CN116874830B - ROMP polymerization cross-linked hyaluronic acid material, preparation and application thereof - Google Patents
ROMP polymerization cross-linked hyaluronic acid material, preparation and application thereof Download PDFInfo
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- CN116874830B CN116874830B CN202310629932.1A CN202310629932A CN116874830B CN 116874830 B CN116874830 B CN 116874830B CN 202310629932 A CN202310629932 A CN 202310629932A CN 116874830 B CN116874830 B CN 116874830B
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- 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 title claims abstract description 84
- 229920002674 hyaluronan Polymers 0.000 title claims abstract description 84
- 229960003160 hyaluronic acid Drugs 0.000 title claims abstract description 84
- 238000007152 ring opening metathesis polymerisation reaction Methods 0.000 title claims abstract description 30
- 239000000463 material Substances 0.000 title claims abstract description 29
- 238000006116 polymerization reaction Methods 0.000 title claims abstract description 25
- 238000002360 preparation method Methods 0.000 title claims abstract description 17
- 239000000243 solution Substances 0.000 claims abstract description 53
- 238000006243 chemical reaction Methods 0.000 claims abstract description 31
- 239000000017 hydrogel Substances 0.000 claims abstract description 24
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims abstract description 20
- 150000001925 cycloalkenes Chemical class 0.000 claims abstract description 17
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 10
- 239000012670 alkaline solution Substances 0.000 claims abstract description 9
- 239000012266 salt solution Substances 0.000 claims abstract description 9
- GXBYFVGCMPJVJX-UHFFFAOYSA-N Epoxybutene Chemical compound C=CC1CO1 GXBYFVGCMPJVJX-UHFFFAOYSA-N 0.000 claims abstract description 7
- PNPBGYBHLCEVMK-UHFFFAOYSA-N benzylidene(dichloro)ruthenium;tricyclohexylphosphanium Chemical compound Cl[Ru](Cl)=CC1=CC=CC=C1.C1CCCCC1[PH+](C1CCCCC1)C1CCCCC1.C1CCCCC1[PH+](C1CCCCC1)C1CCCCC1 PNPBGYBHLCEVMK-UHFFFAOYSA-N 0.000 claims abstract description 7
- 239000011984 grubbs catalyst Substances 0.000 claims abstract description 7
- 238000001556 precipitation Methods 0.000 claims abstract description 7
- 238000001035 drying Methods 0.000 claims abstract description 6
- 239000000945 filler Substances 0.000 claims abstract description 6
- 230000001105 regulatory effect Effects 0.000 claims abstract description 6
- 210000004872 soft tissue Anatomy 0.000 claims abstract description 6
- 238000005406 washing Methods 0.000 claims abstract description 6
- 238000001914 filtration Methods 0.000 claims abstract description 4
- 229920002385 Sodium hyaluronate Polymers 0.000 claims description 26
- 229940010747 sodium hyaluronate Drugs 0.000 claims description 26
- YWIVKILSMZOHHF-QJZPQSOGSA-N sodium;(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- Chemical compound [Na+].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 YWIVKILSMZOHHF-QJZPQSOGSA-N 0.000 claims description 26
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 18
- 230000008961 swelling Effects 0.000 claims description 15
- 238000000034 method Methods 0.000 claims description 13
- 238000002347 injection Methods 0.000 claims description 8
- 239000007924 injection Substances 0.000 claims description 8
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 6
- 239000003513 alkali Substances 0.000 claims description 6
- KDUIUFJBNGTBMD-VXMYFEMYSA-N cyclooctatetraene Chemical compound C1=C\C=C/C=C\C=C1 KDUIUFJBNGTBMD-VXMYFEMYSA-N 0.000 claims description 6
- ZRPFJAPZDXQHSM-UHFFFAOYSA-L 1,3-bis(2,4,6-trimethylphenyl)-4,5-dihydroimidazole;dichloro-[(2-propan-2-yloxyphenyl)methylidene]ruthenium Chemical compound CC(C)OC1=CC=CC=C1C=[Ru](Cl)(Cl)=C1N(C=2C(=CC(C)=CC=2C)C)CCN1C1=C(C)C=C(C)C=C1C ZRPFJAPZDXQHSM-UHFFFAOYSA-L 0.000 claims description 4
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 4
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 4
- MGNZXYYWBUKAII-UHFFFAOYSA-N cyclohexa-1,3-diene Chemical compound C1CC=CC=C1 MGNZXYYWBUKAII-UHFFFAOYSA-N 0.000 claims description 4
- ZSWFCLXCOIISFI-UHFFFAOYSA-N cyclopentadiene Chemical compound C1C=CC=C1 ZSWFCLXCOIISFI-UHFFFAOYSA-N 0.000 claims description 4
- 238000004519 manufacturing process Methods 0.000 claims description 4
- 239000011986 second-generation catalyst Substances 0.000 claims description 4
- 239000011988 third-generation catalyst Substances 0.000 claims description 3
