CN116688222B - Intelligent response hydrogel dressing based on hypoxia exosome and preparation method and application thereof - Google Patents
Intelligent response hydrogel dressing based on hypoxia exosome and preparation method and application thereof Download PDFInfo
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- CN116688222B CN116688222B CN202310761500.6A CN202310761500A CN116688222B CN 116688222 B CN116688222 B CN 116688222B CN 202310761500 A CN202310761500 A CN 202310761500A CN 116688222 B CN116688222 B CN 116688222B
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- sodium alginate
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- carboxymethyl chitosan
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- 206010021143 Hypoxia Diseases 0.000 title claims abstract description 64
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- 239000000017 hydrogel Substances 0.000 title claims abstract description 51
- 238000002360 preparation method Methods 0.000 title claims abstract description 34
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- 239000000661 sodium alginate Substances 0.000 claims abstract description 154
- 229940005550 sodium alginate Drugs 0.000 claims abstract description 154
- HXITXNWTGFUOAU-UHFFFAOYSA-N phenylboronic acid Chemical compound OB(O)C1=CC=CC=C1 HXITXNWTGFUOAU-UHFFFAOYSA-N 0.000 claims abstract description 97
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- LRBQNJMCXXYXIU-PPKXGCFTSA-N Penta-digallate-beta-D-glucose Natural products OC1=C(O)C(O)=CC(C(=O)OC=2C(=C(O)C=C(C=2)C(=O)OC[C@@H]2[C@H]([C@H](OC(=O)C=3C=C(OC(=O)C=4C=C(O)C(O)=C(O)C=4)C(O)=C(O)C=3)[C@@H](OC(=O)C=3C=C(OC(=O)C=4C=C(O)C(O)=C(O)C=4)C(O)=C(O)C=3)[C@H](OC(=O)C=3C=C(OC(=O)C=4C=C(O)C(O)=C(O)C=4)C(O)=C(O)C=3)O2)OC(=O)C=2C=C(OC(=O)C=3C=C(O)C(O)=C(O)C=3)C(O)=C(O)C=2)O)=C1 LRBQNJMCXXYXIU-PPKXGCFTSA-N 0.000 claims abstract description 67
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- LRBQNJMCXXYXIU-NRMVVENXSA-N tannic acid Chemical compound OC1=C(O)C(O)=CC(C(=O)OC=2C(=C(O)C=C(C=2)C(=O)OC[C@@H]2[C@H]([C@H](OC(=O)C=3C=C(OC(=O)C=4C=C(O)C(O)=C(O)C=4)C(O)=C(O)C=3)[C@@H](OC(=O)C=3C=C(OC(=O)C=4C=C(O)C(O)=C(O)C=4)C(O)=C(O)C=3)[C@@H](OC(=O)C=3C=C(OC(=O)C=4C=C(O)C(O)=C(O)C=4)C(O)=C(O)C=3)O2)OC(=O)C=2C=C(OC(=O)C=3C=C(O)C(O)=C(O)C=3)C(O)=C(O)C=2)O)=C1 LRBQNJMCXXYXIU-NRMVVENXSA-N 0.000 claims abstract description 20
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- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 13
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- XIPRTRJDLZVSHO-UHFFFAOYSA-N aminooxy(phenoxy)borinic acid Chemical compound NOB(O)OC1=CC=CC=C1 XIPRTRJDLZVSHO-UHFFFAOYSA-N 0.000 claims description 7
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- DIRRKLFMHQUJCM-UHFFFAOYSA-N (2-aminophenyl)boronic acid Chemical compound NC1=CC=CC=C1B(O)O DIRRKLFMHQUJCM-UHFFFAOYSA-N 0.000 claims description 2
- ZSKXYSCQDWAUCM-UHFFFAOYSA-N 1-(chloromethyl)-2-dodecylbenzene Chemical compound CCCCCCCCCCCCC1=CC=CC=C1CCl ZSKXYSCQDWAUCM-UHFFFAOYSA-N 0.000 claims description 2
- ILOJFJBXXANEQW-UHFFFAOYSA-N aminooxy(phenyl)borinic acid Chemical compound NOB(O)C1=CC=CC=C1 ILOJFJBXXANEQW-UHFFFAOYSA-N 0.000 claims description 2
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Classifications
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L26/00—Chemical aspects of, or use of materials for, wound dressings or bandages in liquid, gel or powder form
- A61L26/0061—Use of materials characterised by their function or physical properties
- A61L26/008—Hydrogels or hydrocolloids
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L26/00—Chemical aspects of, or use of materials for, wound dressings or bandages in liquid, gel or powder form
- A61L26/0009—Chemical aspects of, or use of materials for, wound dressings or bandages in liquid, gel or powder form containing macromolecular materials
- A61L26/0023—Polysaccharides
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L26/00—Chemical aspects of, or use of materials for, wound dressings or bandages in liquid, gel or powder form
- A61L26/0057—Ingredients of undetermined constitution or reaction products thereof
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- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L26/00—Chemical aspects of, or use of materials for, wound dressings or bandages in liquid, gel or powder form
- A61L26/0061—Use of materials characterised by their function or physical properties
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L26/00—Chemical aspects of, or use of materials for, wound dressings or bandages in liquid, gel or powder form
- A61L26/0061—Use of materials characterised by their function or physical properties
- A61L26/0066—Medicaments; Biocides
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
- A61L2300/20—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices containing or releasing organic materials
- A61L2300/23—Carbohydrates
- A61L2300/232—Monosaccharides, disaccharides, polysaccharides, lipopolysaccharides
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- A—HUMAN NECESSITIES
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- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
- A61L2300/40—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices characterised by a specific therapeutic activity or mode of action
- A61L2300/41—Anti-inflammatory agents, e.g. NSAIDs
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- A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
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- A61L2300/412—Tissue-regenerating or healing or proliferative agents
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- A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
- A61L2300/60—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices characterised by a special physical form
- A61L2300/602—Type of release, e.g. controlled, sustained, slow
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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
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Abstract
The invention provides a preparation method of an intelligent response hydrogel dressing based on a hypoxia exosome, which comprises the steps of carrying out hydroformylation modification by utilizing sodium alginate with high G content, and then carrying out phenylboric acid grafting to prepare phenylboric acid grafted hydroformylation sodium alginate (PBA-OSA); carrying out tannic acid modification by using carboxymethyl chitosan to prepare tannic acid modified carboxymethyl chitosan (TA-CMCS); the intelligent response hydrogel dressing based on the hypoxia exosomes is prepared by utilizing Schiff base reaction between aldehyde groups of PBA-OSA and amino groups of TA-CMCS and boric acid ester bond between phenyl boric acid groups of PBA-OSA and hydroxyl groups of TA-CMCS to form a double-network structure polysaccharide-based hydrogel with adjustable mechanical property and crosslinking density, and loading the hypoxia exosomes from stem cells into the polysaccharide-based hydrogel, has better mechanical strength and flexibility, and releases the hypoxia exosomes as required according to high sugar and oxidative stress level of diabetes wound microenvironment, so as to achieve the purposes of continuously promoting wound blood vessel regeneration and promoting wound healing.
