present invention to provide a kind of natural polysaccharide self-healing 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, load medicine in situ can be achieved and irregular wound can be filled, while the service life of dressing can be greatly prolonged.
Third object of the present invention is to provide above-mentioned natural application of the self-healing hydrogel in as 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, include 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 with 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, and it maintains the property of covalent bond and can be stabilized to a certain extent, and they are again
With invertibity, i.e. there is dynamic equilibrium in the fracture of key and generation.These dynamic chemical keys are distributed in whole hydrogel network,
Make uncrosslinked active group in network all the time be present, when hydrogel crushes, 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 surrounding tissue extrude or deformation in the presence of cause damage when, can self-healing quickly, and then improve solidifying
The service life of glue dressing.And hydrogel has good biocompatibility, can in 10s very fast plastic, there is certain machine
Tool intensity, the requirement of injection aquagel is fully met, it is applied 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, comprises the following steps：
1) polyethylene glycol prepares the polyethylene glycol of two terminal modified benzaldehydes with the reaction of 4- carboxyl benzaldehydes；
2) ethylenediamine is introduced into agarose skeleton, ethylenediamine is prepared and repaiies by N, the mode of N '-carbonyl dimidazoles activation
The agarose skeleton of decorations；
3) by the aqueous solution of the polyethylene glycol of two terminal modified benzaldehydes and the aqueous solution of ethylene diamine-modified agarose skeleton
Mixing, is prepared the injectable natural polysaccharide macromolecule hydrogel based on reversible imine linkage.
The present invention is simple as hydrogel backbone, building-up process using the natural polysaccharide material with good biocompatibility
Green, reaction condition are gentle.
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, the method that polyethylene glycol prepares the polyethylene glycol of two terminal modified benzaldehydes with the reaction of 4- carboxyl benzaldehydes,
Comprise the following steps：
Polyethylene glycol, 4- carboxyl benzaldehydes and DMAP are dissolved into tetrahydrofuran, then in protection gas
N, N '-dicyclohexylcarbodiimide are added into system under body protection, the polyethylene glycol of two terminal modified benzaldehydes is obtained 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 too high, N, N '-
Dicyclohexylcarbodiimide is also easy to produce isomers so as to which side reaction occur.
It is further preferred that polyethylene glycol, 4- carboxyl benzaldehydes, DMAP 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 the step of also including being recrystallized the product being prepared.To remove impurity.
Still more preferably, the recrystallization is specially：After reaction terminates, white solid is filtrated to get, white is solid
Body be dissolved in after tetrahydrofuran again thereto add ether recrystallized.Recrystallization process repeats three times, preferably to remove
Impurity.
Preferably, in step 2), the preparation method of ethylene diamine-modified agarose skeleton, comprise the following steps：
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 obtained solution 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 reacted solution use retention molecule enter for 8000-14000 dialysis membrane in distilled water
Row dialysis, the solution dialysed is freezed, obtains ethylene diamine-modified agarose.
It is lyophilized refer to containing substantial amounts of moisture material carry out cooling in advance and be frozen into solid, then under vacuum
Water vapour is set directly to distil removing, in the left ice shelf when freezing of material itself.So dried original structure is constant, profit
In follow-up reaction, be advantageous to improve the performance of hydrogel.By the N of step 2. middle preparation, N '-carbonyl dimidazoles solution adds 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. obtained solution, to ensure ethylenediamine dissolving completely and accelerating reaction process, so adding dropwise
Enter ethylenediamine.
Preferably, step 3. in, by step 2. in obtained solution be added dropwise to step 1. in be in obtained solution
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 24h.
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 application of the self-healing hydrogel in as 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
The one or more in medicine, cell factor or growth factor in gel.
Beneficial effects of the present invention are：
1st, preparation technology of the invention is simply ripe, green, and without organic solvent, plastic speed is fast (within 10s),
And the dynamic characteristic of imine linkage causes hydrogel in the characteristic that macroscopically there is pH to respond to external environment, it is possible to achieve different pH
Medicine controlled release under environment.And gel structure is destroyed rear without can quickly be healed 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.
2nd, 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.
Brief description of the drawings
The Figure of description for forming the part of the application is used for providing further understanding of the present application, and the application's shows
Meaning property embodiment and its illustrate be used for explain the application, do not form the improper restriction to the application.