- FCDPQMAOJARMTG-UHFFFAOYSA-M benzylidene-[1,3-bis(2,4,6-trimethylphenyl)imidazolidin-2-ylidene]-dichlororuthenium;tricyclohexylphosphanium Chemical group C1CCCCC1[PH+](C1CCCCC1)C1CCCCC1.CC1=CC(C)=CC(C)=C1N(CCN1C=2C(=CC(C)=CC=2C)C)C1=[Ru](Cl)(Cl)=CC1=CC=CC=C1 FCDPQMAOJARMTG-UHFFFAOYSA-M 0.000 claims description 2
- 239000007853 buffer solution Substances 0.000 claims description 2
- 239000011985 first-generation catalyst Substances 0.000 claims description 2
- 230000035484 reaction time Effects 0.000 claims description 2
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 2
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 2
- 230000000379 polymerizing effect Effects 0.000 claims 3
- 239000003431 cross linking reagent Substances 0.000 abstract description 18
- 230000015556 catabolic process Effects 0.000 abstract description 6
- 238000006731 degradation reaction Methods 0.000 abstract description 6
- 238000004132 cross linking Methods 0.000 description 11
- 239000000499 gel Substances 0.000 description 9
- 238000012360 testing method Methods 0.000 description 9
- 238000011049 filling Methods 0.000 description 7
- 210000004027 cell Anatomy 0.000 description 6
- 239000002609 medium Substances 0.000 description 6
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 4
- 241000283973 Oryctolagus cuniculus Species 0.000 description 4
- 238000012423 maintenance Methods 0.000 description 4
- 239000002504 physiological saline solution Substances 0.000 description 4
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 3
- 239000007864 aqueous solution Substances 0.000 description 3
- 238000004113 cell culture Methods 0.000 description 3
- 238000010382 chemical cross-linking Methods 0.000 description 3
- 230000001276 controlling effect Effects 0.000 description 3
- 239000012043 crude product Substances 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- 238000002474 experimental method Methods 0.000 description 3
- 239000013642 negative control Substances 0.000 description 3
- 230000003204 osmotic effect Effects 0.000 description 3
- 230000004083 survival effect Effects 0.000 description 3
- 239000004593 Epoxy Substances 0.000 description 2
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 2
- 240000007711 Peperomia pellucida Species 0.000 description 2
- 239000003153 chemical reaction reagent Substances 0.000 description 2
- 231100000263 cytotoxicity test Toxicity 0.000 description 2
- 230000007547 defect Effects 0.000 description 2
- 238000011161 development Methods 0.000 description 2
- 210000005069 ears Anatomy 0.000 description 2
- WGCNASOHLSPBMP-UHFFFAOYSA-N hydroxyacetaldehyde Natural products OCC=O WGCNASOHLSPBMP-UHFFFAOYSA-N 0.000 description 2
- 239000013641 positive control Substances 0.000 description 2
- 239000000758 substrate Substances 0.000 description 2
- OQILSTRGJVCFAG-UHFFFAOYSA-N 1-(oxiran-2-ylmethoxy)butan-1-ol Chemical compound CCCC(O)OCC1CO1 OQILSTRGJVCFAG-UHFFFAOYSA-N 0.000 description 1
- 206010003694 Atrophy Diseases 0.000 description 1
- 206010007269 Carcinogenicity Diseases 0.000 description 1
- 239000006144 Dulbecco’s modified Eagle's medium Substances 0.000 description 1
- 241000283977 Oryctolagus Species 0.000 description 1
- 239000004698 Polyethylene Substances 0.000 description 1
- 239000002202 Polyethylene glycol Substances 0.000 description 1
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical group [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 1
- 230000002159 abnormal effect Effects 0.000 description 1
- 238000002835 absorbance Methods 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 230000037444 atrophy Effects 0.000 description 1
- 230000003796 beauty Effects 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- 230000007670 carcinogenicity Effects 0.000 description 1
- 231100000260 carcinogenicity Toxicity 0.000 description 1
- 230000010261 cell growth Effects 0.000 description 1
- 239000006285 cell suspension Substances 0.000 description 1
- 230000000052 comparative effect Effects 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 238000012258 culturing Methods 0.000 description 1
- 231100000135 cytotoxicity Toxicity 0.000 description 1
- 230000003013 cytotoxicity Effects 0.000 description 1
- 230000007423 decrease Effects 0.000 description 1
- GYZLOYUZLJXAJU-UHFFFAOYSA-N diglycidyl ether Chemical compound C1OC1COCC1CO1 GYZLOYUZLJXAJU-UHFFFAOYSA-N 0.000 description 1
- AFOSIXZFDONLBT-UHFFFAOYSA-N divinyl sulfone Chemical compound C=CS(=O)(=O)C=C AFOSIXZFDONLBT-UHFFFAOYSA-N 0.000 description 1