Description
Technical Field
The invention belongs to the technical field of biological medicine, and particularly relates to an intelligent response hydrogel dressing based on a hypoxia exosome, and a preparation method and application thereof.
Background
Diabetic foot ulcers (Diabetic foot ulcers, DFUs) are common and serious complications of diabetes, and about 70% of amputation worldwide is caused by DFUs, and there is still a lack of sustained effective treatments. The main factors of difficult healing of diabetic foot ulcers include cell dysfunction, changes in the ability to regenerate blood vessels, and the like. The diabetic patients are easy to develop vascular lesions, the vascular regeneration is damaged, so that the cell proliferation, the extracellular matrix synthesis and the remodeling are blocked, and finally, the chronic wound surface which is difficult to heal is formed. The disorder of macrophages is another key reason that chronic wounds of diabetes are difficult to heal, and is represented by a state that proinflammatory cytokines are highly expressed and anti-inflammatory factors and growth factors are low in level, so that the wounds cannot enter a proliferation stage in an inflammatory stage for a long time. In addition, complicated physiological microenvironments exist on wounds difficult to heal due to diabetes, so that the conventional wound dressing cannot achieve an ideal repairing effect. Therefore, it is necessary to develop a hydrogel dressing capable of integrating the functions of regulating inflammatory reaction and promoting angiogenesis and intelligently responding to the microenvironment of the diabetic wound surface.
Disclosure of Invention
In view of the problem that the conventional wound dressing can not achieve the healing of chronic wounds of diabetes at present, the invention provides an intelligent response hydrogel dressing based on a hypoxia exosome, and a preparation method and application thereof.
The invention aims to provide an intelligent response hydrogel dressing based on a hypoxia Exosome, which comprises, by mass, 2-6wt% of phenylboronic acid grafted aldehyde sodium alginate (PBA-OSA), 2-6wt% of tannic acid modified carboxymethyl chitosan (TA-CMCS), 0.5-1.0wt% of the hypoxia Exosome (HExo), and the balance of water.
In the intelligent response hydrogel dressing based on the hypoxia exosome, the boric acid ester bond formed between the phenylboronic acid grafted aldehyde sodium alginate (PBA-OSA) and the tannic acid modified sodium carboxymethylcellulose (TA-CMCS) can respond to high sugar and hydrogen peroxide (H 2O2) in the diabetes wound microenvironment and clear Reactive Oxygen Species (ROS), the hypoxia exosome (HExo) can be intelligently released according to the wound microenvironment, the release amount can be matched with the inflammation degree of the wound, and the release is realized according to the need; the hypoxia exosome has strong capability of promoting blood vessel regeneration, and can improve the damage of chronic wound surface blood vessel regeneration of diabetes, thereby better promoting wound surface healing; in addition, the modified sodium alginate with high G content has the excellent performance of regulating and controlling macrophage phenotype polarization, can promote macrophages to regulate and control inflammatory reaction to anti-inflammatory phenotype polarization, and can eliminate active oxygen and reduce oxidative stress by intelligently responding to boric acid ester bonds in gel dressing, thereby further regulating and controlling inflammatory reaction, improving wound inflammation microenvironment and promoting wound healing.
The second object of the invention is to provide a preparation method of the intelligent response hydrogel dressing based on the hypoxia exosome, which comprises the following steps:
Carrying out hydroformylation modification on sodium alginate with high G content (alpha-L-guluronic acid (G)) and further carrying out phenylboric acid grafting to obtain phenylboric acid grafted hydroformylation sodium alginate (OSA); then using carboxymethyl chitosan to carry out tannic acid (TANNIC ACID, TA) modification to prepare tannic acid modified carboxymethyl chitosan; finally, forming a polysaccharide-based hydrogel with a double-network structure and adjustable mechanical properties and crosslinking density by utilizing Schiff base reaction between aldehyde groups of PBA-OSA and amino groups of TA-CMCS and boric acid ester bonds of phenyl boric acid groups of PBA-OSA and hydroxyl groups of TA-CMCS, and loading a hypoxia exosome from a stem cell source into the polysaccharide-based hydrogel to prepare the intelligent response hydrogel dressing based on the hypoxia exosome.
Further, the method comprises the following steps:
Step 1) taking sodium alginate with high G content as a raw material, and carrying out oxidation reaction on the sodium periodate under a light-shielding condition to prepare aldehyde sodium alginate with different substitution degrees; then carrying out grafting modification on the aldehyde sodium alginate by using aminophenylboric acid to prepare phenyl boric acid grafted aldehyde sodium alginate;
step 2) using carboxymethyl chitosan as a raw material, and preparing tannic acid modified carboxymethyl chitosan with tannic acid under the catalysis of coupling agents of 1-ethyl- (3-dimethylaminopropyl) carbodiimide (EDC) and N-hydroxysuccinimide (NHS);
Step 3) culturing the well-cultured stem cells under the anoxic condition, and obtaining the hypoxia exosomes through centrifugation, filtration and isolation extraction;
Step 4) forming a polysaccharide-based hydrogel with a double-network structure and adjustable mechanical property and crosslinking density by utilizing Schiff base reaction between aldehyde groups of PBA-OSA and amino groups of TA-CMCS and boric acid ester bonds of phenylboronic acid groups of PBA-OSA and hydroxyl groups of TA-CMCS, and loading the hypoxia exosomes into the polysaccharide-based hydrogel to prepare the intelligent response hydrogel dressing based on the hypoxia exosomes.
