CN116850339A - Injectable antibacterial hydrogel, preparation method and application thereof - Google Patents
Injectable antibacterial hydrogel, preparation method and application thereof Download PDFInfo
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- CN116850339A CN116850339A CN202310835884.1A CN202310835884A CN116850339A CN 116850339 A CN116850339 A CN 116850339A CN 202310835884 A CN202310835884 A CN 202310835884A CN 116850339 A CN116850339 A CN 116850339A
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- hyaluronic acid
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- 230000000844 anti-bacterial effect Effects 0.000 title claims abstract description 46
- 239000000017 hydrogel Substances 0.000 title claims abstract description 38
- 238000002360 preparation method Methods 0.000 title abstract description 9
- 239000000499 gel Substances 0.000 claims abstract description 36
- KIUKXJAPPMFGSW-DNGZLQJQSA-N (2S,3S,4S,5R,6R)-6-[(2S,3R,4R,5S,6R)-3-Acetamido-2-[(2S,3S,4R,5R,6R)-6-[(2R,3R,4R,5S,6R)-3-acetamido-2,5-dihydroxy-6-(hydroxymethyl)oxan-4-yl]oxy-2-carboxy-4,5-dihydroxyoxan-3-yl]oxy-5-hydroxy-6-(hydroxymethyl)oxan-4-yl]oxy-3,4,5-trihydroxyoxane-2-carboxylic acid Chemical compound CC(=O)N[C@H]1[C@H](O)O[C@H](CO)[C@@H](O)[C@@H]1O[C@H]1[C@H](O)[C@@H](O)[C@H](O[C@H]2[C@@H]([C@@H](O[C@H]3[C@@H]([C@@H](O)[C@H](O)[C@H](O3)C(O)=O)O)[C@H](O)[C@@H](CO)O2)NC(C)=O)[C@@H](C(O)=O)O1 KIUKXJAPPMFGSW-DNGZLQJQSA-N 0.000 claims abstract description 31
- 229920002674 hyaluronan Polymers 0.000 claims abstract description 31
- 229960003160 hyaluronic acid Drugs 0.000 claims abstract description 31
- 229920000642 polymer Polymers 0.000 claims abstract description 31
- 239000000463 material Substances 0.000 claims abstract description 16
- 125000003172 aldehyde group Chemical group 0.000 claims abstract description 15
- 239000012736 aqueous medium Substances 0.000 claims abstract description 7
- 238000002156 mixing Methods 0.000 claims abstract description 7
- 150000004676 glycans Chemical class 0.000 claims abstract description 4
- 229920001282 polysaccharide Polymers 0.000 claims abstract description 4
- 239000005017 polysaccharide Substances 0.000 claims abstract description 4
- 239000000243 solution Substances 0.000 claims description 50
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 14
- 238000000034 method Methods 0.000 claims description 12
- 150000003230 pyrimidines Chemical class 0.000 claims description 8
- KHIWWQKSHDUIBK-UHFFFAOYSA-N periodic acid Chemical compound OI(=O)(=O)=O KHIWWQKSHDUIBK-UHFFFAOYSA-N 0.000 claims description 5
- 239000002904 solvent Substances 0.000 claims description 4
- 239000004721 Polyphenylene oxide Substances 0.000 claims description 3
- 150000001412 amines Chemical class 0.000 claims description 3
- 239000000178 monomer Substances 0.000 claims description 3
- 238000007254 oxidation reaction Methods 0.000 claims description 3
- 229920000570 polyether Polymers 0.000 claims description 3
- 238000006116 polymerization reaction Methods 0.000 claims description 3
- 230000029663 wound healing Effects 0.000 claims description 3
- 125000003277 amino group Chemical group 0.000 claims description 2
- 230000003110 anti-inflammatory effect Effects 0.000 claims description 2
- 230000003078 antioxidant effect Effects 0.000 claims description 2
- 239000007853 buffer solution Substances 0.000 claims description 2
- 239000002504 physiological saline solution Substances 0.000 claims description 2
- XAEFZNCEHLXOMS-UHFFFAOYSA-M potassium benzoate Chemical compound [K+].[O-]C(=O)C1=CC=CC=C1 XAEFZNCEHLXOMS-UHFFFAOYSA-M 0.000 claims description 2
- 159000000000 sodium salts Chemical group 0.000 claims description 2
- 230000000845 anti-microbial effect Effects 0.000 claims 2
- 229920002118 antimicrobial polymer Polymers 0.000 claims 1
- 238000006243 chemical reaction Methods 0.000 abstract description 7
- 239000003814 drug Substances 0.000 abstract description 7
- 230000015572 biosynthetic process Effects 0.000 abstract description 5
- 206010040872 skin infection Diseases 0.000 abstract description 4
- 239000002262 Schiff base Substances 0.000 abstract description 2
- 150000004753 Schiff bases Chemical class 0.000 abstract description 2
- 125000002485 formyl group Chemical class [H]C(*)=O 0.000 abstract description 2
- 125000000623 heterocyclic group Chemical group 0.000 abstract description 2
- 239000002861 polymer material Substances 0.000 abstract description 2
- 239000008367 deionised water Substances 0.000 description 8