- 239000003792 electrolyte Substances 0.000 description 1
- 230000002349 favourable effect Effects 0.000 description 1
- 210000002950 fibroblast Anatomy 0.000 description 1
- 150000004676 glycans Chemical class 0.000 description 1
- 210000002216 heart Anatomy 0.000 description 1
- 210000003734 kidney Anatomy 0.000 description 1
- 238000002386 leaching Methods 0.000 description 1
- 210000004185 liver Anatomy 0.000 description 1
- 230000001050 lubricating effect Effects 0.000 description 1
- 210000004072 lung Anatomy 0.000 description 1
- 230000004060 metabolic process Effects 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 235000016709 nutrition Nutrition 0.000 description 1
- 230000035764 nutrition Effects 0.000 description 1
- 210000000056 organ Anatomy 0.000 description 1
- 230000035699 permeability Effects 0.000 description 1
- 230000035790 physiological processes and functions Effects 0.000 description 1
- -1 polyethylene Polymers 0.000 description 1
- 229920000573 polyethylene Polymers 0.000 description 1
- 229920001223 polyethylene glycol Polymers 0.000 description 1
- 229920001282 polysaccharide Polymers 0.000 description 1
- 239000005017 polysaccharide Substances 0.000 description 1
- 230000001737 promoting effect Effects 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- 239000002356 single layer Substances 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 210000000952 spleen Anatomy 0.000 description 1
- 230000001954 sterilising effect Effects 0.000 description 1
- 238000004659 sterilization and disinfection Methods 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 238000003860 storage Methods 0.000 description 1
- 239000006228 supernatant Substances 0.000 description 1
- 230000002522 swelling effect Effects 0.000 description 1
- 239000012085 test solution Substances 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 230000002792 vascular Effects 0.000 description 1
- 238000005303 weighing Methods 0.000 description 1
- 230000029663 wound healing Effects 0.000 description 1
- 230000037303 wrinkles Effects 0.000 description 1
Classifications
-
- 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
- A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
- A61L27/14—Macromolecular materials
- A61L27/20—Polysaccharides
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
- A61L27/50—Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
- A61L27/52—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
- A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
- A61L27/50—Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
- A61L27/58—Materials at least partially resorbable by the body
-
- 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
-
- 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
-
- 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
- C08J3/24—Crosslinking, e.g. vulcanising, of macromolecules
-
- 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
-
- 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
- A61L2430/00—Materials or treatment for tissue regeneration
- A61L2430/34—Materials or treatment for tissue regeneration for soft tissue reconstruction
-
- 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
- C08J2305/00—Characterised by the use of polysaccharides or of their derivatives not provided for in groups C08J2301/00 or C08J2303/00
- C08J2305/08—Chitin; Chondroitin sulfate; Hyaluronic acid; Derivatives thereof
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- Chemical & Material Sciences (AREA)
- Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Life Sciences & Earth Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Dispersion Chemistry (AREA)
- Transplantation (AREA)
- Animal Behavior & Ethology (AREA)
- Oral & Maxillofacial Surgery (AREA)
- Dermatology (AREA)
- Veterinary Medicine (AREA)
- Epidemiology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Polymers & Plastics (AREA)
- Organic Chemistry (AREA)
- Molecular Biology (AREA)
- Engineering & Computer Science (AREA)
- Biochemistry (AREA)
- Materials Engineering (AREA)
- Polysaccharides And Polysaccharide Derivatives (AREA)
Abstract
