CN106243410B - A kind of hydroxyethyl chitosan/hyaluronic acid double-network hydrogel and preparation method thereof - Google Patents
A kind of hydroxyethyl chitosan/hyaluronic acid double-network hydrogel and preparation method thereof Download PDFInfo
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- CN106243410B CN106243410B CN201610623929.9A CN201610623929A CN106243410B CN 106243410 B CN106243410 B CN 106243410B CN 201610623929 A CN201610623929 A CN 201610623929A CN 106243410 B CN106243410 B CN 106243410B
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- hyaluronic acid
- hydroxyethyl chitosan
- glycidyl methacrylate
- hydrogel
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- 229920001661 Chitosan Polymers 0.000 title claims abstract description 170
- GAWIXWVDTYZWAW-UHFFFAOYSA-N C[CH]O Chemical group C[CH]O GAWIXWVDTYZWAW-UHFFFAOYSA-N 0.000 title claims abstract description 146
- 229920002674 hyaluronan Polymers 0.000 title claims abstract description 145
- 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 136
- 229960003160 hyaluronic acid Drugs 0.000 title claims abstract description 136
- 239000000017 hydrogel Substances 0.000 title claims abstract description 117
- 238000002360 preparation method Methods 0.000 title claims abstract description 39
- VOZRXNHHFUQHIL-UHFFFAOYSA-N glycidyl methacrylate Chemical compound CC(=C)C(=O)OCC1CO1 VOZRXNHHFUQHIL-UHFFFAOYSA-N 0.000 claims abstract description 102
- 239000007864 aqueous solution Substances 0.000 claims abstract description 19
- 238000006116 polymerization reaction Methods 0.000 claims abstract description 18
- 239000002253 acid Substances 0.000 claims abstract description 12
- 238000000034 method Methods 0.000 claims abstract description 10
- 230000008961 swelling Effects 0.000 claims abstract description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 87
- 239000000243 solution Substances 0.000 claims description 56
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 43
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 36
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 claims description 34
- 230000003252 repetitive effect Effects 0.000 claims description 30
- 238000000502 dialysis Methods 0.000 claims description 23
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 19
- 238000006243 chemical reaction Methods 0.000 claims description 19
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 18
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 18
- CERQOIWHTDAKMF-UHFFFAOYSA-N Methacrylic acid Chemical compound CC(=C)C(O)=O CERQOIWHTDAKMF-UHFFFAOYSA-N 0.000 claims description 18
- 239000008367 deionised water Substances 0.000 claims description 18
- 229910021641 deionized water Inorganic materials 0.000 claims description 18
- 238000013019 agitation Methods 0.000 claims description 16
- 239000000499 gel Substances 0.000 claims description 14
- 125000001301 ethoxy group Chemical group [H]C([H])([H])C([H])([H])O* 0.000 claims description 13
- 238000004108 freeze drying Methods 0.000 claims description 13
- 150000004676 glycans Chemical class 0.000 claims description 11
- 239000000203 mixture Substances 0.000 claims description 11
- KJESGYZFVCIMDE-UHFFFAOYSA-N 1-chloroethanol Chemical compound CC(O)Cl KJESGYZFVCIMDE-UHFFFAOYSA-N 0.000 claims description 9
- 235000019441 ethanol Nutrition 0.000 claims description 9
- KIUKXJAPPMFGSW-MNSSHETKSA-N hyaluronan Chemical compound CC(=O)N[C@H]1[C@H](O)O[C@H](CO)[C@@H](O)C1O[C@H]1[C@H](O)[C@@H](O)[C@H](O[C@H]2[C@@H](C(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-MNSSHETKSA-N 0.000 claims description 9
- 229940099552 hyaluronan Drugs 0.000 claims description 9
- 235000015110 jellies Nutrition 0.000 claims description 9
- 239000008274 jelly Substances 0.000 claims description 9
- 238000002156 mixing Methods 0.000 claims description 9
- 229910052757 nitrogen Inorganic materials 0.000 claims description 9
- JRMUNVKIHCOMHV-UHFFFAOYSA-M tetrabutylammonium bromide Chemical compound [Br-].CCCC[N+](CCCC)(CCCC)CCCC JRMUNVKIHCOMHV-UHFFFAOYSA-M 0.000 claims description 9
- 238000001291 vacuum drying Methods 0.000 claims description 9
- 230000006196 deacetylation Effects 0.000 claims description 8
- 238000003381 deacetylation reaction Methods 0.000 claims description 8
- 230000006835 compression Effects 0.000 claims description 6
- 238000007906 compression Methods 0.000 claims description 6
- QGZKDVFQNNGYKY-UHFFFAOYSA-O Ammonium Chemical compound [NH4+] QGZKDVFQNNGYKY-UHFFFAOYSA-O 0.000 claims description 4
- 239000003292 glue Substances 0.000 claims description 4
- 239000011148 porous material Substances 0.000 claims description 4
- 125000005456 glyceride group Chemical group 0.000 claims description 3
- 239000007788 liquid Substances 0.000 claims description 2
- 230000014759 maintenance of location Effects 0.000 claims description 2
- 239000012956 1-hydroxycyclohexylphenyl-ketone Substances 0.000 claims 1
- MQDJYUACMFCOFT-UHFFFAOYSA-N bis[2-(1-hydroxycyclohexyl)phenyl]methanone Chemical compound C=1C=CC=C(C(=O)C=2C(=CC=CC=2)C2(O)CCCCC2)C=1C1(O)CCCCC1 MQDJYUACMFCOFT-UHFFFAOYSA-N 0.000 claims 1
- 239000006188 syrup Substances 0.000 claims 1
- 235000020357 syrup Nutrition 0.000 claims 1
- RKHXQBLJXBGEKF-UHFFFAOYSA-M tetrabutylphosphanium;bromide Chemical compound [Br-].CCCC[P+](CCCC)(CCCC)CCCC RKHXQBLJXBGEKF-UHFFFAOYSA-M 0.000 claims 1
- 238000005303 weighing Methods 0.000 claims 1
- 206010028980 Neoplasm Diseases 0.000 abstract description 6
- 238000012377 drug delivery Methods 0.000 abstract description 4
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- 230000008929 regeneration Effects 0.000 abstract description 3
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- 230000015572 biosynthetic process Effects 0.000 abstract description 2
- 238000007598 dipping method Methods 0.000 abstract 1
- 239000000047 product Substances 0.000 description 21
- 235000009508 confectionery Nutrition 0.000 description 14
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- 210000004027 cell Anatomy 0.000 description 12
- 230000009977 dual effect Effects 0.000 description 11
- 108010037362 Extracellular Matrix Proteins Proteins 0.000 description 10
- 102000010834 Extracellular Matrix Proteins Human genes 0.000 description 10
- 210000002744 extracellular matrix Anatomy 0.000 description 10
- SVPXDRXYRYOSEX-UHFFFAOYSA-N bentoquatam Chemical compound O.O=[Si]=O.O=[Al]O[Al]=O SVPXDRXYRYOSEX-UHFFFAOYSA-N 0.000 description 9
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 8
- IDGUHHHQCWSQLU-UHFFFAOYSA-N ethanol;hydrate Chemical compound O.CCO IDGUHHHQCWSQLU-UHFFFAOYSA-N 0.000 description 7
- 230000008859 change Effects 0.000 description 6
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 6
- RPQRDASANLAFCM-UHFFFAOYSA-N oxiran-2-ylmethyl prop-2-enoate Chemical compound C=CC(=O)OCC1CO1 RPQRDASANLAFCM-UHFFFAOYSA-N 0.000 description 6
- SWLVFNYSXGMGBS-UHFFFAOYSA-N ammonium bromide Chemical compound [NH4+].[Br-] SWLVFNYSXGMGBS-UHFFFAOYSA-N 0.000 description 5
- 239000004615 ingredient Substances 0.000 description 5
- 239000000463 material Substances 0.000 description 5
- 210000001519 tissue Anatomy 0.000 description 5
- QNODIIQQMGDSEF-UHFFFAOYSA-N (1-hydroxycyclohexyl)-phenylmethanone Chemical class C=1C=CC=CC=1C(=O)C1(O)CCCCC1 QNODIIQQMGDSEF-UHFFFAOYSA-N 0.000 description 4
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 4
- OKUSWAGOKUGEDX-UHFFFAOYSA-N C(CCC)Br(CCCC)(CCCC)CCCC Chemical compound C(CCC)Br(CCCC)(CCCC)CCCC OKUSWAGOKUGEDX-UHFFFAOYSA-N 0.000 description 3
- 239000002994 raw material Substances 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- 238000010792 warming Methods 0.000 description 3
- 229920006318 anionic polymer Polymers 0.000 description 2
- 230000015556 catabolic process Effects 0.000 description 2
