CN108525003A - Based on the double cross of acylhydrazone key and hydrophobe self assembly connection hybridized hydrogel, preparation method and skin histology wound repair agent - Google Patents
Based on the double cross of acylhydrazone key and hydrophobe self assembly connection hybridized hydrogel, preparation method and skin histology wound repair agent Download PDFInfo
- Publication number
- CN108525003A CN108525003A CN201810203150.0A CN201810203150A CN108525003A CN 108525003 A CN108525003 A CN 108525003A CN 201810203150 A CN201810203150 A CN 201810203150A CN 108525003 A CN108525003 A CN 108525003A
- Authority
- CN
- China
- Prior art keywords
- polyethylene glycol
- hydrophobe
- double cross
- self assembly
- glycol oxide
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
- 239000000017 hydrogel Substances 0.000 title claims abstract description 83
- 238000001338 self-assembly Methods 0.000 title claims abstract description 30
- 238000002360 preparation method Methods 0.000 title claims abstract description 20
- 230000037314 wound repair Effects 0.000 title claims abstract description 10
- 239000002202 Polyethylene glycol Substances 0.000 claims abstract description 55
- 229920001223 polyethylene glycol Polymers 0.000 claims abstract description 48
- 239000000499 gel Substances 0.000 claims abstract description 47
- 229920002674 hyaluronan Polymers 0.000 claims abstract description 35
- 229960003160 hyaluronic acid Drugs 0.000 claims abstract description 35
- KIUKXJAPPMFGSW-DNGZLQJQSA-N (2S,3S,4S,5R,6R)-6-[(2S,3R,4R,5S,6R)-3-Acetamido-2-[(2S,3S,4R,5R,6R)-6-[(2R,3R,4R,5S,6R)-3-acetamido-2,5-dihydroxy-6-(hydroxymethyl)oxan-4-yl]oxy-2-carboxy-4,5-dihydroxyoxan-3-yl]oxy-5-hydroxy-6-(hydroxymethyl)oxan-4-yl]oxy-3,4,5-trihydroxyoxane-2-carboxylic acid Chemical compound CC(=O)N[C@H]1[C@H](O)O[C@H](CO)[C@@H](O)[C@@H]1O[C@H]1[C@H](O)[C@@H](O)[C@H](O[C@H]2[C@@H]([C@@H](O[C@H]3[C@@H]([C@@H](O)[C@H](O)[C@H](O3)C(O)=O)O)[C@H](O)[C@@H](CO)O2)NC(C)=O)[C@@H](C(O)=O)O1 KIUKXJAPPMFGSW-DNGZLQJQSA-N 0.000 claims abstract description 34
- 238000006467 substitution reaction Methods 0.000 claims abstract description 34
- 125000003172 aldehyde group Chemical group 0.000 claims abstract description 15
- 239000003125 aqueous solvent Substances 0.000 claims abstract description 15
- 230000004048 modification Effects 0.000 claims abstract description 11
- 238000012986 modification Methods 0.000 claims abstract description 11
- 239000003795 chemical substances by application Substances 0.000 claims abstract description 10
- 239000002994 raw material Substances 0.000 claims abstract description 9
- 239000004743 Polypropylene Substances 0.000 claims description 20
- 239000000203 mixture Substances 0.000 claims description 20
- 229920001155 polypropylene Polymers 0.000 claims description 19
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 17
- 210000000130 stem cell Anatomy 0.000 claims description 12
- 239000003102 growth factor Substances 0.000 claims description 10
- 238000005304 joining Methods 0.000 claims description 8
- 239000002253 acid Substances 0.000 claims description 7
- 238000002156 mixing Methods 0.000 claims description 7
- 229920002683 Glycosaminoglycan Polymers 0.000 claims description 4
- 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 claims description 3
- OVRNDRQMDRJTHS-UHFFFAOYSA-N N-acelyl-D-glucosamine Natural products CC(=O)NC1C(O)OC(CO)C(O)C1O OVRNDRQMDRJTHS-UHFFFAOYSA-N 0.000 claims description 3
- 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 claims description 3
- 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 claims description 3
- 239000000470 constituent Substances 0.000 claims description 3
- 229950006780 n-acetylglucosamine Drugs 0.000 claims description 3
- 239000007787 solid Substances 0.000 claims description 3
- 229910021642 ultra pure water Inorganic materials 0.000 claims description 3
- 239000012498 ultrapure water Substances 0.000 claims description 3
- 125000002252 acyl group Chemical group 0.000 claims 2
- 229920003171 Poly (ethylene oxide) Polymers 0.000 claims 1
- 125000000717 hydrazino group Chemical group [H]N([*])N([H])[H] 0.000 claims 1
- -1 polyoxyethylene Polymers 0.000 claims 1
- 238000004132 cross linking Methods 0.000 abstract description 17
- 230000008901 benefit Effects 0.000 abstract description 10
- 238000011065 in-situ storage Methods 0.000 abstract description 9
- 230000010399 physical interaction Effects 0.000 abstract description 5
- 229920001451 polypropylene glycol Polymers 0.000 abstract description 3
- 210000003491 skin Anatomy 0.000 description 26
- 229920000642 polymer Polymers 0.000 description 23
- 206010052428 Wound Diseases 0.000 description 17
- 208000027418 Wounds and injury Diseases 0.000 description 17
- 229920002521 macromolecule Polymers 0.000 description 14
- 239000000126 substance Substances 0.000 description 13
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 13
- 229920000463 Poly(ethylene glycol)-block-poly(propylene glycol)-block-poly(ethylene glycol) Polymers 0.000 description 11
- 238000009472 formulation Methods 0.000 description 11
- 230000000694 effects Effects 0.000 description 10
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 9
- 210000004027 cell Anatomy 0.000 description 8
- 230000008595 infiltration Effects 0.000 description 8
- 238000001764 infiltration Methods 0.000 description 8
- 230000017423 tissue regeneration Effects 0.000 description 7
- 239000000463 material Substances 0.000 description 6
- 238000000034 method Methods 0.000 description 6
- 210000001519 tissue Anatomy 0.000 description 6
- 230000008859 change Effects 0.000 description 5
- 238000010276 construction Methods 0.000 description 5
- 230000035876 healing Effects 0.000 description 5
- 239000004615 ingredient Substances 0.000 description 5
- 230000005012 migration Effects 0.000 description 5
- 238000013508 migration Methods 0.000 description 5
- 239000000376 reactant Substances 0.000 description 5
- 238000007493 shaping process Methods 0.000 description 5
- GOOHAUXETOMSMM-UHFFFAOYSA-N Propylene oxide Chemical compound CC1CO1 GOOHAUXETOMSMM-UHFFFAOYSA-N 0.000 description 4
- 206010072170 Skin wound Diseases 0.000 description 4
- 230000015572 biosynthetic process Effects 0.000 description 4
- 239000003814 drug Substances 0.000 description 4
- 230000001788 irregular Effects 0.000 description 4
- 230000008439 repair process Effects 0.000 description 4
- 238000003786 synthesis reaction Methods 0.000 description 4
- 230000000975 bioactive effect Effects 0.000 description 3
- 238000005516 engineering process Methods 0.000 description 3
- 239000003292 glue Substances 0.000 description 3
- 230000002209 hydrophobic effect Effects 0.000 description 3
- 210000004969 inflammatory cell Anatomy 0.000 description 3
- 230000003993 interaction Effects 0.000 description 3
- 230000008929 regeneration Effects 0.000 description 3
- 238000011069 regeneration method Methods 0.000 description 3
- 231100000241 scar Toxicity 0.000 description 3
- 238000012360 testing method Methods 0.000 description 3
- 230000029663 wound healing Effects 0.000 description 3
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 2
- 229920000856 Amylose Polymers 0.000 description 2
- 102000008186 Collagen Human genes 0.000 description 2
- 108010035532 Collagen Proteins 0.000 description 2
- RVGRUAULSDPKGF-UHFFFAOYSA-N Poloxamer Chemical compound C1CO1.CC1CO1 RVGRUAULSDPKGF-UHFFFAOYSA-N 0.000 description 2
- 208000025865 Ulcer Diseases 0.000 description 2
- 238000004458 analytical method Methods 0.000 description 2
- 238000007385 chemical modification Methods 0.000 description 2