The invention provides a ROMP polymerization cross-linked hyaluronic acid material, and preparation and application thereof. The preparation method of the hyaluronic acid material comprises the following steps: adding hyaluronic acid into an alkaline solution, and then adding epoxybutene for reaction to obtain a reaction solution I; adjusting the pH of the reaction solution I to 3-5, then adding cycloolefin solution and Grubbs catalyst, and carrying out ROMP polymerization reaction to obtain crosslinked hyaluronic acid reaction solution II; and (3) regulating the pH value of the obtained crosslinked hyaluronic acid reaction solution II to 6-8, adding ethanol for precipitation, filtering, washing and drying to obtain the crosslinked hyaluronic acid. Compared with the prior hyaluronic acid cross-linking agent, the invention has the characteristics of lower residual amount of the cross-linking agent, better biocompatibility and degradation safety by utilizing cycloolefin polymerization. The cross-linked hyaluronic acid prepared by the invention can be dissolved in water or salt solution to prepare various hydrogels for preparing soft tissue fillers.
Description
Technical Field
The invention belongs to the technical field of soft tissue filling, and particularly relates to a ROMP polymerization crosslinked hyaluronic acid material, and preparation and application thereof.
Background
Hyaluronic acid is a polysaccharide widely existing in human bodies, and the unique molecular structure and physicochemical properties of hyaluronic acid show various physiological functions in the bodies, such as lubricating joints, regulating the permeability of vascular walls, regulating proteins, diffusing and running water electrolytes, promoting wound healing and the like. Hyaluronic acid has very good water locking effect. The human skin contains a large amount of hyaluronic acid for improving skin nutrition and metabolism, and making skin tender, smooth and elastic. However, with age, the content of hyaluronic acid in skin gradually decreases, leading to skin wrinkles and atrophy, and at this time, hyaluronic acid needs to be injected to perform the function of filling beauty. Since natural extracted hyaluronic acid is very rapidly degraded when injected into a human body, hyaluronic acid is generally injected subcutaneously after being crosslinked to extend degradation time.
At present, there are two main methods for crosslinking hyaluronic acid: physical crosslinking and chemical crosslinking, wherein the crosslinking method commonly used is chemical crosslinking. The chemical crosslinking method is to uniformly mix a crosslinking agent and hyaluronic acid in a solution, and carry out crosslinking reaction at a constant temperature, wherein the common crosslinking agents are as follows: butanediol glycidyl ether, polyethylene glycol glycidyl ether, divinyl sulfone and the like, but the cross-linking agents are all organic reagents, have strong toxicity and carcinogenicity, and the space network structure after cross-linking has a wrapping effect on unreacted cross-linking agents, so that the removal difficulty is high. In order to solve the above problems, there is also a patent report on the development of a novel crosslinking agent, for example, a branched polyhydric glycol epoxy derivative crosslinking agent having a structure represented by the following formula I is provided in chinese patent document CN109096483 a. Chinese patent document CN107880282A provides a water-soluble polyhydric glycol epoxy derivative cross-linking agent with a structure shown in the following formula II, but the preparation method of the cross-linking agent is complex and has high cost
At present, the existing methods for cross-linking hyaluronic acid have certain defects, such as difficult removal of a large amount of cross-linking agents, difficult control of reaction efficiency, insufficient stability and the like. Therefore, the development of a novel crosslinking process for preparing hyaluronic acid gels is of great importance.
Disclosure of Invention
Aiming at the defects of the prior art, the invention provides a ROMP polymerization reaction cross-linked hyaluronic acid material, and preparation and application thereof. Compared with the current method for crosslinking hyaluronic acid gel crosslinking agent, the method for crosslinking hyaluronic acid gel by utilizing the ROMP polymerization reaction has the characteristics of lower residual quantity of the crosslinking agent, better biocompatibility and degradation safety. The cross-linked hyaluronic acid material prepared by the invention can be dissolved in water or salt solution to prepare hydrogel with biocompatibility, safety and certain mechanical properties, has pH and osmotic pressure suitable for human body, and can be used for preparing soft tissue filler.
