CN116284857A - 一种具有生物相容性的可注射肝素水凝胶的制备方法 - Google Patents
一种具有生物相容性的可注射肝素水凝胶的制备方法 Download PDFInfo
- Publication number
- CN116284857A CN116284857A CN202310210212.1A CN202310210212A CN116284857A CN 116284857 A CN116284857 A CN 116284857A CN 202310210212 A CN202310210212 A CN 202310210212A CN 116284857 A CN116284857 A CN 116284857A
- Authority
- CN
- China
- Prior art keywords
- heparin
- hydrogel
- sodium alginate
- modified
- biocompatibility
- 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.)
- Granted
Links
- 239000000017 hydrogel Substances 0.000 title claims abstract description 76
- HTTJABKRGRZYRN-UHFFFAOYSA-N Heparin Chemical compound OC1C(NC(=O)C)C(O)OC(COS(O)(=O)=O)C1OC1C(OS(O)(=O)=O)C(O)C(OC2C(C(OS(O)(=O)=O)C(OC3C(C(O)C(O)C(O3)C(O)=O)OS(O)(=O)=O)C(CO)O2)NS(O)(=O)=O)C(C(O)=O)O1 HTTJABKRGRZYRN-UHFFFAOYSA-N 0.000 title claims abstract description 73
- 229960002897 heparin Drugs 0.000 title claims abstract description 53
- 229920000669 heparin Polymers 0.000 title claims abstract description 53
- 238000002360 preparation method Methods 0.000 title abstract description 7
- IXPNQXFRVYWDDI-UHFFFAOYSA-N 1-methyl-2,4-dioxo-1,3-diazinane-5-carboximidamide Chemical compound CN1CC(C(N)=N)C(=O)NC1=O IXPNQXFRVYWDDI-UHFFFAOYSA-N 0.000 claims abstract description 46
- 239000000243 solution Substances 0.000 claims abstract description 28
- 235000010413 sodium alginate Nutrition 0.000 claims abstract description 27
- 239000000661 sodium alginate Substances 0.000 claims abstract description 27
- 229940005550 sodium alginate Drugs 0.000 claims abstract description 27
- JQWHASGSAFIOCM-UHFFFAOYSA-M sodium periodate Chemical compound [Na+].[O-]I(=O)(=O)=O JQWHASGSAFIOCM-UHFFFAOYSA-M 0.000 claims abstract description 24
- 238000006243 chemical reaction Methods 0.000 claims abstract description 17
- 238000000502 dialysis Methods 0.000 claims abstract description 16
- ASOKPJOREAFHNY-UHFFFAOYSA-N 1-Hydroxybenzotriazole Chemical compound C1=CC=C2N(O)N=NC2=C1 ASOKPJOREAFHNY-UHFFFAOYSA-N 0.000 claims abstract description 12
- IBVAQQYNSHJXBV-UHFFFAOYSA-N adipic acid dihydrazide Chemical compound NNC(=O)CCCCC(=O)NN IBVAQQYNSHJXBV-UHFFFAOYSA-N 0.000 claims abstract description 8
- 150000001718 carbodiimides Chemical class 0.000 claims abstract description 7
- 238000004108 freeze drying Methods 0.000 claims abstract description 7
- 238000000034 method Methods 0.000 claims description 20
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 claims description 18
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 17
- 238000002156 mixing Methods 0.000 claims description 13
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 12
- 239000002244 precipitate Substances 0.000 claims description 11