- 229920001436 collagen Polymers 0.000 description 2
- 230000007613 environmental effect Effects 0.000 description 2
- 238000007490 hematoxylin and eosin (H&E) staining Methods 0.000 description 2
- 230000014759 maintenance of location Effects 0.000 description 2
- 230000003020 moisturizing effect Effects 0.000 description 2
- 231100000252 nontoxic Toxicity 0.000 description 2
- 230000003000 nontoxic effect Effects 0.000 description 2
- 230000000474 nursing effect Effects 0.000 description 2
- 229920001983 poloxamer Polymers 0.000 description 2
- 229960000502 poloxamer Drugs 0.000 description 2
- 229920000570 polyether Polymers 0.000 description 2
- 229920001282 polysaccharide Polymers 0.000 description 2
- 239000005017 polysaccharide Substances 0.000 description 2
- 150000004804 polysaccharides Chemical class 0.000 description 2
- 230000002441 reversible effect Effects 0.000 description 2
- 231100000075 skin burn Toxicity 0.000 description 2
- 210000004872 soft tissue Anatomy 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- 229920000428 triblock copolymer Polymers 0.000 description 2
- 231100000397 ulcer Toxicity 0.000 description 2
- SMZOUWXMTYCWNB-UHFFFAOYSA-N 2-(2-methoxy-5-methylphenyl)ethanamine Chemical compound COC1=CC=C(C)C=C1CCN SMZOUWXMTYCWNB-UHFFFAOYSA-N 0.000 description 1
- NIXOWILDQLNWCW-UHFFFAOYSA-N 2-Propenoic acid Natural products OC(=O)C=C NIXOWILDQLNWCW-UHFFFAOYSA-N 0.000 description 1
- HRPVXLWXLXDGHG-UHFFFAOYSA-N Acrylamide Chemical compound NC(=O)C=C HRPVXLWXLXDGHG-UHFFFAOYSA-N 0.000 description 1
- 241000894006 Bacteria Species 0.000 description 1
- 229920001661 Chitosan Polymers 0.000 description 1
- 208000017667 Chronic Disease Diseases 0.000 description 1
- LEVWYRKDKASIDU-QWWZWVQMSA-N D-cystine Chemical compound OC(=O)[C@H](N)CSSC[C@@H](N)C(O)=O LEVWYRKDKASIDU-QWWZWVQMSA-N 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
- IAYPIBMASNFSPL-UHFFFAOYSA-N Ethylene oxide Chemical compound C1CO1 IAYPIBMASNFSPL-UHFFFAOYSA-N 0.000 description 1
- 108010010803 Gelatin Proteins 0.000 description 1
- 108010020346 Polyglutamic Acid Proteins 0.000 description 1
- 239000002262 Schiff base Substances 0.000 description 1
- 150000004753 Schiff bases Chemical class 0.000 description 1
- 206010040943 Skin Ulcer Diseases 0.000 description 1
- 208000028990 Skin injury Diseases 0.000 description 1
- 229920002125 Sokalan® Polymers 0.000 description 1
- 229920002472 Starch Polymers 0.000 description 1
- 239000004809 Teflon Substances 0.000 description 1
- 229920006362 Teflon® Polymers 0.000 description 1
- 208000031737 Tissue Adhesions Diseases 0.000 description 1
- 235000009754 Vitis X bourquina Nutrition 0.000 description 1
- 235000012333 Vitis X labruscana Nutrition 0.000 description 1
- 240000006365 Vitis vinifera Species 0.000 description 1
- 235000014787 Vitis vinifera Nutrition 0.000 description 1
- 230000032683 aging Effects 0.000 description 1
- 229920000615 alginic acid Polymers 0.000 description 1
- 239000000783 alginic acid Substances 0.000 description 1
- 235000010443 alginic acid Nutrition 0.000 description 1
- 229960001126 alginic acid Drugs 0.000 description 1
- 150000004781 alginic acids Chemical class 0.000 description 1
- 229910021529 ammonia Inorganic materials 0.000 description 1
- 239000002585 base Substances 0.000 description 1
- 230000006399 behavior Effects 0.000 description 1
- 230000005540 biological transmission Effects 0.000 description 1
- 210000000988 bone and bone Anatomy 0.000 description 1
- 230000015556 catabolic process Effects 0.000 description 1
- 239000001913 cellulose Substances 0.000 description 1
- 229920002678 cellulose Polymers 0.000 description 1
- 235000010980 cellulose Nutrition 0.000 description 1
- 238000006243 chemical reaction Methods 0.000 description 1
- 229940045110 chitosan Drugs 0.000 description 1
- 229920001577 copolymer Polymers 0.000 description 1
- 229960003067 cystine Drugs 0.000 description 1
- 230000006378 damage Effects 0.000 description 1
- 238000005034 decoration Methods 0.000 description 1
- 230000007812 deficiency Effects 0.000 description 1
- 238000006731 degradation reaction Methods 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 238000004043 dyeing Methods 0.000 description 1
- 235000013399 edible fruits Nutrition 0.000 description 1
- 230000009881 electrostatic interaction Effects 0.000 description 1
- 210000002615 epidermis Anatomy 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 238000013467 fragmentation Methods 0.000 description 1
- 238000006062 fragmentation reaction Methods 0.000 description 1
- 239000008273 gelatin Substances 0.000 description 1
- 229920000159 gelatin Polymers 0.000 description 1
- 235000019322 gelatine Nutrition 0.000 description 1
- 235000011852 gelatine desserts Nutrition 0.000 description 1
- 230000012010 growth Effects 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 238000005213 imbibition Methods 0.000 description 1
- 239000007943 implant Substances 0.000 description 1
- 208000015181 infectious disease Diseases 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 230000035800 maturation Effects 0.000 description 1
- 239000012567 medical material Substances 0.000 description 1
- 230000004060 metabolic process Effects 0.000 description 1
- 210000000056 organ Anatomy 0.000 description 1
- 238000010827 pathological analysis Methods 0.000 description 1
- 229920003023 plastic Polymers 0.000 description 1
- 239000004033 plastic Substances 0.000 description 1
- 229920000747 poly(lactic acid) Polymers 0.000 description 1
- 229920002401 polyacrylamide Polymers 0.000 description 1
- 239000004584 polyacrylic acid Substances 0.000 description 1
- 229920001610 polycaprolactone Polymers 0.000 description 1
- 239000004632 polycaprolactone Substances 0.000 description 1
- 229920000728 polyester Polymers 0.000 description 1
- 229920002643 polyglutamic acid Polymers 0.000 description 1
- 239000004626 polylactic acid Substances 0.000 description 1
- 229920002635 polyurethane Polymers 0.000 description 1
- 239000004814 polyurethane Substances 0.000 description 1
- 230000008092 positive effect Effects 0.000 description 1
- 230000008569 process Effects 0.000 description 1
- 230000035755 proliferation Effects 0.000 description 1
- 230000001737 promoting effect Effects 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 230000037380 skin damage Effects 0.000 description 1
- 231100000019 skin ulcer Toxicity 0.000 description 1
- 241000894007 species Species 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 229940032147 starch Drugs 0.000 description 1
- 238000003860 storage Methods 0.000 description 1
- 230000035882 stress Effects 0.000 description 1
- 150000005846 sugar alcohols Polymers 0.000 description 1
- 210000000515 tooth Anatomy 0.000 description 1
- 230000010148 water-pollination 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
- A61L26/00—Chemical aspects of, or use of materials for, wound dressings or bandages in liquid, gel or powder form
- A61L26/0009—Chemical aspects of, or use of materials for, wound dressings or bandages in liquid, gel or powder form containing macromolecular materials
- A61L26/0052—Mixtures of macromolecular compounds
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L26/00—Chemical aspects of, or use of materials for, wound dressings or bandages in liquid, gel or powder form
- A61L26/0061—Use of materials characterised by their function or physical properties
- A61L26/008—Hydrogels or hydrocolloids
-
- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- 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
- C08J3/246—Intercrosslinking of at least two polymers