Further, in the step 1), dispersing sodium alginate with high G content in absolute ethyl alcohol to prepare sodium alginate suspension, then adding sodium periodate solution with the concentration of 6-20wt% to react for 18-32 h under the condition of light shielding, adding glycol with the same mole as sodium periodate to terminate the reaction to obtain a reaction mixture, purifying the reaction mixture, and freeze-drying to prepare the hydroformylation sodium alginate; dissolving the aldehyde sodium alginate in water to prepare an aldehyde sodium alginate solution with the concentration of 3-5 wt%, adding aminophenylboric acid for reaction, filtering after the reaction is finished, and freeze-drying to prepare phenyl boric acid grafted aldehyde sodium alginate;
Wherein the molecular weight of the sodium alginate is 4kDa-50kDa, and the M/G ratio is 1:1-1:3;
The mass volume ratio of the sodium alginate to the absolute ethyl alcohol is 1:4g/mL-1:6g/mL;
The mass ratio of the sodium periodate in the sodium periodate aqueous solution to the sodium alginate in the sodium alginate dispersion liquid is 1:1-6:1;
The mass ratio of the aminophenylboric acid to the aldehyde sodium alginate is 1:5-1:10;
The amino phenylboronic acid is any one or more of 2-amino phenylboronic acid, 3-amino phenylboronic acid and 4-amino phenylboronic acid.
Further, in the step 2), carboxymethyl chitosan and tannic acid are dissolved in water, the concentration of the prepared carboxymethyl chitosan solution is 2-4wt%, and then a coupling agent 1-ethyl- (3-dimethylaminopropyl) carbodiimide and N-hydroxysuccinimide are added for catalytic reaction, so that tannic acid modified carboxymethyl chitosan is prepared;
Wherein the mass ratio of the carboxymethyl chitosan to the tannic acid is 1:1-1:5;
the molar ratio of EDC to NHS in the coupling agent is 3-5:0.5-2.
Further, in the step 3), the well-cultured stem cells are cultured for 24 hours under the anoxic condition, the cell debris and macromolecular proteins are removed by centrifugation for 30 minutes based on 15000rpm, then the culture is filtered by a 0.22 mu m filter, finally, after centrifugation for 1 hour at 57000rpm by a super centrifuge, the supernatant is taken out, and transparent precipitate at the bottom of the centrifuge tube is collected, so as to obtain the hypoxia exosome;
wherein the stem cells are any one or more of fat stem cells, mesenchymal stem cells and human urine-derived stem cells;
The anoxic condition is to use a mixed gas of 85% -94% of N 2、1％-10％ O2 and 5% of CO 2.
Further, in the step 4), dissolving phenyl boric acid grafted aldehyde sodium alginate in water to prepare phenyl boric acid grafted aldehyde sodium alginate solution with the concentration of 2-6wt%, adding 0.5wt% -1.0wt% of hypoxia exosome, stirring and mixing uniformly, and finally adding tannic acid modified carboxymethyl chitosan for stirring, and reacting to prepare the intelligent response hydrogel dressing based on the hypoxia exosome; wherein the mass ratio of the phenylboronic acid grafted aldehyde sodium alginate to the tannic acid modified carboxymethyl chitosan is 1:1-1:2.
The invention further aims to provide an application of the intelligent response hydrogel dressing based on the hypoxia exosome in preparing a medical dressing for promoting the healing of chronic wounds of diabetes.
Compared with the prior art, the invention has the beneficial effects that:
1. The intelligent response gel dressing prepared by the invention has better mechanical strength and flexibility, and better dressing property with wounds, and solves the defect that most of the current medical dressings are not suitable for various complex wounds.
2. The intelligent response gel dressing prepared by the invention has the characteristics of intelligence, can release the hypoxia exosome which is favorable for promoting the regeneration of blood vessels of the wound surface according to the microenvironment of the wound surface as required, and the release amount can be matched with the inflammation degree of the wound surface.
3. The intelligent response gel dressing prepared by the invention plays roles in regulating and controlling inflammation and promoting angiogenesis, can promote the repair of chronic wounds of diabetes, and solves the defect that the traditional medical dressing cannot effectively repair the chronic wounds of diabetes.
Detailed Description
The application will be further illustrated with reference to specific examples. It is to be understood that these examples are illustrative of the present application and are not intended to limit the scope of the present application. Furthermore, it should be understood that various changes and modifications can be made by one skilled in the art after reading the teachings of the present application, and such equivalents are intended to fall within the scope of the application as defined in the appended claims.
The raw materials and reagents used in the examples were conventional products which were obtained commercially, unless otherwise specified; the experimental methods for which specific conditions are not specified in the examples are generally in accordance with the conditions conventional in the art or in accordance with the manufacturer's recommendations.
The sodium alginate powder used in the examples was obtained commercially with a purity of 85% sodium alginate and a content of alpha-L-guluronic acid of 80% -50%. In the following examples, "vigorous stirring" means stirring at a speed of 1200rpm to 1800rpm.
Example 1
The preparation method of the intelligent response hydrogel dressing based on the hypoxia exosome of the embodiment comprises the following steps:
(1) Preparation of phenylboronic acid grafted aldehyde sodium alginate: dispersing 10g of sodium alginate with molecular weight of 50kDa in 50ml of absolute ethyl alcohol to obtain sodium alginate dispersion liquid, adding 20% (w/v) sodium periodate aqueous solution containing 60g of sodium periodate into the sodium alginate dispersion liquid, carrying out light-shielding reaction for 4 hours to obtain a reaction product, and purifying and drying the reaction product to obtain the aldehyde sodium alginate. Adding 2g of oxidized sodium alginate into 100ml of deionized water to prepare 2% aldehyde sodium alginate aqueous solution, adding 3-aminophenylboric acid into the aldehyde sodium alginate solution according to the mass ratio of the 3-aminophenylboric acid to the oxidized sodium alginate of 1:5, reacting for 2h, and purifying the reaction product after the reaction is finished to obtain the phenylboric acid grafted aldehyde sodium alginate.
(2) Preparation of tannic acid modified carboxymethyl chitosan: 2g of carboxymethyl chitosan and 10g of tannic acid are dissolved in 100ml of water to obtain the tannic acid modified carboxymethyl chitosan (TA-CMCS), and then a coupling agent of 0.2g of 1-ethyl- (3-dimethylaminopropyl) carbodiimide (EDC) and 0.1g N-hydroxysuccinimide (NHS) are added to react, and the tannic acid modified carboxymethyl chitosan (TA-CMCS) is prepared by modification under the catalysis of the coupling agent.