- 238000003756 stirring Methods 0.000 claims description 10
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 7
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 6
- 239000000725 suspension Substances 0.000 claims description 6
- 239000007853 buffer solution Substances 0.000 claims description 4
- 239000000499 gel Substances 0.000 abstract description 20
- 239000007864 aqueous solution Substances 0.000 abstract description 14
- 238000004113 cell culture Methods 0.000 abstract description 6
- 239000000463 material Substances 0.000 abstract description 6
- ZNZYKNKBJPZETN-WELNAUFTSA-N Dialdehyde 11678 Chemical group N1C2=CC=CC=C2C2=C1[C@H](C[C@H](/C(=C/O)C(=O)OC)[C@@H](C=C)C=O)NCC2 ZNZYKNKBJPZETN-WELNAUFTSA-N 0.000 abstract description 4
- 239000003937 drug carrier Substances 0.000 abstract description 4
- 241001465754 Metazoa Species 0.000 abstract description 3
- 239000003795 chemical substances by application Substances 0.000 abstract description 3
- 230000004048 modification Effects 0.000 abstract description 3
- 238000012986 modification Methods 0.000 abstract description 3
- 230000003647 oxidation Effects 0.000 abstract description 3
- 238000007254 oxidation reaction Methods 0.000 abstract description 3
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 abstract 1
- 210000004027 cell Anatomy 0.000 description 20
- 239000000843 powder Substances 0.000 description 19
- 239000000203 mixture Substances 0.000 description 12
- 239000008367 deionised water Substances 0.000 description 8
- 229910021641 deionized water Inorganic materials 0.000 description 8
- NPZTUJOABDZTLV-UHFFFAOYSA-N hydroxybenzotriazole Substances O=C1C=CC=C2NNN=C12 NPZTUJOABDZTLV-UHFFFAOYSA-N 0.000 description 7
- 238000002386 leaching Methods 0.000 description 6
- 239000002262 Schiff base Substances 0.000 description 5
- 239000011521 glass Substances 0.000 description 5
- 210000001519 tissue Anatomy 0.000 description 5
- CHADEQDQBURGHL-UHFFFAOYSA-N (6'-acetyloxy-3-oxospiro[2-benzofuran-1,9'-xanthene]-3'-yl) acetate Chemical compound O1C(=O)C2=CC=CC=C2C21C1=CC=C(OC(C)=O)C=C1OC1=CC(OC(=O)C)=CC=C21 CHADEQDQBURGHL-UHFFFAOYSA-N 0.000 description 4
- LMDZBCPBFSXMTL-UHFFFAOYSA-N 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide Chemical compound CCN=C=NCCCN(C)C LMDZBCPBFSXMTL-UHFFFAOYSA-N 0.000 description 4
- FPQQSJJWHUJYPU-UHFFFAOYSA-N 3-(dimethylamino)propyliminomethylidene-ethylazanium;chloride Chemical compound Cl.CCN=C=NCCCN(C)C FPQQSJJWHUJYPU-UHFFFAOYSA-N 0.000 description 4
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 4
- 239000006144 Dulbecco’s modified Eagle's medium Substances 0.000 description 4
- 238000001035 drying Methods 0.000 description 4