-
- 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
-
- 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
- C08J2371/00—Characterised by the use of polyethers obtained by reactions forming an ether link in the main chain; Derivatives of such polymers
- C08J2371/02—Polyalkylene oxides
-
- 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
-
- 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
- C08J2471/00—Characterised by the use of polyethers obtained by reactions forming an ether link in the main chain; Derivatives of such polymers
- C08J2471/02—Polyalkylene oxides
Landscapes
- Chemical & Material Sciences (AREA)
- Health & Medical Sciences (AREA)
- Dispersion Chemistry (AREA)
- Epidemiology (AREA)
- Polymers & Plastics (AREA)
- Organic Chemistry (AREA)
- Engineering & Computer Science (AREA)
- Materials Engineering (AREA)
- Medicinal Chemistry (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Materials For Medical Uses (AREA)
Abstract
The present invention relates to hydrogel preparation fields, more particularly to based on the double cross of acylhydrazone key and hydrophobe self assembly connection hybridized hydrogel, preparation method and skin histology wound repair agent.Double cross joins hybridized hydrogel raw material：The hyaluronic acid HAHZ and aldehyde group modified polyethylene glycol oxide polypropylene oxide polyethylene glycol oxide PFAH of hydrazide group modification；The addition mass ratio of HAHZ and PFAH meets：Ranging from the 20 80% of hydrazide group degree of substitution/aldehyde radical degree of substitution, aqueous solvent surplus.The present invention is based on the advantages that double cross-linked hydrogels of acylhydrazone key and hydrophobe self assembly fully combine covalent cross-linking and Physical interaction, the double cross of preparation joins hybridized hydrogel, with excellent self-healing characteristics, medical gel dressing is advantageously accounted for by the frangible problem of external force；With certain temperature-responsive, there is excellent mechanical performance and formed in situ characteristic, be extremely suitable for restoration care or the treatment of the skin histology surface of a wound.
Description
Technical field
The present invention relates to hydrogel preparation fields, miscellaneous more particularly to being joined based on the double cross of acylhydrazone key and hydrophobe self assembly
Change hydrogel, preparation method and skin histology wound repair agent.
Background technology
Macromolecule hydrogel is that had after water-swellable by three-dimensional network of the high molecular component through chemically or physically preparing
There are certain mechanical strength and elasticity.Macromolecule can be divided into natural and synthesis two major classes by its source.Natural hydrophily high score
Attached bag includes polysaccharide (cellulose, starch, alginic acid, hyaluronic acid, chitosan etc.) and protide (collagen, gelatin, poly- bad ammonia
Sour, poly- Glutamic Acid etc.).The hydrophilic high mol of synthesis includes polyalcohols (polyethylene glycol), modified poly ester (polyurethane, hydrophilic modifying
Polycaprolactone, polylactic acid etc.), (polyacrylic acid, polymethylacrylic acid, polyacrylamide, poly- N- are poly- for acrylic acid and its derivative species
For acrylamide etc.) and its copolymer etc..The cross-linked structure of macromolecule hydrogel can by Physical interaction, covalent bond and
Dynamic covalent bond is completed.Physical interaction includes mainly：Chain entanglement, hydrogen bond, hydrophobic interaction, electrostatic interaction,
Supermolecule interaction etc.；Dynamic covalent bond includes cystine linkage, schiff bases and acylhydrazone key etc.；In addition, some special physics
Or chemical bonding form is also paid close attention to, such as slip ring cross-linked structure, microstructure etc..
As a kind of soft, wet stock, case of the macromolecule hydrogel for clinical treatment is no longer rare, the technology and doctor
The combination for the treatment of is mainly the following：1. anatomic implants are prepared (bone, tooth, soft tissue organs etc.)；2. drug carries
Body and transmission；3. external medical material such as skin repair and nursing etc..Applied to skin burn, mechanical damage or chronic disease ulcer
The surface of a wound can be used for reducing wound temperature, obstruct bacterium, absorb sepage, mitigate pain, wounds is prevented to deepen, and accelerates
Wound healing shortens treatment cycle, mitigates scar proliferation etc..
Application of the macromolecule hydrogel in soft tissue repair at present is received significant attention and is studied, but its ingredient and structure
Complexity, there is also mechanical strength, structure and comprehensive performance etc. can not unify with jointly improve etc. challenges, need to be further improved：
1. the hydrogel for Physical interaction as crosslinking points, intensity is relatively fragile, be unfavorable for its popularization clinically with
Commercialization；2. for the hydrogel that covalent bond is built as crosslinking points, do not have self-repairability and plasticity, mechanical strength carries
When high, the raising of the degree of cross linking is necessarily corresponded to, but improving the degree of cross linking can cause hydrogel network scale too low, influence cell
Infiltration and migration；3. in addition, the molecular weight of most high molecular materials is too high, degradation speed is too fast or excessively slow, uncontrollable or its life
Object compatibility is bad, also restricts its application in the field of medicine.
Invention content
(1) technical problems to be solved
The object of the present invention is to provide based on the double cross of acylhydrazone key and hydrophobe self assembly connection hybridized hydrogel, its preparation side
Method and skin histology wound repair agent solve above-mentioned at least one technical problem.
(2) technical solution
It is miscellaneous based on the double cross of acylhydrazone key and hydrophobe self assembly connection that in order to solve the above technical problem, the present invention provides a kind of
Change hydrogel, raw material includes：The hyaluronic acid HAHZ of hydrazide group modification and aldehyde group modified polyethylene glycol oxide-polyoxygenated third
Alkene-polyethylene glycol oxide PFAH；The addition mass ratio of HAHZ and PFAH meets：The range of hydrazide group degree of substitution/aldehyde radical degree of substitution
For 20-80%, aqueous solvent surplus.
In the present solution, acylhydrazone key be can inverse kinematics covalent bond, based on can inverse kinematics covalent bond prepare hydrogel crosslinking points
Chemical kinetics converted between reactant and product and reach chemistry balance state so that the hydrogel of preparation have self-healing
Characteristic, advantageously account for that current hydrogel medical dressing faces by the frangible problem of external force.Polyethylene glycol oxide (PEO)-is poly-
Propylene oxide (PPO)-polyethylene glycol oxide (PEO) triblock copolymer, each block molecule chain can adjust, and PEO segments are hydrophilic easily
It is dissolved in water, PPO segments are hydrophobic to be insoluble in water, which is easily self-assembly of micella in water.So that the hydrogel has well
Quick in situ shaping characteristic, be more advantageous to the various irregular wounds of fitting, special construction makes possessed by the hydrogel
It has good effect for tissue repair.