(3) The well-cultured stem cells were cultured under anaerobic (94% N2, 1% O2 and 5% CO 2) conditions for 24 hours, the medium was collected, centrifuged at 15000rpm for 30 minutes, cell debris and macromolecular proteins were removed, then filtered with a 0.22 μm filter, finally, after centrifugation at 57000rpm for 1 hour with a ultracentrifuge, the supernatant was removed, and the transparent precipitate at the bottom of the centrifuge tube was collected to obtain a hypoxia Exosome (HExo).
(4) 2G of phenylboronic acid grafted aldehyde sodium alginate is dissolved in 100ml of water to prepare phenylboronic acid grafted aldehyde sodium alginate solution, 1g of hypoxia exosome is added into the solution to be stirred and mixed uniformly, and finally tannic acid modified carboxymethyl chitosan is added according to the mass ratio of the phenylboronic acid grafted aldehyde sodium alginate of 1:1 to be stirred, and the intelligent response hydrogel dressing can be obtained after the reaction.
Example 2
The preparation method of the intelligent response hydrogel dressing based on the hypoxia exosome of the embodiment comprises the following steps:
(1) Preparation of phenylboronic acid grafted aldehyde sodium alginate: dispersing 10g of sodium alginate with molecular weight of 50kDa in 50ml of absolute ethyl alcohol to obtain sodium alginate dispersion liquid, adding 20% (w/v) sodium periodate aqueous solution containing 60g of sodium periodate into the sodium alginate dispersion liquid, carrying out light-shielding reaction for 4 hours to obtain a reaction product, and purifying and drying the reaction product to obtain the aldehyde sodium alginate. Adding 2g of oxidized sodium alginate into 100ml of deionized water to prepare a 2% aldehyde sodium alginate aqueous solution, adding 3-aminophenylboric acid into the aldehyde sodium alginate solution according to the mass ratio of the 3-aminophenylboric acid to the oxidized sodium alginate of 1:8, reacting for 2 hours, and purifying the reaction product after the reaction is finished to obtain the phenylboric acid grafted aldehyde sodium alginate.
(2) Preparation of tannic acid modified carboxymethyl chitosan: 2g of carboxymethyl chitosan and 10g of tannic acid are dissolved in 100ml of water to obtain the tannic acid modified carboxymethyl chitosan (TA-CMCS), and then a coupling agent of 0.2g of 1-ethyl- (3-dimethylaminopropyl) carbodiimide (EDC) and 0.1g N-hydroxysuccinimide (NHS) are added to react, and the tannic acid modified carboxymethyl chitosan (TA-CMCS) is prepared by modification under the catalysis of the coupling agent.
(3) The well-cultured stem cells were cultured under anaerobic (94% N2, 1% O2 and 5% CO 2) conditions for 24 hours, the medium was collected, centrifuged at 15000rpm for 30 minutes, cell debris and macromolecular proteins were removed, then filtered with a 0.22 μm filter, finally, after centrifugation at 57000rpm for 1 hour with a ultracentrifuge, the supernatant was removed, and the transparent precipitate at the bottom of the centrifuge tube was collected to obtain a hypoxia Exosome (HExo).
(4) 2G of phenylboronic acid grafted aldehyde sodium alginate is dissolved in 100ml of water to prepare phenylboronic acid grafted aldehyde sodium alginate solution, 1g of hypoxia exosome is added into the solution to be stirred and mixed uniformly, and finally tannic acid modified carboxymethyl chitosan is added according to the mass ratio of the phenylboronic acid grafted aldehyde sodium alginate of 1:1 to be stirred, and the intelligent response hydrogel dressing can be obtained after the reaction.
Example 3
The preparation method of the intelligent response hydrogel dressing based on the hypoxia exosome of the embodiment comprises the following steps:
(1) Preparation of phenylboronic acid grafted aldehyde sodium alginate: dispersing 10g of sodium alginate with molecular weight of 50kDa in 50ml of absolute ethyl alcohol to obtain sodium alginate dispersion liquid, adding 20% (w/v) sodium periodate aqueous solution containing 60g of sodium periodate into the sodium alginate dispersion liquid, carrying out light-shielding reaction for 4 hours to obtain a reaction product, and purifying and drying the reaction product to obtain the aldehyde sodium alginate. Adding 2g of oxidized sodium alginate into 100ml of deionized water to prepare 2% aldehyde sodium alginate aqueous solution, adding 3-aminophenylboric acid into the aldehyde sodium alginate solution according to the mass ratio of the 3-aminophenylboric acid to the oxidized sodium alginate of 1:10, reacting for 2h, and purifying the reaction product after the reaction is finished to obtain the phenylboric acid grafted aldehyde sodium alginate.
(2) Preparation of tannic acid modified carboxymethyl chitosan: 2g of carboxymethyl chitosan and 10g of tannic acid are dissolved in 100ml of water to obtain the tannic acid modified carboxymethyl chitosan (TA-CMCS), and then a coupling agent of 0.2g of 1-ethyl- (3-dimethylaminopropyl) carbodiimide (EDC) and 0.1g N-hydroxysuccinimide (NHS) are added to react, and the tannic acid modified carboxymethyl chitosan (TA-CMCS) is prepared by modification under the catalysis of the coupling agent.
(3) The well-cultured stem cells were cultured under anaerobic (94% N2, 1% O2 and 5% CO 2) conditions for 24 hours, the medium was collected, centrifuged at 15000rpm for 30 minutes, cell debris and macromolecular proteins were removed, then filtered with a 0.22 μm filter, finally, after centrifugation at 57000rpm for 1 hour with a ultracentrifuge, the supernatant was removed, and the transparent precipitate at the bottom of the centrifuge tube was collected to obtain a hypoxia Exosome (HExo).
(4) 2G of phenylboronic acid grafted aldehyde sodium alginate is dissolved in 100ml of water to prepare phenylboronic acid grafted aldehyde sodium alginate solution, 1g of hypoxia exosome is added into the solution to be stirred and mixed uniformly, and finally tannic acid modified carboxymethyl chitosan is added according to the mass ratio of the phenylboronic acid grafted aldehyde sodium alginate of 1:1 to be stirred, and the intelligent response hydrogel dressing can be obtained after the reaction.
