CN117159786B - Preparation method of bioactive hydrogel for regenerating wound healing - Google Patents
Preparation method of bioactive hydrogel for regenerating wound healing Download PDFInfo
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- 238000002360 preparation method Methods 0.000 title claims abstract description 31
- 230000029663 wound healing Effects 0.000 title claims abstract description 25
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- 230000001172 regenerating effect Effects 0.000 title claims abstract description 11
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- WMBWREPUVVBILR-WIYYLYMNSA-N (-)-Epigallocatechin-3-o-gallate Chemical compound O([C@@H]1CC2=C(O)C=C(C=C2O[C@@H]1C=1C=C(O)C(O)=C(O)C=1)O)C(=O)C1=CC(O)=C(O)C(O)=C1 WMBWREPUVVBILR-WIYYLYMNSA-N 0.000 claims abstract description 42
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Classifications
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
- Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
- Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
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- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicinal Preparation (AREA)
Abstract
The invention provides a preparation method of chitosan hydrogel for regenerating wound healing, which comprises the steps of alternately containing catechol and phenylboronic acid groups through an amination F127 derivative and covalently bonding with EGCG for wound healing. There are many types of dynamic chemical bonds and the resulting bioactive hydrogels are injectable and adaptable. Injectable hydrogels also allow for in situ encapsulation and efficient delivery of EGCG to a wound site as drug delivery systems. In addition, EGCG participates in the hydrogel network, and due to pH-sensitive dynamic covalent incorporation of EGCG, controlled sustained release of EGCG can be provided, and simultaneously, EGCG plays a long-term therapeutic role.
Description
Technical Field
The invention relates to a preparation method of a nano composite hydrogel stent, belongs to the technical field of medical biological materials, and particularly relates to a preparation method of bioactive hydrogel for regenerating wound healing.
Background
Diabetes mellitus is a comprehensive metabolic disease, and the incidence rate of the diabetes mellitus tends to rise year by year. The total number of diabetics in China reaches 1 hundred million and is growing rapidly, and the method is the country with the largest number of diabetics in the world. Among the complications of diabetes, impaired wound healing ability of diabetics is a typical complication of diabetes, and if chronic injury and ulcer occur on the foot, it is possible to cause diabetic foot, and some patients eventually need amputation treatment, bringing a heavy economic burden to the home and society. The wound healing disorder of the diabetic patients seriously affects the daily life of people, and has important clinical significance for effectively preventing and treating the wound healing disorder of the diabetes.
The wound dressing can promote the rapid closing and healing of the wound and is of great importance to wound management. In the existing wound dressing, the vigorously developed hydrogel dressing family stands out due to the unique combination of the hydrogel dressing family, and can provide a physical barrier and maintain a moist microenvironment on a wound bed, so that the wound is protected from external pollution, a relieving effect is provided, and wound healing is promoted. In particular, injectable hydrogels that can be formed in situ under physiological conditions are widely regarded as the most attractive wound dressing, with additional functions including shape adaptation to cover irregularly shaped or deep wounds and in situ drug encapsulation. In addition to rapid coverage of the wound, if the dressing is unable to maintain its integrity during frequent body movements, it may lead to dysfunction and prolonged healing time.
Therefore, an injectable hydrogel with rapid gelling and self-healing capabilities is very attractive for dressings. The introduction of various reversible interactions as cross-linking agents in the construction of hydrogels is considered a reliable method for producing hydrogels with excellent self-healing capabilities. Among them, self-healing gels based on dynamic borate ester bonds are currently becoming potential scaffolds for tissue engineering, electronic skin and flexible sensor applications. These networks are formed by crosslinking cis-diol-rich polymers with boric acid or boric acid derivatives and have transient crosslinking anchors with special kinetics, thus providing hydrogels with remarkable self-healing properties.
