CN116808286A - Inflammatory response on-demand anti-inflammatory hydrogel medical dressing for skin wound healing and preparation method thereof - Google Patents
Inflammatory response on-demand anti-inflammatory hydrogel medical dressing for skin wound healing and preparation method thereof Download PDFInfo
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- CN116808286A CN116808286A CN202310997922.3A CN202310997922A CN116808286A CN 116808286 A CN116808286 A CN 116808286A CN 202310997922 A CN202310997922 A CN 202310997922A CN 116808286 A CN116808286 A CN 116808286A
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- 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
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L26/00—Chemical aspects of, or use of materials for, wound dressings or bandages in liquid, gel or powder form
- A61L26/0009—Chemical aspects of, or use of materials for, wound dressings or bandages in liquid, gel or powder form containing macromolecular materials
- A61L26/0019—Chemical aspects of, or use of materials for, wound dressings or bandages in liquid, gel or powder form containing macromolecular materials obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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- A61L26/00—Chemical aspects of, or use of materials for, wound dressings or bandages in liquid, gel or powder form
- A61L26/0009—Chemical aspects of, or use of materials for, wound dressings or bandages in liquid, gel or powder form containing macromolecular materials
- A61L26/0023—Polysaccharides
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- 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
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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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- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
- A61L2300/40—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices characterised by a specific therapeutic activity or mode of action
- A61L2300/412—Tissue-regenerating or healing or proliferative agents
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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
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Abstract
The invention discloses an inflammation response on-demand anti-inflammatory hydrogel medical dressing for healing skin wounds, which is prepared from hydrophobic drug micelles and inflammation response hydrogel according to the mass ratio of 1:10 to 1: 1000; the particle size of the drug micelle is 100-500 nanometers, the encapsulation rate is 80% -100%, and the drug loading rate is 10% -30%; the inflammation response hydrogel is hydrogel obtained by crosslinking hyaluronic acid by a crosslinking agent with oxidation response groups, wherein the oxidation response groups are oxalic acid polyester or diselenide bond or boric acid ester bond or thioether bond or acyl pyrrolidine-2-carboxamide group or ferrocene-cyclodextrin host guest structure, the crosslinking degree is 30% -80%, and the number of repeated units of the hyaluronic acid is more than 5000. The hydrogel medical dressing can respond to the release of the hydrophobic drugs as required in an inflammatory environment, can better release the hydrophobic drugs in an inflammatory period, and can promote wound healing.
Description
Technical Field
The invention belongs to the field of medical appliances, and relates to an inflammation-responsive on-demand anti-inflammatory hydrogel medical dressing for skin wound healing and a preparation method thereof.
Background
Skin wound healing refers to the healing process after the skin tissue has been broken or defective due to the application of external force. The process comprises a hemostasis stage, an inflammation stage, a proliferation stage and a remodeling stage, wherein the processes are mutually coordinated and partially overlapped in time, and local cells, a vascular system, extracellular matrixes and the like participate in the complex and orderly repair process, and are simultaneously started, regulated, guided and maintained by various cytokines and growth factors. The hemostasis period is an urgent reaction of the human body to external injury, and aims at hemostasis. At this stage, the platelets activate and aggregate, triggering fibrin polymerization, and the formed fibrin network forms a stable clot with the platelet aggregates, thereby occluding the injured blood vessel. The inflammatory phase of the wound is the most critical phase affecting the quality of wound healing, and 1-3 days after skin trauma, the immune system of the human body recruits a large number of immune cells at the wound, and activates M1 type macrophages to enter the wound to clear the outside of invading bacteria and related debris. On the following 4-6 days, following clearance of the external pathogen, M1 type macrophages subside, transforming into M2 type macrophages, continuously secreting cytokines, drawing immune cells into the wound to promote tissue repair. This process is often accompanied by redness, fever and pain in the wound. If smooth inflammation elimination is not achieved on the wound, chronic inflammation is formed, so that the wound can be stopped in an inflammation stage and cannot progress, and chronic wound difficult to heal is formed. The primary physiological process of the proliferation and remodeling phases of a wound is to cover and fill the wound, in which epithelial cells are produced from the wound bed or margin and begin to pass over the wound bed in an ascending manner until the wound completes re-epithelialization of the epidermis. The new granulation tissue fills the wound bed of connective tissue, forming collagen deposits, collagen fibers reorganizes, tissue remodelling and maturing, providing tensile strength to the new skin.
With intensive studies on the physiological process of wound healing, the inflammatory phase of the wound is found to be important, and the inflammatory response of the wound not only bears the important task of resisting the invasion of external pathogens, but also has the effect of influencing the regression of the inflammatory response and the initiation of the subsequent healing stage. Therefore, a moderate inflammatory response can achieve high-quality healing of the wound, and premature and excessive inflammation inhibition cannot normally activate the immune system to thoroughly clear pathogens at the wound, so that persistent infection is easily initiated; the continuous inflammatory reaction can easily cause chronic inflammation of the wound, destroy the normal tissue regeneration microenvironment, and lead the wound to become a chronic wound surface and not be healed. Therefore, how to perform proper inflammation regulation on the wound surface becomes a key factor for promoting wound healing and improving repair quality.
Wound dressings are coverings or protective layers for wounds that can be used to temporarily protect against wound infection by replacing damaged skin during wound healing and treatment, and provide a suitable healing environment for the wound surface. To date, the development of wound dressings has been a thousand years old, ranging from the initial protection of wounds with simple materials to today's modern functional dressings. Although the existing medical dressing can realize the functions of isolating protection, moisturizing, resisting bacteria and the like, the functions of regulating and controlling wound inflammation and promoting healing cannot be realized. With the development of modern chemical disciplines and material disciplines, some novel chemical bonds can generate responsive fracture to redox environment, which provides a basis for the development of novel functional medical dressings. Oxidative stress is an accompanying phenomenon in the inflammatory process, and the inflammatory reaction is usually mediated by oxidative stress and active oxygen free radicals, and inflammatory mediators participate in or induce the occurrence of the inflammatory reaction, and the main effects of the oxidative stress are that blood vessels are dilated, liquid is exuded, and the inflammatory reaction has a guiding effect on directional movement of leucocytes. The inflammatory response is a complex reaction involving multiple cells and multiple factors, and in general, pathogens stimulate host cells to release multiple pro-inflammatory cytokines, induce defensive cells to aggregate to the site of inflammation, and defend cells resist bacterial invasion by generating a large amount of active oxygen, but simultaneously generate excessive active oxygen, so that tissues are subjected to oxidative stress, and in the process, inflammation promotes oxidation through inflammatory mediators, and oxidation aggravates the inflammatory response. If the medical dressing is designed, the corresponding structural change can be generated on the intensity of the oxidative stress at the wound surface, and the functional dressing for regulating and controlling the intensity of the inflammation at the wound surface according to the requirement can be developed.
Hyaluronic acid is a common natural polysaccharide polymer, and hydrogel taking hyaluronic acid as a substrate is often used as a medical dressing for promoting wound healing due to good biocompatibility, water retention and the like. According to the general consensus of the application specialist on the reasonable selection of different relative molecular masses and structures in dermatology published by the dermatology department of the Chinese medical science and Western society of the combination of the traditional Chinese medicine and the Western medicine and the dermatology department of the Chinese senile medical health care society of the science and the dermatology, the molecular weight of the hyaluronic acid can be divided into three levels of high, medium and low, wherein the number of repeated structural units of the hyaluronic acid with the high molecular weight is more than 5000, the number of repeated structural units of the hyaluronic acid with the medium molecular weight is between 1000 and 5000, the number of repeated structural units of the hyaluronic acid with the low molecular weight is less than 1000, and the hyaluronic acid with different molecular weights has different biological functions, so that the relative molecular weight of the hyaluronic acid needs to be selected when designing medical dressing. Meanwhile, when designing the hyaluronic acid-based modified hydrogel, attention should be paid to the degree of crosslinking between the modified hyaluronic acid network backbones. When the crosslinking degree is low, the mechanical strength of the hydrogel is very low, the requirement of clinical skin wound healing cannot be met, and when the crosslinking degree is too high, the hydrogel skeleton network is too compact, so that the hydrogel is difficult to release medicines, the hydrogel is unfavorable for wound healing of skin, and therefore, the crosslinking degree of hyaluronic acid is controlled.
At present, most of anti-inflammatory drugs are fat-soluble drugs, and at present, systemic circulation can only be carried out in an oral mode, and the anti-inflammatory drugs act in a mode of increasing blood concentration. The administration is absorbed by gastrointestinal tract, and is suitable for systemic diseases or internal organ diseases. However, for wounds on the body surface, this mode of administration is poorly available and is prone to side effects on other organs of the body, particularly the gastrointestinal tract where the drug is absorbed. If the medicine is directly sprayed on a wound in a topical way, the solubility of the medicine is poor, the longer the medicine needs to reach the dissolution balance, the poor absorption and the poor bioavailability are. Therefore, as a new functional dressing, there is a need to solve these difficulties in hydrophobic drug availability, so that anti-inflammatory modulation of wounds can be better achieved.
Disclosure of Invention
In view of this, the present invention provides an inflammation responsive on-demand anti-inflammatory hydrogel medical dressing for skin wound healing and a method of preparing the same.