Example 4
The preparation method of the intelligent response hydrogel dressing based on the hypoxia exosome of the embodiment comprises the following steps:
(1) Preparation of phenylboronic acid grafted aldehyde sodium alginate: dispersing 10g of sodium alginate with molecular weight of 50kDa in 50ml of absolute ethyl alcohol to obtain sodium alginate dispersion liquid, adding 20% (w/v) sodium periodate aqueous solution containing 60g of sodium periodate into the sodium alginate dispersion liquid, carrying out light-shielding reaction for 4 hours to obtain a reaction product, and purifying and drying the reaction product to obtain the aldehyde sodium alginate. Adding 2g of oxidized sodium alginate into 100ml of deionized water to prepare 2% aldehyde sodium alginate aqueous solution, adding 3-aminophenylboric acid into the aldehyde sodium alginate solution according to the mass ratio of the 3-aminophenylboric acid to the oxidized sodium alginate of 1:10, reacting for 2h, and purifying the reaction product after the reaction is finished to obtain the phenylboric acid grafted aldehyde sodium alginate.
(2) Preparation of tannic acid modified carboxymethyl chitosan: 2g of carboxymethyl chitosan and 6g of tannic acid are dissolved in 100ml of water to obtain the tannic acid modified carboxymethyl chitosan (TA-CMCS), and then a coupling agent of 0.2g of 1-ethyl- (3-dimethylaminopropyl) carbodiimide (EDC) and 0.1g N-hydroxysuccinimide (NHS) are added to react, and the tannic acid modified carboxymethyl chitosan (TA-CMCS) is prepared by modification under the catalysis of the coupling agent.
(3) The well-cultured stem cells were cultured under anaerobic (94% N2, 1% O2 and 5% CO 2) conditions for 24 hours, the medium was collected, centrifuged at 15000rpm for 30 minutes, cell debris and macromolecular proteins were removed, then filtered with a 0.22 μm filter, finally, after centrifugation at 57000rpm for 1 hour with a ultracentrifuge, the supernatant was removed, and the transparent precipitate at the bottom of the centrifuge tube was collected to obtain a hypoxia Exosome (HExo).
(4) 2G of phenylboronic acid grafted aldehyde sodium alginate is dissolved in 100ml of water to prepare phenylboronic acid grafted aldehyde sodium alginate solution, 1g of hypoxia exosome is added into the solution to be stirred and mixed uniformly, and finally tannic acid modified carboxymethyl chitosan is added according to the mass ratio of the phenylboronic acid grafted aldehyde sodium alginate of 1:1 to be stirred, and the intelligent response hydrogel dressing can be obtained after the reaction.
Example 5
The preparation method of the intelligent response gel dressing of the embodiment comprises the following steps:
(1) Preparation of phenylboronic acid grafted aldehyde sodium alginate: dispersing 10g of sodium alginate with molecular weight of 50kDa in 50ml of absolute ethyl alcohol to obtain sodium alginate dispersion liquid, adding 20% (w/v) sodium periodate aqueous solution containing 60g of sodium periodate into the sodium alginate dispersion liquid, carrying out light-shielding reaction for 4 hours to obtain a reaction product, and purifying and drying the reaction product to obtain the aldehyde sodium alginate. Adding 2g of oxidized sodium alginate into 100ml of deionized water to prepare 2% aldehyde sodium alginate aqueous solution, adding 3-aminophenylboric acid into the aldehyde sodium alginate solution according to the mass ratio of the 3-aminophenylboric acid to the oxidized sodium alginate of 1:10, reacting for 2h, and purifying the reaction product after the reaction is finished to obtain the phenylboric acid grafted aldehyde sodium alginate.
(2) Preparation of tannic acid modified carboxymethyl chitosan: 2g of carboxymethyl chitosan and 2g of tannic acid are dissolved in 100ml of water to obtain the tannic acid modified carboxymethyl chitosan (TA-CMCS), and then a coupling agent of 0.2g of 1-ethyl- (3-dimethylaminopropyl) carbodiimide (EDC) and 0.1g N-hydroxysuccinimide (NHS) are added to react, and the tannic acid modified carboxymethyl chitosan (TA-CMCS) is prepared by modification under the catalysis of the coupling agent.
(3) The well-cultured stem cells were cultured under anaerobic (94% N2, 1% O2 and 5% CO 2) conditions for 24 hours, the medium was collected, centrifuged at 15000rpm for 30 minutes, cell debris and macromolecular proteins were removed, then filtered with a 0.22 μm filter, finally, after centrifugation at 57000rpm for 1 hour with a ultracentrifuge, the supernatant was removed, and the transparent precipitate at the bottom of the centrifuge tube was collected to obtain a hypoxia Exosome (HExo).
(4) 2G of phenylboronic acid grafted aldehyde sodium alginate is dissolved in 100ml of water to prepare phenylboronic acid grafted aldehyde sodium alginate solution, 1.0g of hypoxia exosome is added into the solution to be stirred and mixed uniformly, and finally tannic acid modified carboxymethyl chitosan is added according to the mass ratio of the phenylboronic acid grafted aldehyde sodium alginate of 1:1 to be stirred, and the intelligent response hydrogel dressing can be obtained after the reaction.
Example 6
The preparation method of the intelligent response hydrogel dressing based on the hypoxia exosome of the embodiment comprises the following steps:
(5) Preparation of phenylboronic acid grafted aldehyde sodium alginate: dispersing 10g of sodium alginate with molecular weight of 50kDa in 50ml of absolute ethyl alcohol to obtain sodium alginate dispersion liquid, adding 20% (w/v) sodium periodate aqueous solution containing 60g of sodium periodate into the sodium alginate dispersion liquid, carrying out light-shielding reaction for 4 hours to obtain a reaction product, and purifying and drying the reaction product to obtain the aldehyde sodium alginate. Adding 2g of oxidized sodium alginate into 100ml of deionized water to prepare 2% aldehyde sodium alginate aqueous solution, adding 3-aminophenylboric acid into the aldehyde sodium alginate solution according to the mass ratio of the 3-aminophenylboric acid to the oxidized sodium alginate of 1:10, reacting for 2h, and purifying the reaction product after the reaction is finished to obtain the phenylboric acid grafted aldehyde sodium alginate.
(6) Preparation of tannic acid modified carboxymethyl chitosan: 2g of carboxymethyl chitosan and 10g of tannic acid are dissolved in 100ml of water to obtain the tannic acid modified carboxymethyl chitosan (TA-CMCS), and then a coupling agent of 0.2g of 1-ethyl- (3-dimethylaminopropyl) carbodiimide (EDC) and 0.1g N-hydroxysuccinimide (NHS) are added to react, and the tannic acid modified carboxymethyl chitosan (TA-CMCS) is prepared by modification under the catalysis of the coupling agent.
