CN115197442B - Injectable self-healing hydrogel dressing for treating gastric perforation, preparation method and application - Google Patents
Injectable self-healing hydrogel dressing for treating gastric perforation, preparation method and application Download PDFInfo
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- CN115197442B CN115197442B CN202210505581.9A CN202210505581A CN115197442B CN 115197442 B CN115197442 B CN 115197442B CN 202210505581 A CN202210505581 A CN 202210505581A CN 115197442 B CN115197442 B CN 115197442B
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- Prior art keywords
- ptopt
- hydrogel
- reaction
- hydrogel dressing
- gastric perforation
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- 239000000017 hydrogel Substances 0.000 title claims abstract description 137
- 206010017815 Gastric perforation Diseases 0.000 title claims abstract description 34
- 238000002360 preparation method Methods 0.000 title claims description 6
- 229920000642 polymer Polymers 0.000 claims abstract description 34
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims abstract description 3
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 71
- 238000006243 chemical reaction Methods 0.000 claims description 37
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 31
- 239000000243 solution Substances 0.000 claims description 21
- 206010052428 Wound Diseases 0.000 claims description 18
- 208000027418 Wounds and injury Diseases 0.000 claims description 18
- 238000001035 drying Methods 0.000 claims description 18
- 238000000034 method Methods 0.000 claims description 18
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 17
- CTSLXHKWHWQRSH-UHFFFAOYSA-N oxalyl chloride Chemical compound ClC(=O)C(Cl)=O CTSLXHKWHWQRSH-UHFFFAOYSA-N 0.000 claims description 16
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 14
- BHHGXPLMPWCGHP-UHFFFAOYSA-N Phenethylamine Chemical compound NCCC1=CC=CC=C1 BHHGXPLMPWCGHP-UHFFFAOYSA-N 0.000 claims description 14
- 239000012986 chain transfer agent Substances 0.000 claims description 14
- 239000007788 liquid Substances 0.000 claims description 13
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 claims description 13
- 239000000047 product Substances 0.000 claims description 13
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 12
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 claims description 12
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 10
- 239000007787 solid Substances 0.000 claims description 10
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 9
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 9
- 238000001914 filtration Methods 0.000 claims description 9
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 8
- 230000015572 biosynthetic process Effects 0.000 claims description 8
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- OZAIFHULBGXAKX-UHFFFAOYSA-N 2-(2-cyanopropan-2-yldiazenyl)-2-methylpropanenitrile Chemical compound N#CC(C)(C)N=NC(C)(C)C#N OZAIFHULBGXAKX-UHFFFAOYSA-N 0.000 claims description 7
- WOBHKFSMXKNTIM-UHFFFAOYSA-N Hydroxyethyl methacrylate Chemical compound CC(=C)C(=O)OCCO WOBHKFSMXKNTIM-UHFFFAOYSA-N 0.000 claims description 7
- HFBMWMNUJJDEQZ-UHFFFAOYSA-N acryloyl chloride Chemical compound ClC(=O)C=C HFBMWMNUJJDEQZ-UHFFFAOYSA-N 0.000 claims description 7
- IZUPBVBPLAPZRR-UHFFFAOYSA-N pentachloro-phenol Natural products OC1=C(Cl)C(Cl)=C(Cl)C(Cl)=C1Cl IZUPBVBPLAPZRR-UHFFFAOYSA-N 0.000 claims description 7
- 229940117803 phenethylamine Drugs 0.000 claims description 7
- 238000000746 purification Methods 0.000 claims description 7
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- AOCSUUGBCMTKJH-UHFFFAOYSA-N tert-butyl n-(2-aminoethyl)carbamate Chemical compound CC(C)(C)OC(=O)NCCN AOCSUUGBCMTKJH-UHFFFAOYSA-N 0.000 claims description 7
- -1 2- ((3-oxo-3- (phenethylamino) propyl) amino) ethyl Chemical group 0.000 claims description 6
- PCBZRNYXXCIELG-WYFCWLEVSA-N COC1=CC=C(C[C@H](NC(=O)OC2CCCC3(C2)OOC2(O3)C3CC4CC(C3)CC2C4)C(=O)N[C@@H]2[C@@H](CO)O[C@H]([C@@H]2O)N2C=NC3=C2N=CN=C3N(C)C)C=C1 Chemical compound COC1=CC=C(C[C@H](NC(=O)OC2CCCC3(C2)OOC2(O3)C3CC4CC(C3)CC2C4)C(=O)N[C@@H]2[C@@H](CO)O[C@H]([C@@H]2O)N2C=NC3=C2N=CN=C3N(C)C)C=C1 PCBZRNYXXCIELG-WYFCWLEVSA-N 0.000 claims description 6
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 6
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- 229910052757 nitrogen Inorganic materials 0.000 claims description 6
- 230000002194 synthesizing effect Effects 0.000 claims description 6
- RFOWDPMCXHVGET-UHFFFAOYSA-N (2,3,4,5,6-pentafluorophenyl) prop-2-enoate Chemical compound FC1=C(F)C(F)=C(OC(=O)C=C)C(F)=C1F RFOWDPMCXHVGET-UHFFFAOYSA-N 0.000 claims description 5
- 239000003208 petroleum Substances 0.000 claims description 5
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- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 5
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- FGIUAXJPYTZDNR-UHFFFAOYSA-N potassium nitrate Chemical compound [K+].[O-][N+]([O-])=O FGIUAXJPYTZDNR-UHFFFAOYSA-N 0.000 claims description 4
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- 230000029663 wound healing Effects 0.000 claims description 4
- 239000012267 brine Substances 0.000 claims description 3
- JGHKDVSIFPFNIJ-UHFFFAOYSA-N dodecylsulfanylmethanedithioic acid Chemical group CCCCCCCCCCCCSC(S)=S JGHKDVSIFPFNIJ-UHFFFAOYSA-N 0.000 claims description 3
- 235000019441 ethanol Nutrition 0.000 claims description 3
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- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 claims description 3
- 239000002904 solvent Substances 0.000 claims description 3
- ILWRPSCZWQJDMK-UHFFFAOYSA-N triethylazanium;chloride Chemical compound Cl.CCN(CC)CC ILWRPSCZWQJDMK-UHFFFAOYSA-N 0.000 claims description 3
- 238000001291 vacuum drying Methods 0.000 claims description 3