- 229910021641 deionized water Inorganic materials 0.000 description 8
- 241000894006 Bacteria Species 0.000 description 7
- 206010052428 Wound Diseases 0.000 description 5
- 208000027418 Wounds and injury Diseases 0.000 description 5
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 4
- 206010037888 Rash pustular Diseases 0.000 description 4
- 230000006378 damage Effects 0.000 description 4
- 208000015181 infectious disease Diseases 0.000 description 4
- 238000002347 injection Methods 0.000 description 4
- 239000007924 injection Substances 0.000 description 4
- 208000029561 pustule Diseases 0.000 description 4
- 238000003860 storage Methods 0.000 description 4
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- 238000005481 NMR spectroscopy Methods 0.000 description 3
- 241000191967 Staphylococcus aureus Species 0.000 description 3
- VHILMKFSCRWWIJ-UHFFFAOYSA-N dimethyl acetylenedicarboxylate Chemical compound COC(=O)C#CC(=O)OC VHILMKFSCRWWIJ-UHFFFAOYSA-N 0.000 description 3
- 239000007788 liquid Substances 0.000 description 3
- 230000001954 sterilising effect Effects 0.000 description 3
- 238000004659 sterilization and disinfection Methods 0.000 description 3
- 238000012360 testing method Methods 0.000 description 3
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- 208000035143 Bacterial infection Diseases 0.000 description 2
- WSFSSNUMVMOOMR-UHFFFAOYSA-N Formaldehyde Chemical compound O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 description 2
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 2
- 229960000583 acetic acid Drugs 0.000 description 2
- 239000003242 anti bacterial agent Substances 0.000 description 2
- 229940088710 antibiotic agent Drugs 0.000 description 2
- 208000022362 bacterial infectious disease Diseases 0.000 description 2
- 230000015556 catabolic process Effects 0.000 description 2
- 238000006731 degradation reaction Methods 0.000 description 2
- 238000011161 development Methods 0.000 description 2
- 239000008098 formaldehyde solution Substances 0.000 description 2
- 238000004108 freeze drying Methods 0.000 description 2
- 239000012362 glacial acetic acid Substances 0.000 description 2
- 239000001257 hydrogen Substances 0.000 description 2
- 229910052739 hydrogen Inorganic materials 0.000 description 2
- 238000011534 incubation Methods 0.000 description 2
- 208000014674 injury Diseases 0.000 description 2
- 230000009545 invasion Effects 0.000 description 2
- 239000002207 metabolite Substances 0.000 description 2
- 239000000203 mixture Substances 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- JQWHASGSAFIOCM-UHFFFAOYSA-M sodium periodate Chemical compound [Na+].[O-]I(=O)(=O)=O JQWHASGSAFIOCM-UHFFFAOYSA-M 0.000 description 2
- 238000001228 spectrum Methods 0.000 description 2
- 238000010254 subcutaneous injection Methods 0.000 description 2
- 239000007929 subcutaneous injection Substances 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 1
- 241000699666 Mus <mouse, genus> Species 0.000 description 1
- 241000699670 Mus sp. Species 0.000 description 1
- 108010087230 Sincalide Proteins 0.000 description 1
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 1
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 1
- 206010041925 Staphylococcal infections Diseases 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 238000005576 amination reaction Methods 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 230000001580 bacterial effect Effects 0.000 description 1
- 239000000969 carrier Substances 0.000 description 1
- 238000010609 cell counting kit-8 assay Methods 0.000 description 1
- 230000003833 cell viability Effects 0.000 description 1
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- 239000003795 chemical substances by application Substances 0.000 description 1
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- 238000000502 dialysis Methods 0.000 description 1
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- 230000000694 effects Effects 0.000 description 1
- 230000005489 elastic deformation Effects 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 239000008394 flocculating agent Substances 0.000 description 1
- 238000011010 flushing procedure Methods 0.000 description 1
- 238000001879 gelation Methods 0.000 description 1
- 239000001963 growth medium Substances 0.000 description 1
- 229920002521 macromolecule Polymers 0.000 description 1
- 239000012528 membrane Substances 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- 238000001000 micrograph Methods 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 230000037311 normal skin Effects 0.000 description 1