- 229920006317 cationic polymer Polymers 0.000 description 2
- 239000003795 chemical substances by application Substances 0.000 description 2
- 238000006731 degradation reaction Methods 0.000 description 2
- 238000005516 engineering process Methods 0.000 description 2
- 230000012010 growth Effects 0.000 description 2
- -1 hydroxyl Ethyl Chemical group 0.000 description 2
- 150000002576 ketones Chemical class 0.000 description 2
- 229920001282 polysaccharide Polymers 0.000 description 2
- 239000005017 polysaccharide Substances 0.000 description 2
- 239000013589 supplement Substances 0.000 description 2
- JCZPMGDSEAFWDY-SQOUGZDYSA-N (2r,3s,4r,5r)-2,3,4,5,6-pentahydroxyhexanamide Chemical compound NC(=O)[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO JCZPMGDSEAFWDY-SQOUGZDYSA-N 0.000 description 1
- 102000008186 Collagen Human genes 0.000 description 1
- 108010035532 Collagen Proteins 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- VGGSQFUCUMXWEO-UHFFFAOYSA-N Ethene Chemical compound C=C VGGSQFUCUMXWEO-UHFFFAOYSA-N 0.000 description 1
- 239000005977 Ethylene Substances 0.000 description 1
- 108010022355 Fibroins Proteins 0.000 description 1
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 1
- 108010003272 Hyaluronate lyase Proteins 0.000 description 1
- 102000001974 Hyaluronidases Human genes 0.000 description 1
- WBOHXLDSPBIPTP-UHFFFAOYSA-N N,N-dimethyl-1,8-naphthyridin-4-amine Chemical class CN(C1=CC=NC2=NC=CC=C12)C WBOHXLDSPBIPTP-UHFFFAOYSA-N 0.000 description 1
- OVRNDRQMDRJTHS-UHFFFAOYSA-N N-acelyl-D-glucosamine Natural products CC(=O)NC1C(O)OC(CO)C(O)C1O OVRNDRQMDRJTHS-UHFFFAOYSA-N 0.000 description 1
- OVRNDRQMDRJTHS-FMDGEEDCSA-N N-acetyl-beta-D-glucosamine Chemical compound CC(=O)N[C@H]1[C@H](O)O[C@H](CO)[C@@H](O)[C@@H]1O OVRNDRQMDRJTHS-FMDGEEDCSA-N 0.000 description 1
- MBLBDJOUHNCFQT-LXGUWJNJSA-N N-acetylglucosamine Natural products CC(=O)N[C@@H](C=O)[C@@H](O)[C@H](O)[C@H](O)CO MBLBDJOUHNCFQT-LXGUWJNJSA-N 0.000 description 1
- 229920000615 alginic acid Polymers 0.000 description 1
- 235000010443 alginic acid Nutrition 0.000 description 1
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 229920001436 collagen Polymers 0.000 description 1
- 230000000295 complement effect Effects 0.000 description 1
- 239000003937 drug carrier Substances 0.000 description 1
- 239000003792 electrolyte Substances 0.000 description 1
- 229940088598 enzyme Drugs 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- 238000001879 gelation Methods 0.000 description 1
- 230000014509 gene expression Effects 0.000 description 1
- 239000008103 glucose Substances 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 229960002773 hyaluronidase Drugs 0.000 description 1
- 230000005847 immunogenicity Effects 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 230000003993 interaction Effects 0.000 description 1
- 230000003834 intracellular effect Effects 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- 229950006780 n-acetylglucosamine Drugs 0.000 description 1
- 229920005615 natural polymer Polymers 0.000 description 1
- 210000000056 organ Anatomy 0.000 description 1
- 230000008520 organization Effects 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- 229910052760 oxygen Inorganic materials 0.000 description 1
- 229920000642 polymer Polymers 0.000 description 1
- 230000035755 proliferation Effects 0.000 description 1
- 238000011084 recovery Methods 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 230000003248 secreting effect Effects 0.000 description 1
- 210000002966 serum Anatomy 0.000 description 1
- 238000004088 simulation Methods 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
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Classifications
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- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08L—COMPOSITIONS OF MACROMOLECULAR COMPOUNDS
- C08L5/00—Compositions of polysaccharides or of their derivatives not provided for in groups C08L1/00 or C08L3/00
- C08L5/08—Chitin; Chondroitin sulfate; Hyaluronic acid; Derivatives thereof
-
- 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
- C08B37/0006—Homoglycans, i.e. polysaccharides having a main chain consisting of one single sugar, e.g. colominic acid
- C08B37/0024—Homoglycans, i.e. polysaccharides having a main chain consisting of one single sugar, e.g. colominic acid beta-D-Glucans; (beta-1,3)-D-Glucans, e.g. paramylon, coriolan, sclerotan, pachyman, callose, scleroglucan, schizophyllan, laminaran, lentinan or curdlan; (beta-1,6)-D-Glucans, e.g. pustulan; (beta-1,4)-D-Glucans; (beta-1,3)(beta-1,4)-D-Glucans, e.g. lichenan; Derivatives thereof
- C08B37/0027—2-Acetamido-2-deoxy-beta-glucans; Derivatives thereof
- C08B37/003—Chitin, i.e. 2-acetamido-2-deoxy-(beta-1,4)-D-glucan or N-acetyl-beta-1,4-D-glucosamine; Chitosan, i.e. deacetylated product of chitin or (beta-1,4)-D-glucosamine; Derivatives thereof
-
- 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
- C08F—MACROMOLECULAR COMPOUNDS OBTAINED BY REACTIONS ONLY INVOLVING CARBON-TO-CARBON UNSATURATED BONDS
- C08F2/00—Processes of polymerisation
- C08F2/46—Polymerisation initiated by wave energy or particle radiation
- C08F2/48—Polymerisation initiated by wave energy or particle radiation by ultraviolet or visible light
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- 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
- C08F299/00—Macromolecular compounds obtained by interreacting polymers involving only carbon-to-carbon unsaturated bond reactions, in the absence of non-macromolecular monomers
-
- 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
- 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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- 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
- C08J2405/00—Characterised by the use of polysaccharides or of their derivatives not provided for in groups C08J2401/00 or C08J2403/00
- C08J2405/08—Chitin; Chondroitin sulfate; Hyaluronic acid; Derivatives thereof
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- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08L—COMPOSITIONS OF MACROMOLECULAR COMPOUNDS
- C08L2205/00—Polymer mixtures characterised by other features
- C08L2205/02—Polymer mixtures characterised by other features containing two or more polymers of the same C08L -group
- C08L2205/025—Polymer mixtures characterised by other features containing two or more polymers of the same C08L -group containing two or more polymers of the same hierarchy C08L, and differing only in parameters such as density, comonomer content, molecular weight, structure
Abstract
A kind of hydroxyethyl chitosan/hyaluronic acid double-network hydrogel and preparation method thereof, distinguish modified hydroxyethyl chitosan and hyaluronic acid using glycidyl methacrylate, obtains hydroxyethyl chitosan graft glycidyl methacrylate and hyaluronic acid graft glycidyl methacrylate；Hydroxyethyl chitosan graft glycidyl methacrylate obtains first network structure hydroxyethyl chitosan hydrogel through photochemical polymerization, the aqueous solution of dipping hyaluronic acid graft glycidyl methacrylate and photoinitiator after freeze-dried, implement photochemical polymerization and form the second network readezvous point matter acid hydrogel, obtains hydroxyethyl chitosan/hyaluronic acid double-network hydrogel.Mechanics and swelling behavior of the hydrogel etc. are adjustable；Hydrogel formation speed is fast, simple for process, structural stability is good, can be used for external 3D tumor models structure, drug delivery, regeneration etc..
Description
Technical field
The invention belongs to biomedical materials fields, and in particular to a kind of hydroxyethyl chitosan/hyaluronic acid dual network water
Gel and preparation method thereof.