- 241001274216 Naso Species 0.000 claims description 2
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- PYWVYCXTNDRMGF-UHFFFAOYSA-N rhodamine B Chemical compound [Cl-].C=12C=CC(=[N+](CC)CC)C=C2OC2=CC(N(CC)CC)=CC=C2C=1C1=CC=CC=C1C(O)=O PYWVYCXTNDRMGF-UHFFFAOYSA-N 0.000 description 1
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- 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
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08J—WORKING-UP; GENERAL PROCESSES OF COMPOUNDING; AFTER-TREATMENT NOT COVERED BY SUBCLASSES C08B, C08C, C08F, C08G or C08H
- C08J3/00—Processes of treating or compounding macromolecular substances
- C08J3/02—Making solutions, dispersions, lattices or gels by other methods than by solution, emulsion or suspension polymerisation techniques
- C08J3/03—Making solutions, dispersions, lattices or gels by other methods than by solution, emulsion or suspension polymerisation techniques in aqueous media
- C08J3/075—Macromolecular gels
-
- 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
- A61L26/0014—Chemical aspects of, or use of materials for, wound dressings or bandages in liquid, gel or powder form containing macromolecular materials obtained by reactions only involving carbon-to-carbon unsaturated bonds
-
- 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
-
- 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
-
- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08F—MACROMOLECULAR COMPOUNDS OBTAINED BY REACTIONS ONLY INVOLVING CARBON-TO-CARBON UNSATURATED BONDS
- C08F293/00—Macromolecular compounds obtained by polymerisation on to a macromolecule having groups capable of inducing the formation of new polymer chains bound exclusively at one or both ends of the starting macromolecule
- C08F293/005—Macromolecular compounds obtained by polymerisation on to a macromolecule having groups capable of inducing the formation of new polymer chains bound exclusively at one or both ends of the starting macromolecule using free radical "living" or "controlled" polymerisation, e.g. using a complexing agent
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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
- A61L2300/404—Biocides, antimicrobial agents, antiseptic agents
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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
- A61L2400/00—Materials characterised by their function or physical properties
- A61L2400/06—Flowable or injectable implant compositions
-
- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08F—MACROMOLECULAR COMPOUNDS OBTAINED BY REACTIONS ONLY INVOLVING CARBON-TO-CARBON UNSATURATED BONDS
- C08F2438/00—Living radical polymerisation
- C08F2438/03—Use of a di- or tri-thiocarbonylthio compound, e.g. di- or tri-thioester, di- or tri-thiocarbamate, or a xanthate as chain transfer agent, e.g . Reversible Addition Fragmentation chain Transfer [RAFT] or Macromolecular Design via Interchange of Xanthates [MADIX]
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- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08J—WORKING-UP; GENERAL PROCESSES OF COMPOUNDING; AFTER-TREATMENT NOT COVERED BY SUBCLASSES C08B, C08C, C08F, C08G or C08H
- C08J2353/00—Characterised by the use of block copolymers containing at least one sequence of a polymer obtained by reactions only involving carbon-to-carbon unsaturated bonds; Derivatives of such polymers
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Landscapes
- Chemical & Material Sciences (AREA)
- Health & Medical Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Dispersion Chemistry (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Engineering & Computer Science (AREA)
- Materials Engineering (AREA)
- Epidemiology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Organic Chemistry (AREA)
- Polymers & Plastics (AREA)
- Medicinal Chemistry (AREA)
- Materials For Medical Uses (AREA)
Abstract
The invention relates to an injectable self-healing hydrogel dressing for treating gastric perforation, which is a three-dimensional network structure formed by connecting triblock polymer PTOPT temperature-sensitive blocks dissolved in a solution with pH of 2.5 through temperature-induced self-assembly to form micelles containing ortho amino and aromatic ring components by taking PEG long chains as bridging. The hydrogel has the hydrogel wound dressing PTOPT with the advantages of injectability, temperature sensitivity, self-healing, adhesion, antibacterial adhesion and biocompatibility, can play a positive and effective treatment effect in a gastric perforation model, and is a promising hydrogel dressing.
Description
Technical Field
The invention relates to the field of biomedical materials, in particular to an injectable self-healing hydrogel dressing for treating gastric perforation, a preparation method and application thereof.
Background
Hydrogels are promising alternatives to natural extracellular matrix, with exciting promise on medical biomaterials. In particular to injectable hydrogel, which can reduce the pain of biological invasion and treatment process to the maximum extent when treating wounds (such as internal and irregular wounds) where hydrogel cannot be placed directly. Currently, researchers have designed injectable hydrogels for wound dressings through physical or chemical methods. However, most hydrogels lack adaptation to some complex biological environments, especially for the more acidic stomach environments. Since most hydrogels are hydrolyzed under such strong acidic conditions, the hydrogel is damaged to lose its original therapeutic function, various inflammatory reactions may be brought about, wound healing may be delayed, and serious cases may cause death. Therefore, in the clinical treatment of gastric perforation, it is necessary to develop injectable hydrogels designed to adapt to the complex environment of the stomach.