The invention specifically provides the following technical scheme:
1. an inflammation response type on-demand anti-inflammatory hydrogel medical dressing for skin wound healing is prepared from hydrophobic drug micelle and inflammation response hydrogel according to the mass ratio of 1:10 to 1: 1000; the drug micelle is a micelle formed by a hydrophobic anti-inflammatory drug and an amphiphilic polymer, the particle size is 100-500 nanometers, the encapsulation rate is 80% -100%, and the drug carrying rate is 10% -30%; the inflammation response hydrogel is hydrogel obtained by crosslinking hyaluronic acid by a crosslinking agent with oxidation response groups, wherein the oxidation response groups are oxalic acid polyester or diselenide bond or boric acid ester bond or thioether bond or acyl pyrrolidine-2-carboxamide group or ferrocene-cyclodextrin host guest structure, the crosslinking degree is 30% -80%, and the number of repeated units of the hyaluronic acid is more than 5000.
Further, the amphiphilic polymer is one or more of poloxamer, polyethylene glycol-polycaprolactone, polyethylene glycol-polylactic acid copolymer or polycaprolactone-poly beta-amino ester copolymer.
Further, the hydrophobic anti-inflammatory drug is one or more of berberine, curcumin, indomethacin, acetaminophen, naproxen, ibuprofen, celecoxib, cefuroxime, cefixime, azithromycin or amoxicillin.
Further, the inflammation-responsive hydrogel is oxalic acid polyester crosslinked hyaluronic acid gel, diselenide bond crosslinked hyaluronic acid gel, boric acid ester bond crosslinked hyaluronic acid hydrogel, thioether bond crosslinked hyaluronic acid hydrogel, acyl pyrrolidine-2-carboxamide group crosslinked hyaluronic acid hydrogel, ferrocene-cyclodextrin host structure crosslinked hyaluronic acid hydrogel.
Further, the medical dressing comprises: 1) a mixed product of oxalic acid polyester crosslinked hyaluronic acid hydrogel and a hydrophobic drug micelle, wherein the hydrophobic drug micelle is a micelle formed by hydrophobic anti-inflammatory drug and poloxamer, or 2) a mixed product of diselenide crosslinked hyaluronic acid hydrogel and a hydrophobic drug micelle, the hydrophobic drug micelle is a micelle formed by hydrophobic anti-inflammatory drug and polyethylene glycol-polycaprolactone copolymer, or 3) a mixed product of boric acid ester bond crosslinked hyaluronic acid hydrogel and a hydrophobic drug micelle, the hydrophobic drug micelle is a micelle formed by hydrophobic anti-inflammatory drug and polyethylene glycol-polylactic acid copolymer, or 4) a mixed product of thioether bond crosslinked hyaluronic acid hydrogel and a hydrophobic drug micelle, the hydrophobic drug micelle is a micelle formed by hydrophobic anti-inflammatory drug and poloxamer copolymer, or 5) an acyl pyrrolidine-2-carboxamide group crosslinked hyaluronic acid hydrogel and a hydrophobic drug micelle, the hydrophobic drug micelle is a micelle formed by hydrophobic anti-inflammatory drug and polycaprolactone-poly beta-amino ester copolymer, or 6) a mixed product of ferrocene-cyclodextrin main structure crosslinked hyaluronic acid hydrogel and a hydrophobic drug micelle, and the hydrophobic drug micelle is a guest formed by hydrophobic anti-inflammatory drug and polyethylene glycol-polylactic acid copolymer.
Further, the maximum imbibition rate of the medical dressing is 3-6 times, the water retention time is more than or equal to 24 hours, the maximum deformation amount is 200-500%, and the accumulated release amount of drug micelle in hydrogel is 32-97% in 24 hours in an inflammatory environment.
Further, the medical dressing reduces the level of reactive oxygen species to 10% after 24 hours at the damaged tissue site; after 72 hours, transformation of M1 macrophages to M2 macrophages in the tissue is promoted, and the M1/M2 ratio is less than 25%.
Further, the medical dressing activates CD44 receptor 2-3 times, the re-epithelialization efficiency of epidermis is improved by 70% -80%, and the collagen deposition proportion is improved by 80% -90%.
2. The preparation method of the inflammation-responsive on-demand anti-inflammatory hydrogel medical dressing for skin wound healing is characterized by comprising the following steps of:
1) Respectively dissolving 0.5-20wt% of hydrophobic anti-inflammatory drug and 10-50wt% of amphiphilic polymer in the soluble solvents, fully dissolving the two, uniformly mixing, replacing the solvent with the mixed solution, filtering the mixed solution with the replaced solvent by using a filter membrane, removing unencapsulated hydrophobic drug, and freeze-drying to obtain drug micelle; the solvent replacing method comprises rotary evaporation, adding deionized water, directly dialyzing the mixed solution, and the like; the pore diameter of the filter membrane is between 0.22 micrometers and 0.45 micrometers;
2) Grafting of oxidation-responsive groups onto hyaluronic acid by chemical crosslinking, in particular: mixing a cross-linking agent with an oxidation responsive group, an oxidation responsive group activator and a solution of sodium hyaluronate at 25-50 ℃ and reacting for 2-48 hours to obtain hyaluronic acid hydrogel grafted with the oxidation responsive group;
3) Mixing the drug micelle obtained in the step 1) with the hyaluronic acid hydrogel grafted with the oxidation responsive group obtained in the step 2), dialyzing, and purifying to obtain the inflammation responsive anti-inflammatory hydrogel medical dressing according to requirements.
The invention has the beneficial effects that:
1) The medical dressing of the invention has chemical bonds which can respond to wound inflammation and limit the proper crosslinking density. Thus, for excessive inflammatory reaction, the construction element of the hydrogel dressing can quickly respond to the oxidative stress environment at the wound surface, so that the internal crosslinking density is made, and the diffusion rate of the internal wrapping material is adjusted.
2) The medical dressing of the invention is internally wrapped with the antiphlogistic medicine with micelle structure. Aiming at the problems of low solubility and low bioavailability of anti-inflammatory drugs, the anti-inflammatory drugs cannot be applied to the local part of the wound surface. The micelle encapsulation of the amphiphilic ions realizes high encapsulation rate and drug loading rate of the hydrophobic drugs. Compared with the traditional hydrophobic medicine which can not be distributed in the hydrogel medical dressing for delivery, the hydrophilic medicine micelle can be uniformly distributed in the hydrogel medical dressing and can be directly applied to the local part of the wound surface, thereby avoiding the problems of slow effect and large side effect caused by the traditional gastrointestinal tract administration.
3) The medical dressing can adjust the release rate of the drug micelle according to the intensity of inflammatory reaction at the wound surface, realize the function of release according to the need, not only can not inhibit normal inflammatory reaction, but also can timely release anti-inflammatory drugs locally at the wound surface when the inflammatory reaction is strong, thereby playing the anti-inflammatory function.
4) The medical dressing of the invention adopts hyaluronic acid as raw material, discloses an action target point of the dressing for traditional Chinese medicine in the wound healing process, enhances the target point in the healing process, and can improve the re-epithelialization efficiency of epidermis and the collagen deposition proportion, thereby realizing better wound healing effect. The medical dressing can completely fill the gap of a wound in an injectable mode and the like, realize contact with the surface of the wound, absorb the seepage at the wound, simultaneously moisturize the wound for a long time, and simultaneously has good mechanical properties, thereby meeting the requirements of the hydrogel dressing in the wound healing process.
5) The medical dressing of the invention adopts hyaluronic acid as raw material, selects hyaluronic acid with proper molecular weight range, discloses an action target point of the medical dressing in the wound healing process, enhances the target point in the healing process, and can improve the re-epithelialization efficiency of epidermis and the collagen deposition proportion, thereby realizing better wound healing effect.
6) The hydrophobic anti-inflammatory drug is directly delivered to a wound, the availability is very low, the effective anti-inflammatory effect cannot be exerted, the hydrophobic drug is loaded into the amphiphilic drug micelle by adopting the method, the solubility of the drug is improved, the anti-inflammatory effect of the drug can be well exerted, the level of active oxygen clusters at the wound is reduced, and the number of M2 macrophages is increased.
7) The common medicine diffusion mechanism can not quickly and effectively remove excessive inflammation at the wound surface, and the method is necessary to prepare the inflammation responsive hydrogel by grafting the oxidation responsive structure onto the hyaluronic acid, so that the medicine can be better released in the inflammation period in a mode of realizing responsive release as required in the inflammation environment, thereby effectively removing the excessive inflammation at the wound surface.
8) The mechanical properties of the medical dressing need to be matched with wounds, if the medical dressing cannot be effectively smeared and filled at the wounds, the wrapped medicine cannot exert the anti-inflammatory effect, and the injectable hydrogel can be well adapted to the shape of the wounds only by adopting the injectable hydrogel, so that the medical dressing can be effectively smeared and filled, and the wrapped medicine exerts the anti-inflammatory effect.
9) In the application of promoting wound healing, the healing quality of the regenerated skin is ensured as much as possible, when the hyaluronic acid is selected as the main skeleton of the hydrogel, if a proper molecular weight range cannot be selected, even if the regenerated skin is healed, the high quality of the regenerated skin cannot be realized, and the hyaluronic acid with the molecular weight of more than 100kD can be used for efficiently activating the CD44 receptor, so that the re-epithelialization efficiency of the epidermis and the collagen deposition proportion are improved, and the function of the hydrogel medical dressing on promoting wound healing is further improved.
Detailed Description
Preferred embodiments of the present invention are described in detail below.