Fig. 1 is the polyethylene glycol of two terminal modified benzaldehydes1H nmr spectrums.
Fig. 2 is the infrared absorption spectroscopy 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 spectroscopy 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 SEM 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.
Embodiment
It is noted that described further below is all exemplary, it is intended to provides further instruction to the application.It is unless another
Indicate, all technologies used herein and scientific terminology are with 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 embodiment, 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 this manual using term "comprising" and/or " bag
Include " when, it indicates existing characteristics, step, operation, device, component and/or combinations thereof.
Agarose, is linear polymer, and basic structure is in 3, the 6- that 1, the 3 β-D- galactolipins linked and Isosorbide-5-Nitrae link
The long-chain that ether-L- galactolipins alternately connect.
Embodiment 1
By PEG2000(1.63g, 0.815mmol), 4- carboxyl benzaldehydes (0.49g, 3.26mmol), DMAP
(0.025g) is dissolved into 50ml dry tetrahydrofuran, adds N, N '-dicyclohexyl into system under nitrogen protection afterwards
Carbodiimide (0.84g, 4.075mmol).React at 20 DEG C and stir 18h.After reaction terminates, white solid is filtrated to get, will
White solid adds Diethyl ether recrystallization to remove impurity after being dissolved in tetrahydrofuran, and this process repeats three times.After drying, obtain
The polyethylene glycol of 1.42g (yield 77%) two terminal modified benzaldehydes.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.
100mg agarose is added in 60mL dimethyl sulfoxide (DMSO), being heated to 80 DEG C makes its dissolving.The system for the treatment of 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, 24h is stirred at room temperature.Afterwards, with dialysis membrane, (molecular cut off is
8000-14000, Shanghai Blue Season Technology Development Co., Ltd) dialysed 4 days in distilled water three times.The solution dialysed is freezed,
Obtain ethylene diamine-modified agarose.Its infrared absorption spectroscopy 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, being heated to about 70 DEG C makes its dissolving
Obtain ethylene diamine-modified agarose solution.The polyethylene glycol of the two of 30mg terminal modified benzaldehydes is added into 200 μ L to distill three times
In water, it is added dropwise in ethylene diamine-modified agarose solution, in vortex 10s, obtains 1mL concentration and repaiied for 1wt% ethylenediamines
The hydrogel of the polyethylene glycol of the two terminal modified benzaldehydes of agarose 3wt% of decorations.The infrared absorption spectroscopy of xerogel such as Fig. 6 institutes
Show, thermal gravimetric analysis results are as shown in Figure 7.
Water-setting by 1mL concentration for the polyethylene glycol of two terminal modified benzaldehydes of agarose 3wt% ethylene diamine-modified 1wt%
Xerogel is obtained after jelly is dry.The SEM characterization result of xerogel shows that gel has a loose structure, and aperture is equal
In micron level, as a result as shown in Figure 8.
Water-setting by 1mL concentration for the polyethylene glycol of two terminal modified benzaldehydes of agarose 3wt% ethylene diamine-modified 1wt%
Xerogel is obtained after jelly is dry.The X-ray diffraction of xerogel, which characterizes, proves that gel is undefined structure, as a result as shown in Figure 9.
Mechanical strength test
By the sign of the stress scans of rheometer test, the mechanical strength of sample, fixed ethylene diamine-modified fine jade have been estimated
Lipolysaccharide concentration, increase the Polyethylene glycol of two terminal modified benzaldehydes, gel mechanical strength increase, thus it is speculated that be due to macromolecular chain
Increase, wind even closer between strand, fix two kinds of material rates, while increase both concentration, gel mechanical strength increases
Greatly, thus it is speculated that be due to that 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 life-span of dressing as wound dressing, in order to prove gel from
Healing properties, the self-healing performance for proving gel is tested from macroscopic view：It is the ethylene diamine-modified agaroses of 1wt% by the concentration 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 putting 1 minute, it is found that gel recovery can be into an entirety, by the soak after healing in the PBS that pH is 7.4
5 hours, it is found that gel does not disperse, own wt can be born by being picked up with tweezers, and this is proved at the plane of disruption of gel, aldehyde radical
Reacted with amido, form dynamic schiff bases crosslinking, and simple adhesion 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 1mL concentration is ethylene diamine-modified for 1wt%
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 piece gel thread can be injected by syringe needle.The natural polysaccharide that two pieces are prepared by using syringe
In self-healing hydrogel injection small beaker, compacting is mixed, after 1 minute, the gel pieces in small beaker heal as one piece again
Complete hydrogel is overall, 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 sour environment, and relatively stable 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
The pH responses of hydrogel, it is ethylene diamine-modified for 1wt% that the aqueous solution of 20 microlitres of 3mol/L concentrated hydrochloric acid is added to 1mL concentration
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 add 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 test of cell
1) cell culture
By Human umbilical vein endothelial cells HUVEC cell culture in the DMEM fluid nutrient mediums containing 10% hyclone,
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% hyclone DMEM fluid nutrient mediums distinguish 12 hours and
In 24 hours, as sample.