In some embodiments, preferably, the degree of substitution of hydrazide group is 1.0- in the hyaluronic acid of the hydrazide group modification
50%.
In the present solution, containing great amount of hydroxy group and carboxyl in the chemical constitution of hyaluronic acid, pass through the method for chemical modification
Introduce hydrazide group.
In some embodiments, preferably, the hyaluronic acid is by unit D-Glucose aldehydic acid and N-acetyl-glucosamine
The acid mucopolysaccharide of composition.In the present solution, hyaluronic acid is natural macromolecule amylose hyaluronic acid, there is special water conservation to make
With, be the substance that moisture retention is best in nature, have the function of promote wound healing.Can improve product water retention and
Wound self-healing effect.
In some embodiments, preferably, the aldehyde group modified polyethylene glycol oxide-polypropylene oxide-polyethylene glycol oxide
Replace the hydroxyl of the polyethylene glycol oxide-polypropylene oxide-polyethylene glycol oxide end group for aldehyde radical.In the present solution, PEO-PPO-
PEO triblock polymers are a kind of synthesis macromolecules, and strand is very soft, the preferable polyethers of nontoxic and biological safety.It carries
For a kind of micella of self assembly easy in water, the intensity of product and the life compatibility of raw material are improved.
In some embodiments, preferably, the degree of substitution of the aldehyde radical is 1.0-100%.PEO-PPO-PEO three blocks are poly-
Closing the terminal hydroxyl of object can be replaced by aldehyde radical.
In some embodiments, preferably, the solid content of the double cross connection hybridized hydrogel is 2-22%.In rated condition
The mass percent that remainder accounts for total amount after lower drying is 2-22%.
In some embodiments, preferably, the raw material further includes：Growth factor or stem cell；The aqueous solvent includes
Ultra-pure water.In the present solution, having growth factor or the stem cell promotion of bioactive ingredients by growth factor, stem cell etc.
The reparation and regrowth of skin wound.Reduce the infection probability of skin wound.
The present invention also provides a kind of systems joining hybridized hydrogel based on the double cross of acylhydrazone key and hydrophobe self assembly
Preparation Method comprising：Prepare the hyaluronic acid HAHZ of hydrazide group modification；Prepare aldehyde group modified polyethylene glycol oxide-polyoxygenated third
Alkene-polyethylene glycol oxide PFAH；Under room temperature, hyaluronic acid HAHZ that the hydrazide group is modified and the aldehyde radical are repaiied by preset ratio
Polyethylene glycol oxide-polypropylene oxide-polyethylene glycol oxide the PFAH and aqueous solvent of decorations are mixed；It stirs evenly, it is solidifying to obtain precrosslink
Glue；It stands, pre-crosslinked gel fades to flexible water-swellable three-dimensional network product or hydrogel.In the present solution, HAHZ
Mixing is directly mixed with PFAH and can be obtained pre-crosslinked gel, and gradually becomes required product with standing.
In some embodiments, preferably, in the hyaluronic acid HAHZ for modifying the hydrazide group by preset ratio
Further include in the aldehyde group modified polyethylene glycol oxide-polypropylene oxide-polyethylene glycol oxide PFAH and aqueous solvent mixing：It will
Mixing is added in the growth factor or stem cell for having life active constituent.In the present solution, passing through the tools such as growth factor, stem cell
The growth factor of standby bioactive ingredients or stem cell promote the reparation and regrowth of skin wound.
The present invention also provides a kind of skin histology wound repair agent comprising it is described based on acylhydrazone key and hydrophobe from
The double cross of assembling joins hybridized hydrogel.Be conducive to be bonded various irregular wounds, special construction makes possessed by the hydrogel
Obtain it has good effect for tissue repair.
(3) advantageous effect
Technical solution provided by the invention is fully combined based on acylhydrazone key and double cross-linked hydrogels of hydrophobe self assembly
The advantage of covalent cross-linking and Physical interaction.Acylhydrazone key as it is a kind of it is novel, typically can inverse kinematics covalent bond, based on reversible
The chemical kinetics of hydrogel crosslinking points prepared by dynamic covalent bond is converted between reactant and product and reaches chemical balance shape
State so that the hydrogel of preparation has the characteristic of self-healing, advantageously account for that current hydrogel medical dressing faces by outer
The frangible problem of power.In addition, acylhydrazone key crosslinking points are in the ceaselessly dynamic equilibrium of "on" and "off", it is similar to valve, it will not
Fetter the infiltration and migration of cell.Therefore, the hydrogel in terms of molecular structure for cell behavior and regeneration or reparation
With apparent advantage.Simultaneously as PEO-PPO-PEO triblock polymers can be self-assembled into micella at normal temperatures, assign
The more excellent mechanical property of the macromolecule hydrogel, and the introducings of the PEO-PPO-PEO triblock polymers of Thermo-sensitive
So that there is the hydrogel preferable temperature-responsive, the intensity of gel to have significant increase with the promotion of temperature so that the water
Gel has good quick in situ shaping characteristic, is more advantageous to and is bonded various irregular wounds, possessed by the hydrogel
Special construction makes it have good effect for tissue repair.
Description of the drawings
Fig. 1 is that the gel strength of embodiment 8HAHZ/PFAH double crosses connection hybridized hydrogel changes with time；
Fig. 2 is that the HAHZ/PFAH double crosses described in embodiment 9 join healing and stretching of the hybridized hydrogel under no environmental stimuli
Picture；
Fig. 3 is the dermatopathology H＆E staining analysis when burn described in embodiment 10 is repaired 21 days.
Specific implementation mode
With reference to the accompanying drawings and examples, the specific implementation mode of the present invention is described in further detail.Following instance
For illustrating the present invention, but it is not limited to the scope of the present invention.
Hybridized hydrogel, raw material packet are joined based on the double cross of acylhydrazone key and hydrophobe self assembly the present invention provides a kind of
It includes：The hyaluronic acid HAHZ and aldehyde group modified polyethylene glycol oxide-polypropylene oxide-polyethylene glycol oxide PFAH of hydrazide group modification；
The addition mass ratio of HAHZ and PFAH meets：The ranging from 20-80% of hydrazide group degree of substitution/aldehyde radical degree of substitution, more than aqueous solvent
Amount.Hydrazide group in hyaluronic acid hydroxyl and carboxyl replace, aldehyde radical is to polyethylene glycol oxide-polypropylene oxide-polyethylene glycol oxide
The hydroxyl of the ends PFAH is replaced.
Double cross-linked hydrogels based on acylhydrazone key and hydrophobe self assembly fully combine covalent cross-linking and physics phase interaction
Advantage.Acylhydrazone key as it is a kind of it is novel, typically can inverse kinematics covalent bond, based on can the water-setting for preparing of inverse kinematics covalent bond
The chemical kinetics of glue crosslinking points is converted between reactant and product and reaches chemistry balance state so that the hydrogel of preparation has
The characteristic for having self-healing, advantageously account for that current hydrogel medical dressing faces by the frangible problem of external force.In addition, acylhydrazone key
Crosslinking points are in the ceaselessly dynamic equilibrium of "on" and "off", are similar to valve, will not be fettered the infiltration and migration of cell.Cause
This, which for cell behavior and regeneration or repairs with apparent advantage in terms of molecular structure.