- 239000012074 organic phase Substances 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 238000011056 performance test Methods 0.000 description 1
- -1 polyetheramine D-230 Chemical compound 0.000 description 1
- 230000008569 process Effects 0.000 description 1
- IZTQOLKUZKXIRV-YRVFCXMDSA-N sincalide Chemical compound C([C@@H](C(=O)N[C@@H](CCSC)C(=O)NCC(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CCSC)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CC=1C=CC=CC=1)C(N)=O)NC(=O)[C@@H](N)CC(O)=O)C1=CC=C(OS(O)(=O)=O)C=C1 IZTQOLKUZKXIRV-YRVFCXMDSA-N 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
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- 208000015339 staphylococcus aureus infection Diseases 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 239000002562 thickening agent Substances 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 231100000820 toxicity test Toxicity 0.000 description 1
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
- A61L26/0052—Mixtures of macromolecular compounds
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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
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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
- A61L26/0066—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
- 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
- A61L26/009—Materials resorbable by the body
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- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08B—POLYSACCHARIDES; DERIVATIVES THEREOF
- C08B37/00—Preparation of polysaccharides not provided for in groups C08B1/00 - C08B35/00; Derivatives thereof
- C08B37/006—Heteroglycans, i.e. polysaccharides having more than one sugar residue in the main chain in either alternating or less regular sequence; Gellans; Succinoglycans; Arabinogalactans; Tragacanth or gum tragacanth or traganth from Astragalus; Gum Karaya from Sterculia urens; Gum Ghatti from Anogeissus latifolia; Derivatives thereof
- C08B37/0063—Glycosaminoglycans or mucopolysaccharides, e.g. keratan sulfate; Derivatives thereof, e.g. fucoidan
- C08B37/0072—Hyaluronic acid, i.e. HA or hyaluronan; Derivatives thereof, e.g. crosslinked hyaluronic acid (hylan) or hyaluronates
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- 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
- A61L2300/404—Biocides, antimicrobial agents, antiseptic agents
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- 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
- 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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- A61L2400/00—Materials characterised by their function or physical properties
- A61L2400/06—Flowable or injectable implant compositions
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Abstract
The invention discloses injectable antibacterial hydrogel, a preparation method and application thereof, which belong to the technical field of high polymer materials, and are obtained by mixing an antibacterial component and a gel skeleton which are formed by taking a structure shown in a formula I and aldehyde group functionalized hyaluronic acid in a weak alkaline aqueous medium; the hydrogel takes a polyhydropyrimidine heterocyclic polymer as an antibacterial skeleton, cooperates with aldehyde polysaccharide hyaluronic acid, is crosslinked by a C=N double bond dynamic bond based on Schiff-base reaction, has quick gel formation and self antibacterial property, can be applied to treatment materials of purulent subcutaneous infection, and has wide application in the field of biological medicine materials.
Description
Technical Field
The invention belongs to the technical field of high polymer materials, and particularly relates to injectable antibacterial hydrogel, a preparation method and application thereof.
Background
The purulent bacterial infection is one of the clinical difficulties, and the spread of the purulent bacteria after the invasion of the tissue is not great, but the damage to the local tissue is much serious compared with other strains, and the daily purulent infection is often caused by sharp puncture injuries carrying the purulent bacteria, and the like. Once a pustule is formed on a focus, the resistance to antibiotics can increase exponentially, and the focus is difficult to treat except for open drainage.