Background technology
Hydrogel is a kind of polymer of three-dimensional network, can absorb large quantity of moisture swelling and not dissolve, it has both solid
With liquid double properties, this characteristic makes it be widely used in the fields such as 3D tumor models, organizational project, pharmaceutical carrier.3D is swollen
A key areas of the tumor model as hydrogel, cardinal principle are to utilize various methods and material, make cell that space be presented
Three-dimensional mode increases, and closer to tumor growth pattern, forms the structure of similar in-vivo tissue, i.e., a kind of in-vitro simulated internal life
The model of long environment.The three-dimensional space network structure of hydrogel is similar with natural extracellular matrix, and porous structure is glutinous for cell
Attached, proliferation, growth provide a supporting role and are metabolized space, and can pass through adjustment aperture size, porosity, specific surface area etc., shape
At the microstructure adaptable with specific organization structure.In addition, it is rich in moisture, be conducive to oxygen, nutriment and cell generation
Thank to product transport, friction and mechanical stimulus to surrounding tissue it is small [HP Tan, KG Marra.Injectable,
biodegradable hydrogels for tissue engineering applications.Materials,2010,3
(3):1746-1767]。
The hydrogel that natural macromolecular material is formed has the spies such as good biocompatibility, hypotoxicity, low immunogenicity
Point, is favored extensively, and common natural polymer includes chitosan, hyaluronic acid, collagen, alginates, fibroin albumen
Deng.The two class hydrogels that aquagel and hyaluronic acid gel are concentrated the most as research are with their own characteristics, and chitosan is
A kind of polycation polysaccharide contains the glucose aminoglucan molecule in aminoglucose and N-acetyl-glucosamine, with extracellular matrix
Structure is similar.And main component one of of the hyaluronic acid as extracellular matrix, it is a kind of negatively charged viscous polysaccharide, it can quilt
Hyaluronidase degradation in intracellular or serum, and moisture can be efficiently combined, viscoelasticity is high.Although the hydrogel of the two can
Vitro is preferably simulated, however, extracellular matrix is a kind of molecular complex, it is living containing water, electrolyte and a variety of biologies
Property molecule.Cell in tissue and extracellular matrix are the relationships of a kind of dynamic equilibrium, interaction, interdependence, i.e.,
Cell is simultaneously synthesizing to secrete new substance microenvironment is dynamically transformed, to meet by secreting various enzyme degradation of cell epimatrixs
Own existence needs；And extracellular matrix be capable of regulating cell stick, migrate, being proliferated, breaking up and gene expression etc. is a series of
Biological behaviour [SF Badylak, DJ Weiss, A Caplan, et al.Engineered whole organs and
complex tissues.Lancet,2012, 379:943-952].Therefore, the hydrogel of single component can not simulate completely
The ingredient of extracellular matrix, the raw material that can have complementary advantages by two or more can yet be regarded as one to prepare multicomponent hydrogel
The good solution of kind.
Invention content
The purpose of the present invention is to provide a kind of hydroxyethyl chitosan/hyaluronic acid double-network hydrogel and its preparation sides
Method distinguishes modified hydroxyethyl chitosan and hyaluronic acid first with glycidyl methacrylate, it is poly- to obtain ethoxy shell
Sugared graft glycidyl methacrylate and hyaluronic acid graft glycidyl methacrylate；Then, using photochemistry
Polymerization obtains first network structure hydroxyethyl chitosan hydrogel and the second network readezvous point matter acid hydrogel successively, obtains
Hydroxyethyl chitosan/hyaluronic acid double-network hydrogel.The double-network hydrogel can the more efficiently outer base of analogue body inner cell
Matter, mechanics and swelling behavior etc. are adjustable；Hydrogel formation speed is fast, simple for process, structural stability is good, can be used for external
3D tumor models structure, drug delivery, regeneration etc..
To achieve the above object, the present invention uses following technical scheme：
A kind of preparation method of hydroxyethyl chitosan/hyaluronic acid double-network hydrogel, includes the following steps：
1) preparation of first network hydroxyethyl chitosan hydrogel：Hydroxyethyl chitosan grafted methacrylic acid is shunk sweet
The grease solution soluble in water for forming mass concentration and being 0.5%~4%, is subsequently added into hydroxyethyl chitosan grafted methacrylic acid
The water-soluble light trigger of ethylene oxidic ester quality 0.05%~0.5%, magnetic agitation utilize ultraviolet light irradiation after mixing
0.5 minute~8 minutes, the hydroxyethyl chitosan hydrogel that photochemical polymerization is formed was freeze-dried, obtains first network hydroxyl second
Base aquagel, it is spare；
2) preparation of the second network readezvous point matter acid hydrogel：The first network hydroxyethyl chitosan water-setting that step 1) is obtained
Jelly dry sample is impregnated in the aqueous solution of hyaluronic acid graft glycidyl methacrylate and water-soluble light trigger, until molten
Swollen balance, implements photochemical polymerization 0.5 minute~10 minutes, obtains hydroxyethyl chitosan/hyaluronic acid double-network hydrogel；Its
In, it is 2 that sample and the mass ratio of hyaluronic acid graft glycidyl methacrylate, which is lyophilized, in hydroxyethyl chitosan hydrogel:1~
1:3, the mass concentration of hyaluronic acid graft glycidyl methacrylate is 0.5%~4%, the matter of water-soluble light trigger
Amount is the 0.05%~0.5% of hyaluronic acid graft glycidyl methacrylate quality.
The present invention, which further improves, to be, the preparation of the hydroxyethyl chitosan graft glycidyl methacrylate
Method is as follows：
The hydroxyethyl chitosan solution that mass concentration is 0.2%~2% is prepared, hydroxyethyl chitosan is then added and repeats list
The glycidyl methacrylate that 0.1~0.9 times of first number, then using a concentration of 1mol/L sodium hydroxide solution by pH tune
To 8.0,3 hours~8 hours are then stirred at 65 DEG C~85 DEG C, then through deionized water dialysis 3 days；Finally, product will be contained
Dialyzate it is freeze-dried, obtain hydroxyethyl chitosan graft glycidyl methacrylate.
The present invention, which further improves, to be, the dialysis bag retention molecular weight that the dialysis uses is 3500Da；It is described
Freeze-drying be subzero 20 DEG C keep 72 hours, 20 DEG C keep 4 hours.
The present invention, which further improves, to be, the preparation method of the hydroxyethyl chitosan is as follows：
1) chitosan is scattered in the NaOH solution that mass concentration is 30%~60%, wherein the matter of chitosan and NaOH
Amount is than being 3:5；The aqueous isopropanol of chlorethanol is added thereto, then raises temperature to 65 DEG C of back flow reactions 4 hours~7 hours；Its
Middle shitosan number of repeat unit：Chlorethanol：The molar ratio of isopropanol is 1:3:5~1:6:9；
2) pH value after reaction, is adjusted to neutrality, the second that products therefrom volumetric concentration is 75%~90% with hydrochloric acid
Alcohol and absolute ethyl alcohol are washed for several times, soluble in water after vacuum drying, are dialysed 48 hours, then freeze-dried, and it is poly- to obtain ethoxy shell
Sugar.
The present invention, which further improves, to be, it is 300kDa~1000kDa that the chitosan, which glues equal molecular mass, deacetylated
Degree is more than 90%.
The present invention further improve is, step 1) and 2) in water-soluble light trigger be 2- hydroxyls -4 '-(2- hydroxyls
Ethyoxyl) -2- methyl phenyl ketones or 1- hydroxycyclohexyl phenyl ketones.
The present invention, which further improves, to be, the hyaluronic acid graft glycidyl methacrylate and water solubility
The volume of the aqueous solution of photoinitiator mixtures is equal to the volume of hydroxyethyl chitosan hydrogel freeze-drying sample.
The present invention, which further improves, to be, the parameter of the ultraviolet light irradiation is：Centre wavelength is 365nm, light intensity
For 1200 mJ/cm2~1500mJ/cm2, irradiation distance 15cm；The hyaluronan molecule amount is 100kDa~1000kDa.