Simultaneously as PEO-PPO-PEO triblock polymers can be self-assembled into micella at normal temperatures, the high score is imparted
The more excellent mechanical property of sub- hydrogel, and the introducing of the PEO-PPO-PEO triblock polymers of Thermo-sensitive makes the water
There is gel preferable temperature-responsive, the intensity of gel to have significant increase with the promotion of temperature so that the hydrogel has
Good quick in situ shaping characteristic is more advantageous to and is bonded various irregular wounds, special construction possessed by the hydrogel
So that it has good effect for tissue repair.
Hyaluronic acid (hyaluronic acid, HA) is a kind of natural macromolecular grape glycosaminoglycan, has special guarantor
Water acts on, and is the substance that moisture retention is best in presently found nature, is referred to as ideal natural moisturizing factor (Natural
Moisturizing factor, NMF have the function of promoting wound healing.Also contain a large amount of hyaluronic acid in skin.People
Class skin maturation and ageing process change also with content and the metabolism of hyaluronic acid.In addition, it contains carboxyl and hydroxyl
Base is easy to carry out various reactions, can flexibly synthesize various derivatives.PEO-PPO-PEO triblock polymers are a kind of synthesis
Macromolecule, strand is very soft, the preferable polyethers of nontoxic and biological safety.Therefore, which has excellent
Elegant biocompatibility, is widely used in clinical application, safe.
What this technology obtained joins hybridized hydrogel based on the double cross of acylhydrazone key and hydrophobe self assembly, has excellent self-healing
Characteristic is closed, advantageously accounts for medical gel dressing by the frangible problem of external force；With certain temperature-responsive, have excellent
Mechanical performance and formed in situ characteristic are extremely suitable for restoration care or the treatment of the skin histology surface of a wound.
Hyaluronic acid is a kind of acid mucopolysaccharide, is made of unit D-Glucose aldehydic acid and N-acetyl-glucosamine advanced
Polysaccharide, natural macromolecule amylose hyaluronic acid contain great amount of hydroxy group and carboxyl in chemical constitution, can pass through the side of chemical modification
Method introduces hydrazide group；Hydrazide group modification hyaluronic acid in hydrazide group degree of substitution be 1.0-50%, preferably 10-25%, or
20-40%.
Polyethylene glycol oxide (PEO)-polypropylene oxide (PPO)-polyethylene glycol oxide (PEO) triblock copolymer, macromolecule are total
Polymers, each block molecule chain can adjust, and polyethylene glycol oxide PEO segments are hydrophilic soluble easily in water, and polypropylene oxide PPO segments are hydrophobic
It is insoluble in water, which is easily self-assembly of micella in water；The end group of poloxamer is hydroxyl, chemically modified can be generated
Aldehyde radical；The degree of substitution of aldehyde radical is 1.0-100%.It is preferred that 10-35% or 55-85% or 40-80% etc..
The solid content that the double cross joins hybridized hydrogel is 2-22%.Its raw material is additionally added the growth for having bioactive ingredients
The factor or stem cell etc.；For aqueous solvent as surplus, aqueous solvent includes ultra-pure water, and the sum of mass concentration percentage of all raw materials is
100%.
In view of the deficiencies of the prior art, the present invention is intended to provide a kind of joined based on the double cross of acylhydrazone key and hydrophobe self assembly
Hybridized hydrogel illustrates that it has unique technical advantage in medical domain by the application in skin ultrastructure field
With wide application prospect.The system will utilize physicochemical properties of dynamic covalent bond and hydrophobe self assembly itself, natural
The characteristics of macromolecule and hydrogel itself, regenerates for medical tissue engineering and provides one kind newly with reparation especially skin tissue engineering
Clever and reliable material.Advantage is as follows：
(1) double cross-linked hydrogels based on acylhydrazone key and hydrophobe self assembly fully combine covalent cross-linking and physics is mutual
The advantage of effect.Acylhydrazone key has great advantage as a kind of novel, typical dynamic covalent bond for hydrogel performance.It can
Inverse kinematics covalent bond is similar to valve in the ceaselessly dynamic equilibrium of "on" and "off", will not fetter the infiltration of cell with
Migration.Based on can the chemical kinetics of hydrogel crosslinking points for preparing of inverse kinematics covalent bond convert and reach between reactant and product
To chemistry balance state so that the hydrogel of preparation has self-healing properties and surface of a wound adhesiveness, advantageously accounts for current water
Gel medical dressing face by external force is frangible and problem easy to fall off.Simultaneously as PEO-PPO-PEO triblock polymers are normal
It can be self-assembled into micella under temperature, impart the more excellent mechanical property of the macromolecule hydrogel, and the PEO- of Thermo-sensitive
The introducing of PPO-PEO triblock polymers makes the hydrogel have preferable temperature-responsive, and the intensity of gel is with temperature
Promotion has significant increase so that the hydrogel has good quick in situ shaping characteristic, is more advantageous to fitting and various does not advise
Wound then.
(2) HA all has very outstanding histocompatbility with PEO-PPO-PEO triblock polymers；What hydrazide group was modified
Certain mobility is presented after being mixed with the poloxamer (PFAH) that aldehyde radical is modified in HA (HAHZ), can directly be applied to skin damage
The tissue surface of a wound of wound, quickly becomes the material with some strength, functions similarly to the effect of dressing for skin.Therefore, the water-setting
Glue is applied to dressing for skin, very convenient for clinical application.
(3) there is very strong water imbibition, it can be with absorptive tissue sepage；With certain mechanical strength and tissue adhesion；
It is extremely suitable for restoration care or the treatment of the skin histology surface of a wound；
(4) original ingredient, micro-structure and bioactivity can be stored and kept under 0-37 degree, only regulated and controled with simple temperature
Physical mixed can rapid shaping, be free of photoactive substance, it is safer, be more suitable for daily-use chemical industry, scientific research, clinical medicine,
Application in translational medicine.It is same as the application of nursing field with absolute predominance in skin repair.
The present invention also provides a kind of preparation sides joining hybridized hydrogel based on the double cross of acylhydrazone key and hydrophobe self assembly
Method comprising：
Step 110, the hyaluronic acid HAHZ of hydrazide group modification is prepared；
Step 112, aldehyde group modified polyethylene glycol oxide-polypropylene oxide-polyethylene glycol oxide PFAH is prepared；
Step 114, the hyaluronic acid HAHZ for modifying hydrazide group by preset ratio under room temperature and aldehyde group modified polyoxygenated
Ethylene-polypropylene oxide-polyethylene glycol oxide PFAH and aqueous solvent mixing；
Step 116, it stirs evenly, obtains pre-crosslinked gel；
Step 118, pre-crosslinked gel fades to flexible water-swellable three-dimensional network product or hydrogel.
Wherein, HAHZ and part aqueous agent can be mixed to get mixture one in step 114, by PFAH and part aqueous
Agent is mixed to get mixture two, then mixes mixture one and two, is uniformly mixing to obtain pre-crosslinked gel.Or directly
HAHZ and PFAH are directly mixed with aqueous solvent.
Room temperature, i.e., the natural temperature in the case of any temperature not being added to adjust disturbing factor are mentioned in step 114.Preferably
Temperature value in the range of 22-37 DEG C.
In order to increase the bioactivity that double cross joins hybridized hydrogel, reparation, revival in raising application to skin wound
Fruit, it is poly- in the hyaluronic acid HAHZ and aldehyde group modified polyethylene glycol oxide-polypropylene oxide-for modifying hydrazide group by preset ratio
Further include in ethylene oxide PFAH and aqueous solvent mixing：It will be provided with the growth factor of life active constituent or stem cell be added and mix
It closes.