In recent years, hydrogel has been widely used as an open wound dressing because of its moist and soft characteristics. The injectable hydrogel is generally formed by dynamic chemical bond crosslinking, has self-healing property and viscous flow property, can adaptively fill a wound tissue gap, and can release a loaded medicine into a wound surface to prevent bacterial infection and accelerate wound healing. However, subcutaneous suppurative infection cannot be used for cleaning and changing the medicine of the wound surface just like an open wound surface, and secondary injury can be caused to the focus skin by the operation.
Most of the antibacterial gel at the present stage is mostly used as a carrier of antibiotics, and some gel carriers do not have a crosslinked chemical structure and only consist of flocculating agents, water-retaining agents and thickening agents, so that the antibacterial gel is rapidly degraded and the medicine is released irregularly. In view of the above problems, development of an injectable hydrogel injection which can be antibacterial per se is a good strategy for preparing enemy, but the antibacterial gel injection which can play medicine properties clinically at the present stage is few, and basically in a blank stage, so that development of a novel antibacterial injection has strategic significance.
Disclosure of Invention
In order to overcome the defects in the prior art, the invention provides an injectable antibacterial hydrogel, a preparation method and application thereof, wherein the hydrogel takes a polyhydropyrimidine heterocyclic polymer as an antibacterial skeleton, cooperates with aldehyde polysaccharide hyaluronic acid, is crosslinked by a C=N double bond dynamic bond based on Schiff-base reaction, has quick gel formation and self antibacterial property, can be applied to treatment materials of purulent subcutaneous infection, and has wide application in the field of biological medicine materials.
The invention is realized by the following technical scheme:
an injectable antibacterial hydrogel is prepared by mixing an antibacterial component and a gel skeleton with aldehyde group functionalized hyaluronic acid in a weak alkaline aqueous medium;
wherein m is a polyether amine D-230 monomer repeating unit, n is a positive integer, and n is more than or equal to 10 and less than or equal to 60.
Further, the aldehyde-functionalized hyaluronic acid has a structure represented by formula II:
wherein n is polymerization degree, n is more than or equal to 50 and less than or equal to 1000, m is an oxidized modified structural unit in n, and the proportion of m in n is k, measured, is more than or equal to 20% and less than or equal to 60%.
On the other hand, the invention also provides a preparation method of the injectable antibacterial hydrogel, which specifically comprises the following steps:
firstly, dissolving a hydrogenated pyrimidine antibacterial polymer in a weak alkaline aqueous medium, and then adding an aldehyde group functionalized hyaluronic acid solution to obtain a hydrogel material.
Further, the mass ratio of the hydrogenated pyrimidine antibacterial polymer to the aldehyde group functionalized hyaluronic acid is 1:0.5-5; the molar ratio of the amino groups to the aldehyde groups in the aldehyde group functionalized hyaluronic acid in the hydrogenated pyrimidine antibacterial polymer is 1:0.5-5.
Further, the solvent is weakly alkaline water, physiological saline or buffer solution; wherein the pH of the weak alkaline water is 7.4-8.5; the mass-volume concentration of the aldehyde group functionalized hyaluronic acid is 5% -25%; the mass-volume concentration of the hydrogenated pyrimidine antibacterial polymer is 5% -30%; the mixing temperature is 4-37 ℃.
Further, the aldehyde group functionalized hyaluronic acid is prepared by carrying out oxidation reaction on natural polysaccharide hyaluronic acid and periodate under the condition of light shielding and room temperature, so as to obtain a polymer shown in a structure of a formula II; wherein the solvent used is water, and the periodate includes but is not limited to sodium salt, potassium salt and the like.
In a third aspect, the invention also provides application of the injectable antibacterial hydrogel material, wherein the injectable antibacterial hydrogel material is used as an antibacterial dressing for wound healing and has anti-inflammatory and antioxidant effects.