Infection by bacterial contamination remains one of the barriers to wound healing, particularly chronic wounds. Chronic inflammation is often difficult to treat due to high microbial load and oxidative stress. A wide range of applications using antibiotics or the addition of bioactive molecules (growth factors, antioxidants and anti-inflammatory agents) in dressings have been devoted to solving infections and promoting healing. However, overuse of synthetic antibiotics leads to drug resistance, constitutes a great threat to human health, and creates a socioeconomic burden. Hydrogels do not possess antibiotic properties, but are effective in alleviating bacterial infections, and have attracted extensive research interest in wound therapy. As a bio-sustainable enhancer, a natural polyphenol extracted from green tea, such as epigallocatechin-3-gallate (EGCG), a well-known wound healing agent, has been encapsulated into hydrogels to tailor the performance of multifunctional wound dressings.
In addition to an impressive therapeutic effect, EGCG having reactive catechol groups can form EGCG conjugated polymer networks by forming reversible covalent bonds involving borate complexation chemistry as a bonding motif. Interestingly, catechol groups with cellular affinity facilitate contact of bacterial cells with the hydrogel surface, resulting in exposure of the bacterial cells to the inherently antimicrobial components.
Therefore, the introduction of catechol groups into hydrogels is of interest as an effective method for achieving contact enhanced bactericidal activity. In addition, reversible borate linkages tend to react to the pH and competing hydroxylated compounds present in the medium (e.g., glucose), thereby enabling the biomolecules incorporated into the hydrogels to stimulate responsive release.
Thus, it can be inferred that the integration of polyphenols and/or catechol group-containing polymers as functional building blocks is a viable option for achieving both antibacterial and antioxidant functions of wound dressing based on dynamically crosslinked hydrogels with injectability, self-healing, drug release control and biocompatibility.
The hydrogel dressing has great application value and prospect as a new research for curing chronic wound healing. Compared with the hydrogel dressing which directly acts on the wound, the traditional hydrogel dressing has the problems of limitation, incapacity of healing, poor shape matching, weak wound retention capacity, easiness in wound infection and the like.
Disclosure of Invention
The invention aims to provide a preparation method of bioactive hydrogel for regenerating wound healing, which constructs the used thermosensitive hydrogel through reversible covalent crosslinking among amino F127 derivatives, wherein the F127 derivatives alternately contain catechol and phenylboronic acid groups and are covalently bonded with EGCG for wound healing.
Due to the presence of multiple types of dynamic chemical bonds, the resulting bioactive hydrogels are injectable and adaptable, including covalent borate ester bonds and non-covalent hydrogen bonds. More importantly, the therapeutically active dynamic covalent hydrogels conjugated with EGCG exhibit enhanced antibacterial and antioxidant properties.
The preparation method of the bioactive hydrogel for regenerating wound healing comprises the following process steps of:
step 1): preparation of amino F127
First, F127 was sulfonylated with p-toluenesulfonyl chloride to give F127-p-toluenesulfonate. Then F127-p-toluenesulfonate reacts with ammonia water to obtain aminated F127;
step 2): preparation of catechol functionalized amino F127
Firstly, utilizing condensation reaction of amino and aldehyde group to make amination F127 react with 3, 4-dihydroxybenzaldehyde so as to obtain catechol functionalized amino F127;
step 3): preparation of phenyl boronic acid functionalized amino F127
The amidation reaction of amino and carboxyl is utilized, and under the action of a catalyst, amination F127 reacts with phenylboronic acid to obtain phenylboronic acid functionalized amino F127;
the reaction time of the amination F127 and the phenylboronic acid is 12-36 h; preferably 24 hours;
step 4): preparation of hydrogels
By utilizing a dynamic covalent bond formed between boric acid and catechol groups in amination F127 and combining in-situ encapsulation of green tea derivative epigallocatechin-3-gallate (EGCG), the injectable self-healing hydrogel with antibacterial activity is prepared.
The method specifically comprises the following process steps:
step 1): preparation of amino F127
F127 was weighed into a 150mL dry two-necked flask and dried under vacuum overnight. The anhydrous dichloromethane and pyridine added first dissolve F127, and the system is a clear and transparent solution. The tosyl chloride is weighed, dissolved by anhydrous dichloromethane, and added into the system drop by a constant pressure dropping funnel under the condition of low-temperature ice bath, and the reaction is carried out at room temperature. After the reaction was completed, methylene chloride was added to the system. Washing with 10mL of 1mol/L hydrochloric acid, emulsifying, standing, layering, and removing the lower layer. Then washed with 10mL of saturated sodium bicarbonate solution and finally with 10mL of water. Rotary steaming, removing dichloromethane, vacuum drying for one night, obtaining F127-p-toluene sulfonate.