Among the wound dressings in many injectable hydrogels, the self-healing hydrogel with self-healing capability can self-repair after being subjected to external force, and the service life of the self-healing hydrogel can be greatly prolonged in practical application. The use of injectable hydrogels with self-healing properties in biomedical materials has become a research hotspot. Therefore, it is necessary to design and develop a biocompatible injectable self-healing hydrogel for promoting healing of gastric perforation.
Disclosure of Invention
The invention aims to solve the problem that the existing biological self-adaptive injectable self-healing hydrogel is lack and is used for gastric perforation treatment.
The aim of the invention is realized by the following technical scheme:
a method for preparing an injectable self-healing hydrogel dressing for treating gastric perforation, comprising the following steps:
s1, synthesizing pentafluorophenol acrylate (PFPA)
Mixing pentafluorophenol and dichloromethane, dropwise adding triethylamine and acryloyl chloride under ice bath condition, then reacting at normal temperature, filtering, concentrating, washing, drying and purifying to obtain transparent liquid pentafluorophenol acrylate (PFPA);
s2 Synthesis of 2- ((3-oxo-3- (phenethylamino) propyl) amino) ethyl) carbamate (TBC)
Dissolving phenethylamine and N- (2-amino ethyl) carbamic acid tert-butyl ester into absolute ethyl alcohol, vigorously stirring, reacting, and purifying after vacuum drying to obtain orange oily liquid 2- ((3-oxygen-3- (phenethylamino) propyl) amino) ethyl) carbamate (TBC);
s3, synthesizing macromolecular chain transfer agent PEG-CTA
Trithioesters, 2- (dodecanol)Alkyl trithiocarbonate group) -2-isobutyric acid (RAFT 365 ) Adding oxalyl chloride into a three-neck flask, dissolving in anhydrous dichloromethane for reaction, spin-drying the rest oxalyl chloride and dichloromethane after the reaction is finished, adding PEG and anhydrous dichloromethane for reaction, precipitating after the reaction is finished, and drying to obtain a light yellow product PEG-CTA;
s4 Synthesis of triblock Polymer Poly (EG-co-PFPA) -b-PEO-b-Poly (EG-co-PFPA) (GPOGP)
Dissolving PEG-CTA prepared in S3, oligomeric ethylene glycol methacrylate (PEG-MA), PFPA prepared in S1 and Azodiisobutyronitrile (AIBN) in 1, 4-dioxane, bubbling nitrogen into the whole reaction system, and reacting; after the reaction is finished, precipitating, filtering, purifying and drying to obtain white solid triblock polymer Poly (EG-co-PFPA) -b-PEO-b-Poly (EG-co-PFPA) (GPOGP);
s5 Synthesis of the precursor triblock Polymer Poly (EG-co-TBC) -b-PEO-b-Poly (EG-co-TBC) (PTOPT-Boc)
Dissolving TBC prepared in S2 and triblock polymer GPOGP prepared in S4 in tetrahydrofuran, bubbling a reaction system into nitrogen, and reacting; precipitating, purifying, filtering and drying after the reaction is finished to obtain yellowish solid PTOPT-Boc;
s6, preparation of PTOPT Polymer
Dissolving a precursor triblock polymer PTOPT-Boc in dichloromethane, adding trifluoroacetic acid into the solution, reacting at room temperature, precipitating after the reaction is finished, purifying, and drying to obtain a PTOPT polymer;
s7, preparing hydrogel dressing
The PTOPT polymer was dissolved in acidic ice water to give a biocompatible injectable self-healing hydrogel dressing.
Specifically, in the step S1, pentafluorophenol and methylene dichloride are added into a three-neck flask, and then triethylamine and acryloyl chloride are added dropwise under the condition of-20-10 ℃ for 20-60 minutes; removing ice bath, reacting at 20-40 deg.C for 3-8 hr, filtering to remove triethylamine hydrochloride, concentrating filtrate, and using HCl solution and saturated NaHCO 3 And brine wash; the organic phase is NaSO 4 Or MgSO 4 Drying to remove water, concentrating, using petroleum ether, dichloromethane or n-hexane as eluent, and purifying the residual liquid by column chromatography to obtain transparent liquid; wherein the mass ratio of the pentafluorophenol to the acryloyl chloride is (5-10): (3-5). The addition amount of dichloromethane is 50-100 mL; the concentration of HCl is 0.1mol/L to 1mol/L.
Specifically, in the step S2, phenethylamine and tert-butyl N- (2-aminoethyl) carbamate are dissolved in 10-50 mL of absolute ethyl alcohol and stirred vigorously; stirring the mixture at the reflux temperature of 60-80 ℃ for reaction for 24-48 hours; drying the solvent ethanol in vacuum; purifying residual liquid by column chromatography with petroleum ether, dichloromethane, ethyl acetate or methanol as eluent to obtain TBC product; wherein the mass ratio of the phenethylamine to the N- (2-aminoethyl) carbamic acid tert-butyl ester is (2-10): (3-9).
Specifically, in the S3, RAFT 365 The mass ratio of oxalyl chloride to PEG is (1-3): (3-7): (5-20); wherein the molecular weight of PEG is between 2000 and 40000; the addition amount of the anhydrous methylene dichloride for the first time and the second time is 5-20 mL and 50-200 mL respectively.