The present invention, which further improves, to be, the preparation side of the hyaluronic acid graft glycidyl methacrylate
Method is as follows：
The hyaluronic acid solution that mass concentration is 0.5%~2% is prepared, 4-dimethylaminopyridine, the tetrabutyl are subsequently added into
Ammonium bromide, glycidyl methacrylate react at room temperature 12 hours~48 hours under nitrogen protection, then through deionized water dialysis
It is freeze-dried after 3 days, obtains hyaluronic acid graft glycidyl methacrylate；Wherein, 4-dimethylaminopyridine
Dosage is 0.05~10 times of hyaluronic acid repetitive unit molal quantity, and the dosage of tetrabutylammonium bromide is hyaluronic acid repetitive unit
0.1~3 times of molal quantity, the dosage of glycidyl methacrylate are the 1~20 of hyaluronic acid repetitive unit molal quantity
Times.
A kind of hydroxyethyl chitosan/hyaluronic acid double-network hydrogel, which has the porous structure of connection, average
Aperture is 150 μm, compression modulus 38.69kPa.
Compared with the technology of preparing of existing hydrogel, the beneficial effects of the present invention are：
(1) distinguish modified hydroxyethyl chitosan and hyaluronic acid first with glycidyl methacrylate, obtain hydroxyl
Ethyl chitosan graft glycidyl methacrylate and hyaluronic acid graft glycidyl methacrylate；Then, it adopts
First network structure hydroxyethyl chitosan hydrogel and the second network readezvous point matter sour water are obtained successively with light chemical polymerization process
Gel obtains hydroxyethyl chitosan/hyaluronic acid double-network hydrogel.The raw material for preparing of the hydrogel is cationic polymer hydroxyl
Ethyl chitosan graft glycidyl methacrylate and anionic polymer hyaluronic acid grafted methacrylic acid shrink sweet
Grease, the two biocompatibility is excellent, both ingredients can realize mutual supplement with each other's advantages, preferably can grow micro-loop by analogue body inner cell
Border.
(2) hydrogel has dual network structure, has both the spy of hyaluronic acid gel and hydroxyethyl chitosan hydrogel
Point, mechanical property and structural stability are good.It is 150 μm that the hydrogel, which has the porous structure of connection, average pore size, compression modulus
For 38.69 kPa.
(3) the dual network structure Forming Mechanism of the hydrogel is photochemical polymerization, has that reaction condition is mild, plastic is fast
Degree quickly (a few minutes in complete), the advantages that process is simple.
(4) performance of the double-network hydrogel can pass through the tune such as feed change molecular weight, ingredient composition ratio, crosslink density
Section can more efficiently analogue body extracellular matrix, mechanics and swelling behavior etc. be adjusted；Hydrogel formed speed it is fast,
It is simple for process, structural stability is good, multiple use is applicable to, such as 3D tumor models structure, drug delivery vehicle, porous support
Material etc..
Further, cationic polymer hydroxyethyl chitosan and anionic polymer hyaluronic acid, the two bio-compatible
Property it is excellent, both ingredients can realize mutual supplement with each other's advantages, can preferably analogue body inner cell grow microenvironment.
Description of the drawings
Fig. 1 is hydroxyethyl chitosan/hyalomitome double-network hydrogel modulus situation with frequency change prepared by the present invention,
Curve 1 is hydroxyethyl chitosan hydrogel in figure, and curve 2 is dual network gel.
Fig. 2 is that compression stress-strain of hydroxyethyl chitosan/hyalomitome double-network hydrogel prepared by the present invention is bent
Line, curve 1 is hydroxyethyl chitosan hydrogel in figure, and curve 2 is dual network gel.
Fig. 3 is the stereoscan photograph of hydroxyethyl chitosan/hyalomitome double-network hydrogel prepared by the present invention, and Fig. 3 A are
The stereoscan photograph of hydroxyethyl chitosan hydrogel, B are the stereoscan photograph of dual network gel.
Specific implementation mode
Below by embodiment, the invention will be further described, but the present invention is not limited thereto.
Embodiment 1
1) it is 700kDa by viscous equal molecular mass, to be scattered in mass concentration be 50% to the chitosan of deacetylation 98%
In NaOH solution, the mass ratio of NaOH is 3 wherein in chitosan and NaOH solution:5；The isopropanol of chlorethanol is added thereto
Solution, subsequent 65 DEG C of heating back flow reaction 5 hours；Wherein shitosan number of repeat unit：Chlorethanol：The molar ratio of isopropanol is
1:4.5:7。
2) pH value after reaction, is adjusted to neutrality with hydrochloric acid, the ethyl alcohol and nothing that products therefrom volumetric concentration is 85%
Water-ethanol is washed for several times, soluble in water after vacuum drying, is dialysed 48 hours, then freeze-dried, is obtained hydroxyethyl chitosan.
3) the hydroxyethyl chitosan solution that mass concentration is 2% is prepared, hydroxyethyl chitosan number of repeat unit is then added
0.4 times of glycidyl methacrylate, then pH is adjusted to 8.0 using the sodium hydroxide solution of a concentration of 1mol/L, then
Magnetic agitation 6 hours at 70 DEG C, it is the bag filter of 3500Da through deionized water dialysis 3 days then to use molecular weight；Finally, will
Dialyzate containing product is freeze-dried, specifically keeps 72 hours, 20 DEG C being kept for 4 hours at subzero 20 DEG C, obtains ethoxy shell
Glycan graft glycidyl methacrylate.
4) preparation of first network hydroxyethyl chitosan hydrogel：Hydroxyethyl chitosan grafted methacrylic acid is shunk sweet
The grease solution soluble in water for forming mass concentration and being 3.5%, is subsequently added into the shrink of hydroxyethyl chitosan grafted methacrylic acid
The water-soluble light trigger of glyceride quality 0.1%, magnetic agitation utilize ultraviolet light irradiation 2 minutes after mixing, photochemistry
It is freeze-dried to polymerize the hydroxyethyl chitosan hydrogel formed, obtains first network hydroxyethyl chitosan hydrogel, it is spare.Its
In, the parameter of ultraviolet light irradiation is：Centre wavelength is 365nm, light intensity 1200mJ/cm2~1500mJ/cm2, irradiation distance be
15cm。
5) hyaluronic acid solution that mass concentration is 1% is prepared, 4-dimethylaminopyridine, tetrabutyl bromine are then sequentially added
Change ammonium, glycidyl methacrylate, react at room temperature 24 hours under nitrogen protection, then is carried out after 3 days through deionized water dialysis
Freeze-drying, obtains hyaluronic acid graft glycidyl methacrylate.Wherein, hyaluronan molecule amount is 170kDa.Its
In, the dosage of 4- dimethylamino naphthyridines is 0.1 times of hyaluronic acid repetitive unit molal quantity, and the dosage of tetrabutylammonium bromide is
The dosage of 0.2 times of hyaluronic acid repetitive unit molal quantity, glycidyl methacrylate is that hyaluronic acid repetitive unit rubs
10 times of that number.
6) preparation of the second network readezvous point matter acid hydrogel：The first network hydroxyethyl chitosan water-setting that step 4) is obtained
Jelly dry sample is impregnated in the aqueous solution of hyaluronic acid graft glycidyl methacrylate and water-soluble light trigger, until molten
Swollen balance, implements photochemical polymerization 5 minutes, obtains hydroxyethyl chitosan/hyaluronic acid double-network hydrogel；Wherein, ethoxy
It is 1 that sample and the mass ratio of hyaluronic acid graft glycidyl methacrylate, which is lyophilized, in aquagel:2, hyaluronic acid connects
The mass concentration of branch glycidyl methacrylate is 3.5%, and the quality of water-soluble light trigger is that hyaluronic acid is grafted first
The 0.1% of base glycidyl acrylate quality.
Wherein, step 4) and 6) in water-soluble light trigger be 2- hydroxyls -4 '-(2- hydroxy ethoxies) -2- methylbenzenes third
Ketone or 1- hydroxycyclohexyl phenyl ketones.The hyaluronic acid graft glycidyl methacrylate and water-soluble light draw
The volume for sending out the aqueous solution of agent composition is equal to the volume of hydroxyethyl chitosan hydrogel freeze-drying sample.
The storage modulus (G') of double-network hydrogel is slightly above hydroxyethyl chitosan hydrogel it can be seen from 1 figure, and
As frequency increases, storage modulus (G') and the loss modulus (G ") of dual network gel do not change.It can be seen that double nets
Network hydrogel has higher modulus and structural stability.