Compared with the prior art, the invention has the following advantages:
the invention provides an injectable antibacterial hydrogel, a preparation method and application thereof, wherein the hydrogel is prepared by mixing a polyhydropyrimidine antibacterial polymer and a hyaluronic acid macromolecule oxidized by periodate in a weak alkaline aqueous medium, and has the advantages of rapid gelation, mild reaction condition and good cell compatibility; the hydrogel can respond to slow degradation of acid metabolites of purulent bacteria, and the hydrogel with rapid gel formation and self-antibacterial property can be used as a medicament to be applied to the field of biomedical materials. Compared with the traditional operation intervention of purulent infection, the invention blocks the contact of bacteria and upper normal skin tissues by a nonspecific membrane rupture sterilization mode, simultaneously damages pustule tissues, and the acidic metabolite of purulent flora at the pustule triggers the local degradation of gel to release free antibacterial polymers in the tissues, thereby creating a sterilization microenvironment at the focus to thoroughly block the infection deterioration.
Drawings
In order to more clearly illustrate the embodiments of the present invention or the technical solutions in the prior art, the drawings used in the description of the embodiments or the prior art will be briefly described below. Like elements or portions are generally identified by like reference numerals throughout the several figures. In the drawings, elements or portions thereof are not necessarily drawn to scale.
FIG. 1 is a nuclear magnetic resonance hydrogen spectrum of a polyhydropyrimidine antibacterial polymer prepared in example 1 of the present invention;
FIG. 2 shows the results of mechanical strength test of 10% by mass of the hydrogel prepared in example 5 of the present invention;
FIG. 3 is a graph of the results of testing the self-healing properties of hydrogels at a mass concentration of 10%;
FIG. 4 is a scanning electron microscope image of a hydrogel with a mass concentration of 10%;
FIG. 5 shows the results of toxicity tests of different concentrations of gel material on L929 cells;
FIG. 6 is a graph showing 10% hydrogel surface contact sterilization effect;
figure 7 shows the therapeutic effect of a 10% hydrogel on a model of subcutaneous infection in the back of mice after 5 days of treatment.
Detailed Description
For a clear and complete description of the technical scheme and the specific working process thereof, the following specific embodiments of the invention are provided with reference to the accompanying drawings in the specification:
in the following examples, dimethyl butynedioate, formaldehyde solution, polyetheramine D-230, glacial acetic acid, hyaluronic acid, sodium periodate, all available from Shanghai Ala Dimens Co; wherein the molecular weight of hyaluronic acid is 80-100 ten thousand, and the oxidation degree is 35%.
An injectable antibacterial hydrogel is prepared by mixing an antibacterial component and a gel skeleton with aldehyde group functionalized hyaluronic acid in a weak alkaline aqueous medium;
wherein m is a polyether amine D-230 monomer repeating unit, n is a positive integer, and n is more than or equal to 10 and less than or equal to 60.
The aldehyde-functionalized hyaluronic acid has a structure represented by formula II:
wherein n is polymerization degree, n is more than or equal to 50 and less than or equal to 1000, m is an oxidized modified structural unit in n, and the proportion of m in n is k, measured, is more than or equal to 20% and less than or equal to 60%.
EXAMPLE 1 preparation of polyhydropyrimidine antibacterial Polymer
The embodiment provides a preparation method of a polyhydropyrimidine antibacterial polymer, which comprises the following specific contents:
1.42g of dimethyl butynedioate and 2.3g of polyetheramine D-230 are respectively dissolved in 20mL of methanol, then the polyetheramine solution is slowly dripped into the dimethyl butynedioate solution under stirring, 2.43g of formaldehyde solution and 1.2g of glacial acetic acid are dripped into the reaction system after reacting for 20 minutes; after 48h of reaction at normal temperature, the mixture system is distilled under reduced pressure, washed with 50mL of saturated sodium bicarbonate solution for 3 times respectively, then the organic phase is collected, and excessive anhydrous magnesium sulfate is added for drying overnight; the mixture was concentrated by filtration and distilled under reduced pressure of an oil pump for 3 hours to give a brown viscous sample.
The polyhydropyrimidine obtained above was prepared according to 1: amination is carried out by taking DMF as a reaction solution in 2.5 equivalent ratio, reaction is carried out for 48 hours at 50 ℃, deionized water is used for dialysis for 3 days, brown viscous liquid is obtained through freeze-drying, nuclear magnetic resonance analysis is carried out, and a nuclear magnetic resonance hydrogen spectrum of the polyhydropyrimidine prepared in the embodiment 1 of the invention is shown in FIG. 1.