Example 1
1) The micelle of berberine and poloxamer is prepared, the water and particle size of the micelle are 280nm, the medicine encapsulation rate is 80%, and the medicine carrying rate is 10%. The method comprises the following specific steps:
s1, a berberine dichloromethane solution with the concentration of 10mg/mL and a poloxamer methanol solution with the concentration of 120mg/mL are mixed with 1:1, fully mixing the components in a volume ratio;
s2, performing reduced pressure rotary evaporation on the mixed solution at 35 ℃, then placing the mixed solution in a vacuum drying oven for 12 hours, and removing the solvent to obtain a dried medicine film;
s3, adding deionized water at 45 ℃ into the dried medicine film, stirring for 2 hours, centrifuging the solution at a rotating speed of 1500rpm for 3 minutes, retaining supernatant to obtain uniform medicine micelle solution, and freeze-drying the medicine solution to obtain medicine micelle powder;
2) Preparing hyaluronic acid hydrogel crosslinked by oxalic acid polyester, wherein the molecular formula is as follows:wherein m=5080, n=5720, and the degree of crosslinking is 40%; the preparation method comprises the following specific steps:
s1, refluxing 6.3g of oxalic acid, 7.75g of ethylene glycol, 20g of cyclohexane and stannous dichloride accounting for 0.1% of the mass of a reactant at 50-60 ℃ for 3 hours, stopping the reaction, cooling the reaction mixture, separating liquid, treating to obtain a crude product, washing with water, and drying in vacuum at 90 ℃ for 2 hours to obtain an oxalic acid diethylene glycol product;
S2, mixing hyaluronic acid with specific molecular weight, the product obtained in the step S1, 1-ethyl- (3-dimethylaminopropyl) carbodiimide and N-hydroxysuccinimide in a molar ratio of 1:0.5:2:1 in deionized water, wherein the concentration of the hyaluronic acid is 0.5-3 wt%, and standing for more than 0.5h in an environment of 25-50 ℃ to obtain oxalic acid polyester crosslinked hyaluronic acid hydrogel.
3) Mixing the micelle prepared in the step 1) with the hydrogel prepared in the step 2) in a mass ratio of 1:500, and obtaining the anti-inflammatory hydrogel medical dressing with inflammatory response according to requirements after dialysis and purification.
Example 2
1) The micelle of curcumin and polyethylene glycol-polycaprolactone copolymer is prepared, the water and particle size are 350nm, the medicine encapsulation rate is 85%, and the medicine carrying rate is 23%. The method comprises the following specific steps:
s1, preparing an N, N' -dimethyl amide solution of a polyethylene glycol-polycaprolactone copolymer according to the concentration of 100mg/mL, and stirring for 30 minutes at the temperature of 30 ℃ and the rotating speed of 250rpm to ensure that the polymer is fully dissolved;
s2, adding 15mg/mL of curcumin in methanol solution and ultrapure water into the polymer solution in the previous step, and stirring for 3 hours to ensure that the three are uniformly mixed; controlling the volume ratio of the N, N' -dimethylamide solution of the polyethylene glycol-polycaprolactone copolymer, the methanol solution of curcumin and water to be 1:1:1.
S3, transferring the mixed solution obtained in the S2 into a 3500Da dialysis bag for dialysis, changing water every two hours, and dialyzing for 24 hours;
s4, filtering the solution obtained after the S3 dialysis is finished by using a filter membrane with the diameter of 0.22 microns, removing unencapsulated curcumin, and freeze-drying the solution to obtain powder which is the drug micelle of the curcumin and the polyethylene glycol-polycaprolactone copolymer;
2) Preparing hyaluronic acid hydrogel crosslinked by diselenide bonds, wherein the molecular formula is as follows:wherein m=5910, n=6390, the degree of crosslinking is 30%; the preparation method comprises the following specific steps: selenocysteine dihydrochloride, hyaluronic acid of a specific molecular weight, and 1-ethyl- (3-dimethylaminopropyl) carbodiimide and N-hydroxysuccinimide in a molar ratio of 1:2:4:2 ratio ofMixing in deionized water, wherein the concentration of the hyaluronic acid is 0.5-3 wt%, and standing for more than 0.5h in the environment of 25-50 ℃ to obtain the diselenide cross-linked hyaluronic acid hydrogel.
3) Mixing the micelle prepared in the step 1) with the hydrogel prepared in the step 2) according to the mass ratio of 1:1000, and obtaining the anti-inflammatory hydrogel medical dressing with inflammatory response according to requirements after dialysis and purification.
Example 3
1) The micelle of the indometacin and polyethylene glycol-polylactic acid copolymer is prepared, the water and particle size are 100nm, the medicine encapsulation rate is 85%, and the medicine carrying rate is 15%. The method comprises the following specific steps:
S1, preparing an N, N' -dimethyl amide solution of a polyethylene glycol-polylactic acid copolymer according to the concentration of 150mg/mL, and incubating in a constant-temperature water bath at 45 ℃ for 5 minutes to ensure that the polymer is fully dissolved;
s2, adding 10mg/mL of indomethacin tetrahydrofuran solution and ultrapure water into the polymer solution in the previous step, and stirring for 3 hours to ensure that the three solutions are uniformly mixed; controlling the volume ratio of the N, N' -dimethylamide solution, the indometacin tetrahydrofuran solution and the water of the polyethylene glycol-polylactic acid copolymer to be 1:1:1.
s3, transferring the mixed solution obtained in the step S2 into a 3500Da dialysis bag, dialyzing in deionized water, changing water every 4 hours, and dialyzing for 24 hours;
s4, centrifuging the solution obtained after the S3 dialysis is finished at a rotating speed of 3000rpm for 30 minutes, filtering the obtained supernatant by using a filter membrane with a size of 0.45 microns, removing unencapsulated indometacin, and freeze-drying the obtained solution to obtain powder, namely the medicinal micelle powder of the indometacin and polyethylene glycol-polylactic acid copolymer.
2) Preparing hyaluronic acid hydrogel crosslinked by boric acid ester bonds, wherein the molecular formula is as follows:wherein m=6300, n=5700, and the degree of crosslinking is 35%; the preparation method comprises the following specific steps:
s1, mixing para-aminophenylboric acid and hyaluronic acid according to the following ratio of 1:10, and simultaneously adding 1-ethyl- (3-dimethylaminopropyl) carbodiimide and N-hydroxysuccinimide to hyaluronic acid in a molar ratio of 1:2:1, stirring the mixture for 24 hours in an environment with the concentration of hyaluronic acid being 0.5-3 wt%, dialyzing the product in deionized water by using a dialysis bag with 3500 molecular weight, changing dialysis water every 6 hours, dialyzing for more than 48 hours, freezing the product at-80 ℃ for 12 hours, and freeze-drying to obtain hyaluronic acid grafted with phenylboronic acid;
S2, mixing the product obtained in the step S1 with hyaluronic acid according to the following ratio of 1:1, mixing the components in deionized water to obtain boric acid ester bond crosslinked hyaluronic acid hydrogel;
3) Mixing the micelle prepared in the step 1) with the hydrogel prepared in the step 2) according to the mass ratio of 1:200, and obtaining the anti-inflammatory hydrogel medical dressing with inflammatory response according to requirements after dialysis and purification.
Example 4
1) The micelle of the acetaminophen and poloxamer copolymer is prepared, the water and particle size of the micelle are 500nm, the medicine encapsulation efficiency is 100%, and the medicine carrying rate is 30%. The method comprises the following specific steps:
s1, a methylene dichloride solution of acetaminophen with the concentration of 10mg/mL and a methanol solution of poloxamer with the concentration of 150mg/mL are mixed with 1:1, fully mixing the components in a volume ratio;
s2, performing reduced pressure rotary evaporation on the mixed solution at 35 ℃, then placing the mixed solution in a vacuum drying oven for 12 hours, and removing the solvent to obtain a dried medicine film;
s3, adding deionized water at 40 ℃ into the dried medicine film, stirring for 2 hours, centrifuging the solution at a rotating speed of 1000rpm for 5 minutes, retaining supernatant to obtain uniform medicine micelle solution, and freeze-drying the medicine solution to obtain medicine micelle powder;
2) Preparing a hyaluronic acid hydrogel crosslinked by thioether bonds, which has the molecular formula:where m=6375, n=5500, the degree of crosslinking is 80%. PreparationThe method comprises the following specific steps:
ethylenediamine dimethylene thioketone, hyaluronic acid with specific molecular weight, and 1-ethyl- (3-dimethylaminopropyl) carbodiimide and N-hydroxysuccinimide are mixed according to a molar ratio of 1:2:4:2, wherein the concentration of the hyaluronic acid is 0.5-3 wt%, and the mixture is kept stand for more than 0.5h in the environment of 25-50 ℃ to obtain the thioether bond crosslinked hyaluronic acid hydrogel.
3) Mixing the micelle prepared in the step 1) with the hydrogel prepared in the step 2) according to the mass ratio of 1:20, and obtaining the anti-inflammatory hydrogel medical dressing with inflammatory response according to requirements after mixing and dialysis purification.
Example 5
1) The micelle of the naproxen and polycaprolactone-poly beta-amino ester copolymer is prepared, the water and particle size is 280nm, the medicine encapsulation rate is 96%, and the medicine carrying rate is 27%. The method comprises the following specific steps:
s1, preparing N, N' -dimethyl amide solution of polycaprolactone-poly beta-amino ester copolymer according to the concentration of 150mg/mL, and incubating in a constant-temperature water bath at 50 ℃ for 30 minutes to ensure that the polymer is fully dissolved;
S2, adding 12mg/mL naproxen methanol solution and ultrapure water into the polymer solution in the previous step, and stirring for 3 hours to ensure that the three solutions are uniformly mixed; controlling the volume ratio of N, N' -dimethyl amide solution, naproxen methanol solution and water of the polycaprolactone-poly beta-amino ester copolymer to be 1:1:1.
s3, transferring the mixed solution obtained in the step S2 into a 3500Da dialysis bag, dialyzing in deionized water, changing water every 4 hours, and dialyzing for 24 hours;
s4, centrifuging the solution obtained after the S3 dialysis is finished at a rotating speed of 3000rpm for 30 minutes, filtering the obtained supernatant by using a filter membrane with a diameter of 0.45 micrometer, removing unencapsulated naproxen, and freeze-drying the obtained solution to obtain powder, namely the medicinal micelle powder of the naproxen and polycaprolactone-poly beta-amino ester copolymer
2) Preparing hyaluronic acid hydrogel containing acyl pyrrolidine-2-carboxamide group crosslinking chain segments, wherein the molecular formula is as follows:where m=5360, n=6640, the degree of crosslinking is 32%. The preparation method comprises the following specific steps: an amino compound containing an acyl pyrrolidine-2-carboxamide group, hyaluronic acid of a specific molecular weight, and 1-ethyl- (3-dimethylaminopropyl) carbodiimide and N-hydroxysuccinimide in a molar ratio of 1:2:4:2, wherein the concentration of the hyaluronic acid is 0.5-3 wt%, and the hyaluronic acid hydrogel crosslinked by the acyl pyrrolidine-2-carboxamide group can be obtained after standing for more than 0.5 hours in the environment of 25-50 ℃.