As seen from Figure 2, dual network gel has better deformation recovery capability, in same strain, dual network water
The compression stress of gel is much larger than hydroxyethyl chitosan hydrogel, the pressure of double-network hydrogel in 10%~20% range of strain
Contracting modulus (38.69kPa) is approximately 4 times of (10.4kPa) of hydroxyethyl chitosan hydrogel.This illustrates that double-network hydrogel has
Higher compression modulus.
Referring to Fig. 3, the porous structure being connected to is all had with both hydrogels it can be seen from Fig. 3 (b) by Fig. 3 (a), is had
Conducive to the circulation of moisture and nutriment, it is 150 μm that dual network gel, which has the aperture size being more uniformly distributed, average pore size, and
The thickness of hole wall is more than the thickness of hydroxyethyl chitosan hydrogel, and thicker hole wall is conducive to improve intensity.
Embodiment 2
1) it is 500kDa by viscous equal molecular mass, to be scattered in mass concentration be 40% to the chitosan of deacetylation 95%
In NaOH solution, the mass ratio of NaOH is 3 wherein in chitosan and NaOH solution:5；The isopropanol of chlorethanol is added thereto
Solution, then raises temperature to 65 DEG C of back flow reactions 4 hours；Wherein shitosan number of repeat unit：Chlorethanol：The molar ratio of isopropanol is
1:4:5。
2) pH value after reaction, is adjusted to neutrality with hydrochloric acid, the ethyl alcohol and nothing that products therefrom volumetric concentration is 75%
Water-ethanol is washed for several times, soluble in water after vacuum drying, is dialysed 48 hours, then freeze-dried, is obtained hydroxyethyl chitosan.
3) the hydroxyethyl chitosan solution that mass concentration is 2% is prepared, hydroxyethyl chitosan number of repeat unit is then added
0.2 times of glycidyl methacrylate, then pH is adjusted to 8.0 using the sodium hydroxide solution of a concentration of 1mol/L, then
Magnetic agitation 5 hours at 65 DEG C, it is the bag filter of 3500Da through deionized water dialysis 3 days then to use molecular weight；Finally, will
Dialyzate containing product is freeze-dried, specifically keeps 72 hours, 20 DEG C being kept for 4 hours at subzero 20 DEG C, obtains ethoxy shell
Glycan graft glycidyl methacrylate.
4) preparation of first network hydroxyethyl chitosan hydrogel：Hydroxyethyl chitosan grafted methacrylic acid is shunk sweet
The grease solution soluble in water for forming mass concentration and being 2%, it is sweet to be subsequently added into the shrink of hydroxyethyl chitosan grafted methacrylic acid
The water-soluble light trigger of grease quality 0.05%, magnetic agitation utilize ultraviolet light irradiation 5 minutes after mixing, photochemistry
It is freeze-dried to polymerize the hydroxyethyl chitosan hydrogel formed, obtains first network hydroxyethyl chitosan hydrogel, it is spare.Its
In, the parameter of ultraviolet light irradiation is：Centre wavelength is 365nm, light intensity 1200mJ/cm2, irradiation distance 15cm.
5) hyaluronic acid solution that mass concentration is 2% is prepared, 4-dimethylaminopyridine, tetrabutyl bromine are then sequentially added
Change ammonium, glycidyl methacrylate, react at room temperature 48 hours under nitrogen protection, then is carried out after 3 days through deionized water dialysis
Freeze-drying, obtains hyaluronic acid graft glycidyl methacrylate.Wherein, hyaluronan molecule amount is 100kDa.Its
In, the dosage of 4-dimethylaminopyridine is 0.05 times of hyaluronic acid repetitive unit molal quantity, and the dosage of tetrabutylammonium bromide is
The dosage of 2 times of hyaluronic acid repetitive unit molal quantity, glycidyl methacrylate is hyaluronic acid repetitive unit mole
Several 15 times.
6) preparation of the second network readezvous point matter acid hydrogel：The first network hydroxyethyl chitosan water-setting that step 4) is obtained
Jelly dry sample is impregnated in the aqueous solution of hyaluronic acid graft glycidyl methacrylate and water-soluble light trigger, until molten
Swollen balance, implements photochemical polymerization 8 minutes, obtains hydroxyethyl chitosan/hyaluronic acid double-network hydrogel；Wherein, ethoxy
It is 2 that sample and the mass ratio of hyaluronic acid graft glycidyl methacrylate, which is lyophilized, in aquagel:1, hyaluronic acid connects
The mass concentration of branch glycidyl methacrylate is 4%, and the quality of water-soluble light trigger is that hyaluronic acid is grafted methyl
The 0.5% of glycidyl acrylate quality.
Wherein, step 4) and 6) in water-soluble light trigger be 2- hydroxyls -4 '-(2- hydroxy ethoxies) -2- methylbenzenes third
Ketone or 1- hydroxycyclohexyl phenyl ketones.The hyaluronic acid graft glycidyl methacrylate and water-soluble light draw
The volume for sending out the aqueous solution of agent composition is equal to the volume of hydroxyethyl chitosan hydrogel freeze-drying sample.
Embodiment 3
1) it is 300kDa by viscous equal molecular mass, to be scattered in mass concentration be 30% to the chitosan of deacetylation 93%
In NaOH solution, wherein the mass ratio of chitosan and NaOH solution is 3:5；The aqueous isopropanol of chlorethanol is added thereto, with
After be warming up to 65 DEG C of back flow reactions 7 hours；Wherein shitosan number of repeat unit：Chlorethanol：The molar ratio of isopropanol is 1:3:5.
2) pH value after reaction, is adjusted to neutrality with hydrochloric acid, the ethyl alcohol and nothing that products therefrom volumetric concentration is 75%
Water-ethanol is washed for several times, soluble in water after vacuum drying, is dialysed 48 hours, then freeze-dried, is obtained hydroxyethyl chitosan.
3) the hydroxyethyl chitosan solution that mass concentration is 0.2% is prepared, hydroxyethyl chitosan repetitive unit is then added
The glycidyl methacrylate that 0.9 times of number, then pH is adjusted to 8.0 using the sodium hydroxide solution of a concentration of 1mol/L, so
Magnetic agitation 3 hours at 85 DEG C afterwards, it is the bag filter of 3500Da through deionized water dialysis 3 days then to use molecular weight；Most
Afterwards, the dialyzate containing product is freeze-dried, it specifically keeps 72 hours, 20 DEG C being kept for 4 hours at subzero 20 DEG C, obtains hydroxyl second
Base enclosure glycan graft glycidyl methacrylate.
4) preparation of first network hydroxyethyl chitosan hydrogel：Hydroxyethyl chitosan grafted methacrylic acid is shunk sweet
The grease solution soluble in water for forming mass concentration and being 4%, it is sweet to be subsequently added into the shrink of hydroxyethyl chitosan grafted methacrylic acid
The water-soluble light trigger of grease quality 0.3%, magnetic agitation utilize ultraviolet light irradiation 2 minutes after mixing, and photochemistry is poly-
It is freeze-dried to close the hydroxyethyl chitosan hydrogel formed, obtains first network hydroxyethyl chitosan hydrogel, it is spare.Its
In, the parameter of ultraviolet light irradiation is：Centre wavelength is 365nm, light intensity 1200mJ/cm2, irradiation distance 15cm.
5) hyaluronic acid solution that mass concentration is 1.5% is prepared, 4-dimethylaminopyridine, the tetrabutyl are then sequentially added
The dosage of ammonium bromide, glycidyl methacrylate, 4-dimethylaminopyridine is hyaluronic acid repetitive unit molal quantity
0.05 times, the dosage of tetrabutylammonium bromide is 0.1 times of hyaluronic acid repetitive unit molal quantity, glycidyl methacrylate
Dosage be 1 times of hyaluronic acid repetitive unit molal quantity, reacted at room temperature 12 hours under nitrogen protection, then through deionized water dialysis
It is freeze-dried after 3 days, obtains hyaluronic acid graft glycidyl methacrylate.Wherein, hyaluronan molecule amount is
1000kDa。
6) preparation of the second network readezvous point matter acid hydrogel：The first network hydroxyethyl chitosan water-setting that step 4) is obtained
Jelly dry sample is impregnated in the aqueous solution of hyaluronic acid graft glycidyl methacrylate and water-soluble light trigger, until molten
Swollen balance, implements photochemical polymerization 4 minutes, obtains hydroxyethyl chitosan/hyaluronic acid double-network hydrogel；Wherein, ethoxy
It is 2 that sample and the mass ratio of hyaluronic acid graft glycidyl methacrylate, which is lyophilized, in aquagel:1, hyaluronic acid connects
The mass concentration of branch glycidyl methacrylate is 1%, and the quality of water-soluble light trigger is that hyaluronic acid is grafted methyl
The 0.3% of glycidyl acrylate quality.