The present invention also provides a kind of skin histology wound repair agent comprising above-mentioned acylhydrazone key and the hydrophobe of being based on is from group
The double cross of dress joins hybridized hydrogel.
The wound repair agent of this skin histology is in use, based on hyaluronic acid and polyethylene glycol oxide-polypropylene oxide-polyoxy
Change ethylene and all has very outstanding histocompatbility；The HAHZ and aldehyde group modified obtained PFAH obtained after hydrazide group modification is mixed
Certain mobility is presented after conjunction, can directly be applied to the tissue surface of a wound of skin injury, quickly become with some strength
Material functions similarly to the effect of dressing for skin.Therefore, which is applied to dressing for skin, very square for clinical application
Just.
The preparation of a kind of double cross-linked hydrogels based on acylhydrazone key and hydrophobe self assembly disclosed by the invention and its in skin
Application in skin tissue wound repair, especially burn reparation, wherein acylhydrazone key is a kind of dynamic covalent bond, it is a kind of reversible
The chemical kinetics of key, the hydrogel crosslinking points based on the preparation of dynamic covalent bond is converted between reactant and product and reaches chemistry
Equilibrium state so that the hydrogel of preparation has the characteristic of self-healing, advantageously accounts for current hydrogel medical dressing and faces
By the frangible problem of external force.In addition, acylhydrazone key crosslinking points are in the ceaselessly dynamic equilibrium of "on" and "off", it is similar to valve
Door, will not fetter the infiltration and migration of cell.Therefore, the hydrogel in terms of molecular structure for cell behavior and regeneration
Or it repairs with apparent advantage.Simultaneously as PEO-PPO-PEO triblock polymers at normal temperatures being capable of self assembly plastic
Beam imparts the more excellent mechanical property of the macromolecule hydrogel, and the PEO-PPO-PEO triblock polymers of Thermo-sensitive
Introducing to change hydrogel there is preferable temperature-responsive, the intensity of gel to make with the significant increase of promotion of temperature
Hydrogel, which must be changed, has good formed in situ characteristic, is more advantageous to the various wounds of different shapes of fitting, which is had
Some special constructions make it have good effect for tissue repair.The hydrogel selected materials have outstanding biofacies
Capacitive is widely used in clinical application, safe.
Embodiment 1
The polymer solution of the PFAH of the HAHZ and 5% (w/v) of accurate formulation 5% (w/v) respectively, the two is fully mixed
It closes, stands be cross-linked to form gel at room temperature.
Embodiment 2
The polymer solution of the PFAH of the HAHZ and 10% (w/v) of accurate formulation 5% (w/v) respectively, increases in the solution
Growth factor is sufficiently mixed, and stands be cross-linked to form gel at room temperature.
Embodiment 3
The polymer solution of the PFAH of the HAHZ and 15% (w/v) of accurate formulation 5% (w/v) respectively, increases in the solution
Stem cell is sufficiently mixed, and stands be cross-linked to form gel at room temperature.
Embodiment 4
The polymer solution of the PFAH of the HAHZ and 20% (w/v) of accurate formulation 5% (w/v) respectively, the two is fully mixed
It closes, stands be cross-linked to form gel at room temperature.
Embodiment 5
The polymer solution of the PFAH of the HAHZ and 10% (w/v) of accurate formulation 10% (w/v) respectively, the two is fully mixed
It closes, stands be cross-linked to form gel at room temperature.
Embodiment 6
The polymer solution of the PFAH of the HAHZ and 15% (w/v) of accurate formulation 10% (w/v) respectively, the two is fully mixed
It closes, stands be cross-linked to form gel at room temperature.
Embodiment 7
The polymer solution of the PFAH of the HAHZ and 20% (w/v) of accurate formulation 10% (w/v) respectively, the two is fully mixed
It closes, stands be cross-linked to form gel at room temperature.
The degree of substitution of hydrazide group is 1-50% in HAHZ in embodiment 1-7, such as：10%, 25%, 20% or 40%；
The degree of substitution of aldehyde radical is 1-100% in PFAH in embodiment 1-7, such as：10%, 35%, 55%, 85% etc..
Moreover, hydrazide group and aldehyde radical degree of substitution ratio meet 20-80%, such as 30%, 50%, 75% etc..
The preparation of HAHZ and PFAH is given below：
Embodiment 1-7-1,
Hydroxyl, carboxyl in hyaluronic acid are replaced using hydrazide group, obtain the HAHZ that hydrazide group degree of substitution is 1%.
Embodiment 1-7-2
Hydroxyl, carboxyl in hyaluronic acid are replaced using hydrazide group, obtain the HAHZ that hydrazide group degree of substitution is 10%.
Embodiment 1-7-3
Hydroxyl, carboxyl in hyaluronic acid are replaced using hydrazide group, obtain the HAHZ that hydrazide group degree of substitution is 20%.
Embodiment 1-7-4
Hydroxyl, carboxyl in hyaluronic acid are replaced using hydrazide group, obtain the HAHZ that hydrazide group degree of substitution is 25%.
Embodiment 1-7-5
Hydroxyl, carboxyl in hyaluronic acid are replaced using hydrazide group, obtain the HAHZ that hydrazide group degree of substitution is 40%.
Embodiment 1-7-6
Replace the terminal hydroxyl of polyethylene glycol oxide-polypropylene oxide-polyethylene glycol oxide using aldehyde radical, obtains aldehyde radical degree of substitution
For 1% PFAH.
Embodiment 1-7-7
Replace the terminal hydroxyl of polyethylene glycol oxide-polypropylene oxide-polyethylene glycol oxide using aldehyde radical, obtains aldehyde radical degree of substitution
For 35% PFAH.
Embodiment 1-7-8
Replace the terminal hydroxyl of polyethylene glycol oxide-polypropylene oxide-polyethylene glycol oxide using aldehyde radical, obtains aldehyde radical degree of substitution
For 55% PFAH.
Embodiment 1-7-9
Replace the terminal hydroxyl of polyethylene glycol oxide-polypropylene oxide-polyethylene glycol oxide using aldehyde radical, obtains aldehyde radical degree of substitution
For 100% PFAH.
Embodiment 1-7-10
The polymer for the PFAH that the HAHZ and aldehyde radical degree of substitution that accurate formulation hydrazide group degree of substitution is 20% respectively are 100%
The two is sufficiently mixed by solution, stands be cross-linked to form gel at room temperature.
Embodiment 1-7-11
The polymer for the PFAH that the HAHZ and aldehyde radical degree of substitution that accurate formulation hydrazide group degree of substitution is 40% respectively are 50%
The two is sufficiently mixed by solution, stands be cross-linked to form gel at room temperature.
Embodiment 1-7-12
The polymer for the PFAH that the HAHZ and aldehyde radical degree of substitution that accurate formulation hydrazide group degree of substitution is 32% respectively are 80%
Solution is added stem cell, is sufficiently mixed, and stands be cross-linked to form gel at room temperature.
Embodiment 1-7-12
The polymer for the PFAH that the HAHZ and aldehyde radical degree of substitution that accurate formulation hydrazide group degree of substitution is 6% respectively are 20% is molten
Liquid is added biotic factor, is sufficiently mixed, and stands be cross-linked to form gel at room temperature.
Embodiment 8
Mixed liquor 300ul in embodiment 6 is added on rheometer test platform, under 37 DEG C, 1HZ, 10% stress
The intensity of test gel changes with time.