3) Mixing the micelle prepared in the step S1 with the hydrogel prepared in the step S2 according to the mass ratio of 1:200, and obtaining the anti-inflammatory hydrogel medical dressing with inflammatory response according to requirements after dialysis and purification.
Example 6
1) The micelle of ibuprofen and polyethylene glycol-polylactic acid copolymer is prepared, the water and particle size of the micelle are 500nm, the medicine encapsulation rate is 100%, and the medicine carrying rate is 30%. The method comprises the following specific steps:
s1, preparing an N, N' -dimethyl amide solution of a polyethylene glycol-polylactic acid copolymer according to the concentration of 200mg/mL, and incubating in a constant-temperature water bath at 45 ℃ for 5 minutes to ensure that the polymer is fully dissolved;
s2, adding 10mg/mL of ibuprofen methanol solution and ultrapure water into the polymer solution in the previous step, and stirring for 3 hours to ensure that the three are uniformly mixed; controlling the volume ratio of the N, N' -dimethylamide solution of the polyethylene glycol-polylactic acid copolymer, the methanol solution of the ibuprofen and the ultrapure water to be 1:1:1.
s3, transferring the mixed solution obtained in the step S2 into a 3500Da dialysis bag, dialyzing in deionized water, changing water every 2 hours, and dialyzing for 24 hours;
s4, centrifuging the solution obtained after the S3 dialysis is finished at a rotating speed of 3000rpm for 30 minutes, filtering the obtained supernatant by using a filter membrane with a size of 0.45 microns, removing unencapsulated ibuprofen, and freeze-drying the obtained solution to obtain powder, namely the powder of the ibuprofen and the polyethylene glycol-polylactic acid copolymer;
2) Manufacturing processThe molecular formula of the hyaluronic acid hydrogel crosslinked by the main guest structure of ferrocene-cyclodextrin is as follows:where m=5392, n=6008, and the degree of crosslinking is 72%. The preparation method comprises the following specific preparation steps:
s1, 0.25g of hyaluronic acid, 0.4g of beta cyclodextrin grafted with hexamethylenediamine and 0.35g of condensing agent 4- (4, 6-dimethoxy-triazin-2-yl) -4-methylmorpholine hydrochloride are dissolved in 25mL of MES buffer prepared at a concentration of 50mM, and reacted at 56 ℃ for 12 hours. After the reaction was completed, after the temperature of the mixture was lowered to room temperature, the mixture was dialyzed against deionized water using a dialysis bag having a molecular weight cut-off of 25kDa for 3 days, changing water every 4 hours. Dialysis and freeze-drying to obtain 0.23g white flocculent solid, namely cyclodextrin grafted hyaluronic acid
S2, 100mg of oil-soluble hyaluronic acid, 13mg of ferrocenemethylamine and 500mg of condensing agent PyBop are dissolved in 12mL of DMSO, and reacted for 48 hours at room temperature. After the reaction was completed, the mixture was precipitated with ethyl acetate, and after centrifugation at 1500rpm for 4 minutes, the supernatant was discarded, and the above precipitation step was repeated 3 times to obtain a greenish black flocculent solid. The obtained crude product was placed in a vacuum reduced pressure drying oven, and residual ethyl acetate was removed by reduced pressure drying to obtain a dark green block solid. Deionized water was added to the white dark green bodies and dissolved, and dialyzed in deionized water using a dialysis bag having a molecular weight cut-off of 25kDa for 3 days, changing water every 4 hours. Finally freeze-drying to obtain the dark green flocculent solid, namely the hyaluronic acid grafted with ferrocene.
S3, a PBS solution of hyaluronic acid grafted with ferrocene and a PBS solution of hyaluronic acid grafted with cyclodextrin of 5.6wt% are mixed according to the volume ratio of 1:1 to obtain the cross-linked hyaluronic acid hydrogel with ferrocene-cyclodextrin host guest structure
3) Mixing the micelle prepared in the step 1) with the hydrogel prepared in the step 2) according to the mass ratio of 1:40, and obtaining the anti-inflammatory hydrogel medical dressing with inflammatory response according to requirements after the steps of mixing, dialysis and purification.
Example 7
1) The micelle of celecoxib and polyethylene glycol-polycaprolactone copolymer is prepared, the water and particle size of the micelle is 180nm, the drug encapsulation rate is 88%, and the drug loading rate is 18%. The method comprises the following specific steps:
s1, preparing an N, N' -dimethyl amide solution of a polyethylene glycol-polycaprolactone copolymer according to the concentration of 160mg/mL, and stirring for 30 minutes at the temperature of 30 ℃ and the rotating speed of 250rpm to ensure that the polymer is fully dissolved;
s2, adding 12mg/mL of celecoxib methanol solution and ultrapure water into the polymer solution in the previous step, and stirring for 2 hours to ensure that the three solutions are uniformly mixed; the volume ratio of the N, N' -dimethylamide solution of the polyethylene glycol-polycaprolactone copolymer, the methanol solution of celecoxib and the ultrapure water is controlled to be 1:1:1.
S3, transferring the mixed solution obtained in the S2 into a 3500Da dialysis bag for dialysis, changing water every two hours, and dialyzing for 24 hours;
s4, filtering the solution obtained after the S3 dialysis is finished by using a filter membrane with the diameter of 0.4 micron, and removing unencapsulated celecoxib, wherein the obtained solution is a drug micelle of celecoxib and polyethylene glycol-polycaprolactone copolymer;
2) Preparing a hyaluronic acid hydrogel crosslinked by thioether bonds, which has the molecular formula:where m=5588, n=6812, the degree of crosslinking is 58%. The preparation method is the same as in example 4.
3) Mixing the micelle prepared in the step 1) with the hydrogel prepared in the step 2) according to the mass ratio of 1:30, and obtaining the anti-inflammatory hydrogel medical dressing with inflammatory response according to requirements after mixing and dialysis purification.
Example 8
1) The micelle of cefuroxime and polycaprolactone-poly beta-amino ester copolymer is prepared, the water and particle size of the micelle are 420nm, the drug encapsulation rate is 93%, and the drug loading rate is 27%. The method comprises the following specific steps:
s1, preparing N, N' -dimethyl amide solution of a polycaprolactone-poly beta-amino ester copolymer according to the concentration of 160mg/mL, and stirring for 30 minutes at the temperature of 30 ℃ and the rotating speed of 250rpm to ensure that the polymer is fully dissolved;
s2, adding 10mg/mL of cefuroxime methanol solution and ultrapure water into the polymer solution in the previous step, and stirring for 2 hours to ensure that the three solutions are uniformly mixed; controlling the volume ratio of N, N' -dimethylamide solution, cefuroxime methanol solution and ultrapure water of the polycaprolactone-poly beta-amino ester copolymer to be 1:1:1.
S3, transferring the mixed solution obtained in the S2 into a 3500Da dialysis bag for dialysis, changing water every two hours, and dialyzing for 24 hours;
s4, filtering the solution obtained after the S3 dialysis is finished by using a filter membrane with the diameter of 0.4 micron, and removing unencapsulated cefuroxime to obtain the solution, namely the drug micelle of the cefuroxime and polycaprolactone-poly beta-amino ester copolymer.
2) Preparing hyaluronic acid hydrogel containing acyl pyrrolidine-2-carboxamide group crosslinking chain segments, wherein the molecular formula is as follows:where m=6608, n=5992, the degree of crosslinking is 62%. The preparation was carried out in the same manner as in example 5.
3) Mixing the micelle prepared in the step 1) with the hydrogel prepared in the step 2) according to the mass ratio of 1:100, and obtaining the anti-inflammatory hydrogel medical dressing with inflammatory response according to requirements after dialysis and purification.
Example 9
1) The micelle of cefixime and poloxamer copolymer is prepared, the water and particle size are 380nm, the medicine encapsulation rate is 87%, and the medicine carrying rate is 21%. The method comprises the following specific steps:
s1, an amoxicillin methanol solution with the concentration of 16mg/mL and an ethanol solution of poloxamer with the concentration of 120mg/mL are mixed according to the following ratio of 1:1, fully mixing the components in a volume ratio;
s2, performing reduced pressure rotary evaporation on the mixed solution at the temperature of 30 ℃, then placing the mixed solution in a vacuum drying oven for 12 hours, and removing the solvent to obtain a dried medicine film;
S3, adding deionized water at 40 ℃ into the dried medicine film, stirring for 2 hours, centrifuging the solution at a rotating speed of 1000rpm for 3 minutes, retaining supernatant to obtain uniform medicine micelle solution, and freeze-drying the medicine solution to obtain medicine micelle powder;
2) Preparing a hyaluronic acid hydrogel crosslinked by thioether bonds, which has the molecular formula:where m=5429, n=5871, and the degree of crosslinking was 67%. The preparation method is the same as in example 4.