Specifically, in the step S4, after the reaction is finished, the solution is dropwise added into diethyl ether or n-hexane for precipitation, and the purification process is repeated twice; the product is filtered and dried overnight under vacuum to obtain white solid GPOGP; wherein the mass ratio of PEG-CTA, oligoethylene glycol methacrylate (PEG-MA), PFPA, azodiisobutyronitrile (AIBN) and 1, 4-dioxane is (1-3): (2-8): (0.5-2): (8-30).
Specifically, in the step S5, after the reaction is completed, the reaction solution is added into diethyl ether or n-hexane precipitant drop by drop to precipitate, and the purification process is repeated twice; the product was filtered and dried under vacuum overnight to give a yellowish solid, PTOPT-Boc; wherein, the mass ratio of TBC, GPOGP and tetrahydrofuran is (1-3): (2-10): (20-50).
Specifically, in the above S6, the mass ratio of PTOPT-Boc, methylene chloride and trifluoroacetic acid is (1-3): (10-20): (1-2).
Specifically, in the step S7, the prepared triblock polymer PTOPT with the concentration of 50 mg/mL-200 mg/mL is dissolved in a solution with the pH of 2.5 prepared by acetic acid/potassium nitrate or hydrochloric acid, and the solution is placed in a refrigerating layer of a refrigerator for 10-30 hours to prepare the hydrogel dressing.
The injectable self-healing hydrogel dressing for treating gastric perforation is prepared by the method. The PTOPT hydrogel of the invention has good biocompatibility. The risk in the use process can be effectively reduced.
The prepared hydrogel dressing is used in gastric perforation wound models and other complex wound healing.
The present invention developed a gastric environment compatible hydrogel (PTOPT) as an in vivo wound dressing. By adapting to physiological conditions, the hydrogel dressing can be simply injected at the target site by supramolecular self-assembly of ABA triblock copolymers. The formed supermolecular hydrogel can adapt to the stomach environment, and the rapid self-healing repair characteristic is obtained through the cooperation of hydrophobic interaction and cation-pi interaction, so that the risk caused by damage in the use process is reduced, and the service life of the material is effectively prolonged. Meanwhile, the PTOPT hydrogel dressing can also effectively prevent the accumulation of microorganisms on the surface of the PTOPT hydrogel dressing, and has excellent antibacterial adhesion resistance. And we also determined the cytotoxicity of the hydrogels by CCK-8, with very little toxicity of the hydrogels to gastric mucosal cells and L929 cells. And 2D/3D cell culture is carried out on gastric mucosa cells and L929 cells by using hydrogel, and the data show that the hydrogel has good biocompatibility. In addition, the PTOPT hydrogel dressing has the most advanced advantages over traditional gastric perforation treatments, including simplifying the surgical procedure, reducing post-operative adhesion and promoting angiogenesis. Our design of PTOPT hydrogels provides useful insight for the development of biological environment-adaptive functional materials for various biomedical applications.
The structural formula of the PFPA prepared by the S1 is shown as follows:
the structural formula of the TBC prepared by the S2 is shown as follows:
the structural formula of the macromolecular chain transfer agent PEG-CTA prepared by the S3 is shown as follows:
the structural formula of the triblock polymer GPOGP with active ester prepared by the S4 is shown as the following formula
The structural formula of the precursor triblock polymer PTOPT-Boc prepared by the S5 is shown as the following formula
The structural formula of the target triblock polymer PTOPT prepared by the S6 is shown as the following formula
The beneficial effects of the invention are as follows:
(1) The PTOPT hydrogel has good temperature sensitivity, and the sol-gel transition temperature of the hydrogel is about 22 ℃ and lower than the temperature of a human body (about 37 ℃). Can form stable gel under the induction of human body temperature without other complicated external stimulus.
(2) The PTOPT hydrogel has attractive injectability, and when the temperature is lower than 22 ℃, the hydrogel sol state, liquid-like polymer solution can be well injected to a target site through a syringe and is induced to become stable hydrogel through body temperature. In addition, the shear thinning behavior of the hydrogel also suggests that even the stabilized hydrogels that have been formed have attractive injectability, which can minimize biological infestation and pain during treatment.
(3) The PTOPT hydrogel disclosed by the invention has excellent self-healing performance for stomach environment adaptation. Cation-pi interaction occurs between protonated amino groups and aromatic benzene rings in hydrogel in an environment matched with stomach environment and pH is 2.5, so that the hydrogel can be quickly self-healed after being damaged, the service life of the material is prolonged, and the risk in the use process is reduced.
(4) The PTOPT hydrogel disclosed by the invention has good antibacterial adhesion performance on escherichia coli (E.coli) and staphylococcus aureus (S.aureus). It is important to prevent microorganisms from forming microbial films on the surface of the implanted biological material. The PEG section in the hydrogel can form a strong hydration layer at the wound, plays a role of a barrier to bacteria, can effectively prevent the bacteria from adhering, and can effectively prevent immune reaction or inflammation and other reactions which can possibly be caused by microbial membranes from inhibiting the healing process.
(5) The PTOPT hydrogel of the invention exhibits good adhesion effects by undergoing cationic-pi electrostatic interactions, hydrogen bonding, pi-pi stacking and hydrophobic interactions with tissue surfaces. A wound dressing would be promising when the hydrogel forms a gel in situ on differently shaped wounds, particularly in wet and dynamic human environments.