As a result it is that HAHZ/PFAH double crosses described in embodiment 8 join the gel strength of hybridized hydrogel at any time referring to Fig. 1, Fig. 1
Between variation.As shown in Figure 1, the crosspoint of storage modulus G ' and loss modulus G " are gel point, gel can shape in 5 minutes
At being conducive to be formed in situ gel, that is, illustrate that time gel has the characteristic of formed in situ.As time increases, gel is strong
Degree dramatically increases, and gel strength reaches 1100Pa when 90min, shows that the hydrogel has excellent mechanical strength, can conduct
Dressing for skin provides mechanical support.
Embodiment 9
Mixed liquor 300ul in embodiment 6 is added in the Teflon mould of a diameter of 1cm, crosslinking west is stood
Guo Cheng gels, are drawn off after gel-forming, are arbitrarily divided into three parts, then gel is put into mold, and observation is taken out after 30min
And it stretches.
As a result join hybridized hydrogel under no environmental stimuli referring to such as 2, Fig. 2 for the HAHZ/PFAH double crosses described in embodiment 9
Healing and stretch picture.As shown in Fig. 2, gel, which is arbitrarily divided into three points, places into mold, taken out after 30min, gel energy
Enough healings completely are an entirety, and pipette tips can not be separated, easily can integrally hang gel without falling, show
The excellent healing properties of gel.Further, the gel after healing is stretched, gel not fragmentation and can be stretched, shown
There is gel excellent self-healing performance and tensile property, good mechanical performance to be conducive to the practical application of gel.
Embodiment 10
Deep second degree burn model is established, experimental group and control group are randomly divided into, control group is only covered with gauze, and experimental group is used
Gel for treating described in embodiment 6.At 7 days, 14 days, 21 days, 11 the skin of surface of a wound part is taken to carry out H＆E dyeing respectively, carried out
Pathological analysis.
As a result it is the dermatopathology H＆E staining analysis burnt when repairing 21 days described in embodiment 10 referring to Fig. 3, Fig. 3
(the left side：Control group, the right：Experimental group).As shown in figure 3, experimental group is compared with control group：The scar area of experimental group relatively compares
The scar area range of group is obviously reduced, and inflammatory cell infiltration is significantly reduced compared with control group, and collagen structure form is close normal, real
There is a small amount of inflammatory cell infiltration in subregion when though testing group 21D, has clearly skin three-decker and skin corium has skin
Accessory structure exists；And have a large amount of inflammatory cell infiltrations when control group 21D, and have apparent skin ulcer (ulcer) appearance
And epidermis thickens.Therefore, animal skin burn experiment is the result shows that materials on skin tissue repair has positive effect.
The preferred embodiment of the present invention has been described above in detail, still, during present invention is not limited to the embodiments described above
Detail can carry out a variety of simple variants to technical scheme of the present invention within the scope of the technical concept of the present invention, this
A little simple variants all belong to the scope of protection of the present invention.
It is further to note that specific technical features described in the above specific embodiments, in not lance
In the case of shield, can be combined by any suitable means, in order to avoid unnecessary repetition, the present invention to it is various can
The combination of energy no longer separately illustrates.
In addition, various embodiments of the present invention can be combined randomly, as long as it is without prejudice to originally
The thought of invention, it should also be regarded as the disclosure of the present invention.
Claims (10)
1. a kind of joining hybridized hydrogel based on the double cross of acylhydrazone key and hydrophobe self assembly, which is characterized in that its raw material includes：Acyl
The hyaluronic acid HAHZ and aldehyde group modified polyethylene glycol oxide-polypropylene oxide-polyethylene glycol oxide PFAH of diazanyl modification；HAHZ and
The addition mass ratio of PFAH meets：The ranging from 20-80% of hydrazide group degree of substitution/aldehyde radical degree of substitution, aqueous solvent surplus.
2. joining hybridized hydrogel based on the double cross of acylhydrazone key and hydrophobe self assembly as described in claim 1, which is characterized in that
The degree of substitution of hydrazide group is 1.0-50% in the hyaluronic acid of the hydrazide group modification.
3. joining hybridized hydrogel based on the double cross of acylhydrazone key and hydrophobe self assembly as described in claim 1, which is characterized in that
The hyaluronic acid is the acid mucopolysaccharide being made of unit D-Glucose aldehydic acid and N-acetyl-glucosamine.
4. joining hybridized hydrogel based on the double cross of acylhydrazone key and hydrophobe self assembly as described in claim 1, which is characterized in that
Aldehyde group modified polyethylene glycol oxide-polypropylene oxide-the polyethylene glycol oxide is that aldehyde radical replaces the polyethylene glycol oxide-polyoxygenated
The hydroxyl of propylene-polyethylene glycol oxide end group.
5. joining hybridized hydrogel based on the double cross of acylhydrazone key and hydrophobe self assembly as claimed in claim 4, which is characterized in that
The degree of substitution of the aldehyde radical is 1.0-100%.
6. as described in any one in claim 1-5 join hybridized hydrogel based on the double cross of acylhydrazone key and hydrophobe self assembly,
It is characterized in that, the solid content of the double cross connection hybridized hydrogel is 2-22%.
7. joining hybridized hydrogel based on the double cross of acylhydrazone key and hydrophobe self assembly as claimed in claim 6, which is characterized in that
The raw material further includes：Growth factor or stem cell；The aqueous solvent includes ultra-pure water.
8. a kind of claim 1-7 any one of them joins hybridized hydrogel based on the double cross of acylhydrazone key and hydrophobe self assembly
Preparation method, which is characterized in that including：
Prepare the hyaluronic acid HAHZ of hydrazide group modification；
Prepare aldehyde group modified polyethylene glycol oxide-polypropylene oxide-polyethylene glycol oxide PFAH；
Under room temperature, the hyaluronic acid HAHZ and the aldehyde group modified polyoxyethylene that modify the hydrazide group by preset ratio
Alkene-polypropylene oxide-polyethylene glycol oxide PFAH is mixed to get mixture one, mixture two with aqueous solvent respectively；
Mixture one and mixture two are mixed, stirred evenly, pre-crosslinked gel is obtained；
It stands, pre-crosslinked gel fades to flexible water-swellable three-dimensional network product or hydrogel.
9. preparation method as claimed in claim 8, which is characterized in that by preset ratio modified the hydrazide group described
Hyaluronic acid HAHZ and the aldehyde group modified polyethylene glycol oxide-polypropylene oxide-polyethylene glycol oxide PFAH and aqueous solvent are mixed
Further include in conjunction：Mixing is added in the growth factor or stem cell that will be provided with life active constituent.