3) Mixing the micelle prepared in the step 1) with the hydrogel prepared in the step 2) according to the mass ratio of 1:35, and obtaining the anti-inflammatory hydrogel medical dressing with inflammatory response according to requirements after dialysis and purification.
Example 10
1) The micelle of the azithromycin and polyethylene glycol-polycaprolactone copolymer is prepared, the water and particle size are 160nm, the medicine encapsulation efficiency is 82%, and the medicine carrying rate is 17%. The method comprises the following specific steps:
s1, preparing an N, N' -dimethyl amide solution of a polyethylene glycol-polycaprolactone copolymer according to the concentration of 180mg/mL, and stirring for 30 minutes at the temperature of 30 ℃ and the rotating speed of 250rpm to ensure that the polymer is fully dissolved;
s2, adding 16mg/mL of methanol solution of azithromycin and ultrapure water into the polymer solution in the previous step, and stirring for 4 hours to ensure that the three components are uniformly mixed; controlling the volume ratio of the N, N' -dimethylamide solution of the polyethylene glycol-polycaprolactone copolymer, the methanol solution of the azithromycin and the ultrapure water to be 1:1:1.
S3, transferring the mixed solution obtained in the step S2 into a dialysis bag of 1000Da for dialysis, changing water every two hours, and dialyzing for 24 hours;
s4, filtering the solution obtained after the S3 dialysis is finished by using a filter membrane with the diameter of 0.22 microns, and removing unencapsulated azithromycin to obtain a solution which is a drug micelle of the azithromycin and polyethylene glycol-polycaprolactone copolymer;
2) Preparing hyaluronic acid hydrogel crosslinked by diselenide bonds, wherein the molecular formula is as follows:wherein m=5880, n=5720, and the degree of crosslinking is 45%. The preparation method is the same as in example 2.
3) Mixing the micelle prepared in the step 1) with the hydrogel prepared in the step 2) according to the mass ratio of 1:1000, and obtaining the anti-inflammatory hydrogel medical dressing with inflammatory response according to requirements after dialysis and purification.
Example 11
1) The micelle of the amoxicillin and poloxamer copolymer is prepared, the water and particle diameter of the micelle are 460nm, the medicine encapsulation rate is 94%, and the medicine carrying rate is 29%. The method comprises the following specific steps:
s1, an amoxicillin methanol solution with the concentration of 12mg/mL and an ethanol solution with the concentration of 180 mg/mL/poloxamer are mixed according to the following ratio of 2:1, fully mixing the components in a volume ratio;
s2, performing reduced pressure rotary evaporation on the mixed solution at the temperature of 45 ℃, then placing the mixed solution in a vacuum drying oven for 12 hours, and removing the solvent to obtain a dried medicine film;
S3, adding deionized water at 45 ℃ into the dried medicine film, stirring for 2 hours, centrifuging the solution at a rotating speed of 2000rpm for 3 minutes, retaining supernatant to obtain uniform medicine micelle solution, and freeze-drying the medicine solution to obtain medicine micelle powder;
2) Preparing hyaluronic acid hydrogel crosslinked by a boron ester bond, wherein the molecular formula is as follows:where m=5650, n=5650, and the degree of crosslinking is 50%. The preparation method is the same as in example 3.
3) Mixing the micelle prepared in the step 1) with the hydrogel prepared in the step 2) according to the mass ratio of 1:50, and obtaining the anti-inflammatory hydrogel medical dressing with inflammatory response according to requirements after dialysis and purification.
Example 12
1) The micelle of levofloxacin and polyethylene glycol-polylactic acid copolymer is prepared, the water and particle size of the micelle is 420nm, the medicine encapsulation rate is 88%, and the medicine carrying rate is 25%. The method comprises the following specific steps:
s1, preparing an N, N' -dimethyl amide solution of a polyethylene glycol-polylactic acid copolymer according to the concentration of 220mg/mL, and incubating in a constant-temperature water bath at 45 ℃ for 5 minutes to ensure that the polymer is fully dissolved;
s2, adding 20mg/mL of methanol solution of levofloxacin and ultrapure water into the polymer solution in the previous step, and stirring for 3 hours to ensure that the three are uniformly mixed; controlling the volume ratio of the N, N' -dimethylamide solution of the polyethylene glycol-polylactic acid copolymer, the methanol solution of levofloxacin and ultrapure water to be 1:1:1.
S3, transferring the mixed solution obtained in the step S2 into a 3500Da dialysis bag, dialyzing in deionized water, changing water every 4 hours, and dialyzing for 24 hours;
s4, centrifuging the solution obtained after the S3 dialysis is finished at a rotating speed of 3000rpm for 10 minutes, filtering the obtained supernatant by using a filter membrane with a diameter of 0.45 microns, removing unencapsulated levofloxacin, and freeze-drying the obtained solution to obtain powder, namely the drug micelle powder of the levofloxacin and polyethylene glycol-polylactic acid copolymer;
2) Preparing hyaluronic acid hydrogel containing ferrocene-cyclodextrin host-guest assembled cross-linked structure (its molecular formula is:where m=5450, n=6350, and the degree of crosslinking is 75%. The preparation method is the same as in example 6.
3) Mixing the micelle prepared in the step 1) with the hydrogel prepared in the step 2) according to the mass ratio of 1:40, and obtaining the anti-inflammatory hydrogel medical dressing with inflammatory response according to requirements after the steps of mixing, dialysis and purification.
Comparative example 1
1) Preparing micelle of berberine and poloxamer, wherein the water and particle size of the micelle are 280nm, the medicine encapsulation rate is 80%, and the medicine carrying rate is 10%; the preparation step is to prepare the micelle of berberine and poloxamer according to the solution proportion in the step 1) of the example 1, wherein the water and the particle size are 280nm, the medicine encapsulation efficiency is 80%, and the medicine carrying rate is 10%.
2) Preparing hyaluronic acid hydrogel crosslinked by polyethylene glycol (PEG), wherein the molecular formula is as follows:wherein m=5360, n=6440, the degree of crosslinking is 80%; polyethylene glycol does not have inflammatory responseAnd (5) adaptability. The preparation method comprises the following specific steps:
polyethylene glycol, hyaluronic acid and 4- (4, 6-dimethoxy triazine-2-yl) -4-methylmorpholine hydrochloride are mixed according to the mass ratio of 1:5:1 is dissolved in deionized water and mixed, wherein the concentration of hyaluronic acid is 0.5 to 3 weight percent, and the mixture is stood for 12 hours in an environment of 25 to 50 ℃ to obtain polyethylene glycol (PEG) crosslinked hyaluronic acid hydrogel.
3) Mixing the micelle prepared in the step 1) with the hydrogel prepared in the step 2) according to the mass ratio of 1:500, and obtaining the anti-inflammatory hydrogel medical dressing with inflammatory response according to requirements after dialysis and purification.
Comparative example 2
1) The micelle of berberine and poloxamer is prepared, the water and particle size are 280nm, the medicine encapsulation rate is 80%, and the medicine carrying rate is 10%. Preparing a micelle of berberine and poloxamer according to the solution proportion described in the step 1) of the example 1, wherein the water and the particle size of the micelle are 280nm, the drug encapsulation efficiency is 80%, and the drug loading rate is 10%;
2) Preparing hyaluronic acid hydrogel crosslinked by polyethylene glycol (PEG), wherein the molecular formula is as follows: Where m=5260, n=6540, the degree of crosslinking is 30%, and polyethylene glycol does not have inflammatory responsiveness. The specific procedure for preparation was the same as in comparative example 1.
3) Mixing the micelle prepared in the step S1 with the hydrogel prepared in the step S2 according to the mass ratio of 1:500, and obtaining the anti-inflammatory hydrogel medical dressing with inflammatory response according to requirements after dialysis and purification.
Comparative example 3
1) The preparation method comprises the steps of preparing the hyaluronic acid hydrogel with high crosslinking degree from oxalic acid polyester, and the molecular formula is as follows:
where m=5360, n=6440, the degree of crosslinking is 80%. The specific preparation procedure is the same as in example 1.
2) Pure berberine which is not made into hydrophobic drug micelle and hydrogel prepared in the step 1) are mixed according to the mass ratio of 1:500 to obtain the hydrogel medical dressing.
Comparative example 4
1) Preparing hyaluronic acid hydrogel crosslinked by polyethylene glycol (PEG), wherein the molecular formula is as follows:where m=5260, n=5540, and the degree of crosslinking is 30%. The specific preparation procedure is the same as in example 1;
2) Pure berberine which is not made into hydrophobic drug micelle and hydrogel prepared in the step 1) are mixed according to the mass ratio of 1:500 to obtain the hydrogel medical dressing.
Comparative example 5
1) Preparing micelle of berberine and poloxamer, wherein the water and particle size of the micelle are 280nm, the medicine encapsulation rate is 80%, and the medicine carrying rate is 10%; (same as in example 1);
2) Preparing hyaluronic acid hydrogel crosslinked by oxalic acid polyester, wherein the molecular formula is as follows:where m=5440, n=5360, the degree of crosslinking is 20%, which is lower than the lower limit of the optimal degree of crosslinking by 30%. The specific preparation procedure is the same as in example 1
3) Mixing the micelle prepared in the step 1) with the hydrogel prepared in the step 2) according to the mass ratio of 1:500, and obtaining the anti-inflammatory hydrogel medical dressing with inflammatory response according to requirements after dialysis and purification.