Wherein, step 4) and 6) in water-soluble light trigger be 2- hydroxyls -4 '-(2- hydroxy ethoxies) -2- methylbenzenes
Acetone.The body of the aqueous solution of the hyaluronic acid graft glycidyl methacrylate and water-soluble light trigger mixture
Product is equal to the volume of hydroxyethyl chitosan hydrogel freeze-drying sample.
Embodiment 4
1) it is 1000kDa by viscous equal molecular mass, to be scattered in mass concentration be 60% to the chitosan of deacetylation 91%
In NaOH solution, wherein the mass ratio of chitosan and NaOH solution is 3:5；The aqueous isopropanol of chlorethanol is added thereto, with
After be warming up to 65 DEG C of back flow reactions 4 hours；Wherein shitosan number of repeat unit：Chlorethanol：The molar ratio of isopropanol is 1:4:7.
2) pH value after reaction, is adjusted to neutrality with hydrochloric acid, the ethyl alcohol and nothing that products therefrom volumetric concentration is 90%
Water-ethanol is washed for several times, soluble in water after vacuum drying, is dialysed 48 hours, then freeze-dried, is obtained hydroxyethyl chitosan.
3) the hydroxyethyl chitosan solution that mass concentration is 0.6% is prepared, hydroxyethyl chitosan repetitive unit is then added
The glycidyl methacrylate that 0.7 times of number, then pH is adjusted to 8.0 using the sodium hydroxide solution of a concentration of 1mol/L, so
Magnetic agitation 4 hours at 75 DEG C afterwards, it is the bag filter of 3500Da through deionized water dialysis 3 days then to use molecular weight；Most
Afterwards, the dialyzate containing product is freeze-dried, it specifically keeps 72 hours, 20 DEG C being kept for 4 hours at subzero 20 DEG C, obtains hydroxyl second
Base enclosure glycan graft glycidyl methacrylate.
4) preparation of first network hydroxyethyl chitosan hydrogel：Hydroxyethyl chitosan grafted methacrylic acid is shunk sweet
The grease solution soluble in water for forming mass concentration and being 2%, it is sweet to be subsequently added into the shrink of hydroxyethyl chitosan grafted methacrylic acid
The water-soluble light trigger of grease quality 0.5%, magnetic agitation utilize ultraviolet light irradiation 0.5 minute after mixing, photochemistry
It is freeze-dried to polymerize the hydroxyethyl chitosan hydrogel formed, obtains first network hydroxyethyl chitosan hydrogel, it is spare.Its
In, the parameter of ultraviolet light irradiation is：Centre wavelength is 365nm, light intensity 1500mJ/cm2, irradiation distance 15cm.
5) hyaluronic acid solution that mass concentration is 1.5% is prepared, 4-dimethylaminopyridine, the tetrabutyl are then sequentially added
Ammonium bromide, glycidyl methacrylate, the dosage of 4-dimethylaminopyridine are the 1 of hyaluronic acid repetitive unit molal quantity
Times, the dosage of tetrabutylammonium bromide is 1 times of hyaluronic acid repetitive unit molal quantity, the dosage of glycidyl methacrylate
It is 5 times of hyaluronic acid repetitive unit molal quantity, is reacted at room temperature 20 hours under nitrogen protection, then after deionized water dialysis 3 days
It is freeze-dried, obtains hyaluronic acid graft glycidyl methacrylate.Wherein, hyaluronan molecule amount is
100kDa。
6) preparation of the second network readezvous point matter acid hydrogel：The first network hydroxyethyl chitosan water-setting that step 4) is obtained
Jelly dry sample is impregnated in the aqueous solution of hyaluronic acid graft glycidyl methacrylate and water-soluble light trigger, until molten
Swollen balance, implements photochemical polymerization 10 minutes, obtains hydroxyethyl chitosan/hyaluronic acid double-network hydrogel；Wherein, ethoxy
It is 1 that sample and the mass ratio of hyaluronic acid graft glycidyl methacrylate, which is lyophilized, in aquagel:1, hyaluronic acid connects
The mass concentration of branch glycidyl methacrylate is 4%, and the quality of water-soluble light trigger is that hyaluronic acid is grafted methyl
The 0.5% of glycidyl acrylate quality.
Wherein, step 4) and 6) in water-soluble light trigger be 1- hydroxycyclohexyl phenyl ketones.Described is transparent
The volume of the aqueous solution of matter acid graft glycidyl methacrylate and water-soluble light trigger mixture is equal to ethoxy shell
The volume of sample is lyophilized in glycan hydrogel.
Embodiment 5
1) it will glue that equal molecular mass is 500kDa, to be scattered in mass concentration be 40% to chitosan of the deacetylation more than 99%
NaOH solution in, wherein the mass ratio of chitosan and NaOH solution be 3:5；The aqueous isopropanol of chlorethanol is added thereto,
Then raise temperature to 65 DEG C of back flow reactions 5 hours；Wherein shitosan number of repeat unit：Chlorethanol：The molar ratio of isopropanol is 1:6:
9。
2) pH value after reaction, is adjusted to neutrality with hydrochloric acid, the ethyl alcohol and nothing that products therefrom volumetric concentration is 80%
Water-ethanol is washed for several times, soluble in water after vacuum drying, is dialysed 48 hours, then freeze-dried, is obtained hydroxyethyl chitosan.
3) the hydroxyethyl chitosan solution that mass concentration is 1% is prepared, hydroxyethyl chitosan number of repeat unit is then added
0.5 times of glycidyl methacrylate, then pH is adjusted to 8.0 using the sodium hydroxide solution of a concentration of 1mol/L, then
Magnetic agitation 8 hours at 65 DEG C, it is the bag filter of 3500Da through deionized water dialysis 3 days then to use molecular weight；Finally, will
Dialyzate containing product is freeze-dried, specifically keeps 72 hours, 20 DEG C being kept for 4 hours at subzero 20 DEG C, obtains ethoxy shell
Glycan graft glycidyl methacrylate.
4) preparation of first network hydroxyethyl chitosan hydrogel：Hydroxyethyl chitosan grafted methacrylic acid is shunk sweet
The grease solution soluble in water for forming mass concentration and being 1%, it is sweet to be subsequently added into the shrink of hydroxyethyl chitosan grafted methacrylic acid
The water-soluble light trigger of grease quality 0.1%, magnetic agitation utilize ultraviolet light irradiation 5 minutes after mixing, and photochemistry is poly-
It is freeze-dried to close the hydroxyethyl chitosan hydrogel formed, obtains first network hydroxyethyl chitosan hydrogel, it is spare.Its
In, the parameter of ultraviolet light irradiation is：Centre wavelength is 365nm, light intensity 1300mJ/cm2, irradiation distance 15cm.
5) hyaluronic acid solution that mass concentration is 0.5% is prepared, 4-dimethylaminopyridine, the tetrabutyl are then sequentially added
Ammonium bromide, glycidyl methacrylate, the dosage of 4-dimethylaminopyridine are the 4 of hyaluronic acid repetitive unit molal quantity
Times, the dosage of tetrabutylammonium bromide is 2 times of hyaluronic acid repetitive unit molal quantity, the dosage of glycidyl methacrylate
It is 10 times of hyaluronic acid repetitive unit molal quantity, is reacted at room temperature 30 hours under nitrogen protection, then after deionized water dialysis 3 days
It is freeze-dried, obtains hyaluronic acid graft glycidyl methacrylate.Wherein, hyaluronan molecule amount is
300kDa。
6) preparation of the second network readezvous point matter acid hydrogel：The first network hydroxyethyl chitosan water-setting that step 4) is obtained
Jelly dry sample is impregnated in the aqueous solution of hyaluronic acid graft glycidyl methacrylate and water-soluble light trigger, until molten
Swollen balance, implements photochemical polymerization 1.5 minutes, obtains hydroxyethyl chitosan/hyaluronic acid double-network hydrogel；Wherein, hydroxyl second
It is 4 that sample and the mass ratio of hyaluronic acid graft glycidyl methacrylate, which is lyophilized, in base aquagel:3, hyaluronic acid
The mass concentration of graft glycidyl methacrylate is 0.5%, and the quality of water-soluble light trigger is grafted for hyaluronic acid
The 0.1% of glycidyl methacrylate quality.