3) cell viability determines
With 2000 cells/well density, cell is inoculated in 96 orifice plates.After adherent 24h, adding cell culture fluid sample makes
Its concentration is respectively 80% and 100%.After 24h is handled, 20 μ L, 5mg/mL MTT solution (MTT cell experiments are added per hole
Dyestuff used), after being incubated 4h in incubator, absorbance at 570nm is determined on ELIASA.Every group of absorbance deducts empty
After white solution absorbance value, the absorbance of every hole respective value divided by 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, gel leaching liquid is extracted, HUVEC is cultivated 24-48 hours in gel leaching liquid, find cell survival rate 80%
More than, it was demonstrated that hydrogel prepared by the present invention does not have toxicity, can be with 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.
This experiment is dissected using belly of the operation method in new zealand rabbit (2Kg), and the wound that length is 1cm is made in liver
Scars model is as shown in figure 16.By pad of cotion under wound location be used for absorb wound bleeding, by the weight for weighing gauze
So as to estimate the amount of bleeding of wound.
1st, modeling
By being injected intravenously barbital, that anaesthetizes rabbit, and after the belly cropping of new zealand rabbit, 4% vulcanized sodium takes off
Hair, warm water cleaning, is dried, and dissection spills liver, with the wound that scalpel Cutting Length is 1 centimetre on lobe of the liver.As a result as schemed
Shown in 15.
2nd, 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
Wound hemostasis is not placed in.The gauze weight after sucking blood is weighed so as to estimate amount of bleeding, and the bleeding time is recorded with stopwatch.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 within 10s by 72 ± 11s, it was demonstrated that gel effectively stops
Blood effect.
Embodiment 2
By PEG2000(3.26g, 1.63mmol), 4- carboxyl benzaldehydes (0.98g, 6.52mmol), DMAP
(0.05g) is dissolved into 100ml dry tetrahydrofuran, adds N, N '-dicyclohexyl into system under nitrogen protection afterwards
Carbodiimide (1.68g, 8.15mmol).React at 22 DEG C and stir 20h.After reaction terminates, white solid is filtrated to get, will be white
Color solid dissolving adds Diethyl ether recrystallization to remove impurity after tetrahydrofuran, and this process repeats three times.After drying, obtain
The polyethylene glycol of 2.6g (yield 70%) two terminal modified benzaldehydes.
100mg agarose is added in 70mL dimethyl sulfoxide (DMSO), being heated to 90 DEG C makes its dissolving.The system for the treatment of 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.Afterwards, with dialysis membrane, (molecular cut off is
8000-14000, Shanghai Blue Season Technology Development Co., Ltd) dialysed 5 days in distilled water three times.The solution dialysed is freezed,
Obtain ethylene diamine-modified agarose.
The ethylene diamine-modified agaroses of 8mg are added to 800 μ L three times in distilled water, being heated to about 80 DEG C dissolves it
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 for 0.8wt% obtains 1mL concentration
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 25ml dry tetrahydrofuran, adds N, the hexamethylenes of N '-two into system under nitrogen protection afterwards
Base carbodiimide (0.42g, 2.038mmol).React at 25 DEG C and stir 16h.After reaction terminates, white solid is filtrated to get,
White solid is dissolved in after tetrahydrofuran and adds Diethyl ether recrystallization to remove impurity, this process repeats three times.After drying, obtain
To the polyethylene glycol of 0.74g (yield 80%) two terminal modified benzaldehydes.