(7) The well-cultured stem cells were cultured under anaerobic (90% N2, 5% O2 and 5% CO 2) conditions for 24 hours, the medium was collected, centrifuged at 15000rpm for 30 minutes, cell debris and macromolecular proteins were removed, then filtered with a 0.22 μm filter, finally, after centrifugation at 57000rpm for 1 hour with a ultracentrifuge, the supernatant was removed, and the transparent precipitate at the bottom of the centrifuge tube was collected to obtain a hypoxia Exosome (HExo).
(8) 2G of phenylboronic acid grafted aldehyde sodium alginate is dissolved in 100ml of water to prepare phenylboronic acid grafted aldehyde sodium alginate solution, 1g of hypoxia exosome is added into the solution to be stirred and mixed uniformly, and finally tannic acid modified carboxymethyl chitosan is added according to the mass ratio of the phenylboronic acid grafted aldehyde sodium alginate of 1:1 to be stirred, and the intelligent response hydrogel dressing can be obtained after the reaction.
Example 7
The preparation method of the intelligent response gel dressing of the embodiment comprises the following steps:
(1) Preparation of phenylboronic acid grafted aldehyde sodium alginate: dispersing 10g of sodium alginate with molecular weight of 50kDa in 50ml of absolute ethyl alcohol to obtain sodium alginate dispersion liquid, adding 20% (w/v) sodium periodate aqueous solution containing 60g of sodium periodate into the sodium alginate dispersion liquid, carrying out light-shielding reaction for 4 hours to obtain a reaction product, and purifying and drying the reaction product to obtain the aldehyde sodium alginate. Adding 2g of oxidized sodium alginate into 100ml of deionized water to prepare 2% aldehyde sodium alginate aqueous solution, adding 3-aminophenylboric acid into the aldehyde sodium alginate solution according to the mass ratio of the 3-aminophenylboric acid to the oxidized sodium alginate of 1:10, reacting for 2h, and purifying the reaction product after the reaction is finished to obtain the phenylboric acid grafted aldehyde sodium alginate.
(2) Preparation of tannic acid modified carboxymethyl chitosan: 2g of carboxymethyl chitosan and 10g of tannic acid are dissolved in 100ml of water to obtain the tannic acid modified carboxymethyl chitosan (TA-CMCS), and then a coupling agent of 0.2g of 1-ethyl- (3-dimethylaminopropyl) carbodiimide (EDC) and 0.1g N-hydroxysuccinimide (NHS) are added to react, and the tannic acid modified carboxymethyl chitosan (TA-CMCS) is prepared by modification under the catalysis of the coupling agent.
(3) The well-cultured stem cells were cultured under anaerobic (85% N 2、10％ O2 and 5% CO 2) conditions for 24 hours, the medium was collected, centrifuged at 15000rpm for 30 minutes to remove cell debris and macromolecular proteins, then filtered with a 0.22 μm filter, finally centrifuged at 57000rpm for 1 hour with a ultracentrifuge, the supernatant was removed, and the transparent precipitate at the bottom of the centrifuge tube was collected to obtain a hypoxia Exosome (HExo).
(4) 2G of phenylboronic acid grafted aldehyde sodium alginate is dissolved in 100ml of water to prepare phenylboronic acid grafted aldehyde sodium alginate solution, 1g of hypoxia exosome is added into the solution to be stirred and mixed uniformly, and finally tannic acid modified carboxymethyl chitosan is added according to the mass ratio of the phenylboronic acid grafted aldehyde sodium alginate of 1:1 to be stirred, and the intelligent response hydrogel dressing can be obtained after the reaction.
Comparative example 1
The preparation method of the intelligent response gel dressing of the embodiment comprises the following steps:
(1) Preparation of phenylboronic acid grafted aldehyde sodium alginate: dispersing 10g of sodium alginate with molecular weight of 50kDa in 50ml of absolute ethyl alcohol to obtain sodium alginate dispersion liquid, adding 20% (w/v) sodium periodate aqueous solution containing 60g of sodium periodate into the sodium alginate dispersion liquid, carrying out light-shielding reaction for 4 hours to obtain a reaction product, and purifying and drying the reaction product to obtain the aldehyde sodium alginate.
(2) Preparation of tannic acid modified carboxymethyl chitosan: 2g of carboxymethyl chitosan and 2g of tannic acid are dissolved in 100ml of water to obtain the tannic acid modified carboxymethyl chitosan (TA-CMCS), and then a coupling agent of 0.2g of 1-ethyl- (3-dimethylaminopropyl) carbodiimide (EDC) and 0.1g N-hydroxysuccinimide (NHS) are added to react, and the tannic acid modified carboxymethyl chitosan (TA-CMCS) is prepared by modification under the catalysis of the coupling agent.
(3) The well-cultured stem cells were cultured under anaerobic (85% N 2、10％ O2 and 5% CO 2) conditions for 24 hours, the medium was collected, centrifuged at 15000rpm for 30 minutes to remove cell debris and macromolecular proteins, then filtered with a 0.22 μm filter, finally centrifuged at 57000rpm for 1 hour with a ultracentrifuge, the supernatant was removed, and the transparent precipitate at the bottom of the centrifuge tube was collected to obtain a hypoxia Exosome (HExo).
(4) 2G of aldehyde sodium alginate is dissolved in 100ml of water to prepare aldehyde sodium alginate solution, 1.0g of hypoxia exosome is added into the solution to be stirred and mixed uniformly, and finally tannic acid modified carboxymethyl chitosan is added into the solution to be stirred according to the mass ratio of the aldehyde sodium alginate grafted with phenyl boric acid of 1:1, and the intelligent response hydrogel dressing can be obtained after the reaction.
Experimental example
To verify whether the intelligent response gel dressing of the present invention can achieve the expected effect, mechanical property experiments, slow release experiments, cell proliferation experiments, healing promotion experiments, etc. were performed on the intelligent response gel dressing prepared in examples 1 to 4 and comparative example 1.