F127-p-toluenesulfonate is weighed and dissolved in strong ammonia water (not well dissolved and relatively viscous) and reacted at high temperature by a high-temperature high-pressure reaction kettle. After the reaction, F127-p-toluenesulfonate is found to sink on the lower layer, supernatant and precipitate are treated separately, the supernatant and the precipitate are extracted by dichloromethane with the same volume, then the mixture is stirred by sodium hydroxide with the same volume of 1mol/L, finally water is washed to be neutral, and solvent is removed by rotary evaporation, so that aminated F127 is obtained.
Step 2): preparation of catechol functionalized amino F127
First, F127 was dissolved in deionized water, and NaHCO3 was added to adjust the pH. Then 3, 4-dihydroxybenzaldehyde is added into F127 solution, the temperature is reduced to 25 ℃ by heating and stirring, naBH4 is gradually added at room temperature, and the mixture is vigorously stirred, so that brown suspension is obtained. The sediment was rinsed with water and dissolved in water at an acidic pH. The resulting conjugate was then dialyzed against deionized water in a dialysis tube having an MWCO of 14000D for 3 days. The F127-CA conjugate obtained was freeze-dried and stored at 2-8deg.C.
Step 3): preparation of phenyl boronic acid functionalized amino F127
The amino F127 was dissolved in deionized water, PBA was added to the amino F127 solution in the presence of EDC. HCl and HOBt, and stirred overnight at room temperature at a pH of about 5. The resulting mixture was then precipitated and washed 3 times with isopropanol.
Subsequently, the precipitate was dissolved in deionized water and dialyzed against deionized water in a dialysis tube (MWCO 8000 d) for 3 days. The PBA-bound amino F127 conjugate was then lyophilized and stored at 2-8 ℃ until use.
Step 4): preparation of hydrogels
The sorbitol solution containing EGCG was added to the F127-CA solution and stirred. Then, the F127-PBA solution was added to the homogeneous mixture, and the resulting mixture immediately became a gel.
In the step (1) of the process,
f127 is 3-10 g; preferably 6.9g;
the p-toluenesulfonyl chloride is 0.5 g-2 g; preferably 1.33g;
the room temperature reaction time is 12-48 hours; preferably 24 hours;
the volume of the dichloromethane is 10 mL-40 mL; preferably 30mL;
the amount of F127-p-toluenesulfonate is 1 g-3 g; preferably 2g;
the volume of the concentrated ammonia water is 20-80 mL; preferably 50mL;
the high-temperature reaction temperature is 120-160 ℃; preferably 140 ℃;
the high-temperature reaction time is 4-8 hours; preferably 6h;
the stirring time is 1-3 h; preferably 2 hours.
In the step 2) of the process, the process is carried out,
2-8 g of amino F127; preferably 5g;
the volume of the deionized water is 300-500 mL; preferably 400mL;
6-16 g of 3, 4-dihydroxybenzaldehyde; preferably 11g;
the heating temperature is 40-80 ℃; preferably 60 ℃.
The stirring time is 1-5 h; preferably 3 hours;
3-9 g of sodium borohydride; preferably 6g;
the violent stirring time is 1-5 h; preferably 3 hours.
In the step 3) of the method,
2-8 g of amino F127; preferably 5g;
the volume of the deionized water is 300-700 mL; preferably 500mL;
3-9 g of EDC and HCl; preferably 6.3g;
the HOBt is 3-8 g; preferably 5g;
the PBA is 1-10 g; preferably 5.4g.
The invention provides a preparation method of bioactive hydrogel for regenerating wound healing.
The hydrogel material has injectable, temperature sensitive, EGCG delivery, bioactivity and chronic wound healing. The hydrogel material has good antibacterial and antioxidant functions in the aspects of preventing bacterial infection and scavenging free radicals, and overcomes some problems of the existing hydrogel material for treating chronic wound healing.