(6) The PTOPT hydrogel of the invention has good biocompatibility. In vitro cytotoxicity indicated that the PTOPT hydrogels were non-toxic and were able to promote cell growth and proliferation. In addition, the PTOPT hydrogel is used for 2D/3D cell culture of mouse fibroblasts (L929) and rat gastric epithelial cells (GES), and shows that the PTOPT hydrogel has good biocompatibility without reducing proliferation of cells.
Drawings
FIG. 1 (a) shows the modulus of PTOPT hydrogels as a function of temperature (4 ℃ C. To 45 ℃ C.); (b) Modulus change profile of the PTOPT hydrogel under three thermal cycles of heating (37 ℃) and cooling (12 ℃);
FIG. 2 is a graph of a hydrogel dressing PTOPT liquefied sample of the invention injected into 37℃ deionized water; (rhodamine B stained hydrogel);
FIG. 3 (a) change in modulus with increasing strain (0.1% -1000%) (left) and instantaneous recovery after 1000% strain deformation (right); (b) The PTOPT hydrogels showed self-healing behavior at 37 ℃ in dynamic strain cycling tests (γ=1% or 300%); (c) exhibiting the self-healing properties of a PTOPT hydrogel;
FIG. 4 (a) shows a graph of colony survival of glass plates and PTOPT hydrogel modified glass plates after co-cultivation of E.coli and Staphylococcus aureus for 3 hours; (B) Quantitative data for adhesion of E.coli and Staphylococcus aureus on different glass plates;
FIG. 5 (a) is a stress-strain curve of a PTOPT hydrogel of the invention for different tissues; (b) adhesive strength of the PTOPT hydrogel to different tissues;
FIG. 6 (a) cell viability of L929 cells after 1 day and 7 days of incubation with PTOPT hydrogel; (b) Cell viability after GES cells were incubated with PTOPT hydrogel for 1 day and 7 days, the results were shown as mean ± SD (n=6); (c) (D) 2D and 3D culturing L929 cells using 15w/v% hydrogel. Representative living and dead staining of L929 cells on day 1 after incubation with hydrogel. (e) (f) 2D and 3D culturing of GES cells using 15w/v% hydrogel. Representative living and dead body staining of GES cells on day 1 after incubation with hydrogel.
FIG. 7 (a) is a schematic diagram of gastric perforation treatment; (b) a gastric perforation treatment photomicrograph; (c) an optical photograph of the stomach 7 days after gastric perforation treatment; (d) post-operative tissue adhesion conditions; (E) H & E staining of the stomach 7 days after gastric perforation treatment. Ruler: 1000 μm.
Fig. 8 (a) representative immunofluorescence images of staining of CD31 and (b) CD34 at the wound edge. Brown staining represents blood vessels. The scale bar represents 50 μm. (c) quantification of CD31 and CD34 staining.
Detailed Description
The technical solution of the present invention will be described in further detail with reference to the accompanying drawings, but the scope of the present invention is not limited to the following description.
Example 1
S1, synthesizing pentafluorophenol acrylate (PFPA): to a 100mL three-necked flask was added pentafluorophenol (5.52 g,30 mmol) and 50mL of methylene chloride. Triethylamine (3.24 g,32 mmol) and acryloyl chloride (2.9 g,32 mmol) were then added dropwise over 30 minutes with ice bath. The ice bath was then removed and the reaction was carried out at 25℃for 4 hours. The triethylamine hydrochloride was removed by filtration using a buchner funnel, and the filtrate was concentrated. Then using 0.1M HCl solution (1X 75 mL), saturated NaHCO 3 (1X 75 mL) and brine (1X 75 mL). The organic phase was dried over MgSO 4 Drying to remove water, and concentrating. Petroleum ether is used as eluent, and the residual liquid is purified by column chromatography to obtain transparent liquid.
S2: synthesis of molecular 2- ((3-oxo-3- (phenethylamino) propyl) amino) ethyl) carbamate (TBC) containing both amine (cation) and aromatic (pi): phenethylamine (5.25 g,30 mmol) and tert-butyl N- (2-aminoethyl) carbamate (5.92 g,37 mmol) were dissolved in 25mL absolute ethanol and stirred vigorously. The mixture was stirred at 80℃under reflux and reacted for 48 hours. The solvent ethanol was dried in vacuo. The raffinate was purified by column chromatography using EAC and methanol (V: v=10:1, 1vol.% TEA) as eluent, yielding the TBC product as an orange oily liquid.
S3: synthesizing macromolecular chain transfer agent PEG-CTA: 1g of trithioester 2- (dodecyl trithiocarbonate group) -2-isobutyric acid (RAFT) 365 ) And 2mL of oxalyl chloride were added to a three-necked flask, and the mixture was dissolved in 5mL of anhydrous methylene chloride to react. After the reaction was completed, the oxalyl chloride and dichloromethane remaining in the flask were spin-dried. 5g of PEG (Mn 20000) and 50mL of anhydrous methylene chloride were then added for reaction. After the reaction is finished, n-hexane is used as a precipitator for precipitation, and the light yellow product PEG-CTA is obtained after drying.
S4: triblock polymer Poly (EG-co-PFPA) -b-PEO-b-Poly (EG-co-PFPA) (GPOGP) with active ester was synthesized by RAFT polymerization: PEG-CTA (0.518 g,0.025 mmol), PEG-MA (1.018 g,9 mmol), PFPA (0.238 g,1 mmol) and AIBN (0.002g, 0.0125 mmol) were dissolved in 8mL of 1, 4-dioxane. Nitrogen was bubbled into the whole reaction system for 15 minutes, and the reaction was carried out at 70℃for 12 hours. The solution was then precipitated drop by drop into a large amount of diethyl ether and the purification process was repeated twice. The product was filtered and dried under vacuum overnight to give a white solid.