- 238000011065 in-situ storage Methods 0.000 description 4
- 230000004083 survival effect Effects 0.000 description 4
- 150000004753 Schiff bases Chemical class 0.000 description 3
- 239000006227 byproduct Substances 0.000 description 3
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 3
- 239000000969 carrier Substances 0.000 description 3
- 238000010586 diagram Methods 0.000 description 3
- 238000002474 experimental method Methods 0.000 description 3
- 239000001963 growth medium Substances 0.000 description 3
- 239000011148 porous material Substances 0.000 description 3
- 230000002269 spontaneous effect Effects 0.000 description 3
- -1 sulfonic group Chemical group 0.000 description 3
- 102000010834 Extracellular Matrix Proteins Human genes 0.000 description 2
- 108010037362 Extracellular Matrix Proteins Proteins 0.000 description 2
- 241000192125 Firmicutes Species 0.000 description 2
- NTYJJOPFIAHURM-UHFFFAOYSA-N Histamine Chemical compound NCCC1=CN=CN1 NTYJJOPFIAHURM-UHFFFAOYSA-N 0.000 description 2
- 229920001730 Moisture cure polyurethane Polymers 0.000 description 2
- 230000010261 cell growth Effects 0.000 description 2
- 238000012258 culturing Methods 0.000 description 2
- 230000007547 defect Effects 0.000 description 2
- 238000005538 encapsulation Methods 0.000 description 2
- 210000002744 extracellular matrix Anatomy 0.000 description 2
- 238000001914 filtration Methods 0.000 description 2
- 125000000524 functional group Chemical group 0.000 description 2
- 239000003102 growth factor Substances 0.000 description 2
- 238000003384 imaging method Methods 0.000 description 2
- 238000002347 injection Methods 0.000 description 2
- 239000007924 injection Substances 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- 239000002609 medium Substances 0.000 description 2
- 239000012528 membrane Substances 0.000 description 2
- 229920000642 polymer Polymers 0.000 description 2
- 238000006116 polymerization reaction Methods 0.000 description 2
- 230000008569 process Effects 0.000 description 2
- 108090000623 proteins and genes Proteins 0.000 description 2
- 239000002994 raw material Substances 0.000 description 2
- 238000001878 scanning electron micrograph Methods 0.000 description 2
- 239000013049 sediment Substances 0.000 description 2
- 238000010186 staining Methods 0.000 description 2
- 239000012224 working solution Substances 0.000 description 2
- 244000063299 Bacillus subtilis Species 0.000 description 1
- 235000014469 Bacillus subtilis Nutrition 0.000 description 1
- 241000894006 Bacteria Species 0.000 description 1
- 241000222122 Candida albicans Species 0.000 description 1
- 201000007336 Cryptococcosis Diseases 0.000 description 1