Example 2
100mg of the polyhydropyrimidine prepared in example 1 was dissolved in PBS (2 mL) having a pH of 7.4 to obtain solution 1, oxidized hyaluronic acid (50 mg) was dissolved in deionized water (2 mL) to obtain solution 2, and the solution 1 (50. Mu.L) and the solution 2 (200. Mu.L) were thoroughly mixed to obtain a polymer solution, and the polymer solution was gelled at normal temperature, and the gel was observed by inversion method for 10 seconds.
Example 3
100mg of the polyhydropyrimidine prepared in example 1 was dissolved in PBS (2 mL) having a pH of 7.4 to obtain solution 1, oxidized hyaluronic acid (50 mg) was dissolved in deionized water (2 mL) to obtain solution 2, and the solution 1 (50. Mu.L) and the solution 2 (150. Mu.L) were thoroughly mixed to obtain a polymer solution, and the polymer solution was gelled at normal temperature, and the gel was observed by inversion method for 10 seconds.
Example 4
100mg of the polyhydropyrimidine prepared in example 1 was dissolved in PBS (2 mL) having a pH of 7.4 to obtain solution 1, oxidized hyaluronic acid (50 mg) was dissolved in deionized water (2 mL) to obtain solution 2, and the solution 1 (50. Mu.L) and the solution 2 (100. Mu.L) were thoroughly mixed to obtain a polymer solution, and the polymer solution was gelled at normal temperature, and the gel was observed by inversion method for 10 seconds.
Example 5
100mg of the polyhydropyrimidine prepared in example 1 was dissolved in PBS (2 mL) having a pH of 7.4 to obtain solution 1, oxidized hyaluronic acid (50 mg) was dissolved in deionized water (2 mL) to obtain solution 2, and solution 1 (200. Mu.L) and solution 2 (200. Mu.L) were sufficiently and uniformly mixed to obtain a polymer solution, and the polymer solution was gelled at normal temperature, and the gel was observed by inversion method for 10 seconds;
the prepared hydrogel was subjected to performance test, and the results were as follows:
the gel was transferred to a rotational rheometer after formation and its storage and loss moduli were measured over time, as a result of which, see fig. 2, the elastic modulus was always higher than the loss modulus indicating that a three-dimensional network had formed and that the structure was stable.
After gel formation, the gel is transferred to a rotary rheometer, the change condition of storage modulus and loss modulus with time is alternately tested under the strain of 1% and 1000%, and as a result, referring to fig. 3, the storage modulus of the gel material is always higher than the loss modulus under the strain of 1%, the high elastic state of the gel is maintained by a polymer network, the loss modulus under the strain of 1000% is greater than the storage modulus, the gel is changed from the high elastic state to the viscous state, the crosslinked network is destroyed, the high elastic deformation can be still maintained after the multi-round strain cycle is carried out, and the wrapping capability of the gel on pustules after subcutaneous injection is proved.
The gel material obtained is frozen in liquid nitrogen, shear force is applied to the gel material for brittle fracture, then freeze drying is carried out, metal spraying is carried out on the brittle fracture surface, surrounding microscopic morphology observation is carried out through a scanning electron microscope, the result is shown in fig. 4, the gel presents regular three-dimensional meshes, and the structure of the meshes presents a silk net shape.
The different mass gels were incubated with L929 cells for 24 hours, as shown in FIG. 5, and no significant toxicity of the gel to the cells was seen by testing cell viability by CCK-8.
Placing the gel material in a sterile 24-hole plate, after the surface of the gel material is leveled, dripping staphylococcus aureus bacterial liquid on the surface of the gel material, after 2 hours incubation, flushing and collecting the surface bacteria by using sterile normal saline, coating the surface bacteria on an LB solid culture medium, and after the incubation, observing colony growth conditions, as shown in fig. 6, after the hydrogel injection is contacted with bacteria for 2 hours, completely killing staphylococcus aureus.
The hydrogel prepared in this example was applied to a mouse staphylococcus aureus subcutaneous infection model by subcutaneous injection, and as shown in fig. 7, the antibacterial hydrogel can block the invasion of staphylococcus aureus infection to the skin.
Example 6
100mg of the polyhydropyrimidine prepared in example 1 was dissolved in PBS (2 mL) having a pH of 7.4 to obtain solution 1, oxidized hyaluronic acid (50 mg) was dissolved in deionized water (2 mL) to obtain solution 2, and the solution 1 (200. Mu.L) and the solution 2 (50. Mu.L) were thoroughly mixed to obtain a polymer solution, and the polymer solution was gelled at normal temperature, and the gel was observed by inversion method for 10 seconds.