S5: precursor triblock polymer Poly (EG-co-TBC) -b-PEO-b-Poly (EG-co-TBC) (PTOPT-Boc) was synthesized by transesterification of TBC with active ester triblock polymer GPOGP: TBC (0.67 g,2 mmol) and GPOGP (1.54 g) were dissolved in 20mL tetrahydrofuran and the reaction system bubbled with nitrogen for 20 minutes. The reaction was carried out overnight at 50℃in an oil bath. After the reaction, the reaction solution was added drop by drop to a large amount of diethyl ether to precipitate, and the purification process was repeated twice. The product was filtered and dried under vacuum overnight to give a yellowish solid.
S6: hydrolysis of the precursor triblock polymer PTOPT-Boc by trifluoroacetic acid gives a PTOPT polymer: the precursor triblock polymer PTOPT-Boc was dissolved in 10mL of methylene chloride, then 2mL of trifluoroacetic acid was added to the solution and reacted at 25℃for 4 hours. After the reaction is completed, the mixture is subjected to diethyl ether precipitation and purification twice, and is dried overnight in a room temperature vacuum drying oven, so that the target product triblock polymer PTOPT is obtained.
S7: the PTOPT polymer was dissolved in ice water at ph=2.5 to give a biocompatible injectable self-healing hydrogel: the triblock polymer PTOPT prepared was dissolved at 15% by mass in 100mmol acetic acid and 250mmol KNO at pH 2.5 3 Is used as a buffer solution of (a). Placing into a refrigerating layer of a refrigerator for 12 hours.
The hydrogel wound dressing PTOPT with injectability, temperature sensitivity, self-healing, adhesion, antibacterial adhesion and biocompatibility prepared by the method can play a positive and effective role in treating gastric perforation models. The following is a detailed analysis in conjunction with experimental data.
FIG. 1 (a) shows that the prepared PTOPT hydrogels exhibit excellent thermal response, the storage modulus (G ') and loss modulus (G') of the hydrogels intersecting at 22℃and G 'being greater than G', when the temperature is below 22℃and the PTOPT mixtures exhibit sol properties. When the temperature of the solution exceeds its 22 ℃, G' G "will cross and exceed, at which point the solution is gelatinous. Thus, the PLOPL solution became a free standing gel within 1 minute when heated to 37 ℃. This indicates that the hydrogels have a well-defined sol-gel transition Temperature (TSG). As shown in FIG. 1 (b), this gel-sol-gel transition is completely reversible, with G 'being less than G "below the TSG temperature (12 ℃) being the sol state and G' being less than G" after the temperature has been immediately raised above the TSG temperature (37 ℃) being the gel state. And several cycles may be repeated. These data indicate that hydrogels have good temperature sensitivity.
FIG. 2 is the injectability properties of the PTOPT hydrogels of example 1. The polymer solution stored at a temperature below TSG (4 ℃) was readily injected into a 37℃water bath using a 23G X3/4' syringe and a stable hydrogel was formed immediately.
FIG. 3 is the self-healing properties of the PTOPT hydrogels of example 1. As shown in FIG. 3 (a), G 'and G' are substantially unchanged over a strain range of 0.1% to 10%, and G 'is greater than G', exhibiting gel properties. When the strain increases to 25%, G' intersects G ", which is the critical strain of the hydrogel. Further increasing the strain, G "is greater than G', exhibiting sol-like properties, because when the strain exceeds the critical strain, the polymer chains are broken and the three-dimensional network of the hydrogel is broken. However, immediately after the three-dimensional network of the hydrogel is broken under a large strain (γ=1000%) condition, the small strain (γ=1%) is applied, and G' and g″ are rapidly self-recovered to the initial values (self-recovery efficiency reaches 100% within 3 min). It is shown that the mechanical properties of the hydrogel samples recover rapidly after removal of the large strain. In addition, continuous stepwise strain changes were performed between 300% and 1% to evaluate the healing capacity of the hydrogels. As shown in FIG. 3 (b), when a large breaking strain of 300% was applied for 50 seconds, G 'of the hydrogel was greater than G', indicating that the hydrogel network was broken and that a gel-sol transition occurred. However, after several seconds of hydrogel at lower strain (γ=1%) the G' of the hydrogel quickly recovered to its original value, indicating that the broken hydrogel network can be reconstructed by reversible cation-pi interactions. In addition, the self-healing properties of the hydrogels can also be observed macroscopically. As shown in fig. 3 (c), a round hydrogel was cut into two semicircles, and then the two semicircles were put together, and after 3 minutes of contact without external stimulus, the two semicircles self-healed into one body and were able to support their own weight.
FIG. 4 is the antibacterial adhesion properties of the PTOPT hydrogels of example 1. As shown in FIG. 4 (a), the colony count of E.coli and Staphylococcus aureus on the blank glass slide was much higher than that of the glass slide modified with hydrogel, which indicates that bacteria easily adhered to the surface of the glass slide and formed a microbial film, while the glass slide modified with PTOPT hydrogel had good antibacterial adhesion. This shows that bacteria easily adhere to the surface of the glass sheet and form a microbial film, whereas the glass sheet modified with the PTOPT hydrogel has excellent anti-adhesion properties, and can effectively prevent the formation of a microbial film. As shown in FIG. 4 (b), the quantitative data of the colonies showed much less bacteria on the hydrogel-modified glass sheet, indicating excellent antibacterial adhesion properties. This is due to the presence of the PEG segment in the hydrogel, which forms a strong hydration layer on the glass sheet, which acts as a barrier to bacteria and effectively prevents adhesion of bacteria.