- 241000221204 Cryptococcus neoformans Species 0.000 description 1
- 241000588724 Escherichia coli Species 0.000 description 1
- 231100000002 MTT assay Toxicity 0.000 description 1
- 238000000134 MTT assay Methods 0.000 description 1
- 102000035195 Peptidases Human genes 0.000 description 1
- 108091005804 Peptidases Proteins 0.000 description 1
- 239000004365 Protease Substances 0.000 description 1
- 241000191967 Staphylococcus aureus Species 0.000 description 1
- OUUQCZGPVNCOIJ-UHFFFAOYSA-M Superoxide Chemical compound [O-][O] OUUQCZGPVNCOIJ-UHFFFAOYSA-M 0.000 description 1
- FZWLAAWBMGSTSO-UHFFFAOYSA-N Thiazole Chemical compound C1=CSC=N1 FZWLAAWBMGSTSO-UHFFFAOYSA-N 0.000 description 1
- 238000002835 absorbance Methods 0.000 description 1
- 239000000654 additive Substances 0.000 description 1
- 230000000996 additive effect Effects 0.000 description 1
- 125000003277 amino group Chemical group 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 230000000844 anti-bacterial effect Effects 0.000 description 1
- 230000001093 anti-cancer Effects 0.000 description 1
- 230000000843 anti-fungal effect Effects 0.000 description 1
- 230000000259 anti-tumor effect Effects 0.000 description 1
- 230000000840 anti-viral effect Effects 0.000 description 1
- 239000003146 anticoagulant agent Substances 0.000 description 1
- 229940127219 anticoagulant drug Drugs 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000004071 biological effect Effects 0.000 description 1
- 239000013060 biological fluid Substances 0.000 description 1
- 239000012620 biological material Substances 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 239000000872 buffer Substances 0.000 description 1
- 229940095731 candida albicans Drugs 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 230000021164 cell adhesion Effects 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 238000004140 cleaning Methods 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 238000010276 construction Methods 0.000 description 1
- 230000002380 cytological effect Effects 0.000 description 1
- 231100000135 cytotoxicity Toxicity 0.000 description 1
- 230000003013 cytotoxicity Effects 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 238000012377 drug delivery Methods 0.000 description 1
- 239000000975 dye Substances 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 230000002349 favourable effect Effects 0.000 description 1
- 210000002950 fibroblast Anatomy 0.000 description 1
- 238000011049 filling Methods 0.000 description 1
- 239000007850 fluorescent dye Substances 0.000 description 1
- 239000008187 granular material Substances 0.000 description 1
- 229960001340 histamine Drugs 0.000 description 1