Comparative example 6
1) Preparing micelle of berberine and poloxamer (same as in example 1), wherein the water and particle size are 280nm, the drug encapsulation rate is 80%, and the drug loading rate is 10%;
2) Preparing hyaluronic acid hydrogel crosslinked by oxalic acid polyester, wherein the molecular formula is as follows:where m=5180, n=6620, the degree of crosslinking is 90%, which is higher than the upper limit of 80% of the optimal degree of crosslinking. The specific preparation procedure is the same as in example 1
3) Mixing the micelle prepared in the step 1) with the hydrogel prepared in the step 2) according to the mass ratio of 1:500, and obtaining the anti-inflammatory hydrogel medical dressing with inflammatory response according to requirements after dialysis and purification.
Comparative example 7
1) Preparing micelle of berberine and poloxamer, wherein the water and particle size of the micelle are 280nm, the medicine encapsulation rate is 80%, and the medicine carrying rate is 10%; (same as in example 1)
2) Preparing hyaluronic acid hydrogel crosslinked by oxalic acid polyester, wherein the molecular formula is as follows:wherein m=2290, n=3150, the crosslinking degree is 40%, the number of repeating units of hyaluronic acid is 1000-5000, and the hyaluronic acid is medium molecular weight hyaluronic acid. The specific preparation procedure is the same as in example 1
3) Mixing the micelle prepared in the step 1) with the hydrogel prepared in the step 2) according to the mass ratio of 1:500, and obtaining the anti-inflammatory hydrogel medical dressing with inflammatory response according to requirements after dialysis and purification.
Comparative example 8
1) Preparing micelle of berberine and poloxamer, wherein the water and particle size of the micelle are 280nm, the medicine encapsulation rate is 80%, and the medicine carrying rate is 10%; (same as in example 1)
2) Preparing hyaluronic acid hydrogel crosslinked by oxalic acid polyester, wherein the molecular formula is as follows:where m=554, n=636, the degree of crosslinking is 40%. The repeated unit number of the hyaluronic acid is less than 1000, and the hyaluronic acid is low molecular weight hyaluronic acid. The specific preparation procedure is the same as in example 1
3) Mixing the micelle prepared in the step S1 with the hydrogel prepared in the step S2 according to the mass ratio of 1:500, and obtaining the anti-inflammatory hydrogel medical dressing with inflammatory response according to requirements after dialysis and purification.
Test example 1
In order to realize the on-demand release of the fat-soluble medicine at the wound of the medical dressing, the regulation and control of inflammation in the wound healing process are satisfied. The application provides a technical scheme for combining micelle encapsulation of a fat-soluble drug and inflammatory response crosslinking medical dressing, and verifies the beneficial effect of release on demand.
Hydrogen peroxide solutions of different concentrations were formulated to simulate a normal wound environment (10 μm/L), a low inflammatory wound environment (50 μm/L) and a severe inflammatory wound environment (100 μm/L). The drug release behavior of comparative examples 1 to 4 and examples 1 to 12 in hydrogen peroxide solutions of different concentrations was then determined by high performance liquid chromatography, and the specific test results are shown in table 1.
Table 1 percent drug micelle release in medical dressing at 2, 6, 12, 24 hours (h) at different inflammatory intensities
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As can be seen from table 1:
since the materials of comparative examples 1 and 2 were prepared using a crosslinking segment (polyethylene glycol) that was not an inflammatory response, the release rate did not change significantly in the case of mimicking both mild and severe inflammation.
It can be concluded that when the hydrogel structure in the medical dressing does not contain an oxidation responsive structure, the prepared medical dressing does not have the function of inflammatory response and can not meet the requirement of high drug use in inflammatory environment.
When the medical dressing had a high degree of crosslinking (comparative example 1, 80%) without having an inflammatory response function, the release rate of the drug micelle was slow, and the release rate at 24 hours was 8%. Whereas when the degree of crosslinking of the medical dressing was low (comparative example 2, 30%), the release rate of the drug micelle was relatively fast, and the release rate at 24 hours was 40%.
The result shows that the crosslinking degree of the medical dressing hydrogel can influence the release capacity of the drug micelle, thereby influencing the use effect of the drug micelle.
For the liposoluble drug, since it is slightly soluble in water, the drug (not made into micelle) was directly used to prepare the inflammatory response type medical dressings (comparative example 3 and comparative example 4), which were difficult to release in both the high crosslinking degree (comparative example 3) and the low crosslinking degree (comparative example 4), and which were capable of only 3% release at 24 hours. The improvement in drug release was not achieved in comparative examples 3 and 4 at different inflammatory conditions.
Thus, from the test results of comparative examples 1 to 4, the following conclusions can be drawn:
1) For liposoluble drugs, micelle encapsulation is necessary to release from the medical dressing.
2) In non-inflammatory responsive medical dressings, the drug micelles can only release by means of diffusion, meaning that the release rate depends on the degree of cross-linking of the medical dressing, while the different degree of inflammatory environment cannot change the release rate of the medical dressing to the drug.
From the test results of examples 1-12, the following conclusions can be drawn:
the medical dressings constructed in examples 1 to 12 can achieve different release rates through the change of the degree of crosslinking (30% -80%) in the normal wound environment, and are embodied in that the release rate is 8% -40% in 24 hours, which breaks through the disadvantage that the medicines in comparative example 3 and comparative example 4 cannot be released from the medical dressing.
Examples 1-12 have faster drug micelle release rates under different inflammatory conditions, and in a low inflammatory environment, examples 1-12 have a 16% -81% increase in release rate over 24 hours, which is 1-2 fold greater than the release rate of drug micelles in normal wound conditions. In the severe inflammation environment, the release rate of the medicine micelle in the examples 1-12 is further improved to 56% -97% in 24 hours, and compared with the low-inflammation wound, the release rate of the medicine micelle is further improved by 0.5-1.5 times.
Therefore, the medical dressing prepared by the invention can regulate and control the release rate of the drug micelle along with the inflammation environment, and when inflammation is aggravated, the release rate of the drug micelle is accelerated, and the inflammation is inhibited by higher drug dosage; meanwhile, excessive inhibition of normal beneficial inflammatory reaction can be avoided, and the on-demand regulation and control of the inflammatory reaction at the wound can be realized.
Test example 2
A stress-controlled rotational rheometer (model HR-1, manufacturer: TAInstrument) was used to measure the rheological properties of the hydrogels, the test plates were 20 mm, the storage modulus and loss modulus were measured at 2% strain, the elastic solid was determined based on whether the storage modulus was greater than the loss modulus, and the maximum deformation was measured at a frequency of 1 Hz. The medical dressing was added to a 5mL syringe, pushed back and forth, and continuity of the extruded medical dressing was observed, and injectability was verified. And placing a certain amount of medical dressing on a glass plate, tilting the glass plate for 30 degrees, gradually dripping 20 mu L of deionized water until the medical dressing slides down, weighing the final mass (M1) and the initial mass (M0) of the medical dressing, and calculating to obtain the maximum imbibition multiplying power. Maximum liquid absorption magnification= (M1-M0)/m0×100%. A quantity of the medical dressing was placed in a petri dish, placed in an environment with a temperature of 25 ℃ and a humidity of 45%, and the initial mass (M0) and the mass (M1) at the different time nodes were recorded. Maximum water retention time when m1/m0=20%. According to the above test methods, comparative example 5, comparative example 6 and examples 1 to 12 were subjected to medical dressing performance tests, giving table 2.
Table 2 performance test of medical dressing
As a hydrogel medical dressing, it should be convenient for medical staff to use while meeting specific wound care needs.
These requirements include:
1) It is desirable to have suitable rheological properties that maintain the elastic solid properties of hydrogel medical dressings when applied to wounds, and that provide softness and deformability for application to the wound surface and stretching with the wound.
As can be seen from the data in table 2:
when the hydrogel medical dressing was too low in crosslinking (comparative example 5, 20%), the storage modulus was only 0.3kPa, and at the same time, it was represented as a non-elastic solid, and the maximum deformation could not be measured, and thus it was represented as a viscous fluid at the time of use, and could not be effectively remained at the wound site.
When the hydrogel medical dressing was too high in crosslinking degree (comparative example 6, 90%), although the behavior of elastic solid could be maintained, the deformation ability of the gel was poor due to the too high crosslinking degree, the maximum variable was 100%, and the gel was easily broken under external force. By optimizing the degree of crosslinking, when the degree of crosslinking is in the range of 30% to 80%, examples 1 to 12 have a storage modulus of 1 to 10kPa, have suitable viscoelasticity, adhere well to the skin surface and maintain a gel-like elastic solid.
In addition, examples 1-12 have a maximum deformation of between 200% and 500%, which means that the hydrogel medical dressing can sustain a certain deformation while maintaining the form of gel-like elastic solid in the range of 30% to 80% of crosslinking, thus meeting the requirements of wound application and stretching along with the wound.
2) The medical dressing has injectability, can completely fill the gap of the wound, realizes contact with the surface of the wound, absorbs the seepage of the wound, and simultaneously moisturizes the wound for a long time.
As can be seen from table 2:
although comparative example 5 was a viscous liquid with an injectable property, it became a dilute solution directly after imbibition, and it did not have any liquid absorption, and it could not stay on the surface of the wound in the form of gel-like solid, and it was inconvenient to use. In addition, since the crosslinking degree of comparative example 5 is low (20%), a sufficient crosslinking network cannot be formed to lock moisture, and the maximum moisture retention time of example 5 is only 10 hours, the requirement that the medical dressing is applied to the wound for a long time cannot be satisfied, and frequent dressing change is required.