Fig. 5 is the performance of the PTOPT hydrogels of example 1 in terms of adhesion to tissue. As shown in FIGS. 5 (a) and (b), it can be seen that the adhesion strength of the hydrogel to the pig intestine, pig stomach, pig skin and pig heart was 15.3,2.8, 20.5 and 3.3kPa in this order, which indicates that the hydrogel has good adhesion strength to various tissues. Hydrogels possess adhesion properties to various tissues that benefit from ordered cation-pi sequences in the molecular structure of the hydrogel. The hydrogel adhesion mechanism is shown in figures 3-8, and cation-pi mediated electrostatic interactions, hydrogen bonds, pi-pi stacking and hydrophobic interactions occur between the hydrogel and the tissue surface, while exhibiting good adhesion. These results indicate that hydrogels will be a promising wound dressing when formed into gels in situ on differently shaped wounds, particularly in wet and dynamic human environments.
Fig. 6 is the biocompatibility of the PTOPT hydrogel of example 1. As can be seen from FIGS. 6 (a) and (b), the activities of L929 cells and GES cells were almost stable in a certain concentration range, and all activities were maintained at about 90% or more. In vitro cytotoxicity indicated that the PTOPT hydrogels were non-toxic and were able to promote cell growth and proliferation. Furthermore, we examined their cell compatibility by using the PTOPT hydrogel for 2D/3D cell culture of L929 cells with GES cells. Cells without any treatment served as normal controls. As shown in fig. 6 (c), (D), (e) and (f), after 24 hours of culture, very few dead cells were observed in both the 2D culture group and the 3D group. No obvious difference exists in the evaluation of the density of living cells between the normal group and the hydrogel group, which shows that the PTOPT hydrogel does not reduce proliferation of cells and has good biocompatibility.
Fig. 7 is a schematic illustration of the use of the PTOPT hydrogel of example 1 for treating gastric perforation. An in vivo rat gastric perforation model was constructed as in fig. 7 (a) to demonstrate that the PTOPT hydrogels can be used as sealants for treating gastrointestinal perforation. A perforation of 5mm was made in the antrum, as described above, and as shown in FIG. 7 (b). From macroscopic images on the harvested gastric tissue incision at day 7 post-surgery, the PTOPT hydrogel showed a significant reduction in wound area for treatment, indicating good wound healing effect, as shown in fig. 7 (c). We also captured a representative macroscopic image of the abdominal adhesions. PTOPT hydrogel treated abdominal adhesions were almost absent as shown in FIG. 7 (d). H & E staining showed that the PTOPT hydrogel treatment was almost healed as shown in fig. 7 (E).
FIG. 8 is a schematic representation of the use of PTOPT hydrogel of example 1 for treating revascularization around gastric perforation wounds. We assessed fluorescence intensity at the wound edge by IF staining for CD31 and CD34 (markers of endothelial cells and angiogenesis). As shown in fig. 8, in the results of CD31 and CD34, the positive staining capillary intensity was significantly higher for the PTOPT hydrogel group than for the suture group (P < 0.01) and the incision group (P < 0.05).
Experimental results prove that: the hydrogel wound dressing PTOPT with injectability, temperature sensitivity, self-healing, adhesion, antibacterial adhesion and biocompatibility prepared by the method can play a positive and effective role in treating gastric perforation models. And further evaluate the postoperative tissue adhesion condition, granulation tissue growth, periwound angiogenesis condition and other results, the hydrogel shows good treatment effect. In addition, these hydrogels have stable rheological properties, modulus close to that of human soft tissue, good adhesion properties, self-healing properties, antibacterial adhesion, biocompatibility, etc. Therefore, the hydrogel dressing PTOPT has good application prospect in treating gastric perforation healing.
The foregoing is merely a preferred embodiment of the invention, and it is to be understood that the invention is not limited to the forms disclosed herein and is not to be considered as an exclusive use of other embodiments, but is capable of use in various other combinations, modifications, and alterations and is contemplated as falling within the scope of the invention described herein. And that modifications and variations which do not depart from the spirit and scope of the invention are intended to be within the scope of the appended claims.