- 210000003630 histaminocyte Anatomy 0.000 description 1
- 229920001477 hydrophilic polymer Polymers 0.000 description 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
- 230000005847 immunogenicity Effects 0.000 description 1
- 239000007943 implant Substances 0.000 description 1
- 238000011534 incubation Methods 0.000 description 1
- 230000002757 inflammatory effect Effects 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 230000003993 interaction Effects 0.000 description 1
- 230000001788 irregular Effects 0.000 description 1
- 238000002372 labelling Methods 0.000 description 1
- 210000004185 liver Anatomy 0.000 description 1
- 238000011068 loading method Methods 0.000 description 1
- 210000004072 lung Anatomy 0.000 description 1
- 230000001404 mediated effect Effects 0.000 description 1
- 239000012567 medical material Substances 0.000 description 1
- 230000005012 migration Effects 0.000 description 1
- 238000013508 migration Methods 0.000 description 1
- 238000012978 minimally invasive surgical procedure Methods 0.000 description 1
- 210000004400 mucous membrane Anatomy 0.000 description 1
- 231100001083 no cytotoxicity Toxicity 0.000 description 1
- 230000001590 oxidative effect Effects 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 230000001766 physiological effect Effects 0.000 description 1
- 108090000765 processed proteins & peptides Proteins 0.000 description 1
- 102000004196 processed proteins & peptides Human genes 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
- 230000017854 proteolysis Effects 0.000 description 1
- 230000001172 regenerating effect Effects 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 230000001954 sterilising effect Effects 0.000 description 1
- 238000004659 sterilization and disinfection Methods 0.000 description 1
- 229940126585 therapeutic drug Drugs 0.000 description 1
Images
Classifications
-
- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08J—WORKING-UP; GENERAL PROCESSES OF COMPOUNDING; AFTER-TREATMENT NOT COVERED BY SUBCLASSES C08B, C08C, C08F, C08G or C08H
- C08J3/00—Processes of treating or compounding macromolecular substances
- C08J3/02—Making solutions, dispersions, lattices or gels by other methods than by solution, emulsion or suspension polymerisation techniques
- C08J3/03—Making solutions, dispersions, lattices or gels by other methods than by solution, emulsion or suspension polymerisation techniques in aqueous media
- C08J3/075—Macromolecular gels
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
- A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/06—Ointments; Bases therefor; Other semi-solid forms, e.g. creams, sticks, gels