The hydrogel material of the invention belongs to the combination of various substances, maintains the advantages of the original substances, and solves the defect of single original material performance. The preparation process of the invention has simple operation, the required raw materials are easy to obtain, and the invention is expected to be widely applied in the field of biomedical engineering materials.
By means of the technical scheme, the preparation method of the hydrogel material has the following beneficial effects:
firstly, the invention utilizes dynamic covalent bond formed between boric acid and catechol group in amination F127 and combines in-situ encapsulation of green tea derivative epigallocatechin-3-gallate (EGCG) to prepare the injectable self-healing hydrogel with antibacterial activity.
The prepared natural injectable hydrogel has good antibacterial and antioxidant functions in the aspects of preventing bacterial infection and scavenging free radicals by utilizing the therapeutic action of catechol groups and EGCG.
EGCG loaded hydrogels also exhibit good biocompatibility, as well as contact antibacterial activity through a "capture and kill" strategy. Dynamic covalent bonding shear thins the gel through the syringe and then self-heals rapidly. The hydrogel of the invention has obvious regenerative wound healing performance, and shows great potential as a novel wound treatment dressing.
Drawings
FIG. 1 shows a scanning electron microscope image of a hydrogel;
FIG. 2 shows cytotoxicity of F127-PC and F127-PC/EGCG;
FIG. 3 shows the release profile of EGCG under various conditions;
FIG. 4 shows the bacteriostatic efficacy of F127-PC/EGCG against E.coli and Staphylococcus aureus.
Detailed Description
The present invention will be described in further detail below by reference to the drawings and effect test examples, which are given for the purpose of illustration only and are not limiting the invention.
The invention relates to a method for wound healing by covalent bonding of an aminated F127 derivative alternately containing catechol and phenylboronic acid groups and EGCG. The resulting bioactive hydrogels are injectable and adaptable due to the presence of multiple types of dynamic chemical bonds; injectable hydrogels also allow for in situ encapsulation and efficient delivery of EGCG to a wound site as drug delivery systems.
In addition, EGCG participates in the hydrogel network, and due to pH-sensitive dynamic covalent incorporation of EGCG, controlled sustained release of EGCG can be provided, and simultaneously, EGCG plays a long-term therapeutic role.
The invention prepares the injectable self-healing hydrogel with antibacterial activity by combining dynamic covalent bonds formed between boric acid and catechol groups in amination F127 and in-situ encapsulation of green tea derivative epigallocatechin-3-gallate (EGCG).
The prepared natural injectable hydrogel has good antibacterial and antioxidant functions in the aspects of preventing bacterial infection and scavenging free radicals by utilizing the therapeutic action of catechol groups and EGCG. Dynamic covalent bonding shear thins the gel through the syringe and then self-heals rapidly.
In addition, in vivo wound healing evaluation in a full-thickness skin defect model shows that hydrogel has obvious regenerative wound healing performance, and shows great potential as a novel wound treatment dressing.
The invention provides a preparation method of bioactive hydrogel for regenerating wound healing, which comprises the steps of alternately containing catechol and phenylboronic acid groups through an amination F127 derivative and covalently bonding with EGCG for wound healing;
the method specifically comprises the following process steps:
step 1): preparation of amino F127
First, F127 was sulfonylated with p-toluenesulfonyl chloride to give F127-p-toluenesulfonate. Then F127-p-toluenesulfonate reacts with ammonia water to obtain aminated F127;
step 2): preparation of catechol functionalized amino F127
Firstly, utilizing condensation reaction of amino and aldehyde group to make amination F127 react with 3, 4-dihydroxybenzaldehyde so as to obtain catechol functionalized amino F127;
step 3): preparation of phenyl boronic acid functionalized amino F127
The amidation reaction of amino and carboxyl is utilized, and under the action of a catalyst, amination F127 reacts with phenylboronic acid to obtain phenylboronic acid functionalized amino F127;
step 4): preparation of hydrogels
By utilizing a dynamic covalent bond formed between boric acid and catechol groups in amination F127 and combining in-situ encapsulation of green tea derivative epigallocatechin-3-gallate (EGCG), the injectable self-healing hydrogel with antibacterial activity is prepared.