Wherein, step 4) and 6) in water-soluble light trigger be 2- hydroxyls -4 '-(2- hydroxy ethoxies) -2- methylbenzenes
The body of the aqueous solution of acetone, the hyaluronic acid graft glycidyl methacrylate and water-soluble light trigger mixture
Product is equal to the volume of hydroxyethyl chitosan hydrogel freeze-drying sample.
Embodiment 6
1) it is 600kDa by viscous equal molecular mass, to be scattered in mass concentration be 50% to the chitosan of deacetylation 97%
In NaOH solution, wherein the mass ratio of chitosan and NaOH solution is 3:5；The aqueous isopropanol of chlorethanol is added thereto, with
After be warming up to 65 DEG C of back flow reactions 6 hours；Wherein shitosan number of repeat unit：Chlorethanol：The molar ratio of isopropanol is 1:5:8.
2) pH value after reaction, is adjusted to neutrality with hydrochloric acid, the ethyl alcohol and nothing that products therefrom volumetric concentration is 85%
Water-ethanol is washed for several times, soluble in water after vacuum drying, is dialysed 48 hours, then freeze-dried, is obtained hydroxyethyl chitosan.
3) the hydroxyethyl chitosan solution that mass concentration is 1.5% is prepared, hydroxyethyl chitosan repetitive unit is then added
The glycidyl methacrylate that 0.2 times of number, then pH is adjusted to 8.0 using the sodium hydroxide solution of a concentration of 1mol/L, so
Magnetic agitation 6 hours at 70 DEG C afterwards, it is the bag filter of 3500Da through deionized water dialysis 3 days then to use molecular weight；Most
Afterwards, the dialyzate containing product is freeze-dried, it specifically keeps 72 hours, 20 DEG C being kept for 4 hours at subzero 20 DEG C, obtains hydroxyl second
Base enclosure glycan graft glycidyl methacrylate.
4) preparation of first network hydroxyethyl chitosan hydrogel：Hydroxyethyl chitosan grafted methacrylic acid is shunk sweet
The grease solution soluble in water for forming mass concentration and being 0.5%, is subsequently added into the shrink of hydroxyethyl chitosan grafted methacrylic acid
The water-soluble light trigger of glyceride quality 0.05%, magnetic agitation utilize ultraviolet light irradiation 8 minutes after mixing, photochemical
It is freeze-dried to learn the hydroxyethyl chitosan hydrogel that polymerization is formed, obtains first network hydroxyethyl chitosan hydrogel, it is spare.
Wherein, the parameter of ultraviolet light irradiation is：Centre wavelength is 365nm, light intensity 1400mJ/cm2, irradiation distance 15cm.
5) hyaluronic acid solution that mass concentration is 2% is prepared, 4-dimethylaminopyridine, tetrabutyl bromine are then sequentially added
Change ammonium, glycidyl methacrylate, the dosage of 4-dimethylaminopyridine is 7 times of hyaluronic acid repetitive unit molal quantity,
The dosage of tetrabutylammonium bromide is 3 times of hyaluronic acid repetitive unit molal quantity, and the dosage of glycidyl methacrylate is
15 times of hyaluronic acid repetitive unit molal quantity react at room temperature 40 hours under nitrogen protection, then laggard through deionized water dialysis 3 days
Row freeze-drying, obtains hyaluronic acid graft glycidyl methacrylate.Wherein, hyaluronan molecule amount is 500kDa.
6) preparation of the second network readezvous point matter acid hydrogel：The first network hydroxyethyl chitosan water-setting that step 4) is obtained
Jelly dry sample is impregnated in the aqueous solution of hyaluronic acid graft glycidyl methacrylate and water-soluble light trigger, until molten
Swollen balance, implements photochemical polymerization 0.5 minute, obtains hydroxyethyl chitosan/hyaluronic acid double-network hydrogel；Wherein, hydroxyl second
It is 5 that sample and the mass ratio of hyaluronic acid graft glycidyl methacrylate, which is lyophilized, in base aquagel:3, hyaluronic acid
The mass concentration of graft glycidyl methacrylate is 2%, and the quality of water-soluble light trigger is that hyaluronic acid is grafted first
The 0.05% of base glycidyl acrylate quality.
Wherein, step 4) and 6) in water-soluble light trigger be 2- hydroxyls -4 '-(2- hydroxy ethoxies) -2- methylbenzenes
The body of the aqueous solution of acetone, the hyaluronic acid graft glycidyl methacrylate and water-soluble light trigger mixture
Product is equal to the volume of hydroxyethyl chitosan hydrogel freeze-drying sample.
Embodiment 7
1) it will glue that equal molecular mass is 800kDa, to be scattered in mass concentration be 35% to chitosan of the deacetylation more than 90%
NaOH solution in, wherein the mass ratio of chitosan and NaOH solution be 3:5；The aqueous isopropanol of chlorethanol is added thereto,
Then raise temperature to 65 DEG C of back flow reactions 5.5 hours；Wherein shitosan number of repeat unit：Chlorethanol：The molar ratio of isopropanol is 1:
6:5。
2) pH value after reaction, is adjusted to neutrality with hydrochloric acid, the ethyl alcohol and nothing that products therefrom mass concentration is 80%
Water-ethanol is washed for several times, soluble in water after vacuum drying, is dialysed 48 hours, then freeze-dried, is obtained hydroxyethyl chitosan.
3) the hydroxyethyl chitosan solution that mass concentration is 2% is prepared, hydroxyethyl chitosan number of repeat unit is then added
0.1 times of glycidyl methacrylate, then pH is adjusted to 8.0 using the sodium hydroxide solution of a concentration of 1mol/L, then
Magnetic agitation 5 hours at 80 DEG C, it is the bag filter of 3500Da through deionized water dialysis 3 days then to use molecular weight；Finally, will
Dialyzate containing product is freeze-dried, specifically keeps 72 hours, 20 DEG C being kept for 4 hours at subzero 20 DEG C, obtains ethoxy shell
Glycan graft glycidyl methacrylate.
4) preparation of first network hydroxyethyl chitosan hydrogel：Hydroxyethyl chitosan grafted methacrylic acid is shunk sweet
The grease solution soluble in water for forming mass concentration and being 3%, it is sweet to be subsequently added into the shrink of hydroxyethyl chitosan grafted methacrylic acid
The water-soluble light trigger of grease quality 0.2%, magnetic agitation utilize ultraviolet light irradiation 4 minutes after mixing, and photochemistry is poly-
It is freeze-dried to close the hydroxyethyl chitosan hydrogel formed, obtains first network hydroxyethyl chitosan hydrogel, it is spare.Its
In, the parameter of ultraviolet light irradiation is：Centre wavelength is 365nm, light intensity 1250mJ/cm2, irradiation distance 15cm.
5) hyaluronic acid solution that mass concentration is 1.2% is prepared, 4-dimethylaminopyridine, the tetrabutyl are then sequentially added
Ammonium bromide, glycidyl methacrylate, the dosage of 4-dimethylaminopyridine are the 10 of hyaluronic acid repetitive unit molal quantity
Times, the dosage of tetrabutylammonium bromide is 0.7 times of hyaluronic acid repetitive unit molal quantity, the use of glycidyl methacrylate
Amount was 20 times of hyaluronic acid repetitive unit molal quantity, is reacted at room temperature 48 hours under nitrogen protection, then through deionized water dialysis 3 days
After be freeze-dried, obtain hyaluronic acid graft glycidyl methacrylate.Wherein, hyaluronan molecule amount is
800kDa。
6) preparation of the second network readezvous point matter acid hydrogel：The first network hydroxyethyl chitosan water-setting that step 4) is obtained
Jelly dry sample is impregnated in the aqueous solution of hyaluronic acid graft glycidyl methacrylate and water-soluble light trigger, until molten
Swollen balance, implements photochemical polymerization 7 minutes, obtains hydroxyethyl chitosan/hyaluronic acid double-network hydrogel；Wherein, ethoxy
It is 2 that sample and the mass ratio of hyaluronic acid graft glycidyl methacrylate, which is lyophilized, in aquagel:3, hyaluronic acid connects
The mass concentration of branch glycidyl methacrylate is 3%, and the quality of water-soluble light trigger is that hyaluronic acid is grafted methyl
The 0.2% of glycidyl acrylate quality.