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L26/00—Chemical aspects of, or use of materials for, wound dressings or bandages in liquid, gel or powder form
- A61L26/0009—Chemical aspects of, or use of materials for, wound dressings or bandages in liquid, gel or powder form containing macromolecular materials
- A61L26/0023—Polysaccharides
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- 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
-
- 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
- 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
- C08B37/0075—Heparin; Heparan sulfate; Derivatives thereof, e.g. heparosan; Purification or extraction methods 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
- C08B37/0084—Guluromannuronans, e.g. alginic acid, i.e. D-mannuronic acid and D-guluronic acid units linked with alternating alpha- and beta-1,4-glycosidic bonds; Derivatives thereof, e.g. alginates
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L2400/00—Materials characterised by their function or physical properties
- A61L2400/06—Flowable or injectable implant compositions
-
- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- 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
- C08J2305/04—Alginic 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
- C08J2405/00—Characterised by the use of polysaccharides or of their derivatives not provided for in groups C08J2401/00 or C08J2403/00
- C08J2405/10—Heparin; Derivatives thereof
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
- Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
- Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- Medicinal Chemistry (AREA)
- Animal Behavior & Ethology (AREA)
- Epidemiology (AREA)
- Engineering & Computer Science (AREA)
- Materials Engineering (AREA)
- Organic Chemistry (AREA)
- Polymers & Plastics (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Dispersion Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Molecular Biology (AREA)
- Biochemistry (AREA)
- Inorganic Chemistry (AREA)
- Dermatology (AREA)
- Materials For Medical Uses (AREA)
Abstract
本发明涉及一种具有生物相容性的新型可注射肝素水凝胶的制备方法，其以肝素和海藻酸钠为主要材料，利用碳化二亚胺和1‑羟基苯并三唑作为缩合剂将己二酸二酰肼接枝到肝素上，使肝素具备游离的氨基；再使用高碘酸钠对海藻酸钠进行氧化改性，使海藻酸钠主链糖苷键发生非特异性氧化形成双醛基团，将改性溶液通过透析与冷冻干燥进行纯化，最后将提纯后的改性肝素和改性海藻酸钠在水溶液中形成酰胺键，进而形成网状结构水凝胶。本发明选用的材料是动物体内提取的肝素和具有高度生物相容性的海藻酸钠，制备成的水凝胶有很好的生物相容性，反应体系为水溶液，反应凝胶稳定。本发明水凝胶具有高度生物相容性，可以用于药物载体，细胞培养及伤口敷料等。
Description
技术领域
本发明属于生物组织工程医用材料技术领域，本发明主要涉及一种具有生物相容性的可注射肝素水凝胶及其制备方法，此凝胶可以应用于细胞培养、皮肤创面愈合、软骨损伤修复及作为药物缓释载体等多种组织工程。
背景技术
水凝胶是交联的亲水性聚合物网络，能够吸收大量的水或生物流体。水凝胶作为一种重要的生物材料，在药物传递、组织工程和再生医学方面有着广泛的应用，因而受到人们的广泛关注。从临床角度来看，可注射的原位形成水凝胶系统是非常必要的，如通过简单的混合，微创手术程序容易掺入治疗药物（包括基因，肽，蛋白质）和细胞，使不规则的手术缺陷得到完全填充，并减少植入物迁移的风险。在组织工程领域，可注射的水凝胶被设计用作临时和人工细胞外间质（ECM）。