The present invention will be described in further detail with reference to specific preferred examples in conjunction with effect test examples, but the present invention is not limited to the following examples.
Example 1: preparation of amino F127
6.9g F127 was weighed into a 150mL dry two-necked flask and dried under vacuum overnight. First, 12.5mL of anhydrous dichloromethane and 12.5mL of pyridine were added to dissolve F127, and the system was a clear and transparent solution. 1.33g of p-toluenesulfonyl chloride was weighed, dissolved in 12.5mL of anhydrous dichloromethane, and the system was added dropwise under low-temperature ice bath conditions using a constant pressure dropping funnel. (after a few drops were added dropwise, the system became a golden clear solution) and reacted at room temperature for 24 hours.
After the completion of the reaction, 30mL of methylene chloride was added to the system. Washing with 10mL of 1mol/L hydrochloric acid, emulsifying, standing, layering, and removing the lower layer. Then washed with 10mL of saturated sodium bicarbonate solution and finally with 10mL of water. The dichloromethane was removed by rotary evaporation and dried in vacuo overnight. 5.4g of F127-p-toluenesulfonate were obtained. 2g of F127-p-toluenesulfonate was weighed, dissolved in 50mL of concentrated aqueous ammonia (not well soluble, relatively viscous.) and reacted at 140℃for 6 hours using a high temperature and high pressure autoclave.
After the reaction, F127-p-toluenesulfonate is found to sink on the lower layer, supernatant and precipitate are treated separately, the supernatant and the precipitate are extracted by dichloromethane with the same volume, then the mixture is stirred for 2 hours by sodium hydroxide with the same volume of 1mol/L, finally the mixture is washed to be neutral by water, and the solvent is removed by rotary evaporation.
Example 2: preparation of catechol functionalized amino F127
First, 5g of F127 was dissolved in deionized water (400 mL) and the pH was adjusted to 7.0 by the addition of NaHCO 3. Then 11g of 3, 4-dihydroxybenzaldehyde was added to the F127 solution, stirred at 60℃for 3 hours, the temperature was lowered to 25℃and NaBH4 (6 g) was gradually added at room temperature, and stirred vigorously for 3 hours to give a brown suspension. The sediment was rinsed with water and dissolved in water at a pH of about 4. The resulting product was then dialyzed against deionized water in a dialysis bag (14000D) for 3 days. The F127-CA conjugate obtained was freeze-dried and stored at 2-8deg.C.
Example 3: phenyl boronPreparation of acid functionalized amino F127
Briefly, 5g of amino F127 was dissolved in deionized water (500 mL), 5.4g of PBA was added to the amino F127 solution in the presence of EDC. HCl (6.3 g) and HOBt (5 g), and stirred at room temperature overnight at a pH of about 5. The resulting mixture was then precipitated and washed 3 times with isopropanol. Subsequently, the precipitate was dissolved in deionized water and dialyzed against deionized water in a dialysis tube (MWCO 8000 d) for 3 days. The PBA-bound amino F127 conjugate was then lyophilized and stored at 2-8 ℃ until use.
Example 4: preparation of hydrogels
A sorbitol solution containing 5mg of EGCG was added to the F127-CA solution and stirred. Then, the F127-PBA solution was added to the homogeneous mixture, and the resulting mixture immediately became a gel. Also, in the absence of EGCG, EGCG-free hydrogels were prepared using the same method. Composition of the hydrogel (component concentration F127-PBA 3.5wt%, F127-CA 5.0wt%, sorbitol 50 wt%). EGCG was dissolved in sorbitol solution followed by F127-CA solution. Respectively designated as F127-PC or F127-PC/EGCG.
As shown in fig. 1, the morphology of the hydrogel was observed with a scanning electron microscope. The hydrogel exhibits a porous crosslinked network structure.
The hydrogel products of the examples of the present invention are described in further detail below by way of efficacy test examples.