Description of the terminology:
room temperature: has the meaning known in the art, meaning 25.+ -. 5 ℃.
The technical scheme of the invention is as follows:
a preparation method of a roMP polymerization reaction cross-linked hyaluronic acid material comprises the following steps:
(1) Adding hyaluronic acid into an alkaline solution, and then adding epoxybutene for reaction to obtain a reaction solution I;
(2) Adjusting the pH value of the reaction solution I obtained in the step (1) to 3-5, then adding cycloolefin solution and Grubbs catalyst, and carrying out ROMP polymerization reaction to obtain crosslinked hyaluronic acid reaction solution II;
(3) And (3) regulating the pH value of the crosslinked hyaluronic acid reaction solution II obtained in the step (2) to 6-8, adding ethanol for precipitation, filtering, washing and drying to obtain the cross-linked hyaluronic acid material of the ROMP polymerization reaction.
According to the invention, the hyaluronic acid in step (1) preferably has a molecular weight of 10-3000kDa, more preferably 100-2500kDa.
Preferably according to the present invention, the alkaline solution in step (1) is sodium hydroxide solution, potassium hydroxide solution or sodium carbonate solution; the mass fraction of the alkaline solution is 0.5-2%; the ratio of the volume of the alkaline solution to the mass of the hyaluronic acid is 20-100 mL/1 g.
According to the invention, the mass ratio of epoxybutene to hyaluronic acid in step (1) is preferably 0.02-0.2:1, more preferably 0.05-0.1:1.
Preferably according to the invention, the reaction time in step (1) is from 4 to 16 hours; the temperature of the reaction was room temperature.
According to the present invention, preferably, in the step (2), the pH of the reaction solution I is adjusted to 3 to 5 using an HCl solution having a concentration of 10 to 200mmol/L.
According to a preferred embodiment of the invention, the cycloolefin in step (2) is cyclooctatetraene, cyclopentadiene or cyclohexadiene; the mass ratio of cycloolefin to hyaluronic acid is 0.01-0.5:1, more preferably 0.1-0.2:1.
According to the present invention, it is preferable that the cycloolefin solution in the step (2) is obtained by dissolving cycloolefin in tetrahydrofuran, and the concentration of the cycloolefin solution is 0.01 to 0.05g/mL.
Preferably, according to the present invention, the Grubbs catalyst in step (2) is a Grubbs second generation catalyst, a Grubbs third generation catalyst, a Hoveyda-Grubbs first generation catalyst or a Hoveyda-Grubbs second generation catalyst; the adding mass of the Grubbs catalyst is 0.1-1 per mill of the mass of the hyaluronic acid.
According to the present invention, preferably, the temperature of the ROMP polymerization in step (2) is 20 to 60 ℃, and the time of the ROMP polymerization is 0.5 to 6 hours.
According to the present invention, preferably, in the step (3), the pH of the crosslinked hyaluronic acid reaction solution II is adjusted to 6-8 using an alkali solution; the alkali solution is sodium hydroxide solution or potassium hydroxide solution; the mass fraction of the alkali solution is 0.5-1.5%.
According to the invention, the ratio of the added volume of the ethanol to the volume of the crosslinked hyaluronic acid reaction solution II in the step (3) is preferably 2-10:1; the time of the precipitation is 2-24h.
Preferably according to the invention, the washing in step (3) is 3-5 times with ethanol; the drying is carried out at 30-60 ℃ for 4-24h.
The invention also provides a ROMP polymerization cross-linked hyaluronic acid material prepared by the preparation method.
The invention also provides a cross-linked sodium hyaluronate hydrogel, which is obtained by adding the cross-linked hyaluronic acid material obtained by the ROMP polymerization reaction into water or salt solution and swelling; preferably, the ratio of the volume of the water or salt solution to the mass of the ROMP polymerized crosslinked hyaluronic acid material is 30-100ml:1g; the salt solution is PBS buffer solution; the swelling time is 2-4h. The hydrogel provided by the invention has biocompatibility, safety and certain mechanical properties, and has pH and osmotic pressure suitable for human bodies.