1. Experiment of mechanical Properties
Samples of the intelligent response gel dressings of each group of examples 1-4 and comparative example 1 were prepared by using a polytetrafluoroethylene cylindrical die with a height of 1cm and a diameter of 2cm, and after the samples were completely molded, the samples were placed on a sample platform of a universal tester for compression testing at a compression rate of 0.5mm/min until the samples were broken. The compressive strength and elongation at break of each set of smart responsive gel dressings were calculated and the results are set forth in table 1.
Table 1 compressive strength and elongation at break of each set of smart responsive gel dressings
| Sample of | Compressive Strength (MPa) | Elongation at break (%) |
| Example 1 | 0.2967±0.0021 | 64.81±0.11 |
| Experimental example 2 | 0.2870±0.0035 | 63.68±0.079 |
| Experimental example 3 | 0.2763±0.0019 | 62.56±0.082 |
| Experimental example 4 | 0.2618±0.0013 | 61.79±0.10 |
| Example 5 | 0.2485±0.0008 | 60.985±0.035 |
| Experimental example 6 | 0.2759±0.0027 | 62.62±0.13 |
| Example 7 | 0.2631±0.0004 | 61.93±0.095 |
| Comparative example 1 | 0.1011±0.0004 | 48.88±0.02 |
As can be seen from table 1, the smart responsive gel dressings prepared in examples 1 to 4 have better mechanical strength and flexibility than comparative example 1.
2. Sustained release experiments
The prepared intelligent response gel dressings of each group of examples 1-4 and comparative example 1 were added to a high-sugar PBS solution to simulate the microenvironment of the diabetic wound surface. At certain time intervals, the supernatant was collected, ferric chloride solution was added, and fresh high-sugar PBS buffer was added to keep the volume constant. The concentration of HExo released from the hydrogels was analyzed by uv-vis spectroscopy and the release rate of HExo at various time points in each set of smart responsive gel dressings was calculated and the results are shown in table 2.
TABLE 2 Release Rate of HExo in Each set of Smart responsive gel dressings at each time
As can be seen from table 2, the smart response gel dressings prepared in examples 1 to 7 have sustained release performance of the hypoxia exosomes, compared to comparative example 1, wherein the smart response gel dressing prepared in example 1 has better sustained release performance.
3. Cell proliferation assay
At the cellular level, to simulate revascularization in high-sugar environments, human Umbilical Vein Endothelial Cells (HUVECs) were treated with glucose (high sugar) for 24h, and a high-sugar human umbilical vein endothelial cell (HG-HUVECs) model was established. The smart responsive gel dressings prepared in each of examples 1-4 and comparative example were co-cultured with high sugar human umbilical vein endothelial cells (HG-HUVECs) and the cell activity of HUVECs was examined by CCK-8 method, and the results are shown in Table 3.
TABLE 3 cell Activity of various groups of Smart response gel dressings on HUVECs
As can be seen from table 3, the smart responsive gel dressings prepared in examples 1 to 5 have better cell proliferation function than comparative example 1.
4. Test experiment for healing promoting performance
36 SD male rats of 200-250 g diabetes model are selected, and the rats are randomly divided into a control group and an experimental group which are 1-5, and 6 rats are selected in each group. The rat is breathed and anesthetized, a circular wound with the diameter of 1cm is formed at the position of the back center of the rat, which is 4cm away from the postaural midline, after skin preparation and sterilization, the wound is treated by the following methods:
experiment group 1: the wound was wrapped with the intelligent response gel dressing of example 1, covering a double layer spun wrap.
Experiment group 2: the wound was wrapped with the intelligent response gel dressing of example 2, covering a double layer spun wrap.
Experiment group 3: the wound was wrapped with the intelligent response gel dressing of example 3, covering a double layer spun wrap.
Experiment group 4: the wound was wrapped with the intelligent response gel dressing of example 4, covering a double layer spun wrap.
Control group: the wound was wrapped with the intelligent response gel dressing of comparative example 1 over a double layer spun yarn.
The intelligent response gel dressing and spinning are changed every 3 days, the wound is cleaned every time the intelligent response gel dressing and spinning are changed, and the wound healing condition is recorded. The wound healing rate of each group of rats at day 14 of wound formation is shown in table 4.
Table 4 wound healing rate of rats of each group on day 14 of wound formation
As can be seen from table 4, the smart response gel dressings prepared in examples 1 to 7 have excellent wound healing properties as compared to comparative example 1, with the smart response gel dressing prepared in example 1 having the best healing promoting effect.
It is to be understood that the above examples of the present invention are provided by way of illustration only and not by way of limitation of the embodiments of the present invention; other variations or modifications of the various aspects will be apparent to persons skilled in the art from the foregoing description, and it is not necessary or exhaustive of all embodiments; any modification, equivalent replacement, improvement, etc. which come within the spirit and principles of the invention are desired to be protected by the following claims.
Claims (9)
1. Intelligent response hydrogel dressing based on hypoxia exosome, its characterized in that: comprises 2 to 6 weight percent of phenylboronic acid grafted aldehyde sodium alginate PBA-OSA, 2 to 6 weight percent of tannic acid modified carboxymethyl chitosan TA-CMCS, 0.5 to 1.0 weight percent of hypoxia Exosome (HExo) and the balance of water; wherein,
The phenyl boric acid grafted aldehyde sodium alginate is prepared by the following preparation method: dispersing sodium alginate with high G content in absolute ethyl alcohol to prepare sodium alginate suspension, then adding sodium periodate solution with the concentration of 6 wt% -20% wt% to react for 18h-32h under the condition of light shielding, adding glycol with the same mole as sodium periodate to terminate the reaction to obtain a reaction mixture, purifying the reaction mixture, and freeze-drying to prepare aldehyde sodium alginate; dissolving the aldehyde sodium alginate in water to prepare an aldehyde sodium alginate solution with the concentration of 3 wt-5 wt%, adding aminophenylboric acid for reaction, filtering after the reaction is finished, and freeze-drying to obtain the sodium alginate; the M/G ratio of the sodium alginate is 1:1-1:3;
The tannic acid modified carboxymethyl chitosan is prepared by the following preparation method: dissolving carboxymethyl chitosan and tannic acid in water to obtain carboxymethyl chitosan solution with concentration of 2-wt-4-wt%, and adding coupling agent 1-ethyl- (3-dimethyl amino propyl) carbodiimide and N-hydroxy succinylene for catalytic reaction.