Test example 1: cytotoxicity of cells
The toxic effects of F127-PC or F127-PC/EGCG on mouse fibroblast L929 were evaluated by the method of detecting cell activity using CCK-8. The specific operation steps are as follows:
first, mouse fibroblast L929 was inoculated into a 96-well plate at a density of 5000 cells/well, and then placed in a carbon dioxide incubator to culture and adhere overnight. Subsequently, the original medium was aspirated and replaced with fresh complete medium extracts containing F127-PC or F127-PC/EGCG, 5 in parallel for each concentration. The cells were then incubated in an incubator for 24h, 48h and 72h, washed once with PBS after incubation and 100. Mu.L of fresh medium (containing 10% CCK-8) was added to each well.
Incubation in incubator for a period of time, and finally detection and recording of absorbance at 450nm wavelength using a microplate reader, cell viability was calculated by the following formula: cell viability (%) = (experimental group absorbance-blank group absorbance)/(negative control group absorbance-blank group absorbance) ×100%.
As shown in FIG. 2, the cell viability was high at different times for either F127-PC or F127-PC/EGCG, and none of them produced any cytotoxicity to mouse fibroblast L929.
Therefore, it is believed that F127-PC or F127-PC/EGCG materials have excellent biocompatibility and can be used as safe gel materials for the study of chronic wound therapy.
Test example 2: EGCG Release
The pH-dependent degradation of hydrogels and the in vitro drug release behavior were studied. 3.0mL of acetic acid buffers (0.1M) of different pH values (5.0 and 7.4) were carefully added to the test tube as a release medium, and the test tube was placed in a constant temperature shaking water bath (Shanghai's signal laboratory apparatus Co., ltd.) at 37℃for in vitro release experiments, with a shaking rate of 60rad/min. At intervals, 1.5mL of release solution was carefully removed from the supernatant to be tested, and fresh 1.5mL of PBS buffer was then added to the tube. The in vitro release profile of EGCG was calculated using UV measurement of the absorbance peak at 275 nm. The results are shown in figure 3, where an initial burst release of EGCG was observed in both physiological and acidic media. And EGCG is released faster at pH 5.0 than at pH 7.4. Thus, the increased release of EGCG in acidic media under physiological conditions predominates throughout the release time window.
Test example 3: antibacterial property
The prepared hydrogels were evaluated for their bacteriostatic activity against E.coli (E.coli) and Staphylococcus aureus (S.aureus) using an agar disc diffusion test and a surface contact test.
Coli and staphylococcus aureus were revived overnight in Luria-Bertani (LB) broth at 37 ℃. All hydrogel samples were sterilized by uv irradiation prior to detection.
As shown in FIG. 4, the F127-PC/EGCG hydrogel can obviously inhibit the growth of escherichia coli and staphylococcus aureus, and has good antibacterial property.
The present invention is not limited to the preferred embodiments, but can be modified, equivalent, and modified in any way without departing from the technical scope of the present invention.
Claims (8)
1. A method for preparing a bioactive hydrogel for regenerating wound healing, characterized in that the method comprises alternately containing catechol and phenylboronic acid groups through an amination F127 derivative and covalently bonding epigallocatechin-3-gallate EGCG for wound healing;
the method specifically comprises the following process steps:
step 1): preparation of amino F127
Firstly, F127 is sulfonylated by utilizing p-toluenesulfonyl chloride to obtain F127-p-toluenesulfonate; then F127-p-toluenesulfonate reacts with ammonia water to obtain aminated F127;
step 2): preparation of catechol functionalized amino F127
Firstly, utilizing condensation reaction of amino and aldehyde group to make amination F127 react with 3, 4-dihydroxybenzaldehyde so as to obtain catechol functionalized amino F127;
step 3): preparation of phenyl boronic acid functionalized amino F127
The amidation reaction of amino and carboxyl is utilized, and under the action of a catalyst, amination F127 reacts with phenylboronic acid to obtain phenylboronic acid functionalized amino F127;
step 4): preparation of hydrogels
By utilizing a dynamic covalent bond formed between boric acid and catechol groups in amination F127 and combining in-situ encapsulation of green tea derivative epigallocatechin-3-gallate (EGCG), the injectable self-healing hydrogel with antibacterial activity is prepared.