肝素是由肝脏、粘膜和肺合成的天然抗凝血剂，分子量约为7000-25000 Da。肝素是一种主链含有五碳糖环的戊聚糖，含有羧基、磺酸基和羟基等官能团。肝素发生在炎症介质，蛋白酶和组胺的相互作用中，并存在于体内肥大细胞颗粒中。在水凝胶的构造中使用肝素被证明有利于改善生物相容性和功效。因此，水凝胶可用作生长因子载体、细胞载体和抗癌载体。肝素中含有丰富的功能基团，可与生物分子结合，增加生物相容性和功效，促进细胞粘附，允许细胞介导的蛋白质降解，并可控制生长因子的载荷和释放行为。但相关水凝胶大都把肝素作为成胶中的添加成分，很少有将肝素作为主要成胶材料的水凝胶，这无疑限制了肝素水凝胶的发展前景。
海藻酸钠是天然的线性高分子，因为具有良好的生物相容性、生物降解性、无毒性、低免疫原性等优良性能，海藻酸钠广泛应用在组织工程及生物医用领域。但应用成胶时大多利用海藻酸钠的羧基，可是海藻酸钠的分子链上羧基十分有限，需要使用其他小分子试剂提高羧基活性，但是会影响其生物相容性，降低实用性能，所以对海藻酸钠进行功能化改性是使海藻酸钠在医用组织工程的应用更广的必要的步骤。
席夫碱反应，由于席夫碱类化合物具有一定的药理学和生理学活性，一直是引人注目的研究对象。席夫碱化合物具有很好的抗菌、抗真菌作用，例如，金黄色葡萄球菌、革兰氏阳性菌、枯草杆菌、革兰氏阳性菌、大肠杆菌、革兰氏阴性菌等，对新型隐球菌和白色念珠球菌也有很好的抑制作用。同时，这些化合物均对超氧阴离子自由基有较好的抑制。在医学领域，席夫碱具有抑菌、杀菌、抗肿瘤、抗病毒的生物活性。
发明内容
本发明目的在于克服现有技术缺陷，提供一种具有生物相容性的可注射肝素水凝胶，该水凝胶具有原位可注射和高度生物相容性的特点，操作简单，成胶时间可控且成胶时没有副产物，可以用于药物载体，细胞培养及伤口敷料等。
本发明还提供了上述具有生物相容性的可注射肝素水凝胶的制备方法。
为实现上述目的，本发明采用如下技术方案：
一种具有生物相容性的可注射肝素水凝胶的制备方法，其包括如下步骤：
1）将肝素溶于水中，加入己二酸二酰肼（ADH）、碳化二亚胺（EDC）和1-羟基苯并三唑（HOBt）混匀，然后调节pH至6.0-7.5，搅拌反应9-15h，经透析、冷冻干燥，获得改性肝素；
2）将海藻酸钠与无水乙醇搅拌混合形成混悬液，加入高碘酸钠避光搅拌反应5-10h，再加入相对于高碘酸钠等摩尔量或过量乙二醇终止反应，静置（25-60min），收集沉淀物，经透析、冷冻干燥，获得改性海藻酸钠（也可以称为是高碘酸钠二醛衍生物）；；
3）将步骤1）获得的改性肝素、步骤2）获得的改性海藻酸钠分别溶于水或PBS缓冲液中，混合，形成稳定的水凝胶。
具体的，步骤1）中，所述肝素、己二酸二酰肼、碳化二亚胺和1-羟基苯并三唑的摩尔比可以为1：1-35：1：1。用来改性肝素的缩合剂，选用碳化二亚胺（1-(3-二甲基氨基丙基)-3-乙基碳二亚胺，简称EDC）、1-羟基苯并三唑（简称HOBt）。
进一步的，步骤1）和步骤2）中，所述透析所用透析袋的截留分子量可以为3-4kDa，透析时间可以为2-5天。
进一步的，步骤1）和步骤2）中，所述冷冻干燥为-1~ -2℃干燥40-50h。
具体的，步骤2）中，高碘酸钠与海藻酸钠的摩尔比为0.2-1.0：1。10g海藻酸钠一般加入100-150ml无水乙醇。
进一步的，步骤1）中，可以使用盐酸或氢氧化钠水溶液调节pH为至6.0-7.8。
具体的，步骤3）制备所得水凝胶中溶质的质量分数可以在2.5-10%，所述溶质为改性肝素和改性海藻酸钠。
本发明还提供了采用上述方法制备得到的具有生物相容性的可注射肝素水凝胶。
本发明具有生物相容性的可注射肝素水凝胶制备时，以肝素和海藻酸钠为主要原料，利用碳化二亚胺（EDC）和1-羟基苯并三唑（HOBt）作为缩合剂将己二酸二酰肼（ADH）接枝到肝素上进行改性，使肝素具备游离的氨基；使用高碘酸钠对海藻酸钠进行氧化改性，使海藻酸钠主链糖苷键发生非特异性氧化形成双醛基团，形成带双醛基的海藻酸钠衍生物；再将得到的两种改性材料溶液通过透析与冷冻干燥进行纯化制成固体粉末；最后将提纯后的改性肝素和改性海藻酸钠在水溶液中进行席夫碱反应形成酰胺键，进而形成网状水凝胶结构。这两种材料在成胶时质量分数相同，当溶液质量分数从2.5 - 10%依次增高时，室温水凝胶成胶时间从30s-2h不等。
本发明的创新点和核心在于肝素与海藻酸钠的改性、常温下自发反应成胶方式以及成胶时间可在几十秒到几小时自行调节及可注射特性。
和现有技术相比，本发明的有益效果如下：
1）本发明水凝胶具有原位可注射和高生物相容性的特点，制备过程操作简单，成胶时间可控且成胶时没有副产物；
2）本发明选用的材料是动物体内提取的肝素和具有高度生物相容性的海藻酸钠，制备所得的水凝胶具有很好的生物相容性，反应体系为水溶液，反应凝胶稳定；
3）本发明水凝胶为常温下自发反应成胶方式，成胶时间可在几十秒到几小时自行调节。本发明方法制备的水凝胶具有高度生物相容性，可以用于药物载体，细胞培养及伤口敷料等。
附图说明
图1为本发明水凝胶制备时通过注射器注射的示意图；
图2为本发明水凝胶中所含溶质不同质量分数的成胶图；
图3为本发明实施例3制备所得水凝胶的SEM图；
图4为本发明水凝胶浸提液的细胞毒性MTT结果分析示意图；
图5为本发明水凝胶细胞封装24h后FDA染色共聚焦3D成像（a.俯视图，b.主视图，c.立体图，d.右侧视图）。
具体实施方式
以下结合实施例对本发明的技术方案作进一步地详细介绍，但本发明的保护范围并不局限于此。
下述实施例中，所用原料均为可以直接购买到的普通市售产品，或按照本领域常规方法均可以制备获得。
实施例1：溶质质量分数为2.5%的水凝胶体系：
一种具有生物相容性的可注射肝素水凝胶的制备方法，其包括如下步骤：
1）将1g（0.881mmol）肝素溶于25ml去离子水中，加入5.37213g（30.84mmol）ADH、0.13678g（0.881mmol）EDC HCl、0.11906g（0.881mmol）HOBt混匀，用盐酸调节pH至6.8，搅拌过夜（12h）后，收集溶液，用截留分子量为3.5kDa的透析袋透析3天，冷冻干燥（在-1.3℃、真空度7Pa下干燥时间45h），得到纯化的改性肝素粉末；