10. a kind of skin histology wound repair agent, which is characterized in that it includes that claim 1-7 any one of them is based on acyl
The double cross of hydrazone bond and hydrophobe self assembly joins hybridized hydrogel.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201810203150.0A CN108525003A (en) | 2018-03-13 | 2018-03-13 | Based on the double cross of acylhydrazone key and hydrophobe self assembly connection hybridized hydrogel, preparation method and skin histology wound repair agent |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201810203150.0A CN108525003A (en) | 2018-03-13 | 2018-03-13 | Based on the double cross of acylhydrazone key and hydrophobe self assembly connection hybridized hydrogel, preparation method and skin histology wound repair agent |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN108525003A true CN108525003A (en) | 2018-09-14 |
Family
ID=63484420
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201810203150.0A Pending CN108525003A (en) | 2018-03-13 | 2018-03-13 | Based on the double cross of acylhydrazone key and hydrophobe self assembly connection hybridized hydrogel, preparation method and skin histology wound repair agent |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN108525003A (en) |
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110522948A (en) * | 2019-08-29 | 2019-12-03 | 南京工业大学 | injectable hydrogel and preparation method and application thereof |
| WO2021137242A1 (en) * | 2020-01-02 | 2021-07-08 | Inteligels Ltd. | Smart wound dressings |
| CN113827501A (en) * | 2021-10-09 | 2021-12-24 | 湖南大学 | Hyaluronic acid hydrogel mask with skin repairing function and preparation method thereof |
| CN114432493A (en) * | 2021-12-23 | 2022-05-06 | 南方医科大学顺德医院(佛山市顺德区第一人民医院) | Injectable biodegradable temperature-sensitive hydrogel and application thereof |
Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPH0959303A (en) * | 1995-08-22 | 1997-03-04 | Shiseido Co Ltd | Biocompatible hyaluronic acid gel and its application |
| CN101035572A (en) * | 2004-10-07 | 2007-09-12 | 纳幕尔杜邦公司 | Polysaccharide-based polymer tissue adhesive for medical use |
| CN103536960A (en) * | 2013-10-30 | 2014-01-29 | 无锡灵锡医疗器械科技有限公司 | Hydrogel capable of slowly releasing antibacterial peptide as well as preparation method thereof |
| CN103611181A (en) * | 2013-10-25 | 2014-03-05 | 无锡灵锡医疗器械科技有限公司 | Antibacterial peptide hydrogel and preparation method thereof |
| CN103623405A (en) * | 2003-08-06 | 2014-03-12 | 美国政府健康及人类服务部 | Polysaccharide-protein conjugate vaccines |
| CN103910894A (en) * | 2014-03-28 | 2014-07-09 | 西安交通大学 | Preparation method of injectable natural polysaccharide self-healing hydrogel |
-
2018
- 2018-03-13 CN CN201810203150.0A patent/CN108525003A/en active Pending
Patent Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPH0959303A (en) * | 1995-08-22 | 1997-03-04 | Shiseido Co Ltd | Biocompatible hyaluronic acid gel and its application |
| CN103623405A (en) * | 2003-08-06 | 2014-03-12 | 美国政府健康及人类服务部 | Polysaccharide-protein conjugate vaccines |
| CN101035572A (en) * | 2004-10-07 | 2007-09-12 | 纳幕尔杜邦公司 | Polysaccharide-based polymer tissue adhesive for medical use |
| CN103611181A (en) * | 2013-10-25 | 2014-03-05 | 无锡灵锡医疗器械科技有限公司 | Antibacterial peptide hydrogel and preparation method thereof |
| CN103536960A (en) * | 2013-10-30 | 2014-01-29 | 无锡灵锡医疗器械科技有限公司 | Hydrogel capable of slowly releasing antibacterial peptide as well as preparation method thereof |
| CN103910894A (en) * | 2014-03-28 | 2014-07-09 | 西安交通大学 | Preparation method of injectable natural polysaccharide self-healing hydrogel |
Non-Patent Citations (4)
| Title |
|---|
| YI LUO ET AL: "Cross-linked hyaluronic acid hydrogel films: new biomaterials for drug delivery", 《JOURNAL OF CONTROLLED RELEASE》 * |
| 赵玲玲等: "温度、pH双敏感可注射凝胶药物载体", 《2011年全国高分子学术论文报告会论文摘要集》 * |
| 金艳等: "透明质酸在皮肤创伤修复中的应用", 《食品与药品》 * |
| 顾其胜等: "《海藻酸盐基生物医用材料与临床医学》", 30 April 2015, 上海科学技术出版社 * |
Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110522948A (en) * | 2019-08-29 | 2019-12-03 | 南京工业大学 | injectable hydrogel and preparation method and application thereof |
| CN110522948B (en) * | 2019-08-29 | 2021-08-06 | 南京工业大学 | Injectable hydrogel and preparation method and application thereof |
| WO2021137242A1 (en) * | 2020-01-02 | 2021-07-08 | Inteligels Ltd. | Smart wound dressings |
| EP4084834A4 (en) * | 2020-01-02 | 2024-01-03 | Yissum Research Development Company of the Hebrew University of Jerusalem Ltd. | Smart wound dressings |
| CN113827501A (en) * | 2021-10-09 | 2021-12-24 | 湖南大学 | Hyaluronic acid hydrogel mask with skin repairing function and preparation method thereof |
| CN114432493A (en) * | 2021-12-23 | 2022-05-06 | 南方医科大学顺德医院(佛山市顺德区第一人民医院) | Injectable biodegradable temperature-sensitive hydrogel and application thereof |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN108478867B (en) | Injectable polymer hydrogel based on acylhydrazone bond, preparation method thereof and polymer hydrogel injection | |
| CN110128682B (en) | Sulfhydryl-aldehyde crosslinking hydrogel material and preparation method and application thereof | |
| Wei et al. | Photo-induced adhesive carboxymethyl chitosan-based hydrogels with antibacterial and antioxidant properties for accelerating wound healing | |
| CN108525003A (en) | Based on the double cross of acylhydrazone key and hydrophobe self assembly connection hybridized hydrogel, preparation method and skin histology wound repair agent | |
| Dash et al. | Ulvan-chitosan polyelectrolyte complexes as matrices for enzyme induced biomimetic mineralization | |
| Tang et al. | Stable antibacterial polysaccharide-based hydrogels as tissue adhesives for wound healing | |
| CN108912352A (en) | A kind of antibacterial adherency injection aquagel dressing and its preparation method and application | |
| Zhao et al. | Electroactive injectable hydrogel based on oxidized sodium alginate and carboxymethyl chitosan for wound healing | |
| CN107708675A (en) | The composition and kit of pseudoplastic behavior microgel matrix | |
| CN110201219A (en) | A kind of composite hydrogel and preparation method thereof of injectable and quick-gelatinizing | |
| JP2003508564A (en) | Composition forming an interpenetrating polymer network for use as a high strength medical sealant | |
| Han et al. | A multifunctional mussel-inspired hydrogel with antioxidant, electrical conductivity and photothermal activity loaded with mupirocin for burn healing | |
| KR101678402B1 (en) | Alginate hydrogel for wound healing and manufacturing method of the same | |
| Huang et al. | A tannin-functionalized soy protein-based adhesive hydrogel as a wound dressing | |
| Ding et al. | Designing self-healing hydrogels for biomedical applications | |
| CN113372585A (en) | Preparation method and application of hydrogel with high-adhesion composite function | |
| CN108498847A (en) | Macromolecule hydrogel, preparation method based on acylhydrazone key and skin histology adhesive | |
| CN110448721A (en) | A kind of conductive oxidation resistant injectable composite hydrogel and its preparation method and application that stops blooding of antibacterial adherency | |
| CN112121032A (en) | Hydrogel patch for skin care and preparation method thereof | |
| CN106866996A (en) | A kind of fast preparation method of silk fibroin matter gel | |
| CN113425893A (en) | Preparation method and application of drug-loaded hydrogel | |
| CN114452436B (en) | Collagen-based injectable self-repairing hydrogel and preparation method thereof | |
| CN109431971A (en) | A kind of injectable carries liquid medicine gel and preparation method thereof | |
| Zhang et al. | Conductive hydrogels with hierarchical biofilm inhibition capability accelerate diabetic ulcer healing | |
| CN1337270A (en) | Wound dressing and its prepn. |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| RJ01 | Rejection of invention patent application after publication | ||
| RJ01 | Rejection of invention patent application after publication |
Application publication date: 20180914 |