2. The method for preparing the intelligent response hydrogel dressing based on the hypoxia exosome, according to claim 1, is characterized by comprising the following steps:
Carrying out hydroformylation modification by utilizing sodium alginate with high G content, and further carrying out phenylboronic acid grafting to obtain phenylboronic acid grafted hydroformylation sodium alginate; then using carboxymethyl chitosan to carry out tannic acid (TANNIC ACID, TA) modification to prepare tannic acid modified carboxymethyl chitosan; finally, forming a polysaccharide-based hydrogel with a double-network structure and adjustable mechanical properties and crosslinking density by utilizing Schiff base reaction between aldehyde groups of PBA-OSA and amino groups of TA-CMCS and boric acid ester bonds of phenyl boric acid groups of PBA-OSA and hydroxyl groups of TA-CMCS, and loading a hypoxia exosome from a stem cell source into the polysaccharide-based hydrogel to prepare the intelligent response hydrogel dressing based on the hypoxia exosome.
3. The method for preparing the intelligent response hydrogel dressing based on the hypoxia exosome according to claim 2, which is characterized by comprising the following steps:
Step 1) taking sodium alginate with high G content as a raw material, and carrying out oxidation reaction on the sodium periodate under a light-shielding condition to prepare aldehyde sodium alginate with different substitution degrees; then carrying out grafting modification on the aldehyde sodium alginate by using aminophenylboric acid to prepare phenyl boric acid grafted aldehyde sodium alginate;
Step 2) using carboxymethyl chitosan as a raw material, and preparing tannic acid modified carboxymethyl chitosan with tannic acid under the catalysis of coupling agents of 1-ethyl- (3-dimethylaminopropyl) carbodiimide (EDC) and N-hydroxysuccinimide (NHS);
Step 3) culturing the well-cultured stem cells under the anoxic condition, and obtaining the hypoxia exosomes through centrifugation, filtration and isolation extraction;
step 4) forming a polysaccharide-based hydrogel with a double-network structure and adjustable mechanical property and crosslinking density by utilizing Schiff base reaction between aldehyde groups of PBA-OSA and amino groups of TA-CMCS and boric acid ester bonds of phenylboronic acid groups of PBA-OSA and hydroxyl groups of TA-CMCS, and loading the hypoxia exosomes into the polysaccharide-based hydrogel to prepare the intelligent response hydrogel dressing based on the hypoxia exosomes.
4. The method for preparing the intelligent response hydrogel dressing based on the hypoxia exosome, according to claim 3, wherein the method comprises the following steps: in the step 1), dispersing sodium alginate with high G content in absolute ethyl alcohol to prepare sodium alginate suspension, then adding sodium periodate solution with the concentration of 6 wt-20% and wt% to react for 18-32 h under the condition of light shielding, adding glycol with the same mole as sodium periodate to terminate the reaction to obtain a reaction mixture, purifying the reaction mixture, and freeze-drying to prepare the aldehyde sodium alginate; dissolving the aldehyde sodium alginate in water to prepare an aldehyde sodium alginate solution with the concentration of 3 wt-5 wt%, adding aminophenylboric acid for reaction, filtering after the reaction is finished, and freeze-drying to prepare phenyl boric acid grafted aldehyde sodium alginate;
Wherein the molecular weight of the sodium alginate is 4kDa-50kDa, and the M/G ratio is 1:1-1:3;
The mass volume ratio of the sodium alginate to the absolute ethyl alcohol is 1:4 g/mL-1:6 g/mL;
The mass ratio of the sodium periodate in the sodium periodate aqueous solution to the sodium alginate in the sodium alginate dispersion liquid is 1:1-6:1;
The mass ratio of the aminophenylboric acid to the aldehyde sodium alginate is 1:5-1:10;
The amino phenylboronic acid is any one or more of 2-amino phenylboronic acid, 3-amino phenylboronic acid and 4-amino phenylboronic acid.
5. The method for preparing the intelligent response hydrogel dressing based on the hypoxia exosome, according to claim 3, wherein the method comprises the following steps: in the step 2), carboxymethyl chitosan and tannic acid are dissolved in water, the concentration of the prepared carboxymethyl chitosan solution is 2 wt-4 wt%, and then a coupling agent 1-ethyl- (3-dimethylaminopropyl) carbodiimide and N-hydroxysuccinimide are added for catalytic reaction to prepare tannic acid modified carboxymethyl chitosan;
Wherein the mass ratio of the carboxymethyl chitosan to the tannic acid is 1:1-1:5;
the molar ratio of EDC to NHS in the coupling agent is 3-5:0.5-2.
6. The method for preparing the intelligent response hydrogel dressing based on the hypoxia exosome, according to claim 3, wherein the method comprises the following steps: in the step 3), the well-cultured stem cells are cultured for 24 hours under the anoxic condition, the collected culture is centrifuged for 25 min-35min based on 14000rpm-16000rpm to remove cell fragments and macromolecular proteins, then a 0.2-0.45 μm filter is used for filtering, finally, after the centrifugal process is carried out for 1 hour by a ultracentrifuge at 55000rpm-59000rpm, the supernatant is taken out, and transparent sediment at the bottom of the centrifuge tube is collected to obtain the hypoxia exosomes;
wherein the stem cells are any one or more of fat stem cells, mesenchymal stem cells and human urine-derived stem cells;
The anoxic condition is to use a mixed gas of 85% -94% of N 2、1%-10% O2 and 5% of CO 2.
7. The method for preparing the intelligent response hydrogel dressing based on the hypoxia exosome, according to claim 3, wherein the method comprises the following steps: in the step 4), dissolving phenyl boric acid grafted aldehyde sodium alginate in water to prepare phenyl boric acid grafted aldehyde sodium alginate solution with the concentration of 2 wt-6 wt%, adding 0.5-wt-1.0 wt% of hypoxia exosomes, stirring and mixing uniformly, and finally adding tannic acid modified carboxymethyl chitosan for stirring, and reacting to prepare the intelligent response hydrogel dressing based on the hypoxia exosomes; wherein the mass ratio of the phenylboronic acid grafted aldehyde sodium alginate to the tannic acid modified carboxymethyl chitosan is 1:1-1:2.
8. The use of an intelligent response hydrogel dressing based on a hypoxia exosome according to claim 1 in the preparation of a medical dressing for promoting the healing of chronic wounds of diabetes.
9. The use of an intelligent response hydrogel dressing obtained by the method for preparing an intelligent response hydrogel dressing based on a hypoxia exosome according to any one of claims 2-7 for preparing a medical dressing for promoting the healing of chronic wounds of diabetes.
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