According to the invention, the cross-linked sodium hyaluronate hydrogel is applied to the preparation of soft tissue injection fillers. The injection filler obtained by the invention takes the hyaluronic acid crosslinked by the ROMP polymerization reaction as a main component, has pH and osmotic pressure suitable for human bodies, and can be injected into the parts needing to be filled, such as the face, the hands, the neck and the like, through high-pressure sterilization.
The invention has the technical characteristics and beneficial effects that:
1. the invention applies the ROMP reaction to the preparation of the crosslinked hyaluronic acid material, and the prepared hydrogel prepared by dissolving the crosslinked hyaluronic acid material in water or salt solution has better biocompatibility and degradation safety compared with the hyaluronic acid hydrogel studied at present, and the prepared crosslinked hyaluronic acid hydrogel can be used for preparing soft tissue fillers.
2. Compared with the current method for crosslinking hyaluronic acid crosslinking agent, the method for crosslinking hyaluronic acid by utilizing the ROMP polymerization reaction obtains the solid crosslinked sodium hyaluronate material by means of alcohol precipitation, is favorable for storage and transportation, and has the characteristics of lower residual quantity of the crosslinking agent, better biocompatibility and degradation safety.
3. The preparation method of the crosslinked hyaluronic acid hydrogel can adjust the swelling degree, degradation rate and other performances of the crosslinked hyaluronic acid hydrogel by controlling the molecular weight of hyaluronic acid and the dosage of cycloolefin
Detailed Description
The following description of the embodiments of the invention is intended to be illustrative of the invention and is not intended to be limiting in any way. The method of the invention is a conventional method in the art unless specifically stated otherwise. The reagents of the invention are commercially available unless otherwise specified.
Example 1
A preparation method of crosslinked sodium hyaluronate hydrogel comprises the following steps:
(1) Weighing 2g of hyaluronic acid with the molecular weight of 1000kDa, adding into 100mL of NaOH aqueous solution with the mass fraction of 1%, adding 0.1g of epoxybutene, uniformly stirring, and reacting at room temperature for 6 hours to increase C=C bonds on sodium hyaluronate molecules to obtain a reaction solution I;
(2) 0.2g of cyclooctatetraene was dissolved in 10mL of THF to obtain cyclooctatetraene solution;
(3) Regulating the pH value of the reaction solution I obtained in the step (1) to 4 by using an aqueous solution of HCl with the concentration of 0.01mol/L, then adding the cyclooctatetraene solution obtained in the step (2), adding 1mg of Grubbs third-generation catalyst, and reacting for 2 hours at the temperature of 40 ℃ to obtain a crosslinked hyaluronic acid reaction solution II;
(4) Adjusting the pH value of the crosslinked hyaluronic acid reaction solution II in the step (3) to 7 by using a sodium hydroxide aqueous solution with the mass fraction of 1%, and adding 600mL of ethanol to precipitate for 6 hours to obtain a crosslinked sodium hyaluronate crude product;
(5) Filtering, collecting a crude product of crosslinked hyaluronic acid, washing with ethanol for 3 times, and drying at 40 ℃ for 8 hours to obtain a crosslinked sodium hyaluronate material, namely the crosslinked hyaluronic acid material obtained by ROMP polymerization reaction;
(6) And (3) adding 2g of the crosslinked sodium hyaluronate material prepared in the step (5) into 100mL of PBS solution, and swelling for 3h to prepare the crosslinked sodium hyaluronate hydrogel.
EXAMPLE 2 preparation of crosslinked sodium hyaluronate hydrogel
Hyaluronic acid having a molecular weight of 2000kDa was used, and the other conditions were the same as in example 1.
EXAMPLE 3 preparation of crosslinked sodium hyaluronate hydrogel
The amount of cyclooctatetraene added in the step (2) was 0.4g, and the other conditions were the same as in example 1.
Comparative example 1
As described in example 1, except that the pH was adjusted to 7 in the step (3), the reaction solution II obtained could not be subjected to alcohol precipitation in the step (4) to obtain a crude product of crosslinked sodium hyaluronate.
Test example 1: swelling degree Experimental analysis
For evaluating the swelling property of the crosslinked sodium hyaluronate hydrogel in the present invention, the dried gel was weighed and recorded as M1 using an electronic balance, then the gel was put in physiological saline to perform a swelling test at 37 ℃, and after 0.5h, the excess water was sucked up with filter paper, and the weighed and recorded as M2, and the swelling degree was calculated by (M2-M1)/M1, respectively.