Comparative example 6 was an elastic gel solid due to the too high degree of crosslinking (90%), and had no injectability and filling characteristics, and could not meet the demand of conformal filling when the medical dressing was applied to a wound. Meanwhile, in example 6, the maximum imbibition rate is limited due to excessive crosslinking, only 1 time of liquid can be absorbed, exudates at the wound surface can not be absorbed for a long time, and the dressing needs to be frequently replaced to imbibe, so that the dressing is not suitable as an ideal medical dressing.
Embodiments 1-12 of the present invention are injectable and meet the need for filling the wound gap; the maximum imbibition rate is 3-6 times, so that the wound can effectively absorb exudates at the wound surface and simultaneously keep good adhesiveness, and the wound surface is maintained; the water retention time is more than or equal to 24 hours, the dressing change frequency can be reduced, the 1 day 1 dressing change requirement of the medical dressing is met, and the moist environment of the wound surface is maintained for a long time.
Test example 3
A diabetic ulcer wound mouse model was prepared, active oxygen cluster index at the wound ulcer was detected, comparative examples 1 to 6 and examples 1 to 12 were applied as medical dressings to the wound surface wound, the active oxygen cluster index at the wound surface was detected again after 24 hours, then skin tissue of the wound surface was harvested after 72 hours, immunofluorescence analysis was performed on macrophage phenotype in the tissue, and table 3 was obtained by summarizing the results. After 7 days, wound surface granulation tissue was collected, and the tissue was subjected to histological analysis, and the CD44 receptor expression amount, the epidermal re-epithelialization efficiency and the collagen deposition efficiency were measured, and summarized to obtain table 3.
Table 3 wound inflammation test of medical dressing
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Excessive inflammatory response is one of the characteristics of chronic wounds, and thus, a diabetic ulcer wound mouse model was selected to study the modulating effect of medical dressings on inflammation after application to wounds. The index of active oxygen at the wound can reflect the intensity of inflammatory reaction at the wound.
As can be seen from Table 3In the initial wound, the index of active oxygen is 1.2-1.3X10 9 After nursing using the medical dressings of comparative examples 1 and 2, the reactive oxygen species were reduced to 0.8X10 after 24 hours, respectively 9 And 0.6X10 9 The active oxygen reduction ratios were 66.67% and 46.15%, respectively.
This illustrates: the drug micelles encapsulated in comparative examples 1 and 2 can enter the wound tissue by conventional diffusion and exert a certain anti-inflammatory effect, and the rate of drug diffusion is mainly dependent on the degree of crosslinking of the medical dressing. When the degree of crosslinking of the medical dressing is high (comparative example 1, 80%), the drug diffusion rate is slow, and thus the therapeutic efficiency is low (66.67%); while the medical dressing had a low degree of crosslinking (comparative example 2, 30%) and a fast drug diffusion rate, the therapeutic efficiency was relatively high (46.15%).
Since comparative examples 1 and 2 do not have the characteristic of inflammatory response, the release rate of the drug cannot be actively controlled, thereby suppressing inflammation. Thus, active oxygen was not reduced below normal levels (10%) within 24 hours, while after 72 hours, M1 type macrophages were compared to M2 type macrophages, with M1/M2 ratios of 456% and 186%, respectively. This indicates that the treated wounds are still mainly M1 type macrophages, and these M1 type macrophages have pro-inflammatory functions, promote immune responses at the early stages of skin wound repair, kill foreign pathogens and bacteria, indicate that the wounds are still in the inflammatory reaction stage, and do not achieve smooth excessive healing.
Comparative example 3 and comparative example 4 did not exert any inflammatory control effect, and after 24 hours, the active oxygen ratio did not decrease. Meanwhile, at 72 hours, the wound was mostly M1 type macrophages, accounting for 95% (table 1). This is because hydrophobic drugs are not made into micelles and cannot be released from medical dressings, and thus cannot exert anti-inflammatory effects, resulting in a sustained inflammation stage of the wound.
Comparative example 5 also does not have any anti-inflammatory effect because the medical dressing of comparative example 5 is liquid in use, cannot be fixed to the surface of a wound in use, and easily flows along the rugged wound surface, and thus cannot effectively deliver a drug at the wound, resulting in no inflammatory regulation effect.
The wound treated in comparative example 6 was reduced to only 83.33% active oxygen after 24 hours and the M1/M2 macrophage ratio at 733% at 72 hours did not have an effective inflammation inhibiting effect because the comparative example was too highly crosslinked to completely fill and cover the wound in use, making the drug delivery to the wound ineffective. In addition, comparative example 6 reached a swelling balance during use, and could not continuously absorb wound exudate, achieving diffusion of the drug at the site of wound exudate, resulting in failure to achieve effective inflammation inhibition.
As can be seen from Table 3, after 24 hours of use of the medical dressings of examples 1 to 12 of the present invention, the active oxygen index of the wound was reduced to less than 10% of the initial value, showing effective inhibition of excessive inflammation. Meanwhile, at 72 hours, the macrophages in the tissue are mainly of M2 type, and the proportion of M1/M2 macrophages is reduced to below 25%. This suggests that inflammation at the injured tissue has been effectively controlled and is in the phase of inflammation resolution. These rapid inflammatory resolutions are mainly due to:
1) Examples 1-12 have an inflammatory response and release of anti-inflammatory drugs on demand. As can be seen from Table 1, examples 1-12 spontaneously increased the drug release rate in severe inflammatory conditions, and the release rate at 24 hours could reach 56% -97%. The increased local drug concentration can effectively exert anti-inflammatory effect, thereby realizing effective inhibition of excessive inflammation at the wound surface in 24 hours and reducing the oxidative stress level at the wound surface to a normal level within 10 percent.
2) The medical dressing of examples 1-12 has proper mechanical properties, can be continuously and effectively applied on the surface of a wound, and can continuously release drug micelles, so that the utilization rate of the wrapped drug micelles is improved, the anti-inflammatory effect can be effectively exerted, and finally, the effective elimination of inflammation is realized in 72 hours, and the specific expression is that macrophages in tissues are mainly M2 type, and the proportion of M1/M2 macrophages is reduced to below 25%.
Test example 4
The inflammatory response of the wound and the nursing effect of the medical dressing directly affect the healing quality of the final wound. As a cell adhesion molecule expressed in a broad spectrum, the type I transmembrane glycoprotein CD44 participates in biological processes such as cell proliferation, differentiation, migration, angiogenesis and the like, and plays a key role in mediating cell signal transduction, regulating functions such as tissue homeostasis and the like. In particular, the kinetics of cell adhesion mediated by CD 44-hyaluronan interactions plays an important role in classical inflammatory responses. The CD44 receptor not only regulates inflammation at the wound site, but is also responsible for recruiting fibroblasts from the surrounding tissue into the wound area, promoting wound healing. The hyaluronic acid can be used as a ligand, is better specifically combined with a CD44 receptor, triggers cascade reaction, can inhibit inflammatory factors, regulate inflammatory level and recruit fibroblasts, thereby promoting the skin wound to heal more quickly. To further explore the CD44 activation rates of hyaluronic acid of different molecular weights and their effects on wound healing under high inflammatory conditions, we collected wound tissue on day 7 and stained the treated tissue sections by means of a CD44 monoclonal antibody label with a fluorescent group on the full-thickness defect model of diabetic mice constructed in test example 3, and statistically analyzed the fluorescence content at the wound by software to obtain the activation rate of CD 44.
According to the general application expert consensus of different relative molecular masses and structures of hyaluronic acid in dermatology, which is published by the dermatology division of the Chinese traditional and Western medicine combination society, namely eczema dermatitis science group and the dermatology division of the Chinese senile medical health care research institute, which are published by the national dermatology integration medical forum in 2022 for the first year, the molecular weight of hyaluronic acid can be divided into three levels of high, medium and low, wherein the number of the repeated structural units of the hyaluronic acid with high molecular weight is more than 5000, the number of the repeated structural units of the hyaluronic acid with medium molecular weight is between 1000 and 5000, and the number of the repeated structural units of the hyaluronic acid with low molecular weight is below 1000.
Table 4 shows the results of the test of CD44 activation rate at wounds caused by hydrogels of hyaluronic acid of different molecular weights. As can be seen from table 4:
when hyaluronic acid is of medium molecular weight (comparative example 7) and low molecular weight (comparative example 8), the activation rate of CD44 at the wound surface is only 1.2 times and 0.4 times. When the molecular weight of hyaluronic acid is in the high molecular weight range (comparative examples 1-4, examples 1-12), the activation rate of CD44 at the wound surface is 2-3 times, which can trigger the cascade reaction of CD44 receptor better. Therefore, in the selection of the final medical dressing, we should choose high molecular weight hyaluronic acid as the scaffold of the hydrogel.
Table 4 CD44 activation efficiency test of medical dressing
Test example 5
The healing effect of the wound surface is not only related to the activation rate of CD44, but also related to the normal inflammation elimination before the wound. With the resolution of inflammation, the wound transitions from an inflammatory phase to a proliferative phase and a remodelling phase, during which the tissue at the wound gradually reverts to a pre-healing state, embodying re-epithelialization of the epidermis and reasonable deposition of collagen. Therefore, we need to count the re-epithelialization of the wound surface and the deposition rate of collagen, so as to count the healing effect of the wound comprehensively.
We still selected the tissues of the full-thickness defect model of diabetic mice for statistical analysis, and on the seventh day of tissue sections were hematoxylin-eosin stained and masson trichromatic stained, and statistical table 5 was wound repair test data of medical dressing for wound re-epithelialization effect and collagen deposition rate, respectively, as can be seen from table 5:
comparative examples 1 to 4, although the activation rate of CD44 at wound surface was 2.3 to 2.6 times, the final wound epidermis re-epithelialization rate was 22 to 52%, collagen deposition rate was 28 to 55%, and far lower than the wound epidermis re-epithelialization rate (70 to 80%) and collagen deposition rate (80 to 90%) of examples 1 to 12 of the present invention, because they did not have good inflammation inhibition effect (see data of Table 3)
This shows that the medical dressing of the invention not only has good inflammation inhibition effect, but also can improve the re-epithelialization rate of epidermis and the collagen deposition rate and promote the healing quality.