Wherein, step 4) and 6) in water-soluble light trigger be 2- hydroxyls -4 '-(2- hydroxy ethoxies) -2- methylbenzenes
The body of the aqueous solution of acetone, the hyaluronic acid graft glycidyl methacrylate and water-soluble light trigger mixture
Product is equal to the volume of hydroxyethyl chitosan hydrogel freeze-drying sample.
The hydroxyethyl chitosan and hyaluronic acid that the present invention is modified using glycidyl methacrylate as raw material, using point
Photochemical polymerization method is walked, is prepared for using hydroxyethyl chitosan as first network and dual network water that hyaluronic acid is the second network
Gel.The chemical composition of the double-network hydrogel is hydroxyethyl chitosan and hyaluronic acid, has excellent biocompatibility, can
The ingredient of more preferable simulation extracellular matrix, microenvironment similar with extracellular matrix is provided for cell adherence and growth.The water
Gel has that pore size is suitable, porous structure of size uniform, is conducive to sticking and growing for cell, and can pass through adjusting
Mechanical property, the swelling behavior etc. of the state modulators hydrogel such as component ratio, solution concentration, can be used for 3D tumor models structure,
Drug delivery, regeneration and restoration etc..
Claims (10)
1. a kind of preparation method of hydroxyethyl chitosan/hyaluronic acid double-network hydrogel, which is characterized in that including walking as follows
Suddenly：
1) preparation of first network hydroxyethyl chitosan hydrogel：By hydroxyethyl chitosan graft glycidyl methacrylate
The solution soluble in water for forming mass concentration and being 0.5%~4%, is subsequently added into the shrink of hydroxyethyl chitosan grafted methacrylic acid
The water-soluble light trigger of glyceride quality 0.05%~0.5%, magnetic agitation are divided using ultraviolet light irradiation 0.5 after mixing
Clock~8 minute, the hydroxyethyl chitosan hydrogel that photochemical polymerization is formed is freeze-dried, and it is poly- to obtain first network ethoxy shell
Syrup gel, it is spare；
2) preparation of the second network readezvous point matter acid hydrogel：The first network hydroxyethyl chitosan water-setting jelly that step 1) is obtained
Dry sample is impregnated in the aqueous solution of hyaluronic acid graft glycidyl methacrylate and water-soluble light trigger, until swelling is flat
Weighing apparatus, implements photochemical polymerization 0.5 minute~10 minutes, obtains hydroxyethyl chitosan/hyaluronic acid double-network hydrogel；Wherein,
It is 2 that sample and the mass ratio of hyaluronic acid graft glycidyl methacrylate, which is lyophilized, in hydroxyethyl chitosan hydrogel:1~1:3,
The mass concentration of hyaluronic acid graft glycidyl methacrylate is 0.5%~4%, and the quality of water-soluble light trigger is
The 0.05%~0.5% of hyaluronic acid graft glycidyl methacrylate quality；
The preparation method of the hyaluronic acid graft glycidyl methacrylate is as follows：
The hyaluronic acid solution that mass concentration is 0.5%~2% is prepared, 4-dimethylaminopyridine, tetrabutyl phosphonium bromide are subsequently added into
Ammonium, glycidyl methacrylate reacted at room temperature 12 hours~48 hours under nitrogen protection, then through deionized water dialysis 3 days
After be freeze-dried, obtain hyaluronic acid graft glycidyl methacrylate；Wherein, the hyaluronan molecule amount is
100kDa~1000kDa.
2. a kind of preparation method of hydroxyethyl chitosan/hyaluronic acid double-network hydrogel according to claim 1, special
Sign is that the preparation method of the hydroxyethyl chitosan graft glycidyl methacrylate is as follows：
The hydroxyethyl chitosan solution that mass concentration is 0.2%~2% is prepared, hydroxyethyl chitosan number of repeat unit is then added
0.1~0.9 times of glycidyl methacrylate, then pH is adjusted to 8.0 using the sodium hydroxide solution of a concentration of 1mol/L,
Then 3 hours~8 hours are stirred at 65 DEG C~85 DEG C, then through deionized water dialysis 3 days；Finally, by the dialysis containing product
Liquid is freeze-dried, obtains hydroxyethyl chitosan graft glycidyl methacrylate.
3. a kind of preparation method of hydroxyethyl chitosan/hyaluronic acid double-network hydrogel according to claim 2, special
Sign is that the dialysis bag retention molecular weight that the dialysis uses is 3500Da；The freeze-drying is subzero 20 DEG C holdings
It is kept for 4 hours within 72 hours, 20 DEG C.
4. a kind of preparation method of hydroxyethyl chitosan/hyaluronic acid double-network hydrogel according to claim 2, special
Sign is that the preparation method of the hydroxyethyl chitosan is as follows：
1) chitosan is scattered in the NaOH solution that mass concentration is 30%~60%, wherein the mass ratio of chitosan and NaOH
It is 3:5；The aqueous isopropanol of chlorethanol is added thereto, then raises temperature to 65 DEG C of back flow reactions 4 hours~7 hours；Wherein shell
Glycan number of repeat unit：Chlorethanol：The molar ratio of isopropanol is 1:3:5~1:6:9；
2) pH value after reaction, is adjusted to neutrality with hydrochloric acid, ethyl alcohol that products therefrom volumetric concentration is 75%~90% and
Absolute ethyl alcohol is washed for several times, soluble in water after vacuum drying, is dialysed 48 hours, then freeze-dried, is obtained hydroxyethyl chitosan.
5. a kind of preparation method of hydroxyethyl chitosan/hyaluronic acid double-network hydrogel according to claim 4, special
Sign is that it is 300kDa~1000kDa that the chitosan, which glues equal molecular mass, and deacetylation is more than 90%.
6. a kind of preparation method of hydroxyethyl chitosan/hyaluronic acid double-network hydrogel according to claim 1, special
Sign is, step 1) and 2) in water-soluble light trigger be 2- hydroxyls -4 '-(2- hydroxy ethoxies) -2- methyl phenyl ketones or 1-
Hydroxycyclohexyl phenyl ketone.
7. a kind of preparation method of hydroxyethyl chitosan/hyaluronic acid double-network hydrogel according to claim 1, special
Sign is, the aqueous solution of the hyaluronic acid graft glycidyl methacrylate and water-soluble light trigger mixture
Volume is equal to the volume of hydroxyethyl chitosan hydrogel freeze-drying sample.
8. a kind of preparation method of hydroxyethyl chitosan/hyaluronic acid double-network hydrogel according to claim 1, special
Sign is that the parameter of the ultraviolet light irradiation is：Centre wavelength is 365nm, light intensity 1200mJ/cm2~1500mJ/cm2、
Irradiation distance is 15cm.
9. a kind of preparation method of hydroxyethyl chitosan/hyaluronic acid double-network hydrogel according to claim 1, special
Sign is that the dosage of 4-dimethylaminopyridine is 0.05~10 times of hyaluronic acid repetitive unit molal quantity, tetrabutylammonium bromide
Dosage be 0.1~3 times of hyaluronic acid repetitive unit molal quantity, the dosage of glycidyl methacrylate is hyaluronic acid
1~20 times of repetitive unit molal quantity.
10. hydroxyethyl chitosan/hyaluronic acid double-network hydrogel prepared by a kind of method according to claim 1, special
Sign is that it is 150 μm that the hydrogel, which has the porous structure of connection, average pore size, compression modulus 38.69kPa.
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| CN113150323B (en) * | 2021-04-09 | 2024-03-29 | 西安交通大学 | N- (2-hydroxypropyl) methacrylamide hyaluronic acid hydrogel, preparation method and application |
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