Table 1 results of swelling degree for each example
| Group of | Swelling degree |
| Example 1 | 45.6 |
| Example 2 | 28.3 |
| Example 3 | 34.2 |
As can be seen from the data in table 1, the obtained gels have different swelling degrees by using sodium hyaluronate with different molecular weights as a substrate; sodium hyaluronate with the same molecular weight is used as a substrate, the dosage of the cross-linking agent is different, and the swelling degree of the finally obtained gel is also different. Thus, it was found that the gel swelling degree was related to the molecular weight of sodium hyaluronate and the amount of the crosslinking agent, and that a crosslinked sodium hyaluronate hydrogel having a target swelling degree could be obtained by controlling the molecular weight of hyaluronic acid and the amount of the crosslinking agent.
Test example 2: cytotoxicity test
The crosslinked sodium hyaluronate gels prepared in examples 1-3 were each subjected to a cytotoxicity test as follows:
1.0g of each sample was weighed and placed in 30mL of a cell culture solution (10% NBCS,1% PS DMEM), and the extract was prepared by shaking and leaching at 60rpm for 24 hours at 37℃and the supernatant was centrifuged to obtain a test solution. Using mouse fibroblast L929, the experiment was carried out with cells that grew vigorously by passage 48-72h to prepare a cell suspension (concentration 1X 10 5 And (3) incubating for 24 hours in an incubator to form nearly-confluent monolayer cells, ensuring that the cell growth of each well plate is relatively equal, sucking out the culture solution, adding 100 mu L of the to-be-detected solution into each row of 6 wells respectively, placing the cells in the cell incubator for culturing for 24 hours, and observing the cell morphology of each well plate under a microscope. After removal of the medium, 50. Mu. LMTT medium was added, and after 2h of continuous culture in a cell incubator, isopropanol was added, and the absorbance was measured with a microplate reader according to the formula: survival (%) = (100×od Sample of ）/OD Medium (D) Survival was calculated.
Negative, positive and medium controls were set. The positive control group is 10% DMSO solution, which is prepared for use at present; the negative control group was polyethylene at a rate of 6cm 2 The ratio of negative control to 1mL of cell culture solution is leached for 24 hours at 37 ℃ under the condition of 60 rmp; the medium control group was a cell culture broth without test sample, and the same test group was treated.
TABLE 2 cytotoxicity results for the examples
| Group of | Survival (%) |
| Example 1 | 95% |
| Example 2 | 93% |
| Example 3 | 94% |
| Medium control group | 100% |
| Negative control group | 95% |
| Positive control group | 6% |
Test example 3: skin filling test of Rabbit ear
In order to maintain the filling effect of the crosslinked sodium hyaluronate hydrogel of the present invention, the back skin of rabbit was subjected to intradermal injection, and the skin doming state was observed for a period of time. Healthy New Zealand rabbits were selected 3, 1 as a blank control without injection and 2 as a skin filling test. 5 injection sites were selected for the ears of test rabbits, and 0.1mL of physiological saline and the crosslinked sodium hyaluronate hydrogels prepared in example 1, example 2, and example 3 were injected, respectively. The rabbit ear skin was observed 24 weeks after injection, and the time for the skin at the filling site to maintain the elevated state was recorded.
TABLE 3 skin fill maintenance time for various embodiments
| Group of | Maintenance time |
| Physiological saline | < 1 week |
| Example 1 | For 10 weeks |
| Example 2 | 15 weeks |
| Example 3 | For 16 weeks |
After the crosslinked sodium hyaluronate hydrogel is injected into the skin of rabbit ears, the physiological saline group and the example group can generate local slight redness at the injection site and can recover within 3-7 days. After the experiment is finished, compared with a blank control group, the rabbit blood of the experiment group is normal, and main organs such as heart, liver, spleen, lung, kidney and the like are not obviously abnormal.
Compared with the normal saline group, the filling maintenance time of the cross-linked sodium hyaluronate hydrogel of the embodiment can reach about 10-16 weeks, and the cross-linked sodium hyaluronate hydrogel with different maintenance time can be obtained by controlling the molecular weight of hyaluronic acid and the dosage of cycloolefin.