Claims (10)
1. The preparation method of the injectable self-healing hydrogel dressing for treating gastric perforation is characterized by comprising the following steps of: the method comprises the following steps:
s1, synthesizing pentafluorophenol acrylate (PFPA)
Mixing pentafluorophenol and dichloromethane, dropwise adding triethylamine and acryloyl chloride under ice bath condition, then reacting at normal temperature, filtering, concentrating, washing, drying and purifying to obtain transparent liquid pentafluorophenol acrylate (PFPA);
s2 Synthesis of 2- ((3-oxo-3- (phenethylamino) propyl) amino) ethyl) carbamate (TBC)
Dissolving phenethylamine and N- (2-amino ethyl) carbamic acid tert-butyl ester into absolute ethyl alcohol, vigorously stirring, reacting, and purifying after vacuum drying to obtain orange oily liquid 2- ((3-oxygen-3- (phenethylamino) propyl) amino) ethyl) carbamate (TBC);
s3, synthesizing macromolecular chain transfer agent PEG-CTA
Adding trithio ester, 2- (dodecyl trithiocarbonate group) -2-isobutyric acid and oxalyl chloride into a three-neck flask, dissolving in anhydrous dichloromethane for reaction, spin-drying the rest oxalyl chloride and dichloromethane after the reaction is finished, adding polyethylene glycol (PEG) for reaction with the anhydrous dichloromethane, precipitating and drying after the reaction is finished to obtain a light yellow product PEG-CTA;
s4 Synthesis of triblock Polymer Poly (EG-co-PFPA) -b-PEO-b-Poly (EG-co-PFPA) (GPOGP)
Dissolving PEG-CTA prepared in S3, oligomeric ethylene glycol methacrylate (PEG-MA), PFPA prepared in S1 and Azodiisobutyronitrile (AIBN) in 1, 4-dioxane, bubbling nitrogen into the whole reaction system, and reacting; after the reaction is finished, precipitating, filtering, purifying and drying to obtain a white solid triblock polymer;
s5 Synthesis of the precursor triblock Polymer Poly (EO-co-TBC) -b-PEO-b-Poly (EO-co-TBC) (PTOPT-Boc)
Dissolving TBC prepared by S2 and triblock polymer GPOGP prepared by S4 in tetrahydrofuran, bubbling a reaction system into nitrogen, and reacting; precipitating, purifying, filtering and drying after the reaction is finished to obtain yellowish solid PTOPT-Boc;
s6, preparation of PTOPT Polymer
Dissolving a precursor triblock polymer PTOPT-Boc in dichloromethane, adding trifluoroacetic acid into the solution, reacting at room temperature, precipitating after the reaction is finished, purifying, and drying to obtain a PTOPT polymer;
s7, preparing hydrogel dressing
The PTOPT polymer was dissolved in acidic ice water to give a biocompatible injectable self-healing hydrogel dressing.
2. The method of preparing an injectable self-healing hydrogel dressing for treating gastric perforation according to claim 1, wherein: in the step S1, pentafluorophenol and methylene dichloride are added into a three-neck flask, and then triethylamine and acryloyl chloride are added dropwise for 20-60 minutes at the temperature of minus 20-10 ℃; removing ice bath, reacting at 20-40 deg.C for 3-8 hr, filtering to remove triethylamine hydrochloride, concentrating filtrate, and using HCl solution and saturated NaHCO 3 And brine wash; the organic phase is NaSO 4 Or MgSO 4 Drying to remove water, concentrating, using petroleum ether, dichloromethane or n-hexane as eluent, and purifying the residual liquid by column chromatography to obtain transparent liquid; wherein the mass ratio of the pentafluorophenol to the acryloyl chloride is (5-10): (3-5).
3. The method of preparing an injectable self-healing hydrogel dressing for treating gastric perforation according to claim 1, wherein: in the step S2, phenethylamine and N- (2-aminoethyl) carbamic acid tert-butyl ester are dissolved in 10-50 mL absolute ethyl alcohol and stirred vigorously; stirring the mixture at the reflux temperature of 60-80 ℃ for reaction for 24-48 hours; drying the solvent ethanol in vacuum; purifying residual liquid by column chromatography with petroleum ether, dichloromethane, ethyl acetate or methanol as eluent to obtain TBC product; wherein the mass ratio of the phenethylamine to the N- (2-aminoethyl) carbamic acid tert-butyl ester is (2-10): (3-9).
4. The method of preparing an injectable self-healing hydrogel dressing for treating gastric perforation according to claim 1, wherein: in the S3, the mass ratio of the 2- (dodecyl trithiocarbonate group) -2-isobutyric acid, oxalyl chloride and PEG is (1-3): (3-7): (5-20).
5. The method of preparing an injectable self-healing hydrogel dressing for treating gastric perforation according to claim 1, wherein: in the step S4, after the reaction is finished, dropwise adding the solution into diethyl ether or n-hexane for precipitation, and repeating the purification process twice; the product was filtered and dried under vacuum overnight to give GPOGP as a white solid.
6. The method of preparing an injectable self-healing hydrogel dressing for treating gastric perforation according to claim 1, wherein: in the step S5, after the reaction is finished, adding the reaction liquid into diethyl ether or normal hexane precipitant drop by drop for precipitation, and repeating the purification process twice; the product was filtered and dried under vacuum overnight to give a yellowish solid, PTOPT-Boc; wherein, the mass ratio of TBC, GPOGP and tetrahydrofuran is (1-3): (2-10): (20-50).
7. The method of preparing an injectable self-healing hydrogel dressing for treating gastric perforation according to claim 1, wherein: in the step S6, the mass ratio of PTOPT-Boc, methylene dichloride and trifluoroacetic acid is (1-3): (10-20): (1-2).
8. The method of preparing an injectable self-healing hydrogel dressing for treating gastric perforation according to claim 1, wherein: in the step S7, the prepared triblock polymer PTOPT with the concentration of 50 mg/mL-200 mg/mL is dissolved in a solution with the pH of 2.5 prepared by acetic acid/potassium nitrate or hydrochloric acid, and the solution is placed in a refrigerating layer of a refrigerator for 10-30 hours to prepare the hydrogel dressing.
9. An injectable self-healing hydrogel dressing for treating gastric perforation, characterized in that: an injectable self-healing hydrogel dressing for treating gastric perforation prepared by the method of any one of claims 1 to 8.
10. Use of an injectable self-healing hydrogel dressing for treating gastric perforation according to claim 9, characterized in that: the hydrogel dressing is used in gastric perforation wound models and other complex wound healing dressings.
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