2. The method of manufacturing according to claim 1, wherein: the specific steps of the step 1) are as follows:
f127 was weighed into a 150mL dry two-necked flask and dried under vacuum overnight; firstly, adding anhydrous dichloromethane and pyridine to dissolve F127, wherein the system is a clear and transparent solution; weighing p-toluenesulfonyl chloride, dissolving the p-toluenesulfonyl chloride with anhydrous dichloromethane, dropwise adding the solution into a system by using a constant-pressure dropping funnel under the low-temperature ice bath condition, and reacting at room temperature; after the reaction is finished, adding methylene dichloride into the system; washing with 10mL of 1mol/L hydrochloric acid, emulsifying, standing, layering, and taking out the lower layer; then washed with 10mL of saturated sodium bicarbonate solution and finally with 10mL of water; rotary steaming, removing dichloromethane, and vacuum drying for one night to obtain F127-p-toluenesulfonate;
weighing F127-p-toluenesulfonate, and dissolving in concentrated ammonia water; high-temperature high-pressure reaction in a high-temperature high-pressure reaction kettle; after the reaction, F127-p-toluenesulfonate is found to sink on the lower layer, supernatant and precipitate are treated separately, the supernatant and the precipitate are extracted by dichloromethane with the same volume, then the mixture is stirred by sodium hydroxide with the same volume of 1mol/L, finally water is washed to be neutral, and solvent is removed by rotary evaporation, so that aminated F127 is obtained.
3. The method of manufacturing according to claim 1, wherein: the step 2) comprises the following specific steps:
first, F127 is dissolved in deionized water, naHCO is added 3 Adjusting the pH; then adding 3, 4-dihydroxybenzaldehyde into the F127 solution, heating and stirring, cooling to 25 ℃, gradually adding sodium borohydride at room temperature, and vigorously stirring to obtain brown suspension; the sediment is washed by water and is dissolved in water with acidic pH value;
the resulting conjugate was then dialyzed against deionized water in a dialysis tube having an MWCO of 14000D for 3 days, and the resulting F127-CA conjugate was lyophilized and stored at 2-8deg.C.
4. The method of manufacturing according to claim 1, wherein: the step 3) comprises the following specific steps:
dissolving amino F127 in deionized water, adding phenylboronic acid into the amino F127 solution in the presence of EDC, HCl and HOBt, and stirring at room temperature overnight, wherein the pH is 5;
the resulting mixture precipitate was then washed 3 times with isopropanol; subsequently, the precipitate was dissolved in deionized water and dialyzed against deionized water in a dialysis tube with MWCO 8000D for 3 days;
the PBA-bonded amino F127 conjugate F127-PBA was then lyophilized and stored at 2-8 ℃ until use.
5. The method of manufacturing according to claim 4, wherein: the specific steps of the step 4) are as follows:
adding the sorbitol solution containing EGCG into the F127-CA solution, and stirring; then, the F127-PBA solution was added to the homogeneous mixture, and the resulting mixture immediately became a gel.
6. The method of manufacturing as claimed in claim 2, wherein: in the step (1) of the above-mentioned process,
f127 is 3-10 g;
the p-toluenesulfonyl chloride is 0.5 g-2 g;
the room temperature reaction time is 12-48 hours;
the volume of the dichloromethane is 10 mL-40 mL;
the amount of F127-p-toluenesulfonate is 1 g-3 g;
the volume of the concentrated ammonia water is 20-80 mL;
the high-temperature reaction temperature is 120-160 ℃;
the high-temperature reaction time is 4-8 hours;
the stirring time is 1-3 h.
7. A method of preparation as claimed in claim 3, wherein: in the step 2), the amino F127 is 2-8 g;
the volume of the deionized water is 300-500 mL;
6-16 g of 3, 4-dihydroxybenzaldehyde;
the heating temperature is 40-80 ℃;
the stirring time is 1-5 h;
3-9 g of sodium borohydride;
the violent stirring time is 1-5 h.
8. The method of manufacturing according to claim 4, wherein: in the step 3), the amino F127 is 2-8 g;
the volume of the deionized water is 300-700 mL;
3-9 g of EDC and HCl;
the HOBt is 3-8 g;
the phenylboronic acid is 1-10 g.
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