Claims (10)
1. A preparation method of a roMP polymerization reaction cross-linked hyaluronic acid material comprises the following steps:
(1) Adding hyaluronic acid into an alkaline solution, and then adding epoxybutene for reaction to obtain a reaction solution I; the molecular weight of the hyaluronic acid is 10-3000kDa; the mass ratio of the epoxybutene to the hyaluronic acid is 0.02-0.2:1;
(2) Adjusting the pH value of the reaction solution I obtained in the step (1) to 3-5, then adding cycloolefin solution and Grubbs catalyst, and carrying out ROMP polymerization reaction to obtain crosslinked hyaluronic acid reaction solution II; the mass ratio of the cycloolefin to the hyaluronic acid is 0.01-0.5:1;
(3) And (3) regulating the pH value of the crosslinked hyaluronic acid reaction solution II obtained in the step (2) to 6-8, adding ethanol for precipitation, filtering, washing and drying to obtain the cross-linked hyaluronic acid material of the ROMP polymerization reaction.
2. The method of preparing a ROMP polymerization crosslinked hyaluronic acid material according to claim 1, wherein the molecular weight of the hyaluronic acid in step (1) is 100-2500kDa;
the alkaline solution is sodium hydroxide solution, potassium hydroxide solution or sodium carbonate solution; the mass fraction of the alkaline solution is 0.5-2%; the ratio of the volume of the alkaline solution to the mass of the hyaluronic acid is 20-100 mL/1 g.
3. The method for preparing a ROMP polymerization crosslinked hyaluronic acid material according to claim 1, wherein the mass ratio of epoxybutene to hyaluronic acid in step (1) is 0.05-0.1:1;
the reaction time is 4-16h; the temperature of the reaction was room temperature.
4. The method for producing a ROMP polymerization-crosslinked hyaluronic acid material according to claim 1, wherein in the step (2), the pH of the reaction solution I is adjusted to 3 to 5 using an HCl solution having a concentration of 10 to 200mmol/L;
the cycloolefin is cyclooctatetraene, cyclopentadiene or cyclohexadiene; the mass ratio of the cycloolefin to the hyaluronic acid is 0.1-0.2:1.
5. The method for producing a ROMP polymerization-crosslinked hyaluronic acid material according to claim 1, wherein the cycloolefin solution in the step (2) is obtained by dissolving cycloolefin in tetrahydrofuran, and the concentration of the cycloolefin solution is 0.01 to 0.05g/mL;
the Grubbs catalyst is a Grubbs second-generation catalyst, a Grubbs third-generation catalyst, a Hoveyda-Grubbs first-generation catalyst or a Hoveyda-Grubbs second-generation catalyst; the adding mass of the Grubbs catalyst is 0.1-1 per mill of the mass of the hyaluronic acid.
6. The method for preparing a ROMP polymerizing cross-linked hyaluronic acid material according to claim 1, wherein the ROMP polymerizing temperature in the step (2) is 20-60 ℃, and the ROMP polymerizing time is 0.5-6 hours.
7. The method for producing a ROMP polymerization-crosslinked hyaluronic acid material according to claim 1, wherein the pH of the crosslinked hyaluronic acid reaction solution II is adjusted to 6 to 8 in the step (3) using an alkali solution; the alkali solution is sodium hydroxide solution or potassium hydroxide solution; the mass fraction of the alkali solution is 0.5-1.5%;
the ratio of the added volume of the ethanol to the volume of the crosslinked hyaluronic acid reaction solution II is 2-10:1; the time of the precipitation is 2-24 hours;
the washing is to wash 3-5 times with ethanol; the drying is carried out at 30-60 ℃ for 4-24h.
8. A ROMP polymerized cross-linked hyaluronic acid material prepared by the method of claim 1.
9. A crosslinked sodium hyaluronate hydrogel, wherein the crosslinked sodium hyaluronate hydrogel is prepared by dissolving the ROMP polymerization crosslinked hyaluronic acid material of claim 8 in water or a salt solution, and swelling; the ratio of the volume of the water or salt solution to the mass of the ROMP polymerization crosslinked hyaluronic acid material is 30-100ml:1g; the salt solution is PBS buffer solution; the swelling time is 2-4h.
10. Use of the crosslinked sodium hyaluronate hydrogel of claim 9 in the preparation of a soft tissue injection filler.
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