Table 5 wound repair test of medical dressing
| Re-epithelialization rate of epidermis (%) | Collagen deposition Rate (%) | |
| Comparative example 1 | 45 | 53 |
| Comparative example 2 | 52 | 55 |
| Comparative example 3 | 22 | 28 |
| Comparative example 4 | 24 | 29 |
| Comparative example 7 | 28 | 32 |
| Comparative example 8 | 27 | 23 |
| Example 1 | 76 | 87 |
| Example 2 | 77 | 87 |
| Example 3 | 80 | 90 |
| Example 4 | 78 | 88 |
| Example 5 | 74 | 85 |
| Example 6 | 70 | 80 |
| Example 7 | 73 | 82 |
| Example 8 | 73 | 83 |
| Example 9 | 71 | 81 |
| Example 10 | 73 | 83 |
| Example 11 | 74 | 85 |
| Example 12 | 79 | 89 |
By combining the data of tables 1-5, the following conclusions can be drawn:
after 24 hours of use of the medical dressings of examples 1-12 of the present invention, the active oxygen index of the wound was reduced to less than 10% of the initial value, showing effective inhibition of excessive inflammation. Meanwhile, at 72 hours, the macrophages in the tissue are mainly of M2 type, and the proportion of M1/M2 macrophages is reduced to below 25%. This suggests that inflammation at the injured tissue has been effectively controlled and is in the phase of inflammation resolution. These rapid inflammatory resolutions are mainly due to:
1) Examples 1-12 have an inflammatory response and release of anti-inflammatory drugs on demand. As can be seen from Table 1, examples 1-12 spontaneously increased the drug release rate in severe inflammatory conditions, and the release rate at 24 hours could reach 56% -97%. The increased local drug concentration can effectively exert anti-inflammatory effect, thereby realizing effective inhibition of excessive inflammation at the wound surface in 24 hours and reducing the oxidative stress level at the wound surface to a normal level within 10 percent.
2) The medical dressing of examples 1-12 has proper mechanical properties, can be continuously and effectively applied on the surface of a wound, and can continuously release drug micelles, so that the utilization rate of the wrapped drug micelles is improved, the anti-inflammatory effect can be effectively exerted, and finally, the effective elimination of inflammation is realized in 72 hours, and the specific expression is that macrophages in tissues are mainly M2 type, and the proportion of M1/M2 macrophages is reduced to below 25%.
3) The hyaluronic acid selected in examples 1-12 has a molecular structure unit number of more than 5000, belongs to high molecular weight hyaluronic acid, and can activate CD44 receptor 2-3 times as compared with medium molecular weight hyaluronic acid and low molecular weight hyaluronic acid, the re-epithelialization efficiency of epidermis is improved by 70% -80%, and the collagen deposition proportion is improved by 80% -90%, so that the function of the hydrogel medical dressing in promoting wound healing is further improved.
Finally, it is noted that the above-mentioned preferred embodiments are only intended to illustrate rather than limit the invention, and that, although the invention has been described in detail by means of the above-mentioned preferred embodiments, it will be understood by those skilled in the art that various changes in form and details may be made therein without departing from the scope of the invention as defined by the appended claims.
Claims (9)
1. An inflammation response on-demand anti-inflammatory hydrogel medical dressing for skin wound healing, which is characterized by comprising hydrophobic drug micelle and inflammation response hydrogel according to a mass ratio of 1:10-1: 1000; the drug micelle is a micelle formed by a hydrophobic anti-inflammatory drug and an amphiphilic polymer, the particle size is 100-500 nanometers, the encapsulation rate is 80% -100%, and the drug carrying rate is 10% -30%; the inflammation response hydrogel is hydrogel obtained by crosslinking hyaluronic acid by a crosslinking agent with oxidation response groups, wherein the oxidation response groups are oxalic acid polyester or diselenide bond or boric acid ester bond or thioether bond or acyl pyrrolidine-2-carboxamide group or ferrocene-cyclodextrin host guest structure, the crosslinking degree is 30% -80%, and the number of repeated units of the hyaluronic acid is more than 5000.
2. The medical hydrogel dressing for skin wound healing with inflammation response on demand according to claim 1, wherein the amphiphilic polymer is one or more of poloxamer, polyethylene glycol-polycaprolactone, polyethylene glycol-polylactic acid copolymer or polycaprolactone-poly beta-amino ester copolymer.
3. The inflammation responsive on-demand anti-inflammatory hydrogel medical dressing for skin wound healing according to claim 1, wherein the hydrophobic anti-inflammatory drug is one or more of berberine, curcumin, indomethacin, acetaminophen, naproxen, ibuprofen, celecoxib, cefuroxime, cefixime, azithromycin or amoxicillin.
4. The inflammation-responsive on-demand anti-inflammatory hydrogel medical dressing for skin wound healing according to claim 1, wherein the inflammation-responsive hydrogel is oxalic acid polyester crosslinked hyaluronic acid gel, diselenide bond crosslinked hyaluronic acid gel, boric acid ester bond crosslinked hyaluronic acid hydrogel, thioether bond crosslinked hyaluronic acid hydrogel, acyl pyrrolidine-2-carboxamide group crosslinked hyaluronic acid hydrogel, ferrocene-cyclodextrin host structure crosslinked hyaluronic acid hydrogel.
5. An inflammatory responsive on-demand anti-inflammatory hydrogel medical dressing for skin wound healing according to claim 1, wherein said medical dressing is: 1) a mixed product of oxalic acid polyester crosslinked hyaluronic acid hydrogel and a hydrophobic drug micelle, wherein the hydrophobic drug micelle is a micelle formed by hydrophobic anti-inflammatory drug and poloxamer, or 2) a mixed product of diselenide crosslinked hyaluronic acid hydrogel and a hydrophobic drug micelle, the hydrophobic drug micelle is a micelle formed by hydrophobic anti-inflammatory drug and polyethylene glycol-polycaprolactone copolymer, or 3) a mixed product of boric acid ester bond crosslinked hyaluronic acid hydrogel and a hydrophobic drug micelle, the hydrophobic drug micelle is a micelle formed by hydrophobic anti-inflammatory drug and polyethylene glycol-polylactic acid copolymer, or 4) a mixed product of thioether bond crosslinked hyaluronic acid hydrogel and a hydrophobic drug micelle, the hydrophobic drug micelle is a micelle formed by hydrophobic anti-inflammatory drug and poloxamer copolymer, or 5) an acyl pyrrolidine-2-carboxamide group crosslinked hyaluronic acid hydrogel and a hydrophobic drug micelle, the hydrophobic drug micelle is a micelle formed by hydrophobic anti-inflammatory drug and polycaprolactone-poly beta-amino ester copolymer, or 6) a mixed product of ferrocene-cyclodextrin main structure crosslinked hyaluronic acid hydrogel and a hydrophobic drug micelle, and the hydrophobic drug micelle is a guest formed by hydrophobic anti-inflammatory drug and polyethylene glycol-polylactic acid copolymer.
6. The medical hydrogel dressing for on-demand anti-inflammatory treatment of skin wound healing according to claim 1, wherein the maximum liquid absorption rate of the medical dressing is 3-6 times, the water retention time is more than or equal to 24 hours, the maximum deformation amount is 200-500%, and the accumulated release amount of drug micelle in hydrogel is 32-97% within 24 hours in an inflammatory environment.
7. An inflammation responsive on demand anti-inflammatory hydrogel medical dressing for skin wound healing according to claim 1, wherein said medical dressing reduces reactive oxygen species levels to 10% after 24 hours at the damaged tissue site; after 72 hours, transformation of M1 macrophages to M2 macrophages in the tissue is promoted, and the M1/M2 ratio is less than 25%.
8. An inflammatory response on-demand anti-inflammatory hydrogel medical dressing for skin wound healing according to claim 1, wherein the medical dressing activates CD44 receptor 2-3 times, the epidermal re-epithelialization efficiency is increased by 70% -80%, and the collagen deposition ratio is increased by 80% -90%.
9. A method of preparing an inflammation responsive on demand anti-inflammatory hydrogel medical dressing for skin wound healing according to any one of claims 1-8, comprising the steps of:
1) Respectively dissolving 0.5-20wt% of hydrophobic anti-inflammatory drug and 10-50wt% of amphiphilic polymer in the soluble solvents, fully dissolving the two, uniformly mixing, replacing the solvent with the mixed solution, filtering the mixed solution with the replaced solvent by using a filter membrane, removing unencapsulated hydrophobic drug, and freeze-drying to obtain drug micelle; the solvent replacing method comprises rotary evaporation, adding deionized water, directly dialyzing the mixed solution, and the like; the pore diameter of the filter membrane is between 0.22 micrometers and 0.45 micrometers;
2) Grafting of oxidation-responsive groups onto hyaluronic acid by chemical crosslinking, in particular: mixing a cross-linking agent with an oxidation responsive group, an oxidation responsive group activator and a solution of sodium hyaluronate at 25-50 ℃ and reacting for 2-48 hours to obtain hyaluronic acid hydrogel grafted with the oxidation responsive group;
3) Mixing the drug micelle obtained in the step 1) with the hyaluronic acid hydrogel grafted with the oxidation responsive group obtained in the step 2), dialyzing, and purifying to obtain the inflammation responsive anti-inflammatory hydrogel medical dressing according to requirements.
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