100mg agarose is added in 80mL dimethyl sulfoxide (DMSO), being heated to 80 DEG C makes its dissolving.The system for the treatment of 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.Afterwards, with dialysis membrane, (molecular cut off is
8000-14000, Shanghai Blue Season Technology Development Co., Ltd) dialysed 6 days in distilled water three times.The solution dialysed is freezed,
Obtain ethylene diamine-modified agarose.
The ethylene diamine-modified agaroses of 12mg are added to 800L three times in distilled water, being heated to about 80 DEG C dissolves it
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 for 1.2wt% obtains 1mL concentration
Two terminal modified benzaldehydes of agarose 3.6wt% polyethylene glycol hydrogel.
The preferred embodiment of the application is the foregoing is only, is not limited to the application, for the skill of this area
For art personnel, the application can have various modifications and variations.It is all within spirit herein and principle, made any repair
Change, equivalent substitution, improvement etc., should be included within the protection domain of the application.
Claims (10)
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；
Preferably, the weight average molecular weight of the polyethylene glycol is 1500-3000, and preferably weight average molecular weight is 1700-2500, most
Preferably 2000.
2. the preparation method of the natural polysaccharide self-healing hydrogel of the injectable described in claim 1, it is characterised in that：Including such as
Lower step：
1) polyethylene glycol prepares the polyethylene glycol of two terminal modified benzaldehydes with the reaction of 4- carboxyl benzaldehydes；
2) ethylenediamine is introduced into agarose skeleton, prepared ethylene diamine-modified by N, 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.
3. preparation method according to claim 2, it is characterised in that：In step 1), the Weight-average molecular of the polyethylene glycol
Measure as 1500-3000；Preferably weight average molecular weight is 1700-2500, most preferably 2000.
4. preparation method according to claim 2, it is characterised in that：In step 1), polyethylene glycol and 4- carboxyl benzaldehydes
The method that reaction prepares the polyethylene glycol of two terminal modified benzaldehydes, comprises the following steps：
Polyethylene glycol, 4- carboxyl benzaldehydes and DMAP are dissolved into tetrahydrofuran, then protected in protective gas
N, N '-dicyclohexylcarbodiimide are added under shield into system, the polyethylene glycol of two terminal modified benzaldehydes is obtained after reaction；
Preferably, the temperature of reaction is 18-22 DEG C, and the time of reaction is 15-20h；
Preferably, polyethylene glycol, 4- carboxyl benzaldehydes, DMAP and N, N '-dicyclohexylcarbodiimide quality
Than for 1.63:0.49:0.025:0.84.
5. preparation method according to claim 2, it is characterised in that：Also include the injectable that will be prepared in step 3)
The step of natural polysaccharide macromolecule hydrogel is recrystallized；
Preferably, the recrystallization is specially：After reaction terminates, white solid is filtrated to get, white solid is dissolved in tetrahydrochysene
Ether is added after furans thereto again to be recrystallized.
6. preparation method according to claim 2, it is characterised in that：In step 2), ethylene diamine-modified agarose skeleton
Preparation method, comprise the following steps：
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 obtained solution be added dropwise to step 1. in obtained solution, after stirring setting time, dropwise
Ethylenediamine is instilled, reacts setting time；
4. by step 3. in reacted solution to use retention molecule to carry out in distilled water for 8000-14000 dialysis membrane saturating
Analysis, the solution dialysed is freezed, obtains ethylene diamine-modified agarose.
7. preparation method according to claim 6, it is characterised in that：Step 3. in, by step 2. in obtained solution by
Carried out in the solution obtained in being added dropwise to step 1. at 20-35 DEG C；
Preferably, step 3. in, the time of stirring 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, optimal
Elect 24h as.
8. preparation method according to claim 6, it is characterised in that：Step 4. in, time of dialysis is 3.5-4.5 days,
The distilled water is distilled water three times.
9. natural application of the self-healing hydrogel in as wound dressing described in claim 1.
A kind of 10. wound dressing, it is characterised in that：Including natural polysaccharide self-healing hydrogel described in claim 1 and it is carried on
The one or more in medicine, cell factor or growth factor in the natural polysaccharide self-healing hydrogel.
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