Example 7
100mg of the polyhydropyrimidine prepared in example 1 was dissolved in PBS (2 mL) having a pH of 7.4 to obtain solution 1, oxidized hyaluronic acid (50 mg) was dissolved in deionized water (2 mL) to obtain solution 2, and the solution 1 (150. Mu.L) and the solution 2 (50. Mu.L) were thoroughly mixed to obtain a polymer solution, and the polymer solution was gelled at normal temperature, and the gel was observed by inversion method for 10 seconds.
Example 8
100mg of the polyhydropyrimidine prepared in example 1 was dissolved in PBS (2 mL) having a pH of 7.4 to obtain solution 1, oxidized hyaluronic acid (50 mg) was dissolved in deionized water (2 mL) to obtain solution 2, and the solution 1 (100. Mu.L) and the solution 2 (50. Mu.L) were thoroughly mixed to obtain a polymer solution, and the polymer solution was gelled at normal temperature, and the gel was observed by inversion method for 10 seconds.
The preferred embodiments of the present invention have been described in detail above with reference to the accompanying drawings, but the present invention is not limited to the specific details of the above embodiments, and various simple modifications can be made to the technical solution of the present invention within the scope of the technical concept of the present invention, and all the simple modifications belong to the protection scope of the present invention.
In addition, the specific features described in the above embodiments may be combined in any suitable manner, and in order to avoid unnecessary repetition, various possible combinations are not described further.
Moreover, any combination of the various embodiments of the invention can be made without departing from the spirit of the invention, which should also be considered as disclosed herein.
Claims (7)
1. An injectable antibacterial hydrogel is characterized in that the structure shown in the formula I is used as an antibacterial component and a gel skeleton, and the injectable antibacterial hydrogel is obtained by mixing the antibacterial component and the gel skeleton with aldehyde group functionalized hyaluronic acid in a weak alkaline aqueous medium;
wherein m is a polyether amine D-230 monomer repeating unit, n is a positive integer, and n is more than or equal to 10 and less than or equal to 60.
2. An injectable antimicrobial hydrogel according to claim 1, wherein the aldehyde-functionalized hyaluronic acid has the structure of formula II:
wherein n is polymerization degree, n is more than or equal to 50 and less than or equal to 1000, m is an oxidized modified structural unit in n, and the proportion of m in n is k, measured, is more than or equal to 20% and less than or equal to 60%.
3. The method for preparing the injectable antibacterial hydrogel according to claim 1, which comprises the following steps:
firstly, dissolving a hydrogenated pyrimidine antibacterial polymer in a weak alkaline aqueous medium, and then adding an aldehyde group functionalized hyaluronic acid solution to obtain a hydrogel material.
4. A method of preparing an injectable antimicrobial hydrogel according to claim 3, wherein the mass ratio of the hydrogenated pyrimidine antimicrobial polymer to the aldehyde-functionalized hyaluronic acid is 1:0.5-5; the molar ratio of the amino groups to the aldehyde groups in the aldehyde group functionalized hyaluronic acid in the hydrogenated pyrimidine antibacterial polymer is 1:0.5-5.
5. A method of preparing an injectable antibacterial hydrogel according to claim 3 wherein the solvent is weakly alkaline water, physiological saline or a buffer solution; wherein the pH of the weak alkaline water is 7.4-8.5; the mass-volume concentration of the aldehyde group functionalized hyaluronic acid is 5% -25%; the mass-volume concentration of the hydrogenated pyrimidine antibacterial polymer is 5% -30%; the mixing temperature is 4-37 ℃.
6. The method for preparing the injectable antibacterial hydrogel according to claim 3, wherein the aldehyde group functionalized hyaluronic acid is prepared by carrying out oxidation reaction on natural polysaccharide hyaluronic acid and periodate under the conditions of light shielding and room temperature, so as to obtain a polymer shown in a structure of a formula II; wherein the solvent is water, and the periodate is sodium salt or potassium salt.
7. Use of an injectable antibacterial hydrogel according to claim 1, as an antibacterial dressing for wound healing, with anti-inflammatory and antioxidant effects.
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