2）将10g（0.04627mol）海藻酸钠放入100ml无水乙醇搅拌混合形成混悬液，加入9.89g（0.04627mol）高碘酸钠避光搅拌反应6h，再加入0.77ml（0.04627mol）乙二醇搅拌0.5h终止反应，静置1h,收集沉淀物，把沉淀物用截留分子量为3.5kDa的透析袋去离子水透析3天后，冷冻干燥（在-1.3℃、真空度7Pa下干燥时间45h），得到纯化的改性海藻酸钠粉末；
3）将步骤1）所得改性肝素粉末和步骤2）所得改性海藻酸钠粉末分别溶于水中配制成质量浓度2.5%的水溶液体系，然后等体积混合，室温静置2h，形成水凝胶。
实施例2：溶质质量分数为5%的水凝胶体系
一种具有生物相容性的可注射肝素水凝胶的制备方法，其包括如下步骤：
1）将1g（0.881mmol）肝素溶于25ml去离子水中，加入5.37213g（30.84mmol）ADH、0.13678g（0.881mmol）EDC HCl、0.11906g（0.881mmol）HOBt混匀，用盐酸调节pH至6.8，搅拌过夜（12h）后，收集溶液，用截留分子量为3.5kDa的透析袋透析3天，冷冻干燥（在-1.3℃、真空度7Pa下干燥时间45h），得到纯化的改性肝素粉末；
2）将10g（0.04627mol）海藻酸钠放入100ml无水乙醇搅拌混合形成混悬液，加入9.89g（0.04627mol）高碘酸钠避光搅拌反应6h，再加入0.77ml（0.04627mol）乙二醇搅拌0.5h终止反应，静置1h，s收集沉淀物，沉淀物用截留分子量为3.5kDa的透析袋去离子水透析3天后，冷冻干燥（在-1.3℃、真空度7Pa下干燥时间45h），得到纯化的改性海藻酸钠粉末；
3）将步骤1）所得改性肝素粉末和步骤2）所得改性海藻酸钠粉末分别溶于水中配制成质量浓度5%的水溶液体系，然后等体积混合，室温静置4min，形成水凝胶。
实施例3：溶质质量分数为10%的水凝胶体系
一种具有生物相容性的可注射肝素水凝胶的制备方法，其包括如下步骤：
1）将1g（0.881mmol）肝素溶于25ml去离子水中，加入5.37213g（30.84mmol）ADH、0.13678g（0.881mmol）EDC HCl、0.11906g（0.881mmol）HOBt混匀，用盐酸调节pH至6.8，搅拌过夜（12h）后，收集溶液，用截留分子量为3.5kDa的透析袋透析3天，冷冻干燥（在-1.3℃、真空度7Pa下干燥时间45h），得到纯化的改性肝素粉末；
2）将10g（0.04627mol）海藻酸钠放入100ml无水乙醇搅拌混合形成混悬液，加入9.89g（0.04627mol）高碘酸钠避光搅拌反应6h，再加入0.77ml（0.04627mol）乙二醇搅拌0.5h终止反应，静置1h，收集沉淀，把沉淀物用截留分子量为35kDa的透析袋去离子水透析3天后，冷冻干燥（在-1.3℃、真空度7Pa下干燥时间45h），得到纯化的改性海藻酸钠粉末；
3）将步骤1）所得改性肝素粉末和步骤2）所得改性海藻酸钠粉末分别溶于水中配制成质量浓度10%的水溶液体系，然后等体积混合，室温静置30s，形成水凝胶。
实施例4：改性肝素和改性海藻酸钠的水溶液质量分数都为10%体系：
一种具有生物相容性的可注射肝素水凝胶的制备方法，其包括如下步骤：
1）将1g（0.881mmol）肝素溶于25ml去离子水中，加入5.37213g（30.84mmol）ADH、0.13678g（0.881mmol）EDC HCl、0.11906g（0.881mmol）HOBt混匀，用盐酸调节pH至6.8，搅拌过夜（12h）后，收集溶液，用截留分子量为3.5kDa的透析袋透析3天，冷冻干燥（在-1.3℃、真空度7Pa下干燥时间45h），得到纯化的改性肝素粉末；
2）将10g（0.04627mol）海藻酸钠放入100ml无水乙醇搅拌混合形成混悬液，加入9.89g（0.04627mol）高碘酸钠避光搅拌反应6h，再加入0.77ml（0.04627mol）乙二醇搅拌0.5h终止反应，静置1h，收集沉淀物，把沉淀物用截留分子量为3.5kDa的透析袋去离子水透析3天后，冷冻干燥（在-1.3℃、真空度7Pa下干燥时间45h），得到纯化的改性海藻酸钠粉末；
3）将步骤1）所得改性肝素粉末和步骤2）所得改性海藻酸钠粉末分别溶于水中配制成质量浓度10%的水溶液体系，然后按体积比2：1混合，室温静置30s，形成水凝胶。
实施例5：溶质质量分数为5%的水凝胶体系
参照实施例3，不同之处在于：肝素与己二酸二酰肼（ADH）的摩尔比为1：3。
实施例6：溶质质量分数为5%的水凝胶体系
参照实施例3，不同之处在于：肝素与己二酸二酰肼（ADH）的摩尔比为1：15。
图1给出了本发明水凝胶制备时，将实施例中所得质量浓度2.5%、5%、10%的改性肝素水溶液体系、以及质量浓度2.5%、5%、10%的改性海藻酸钠水溶液体系（也可以称为预聚液）分别通过注射器注射的示意图。可将两种水溶液体系分别装入注射器中，再通过三通阀同时注入玻璃瓶中。由此说明本发明两种预聚液具有可注射性。
图2给出了本发明水凝胶中所含溶质不同质量分数的成胶图。采用图1注射方法将两种预聚液经三通阀同时注入玻璃瓶后，静置，再将玻璃瓶倾斜倒置，图中可以看出：未见有液体流出，玻璃瓶底部形成水凝胶；并且当水凝胶的质量浓度由2.5%增加到10%时，均可以形成水凝胶。
图3给出了本发明实施例3制备所得水凝胶的SEM图；图中可以看出，水凝胶内部形成多孔结构，孔与孔之间相互连接，呈现出明显的三维网络结构，孔径在100-200微米之间，符合细胞生长所需孔径要求。
下述以实施例制备获得的水凝胶进行相关的细胞学实验。
水凝胶浸提液MTT实验：
1）将实施例1、2、3制备的水凝胶取样分别放入无菌50ml离心管，按0.01g：1mL加入DMEM培养基后，置于细胞培养箱中37℃培养3天，0.22μm滤膜过滤，分别得到不同溶质质量分数无菌的水凝胶浸提液；
2）将L929细胞(小鼠成纤维细胞)在96孔板中培养24h，令细胞贴壁后吸去原来的DMEM培养基，PBS缓冲液清洗一遍后，实验组分别加入不同溶质质量分数的无菌水凝胶浸提液，空白组加入DMEM培养基，然后在空白组和实验组细胞培养的第1、2、3天，分别每孔加入100μl MTT（3-(4，5-二甲基噻唑-2)-2，5-二苯基四氮唑溴盐，噻唑蓝）工作液（0.5mg/ml），放入37℃培养箱孵化4h后吸去MTT溶液，加入150μl二甲基亚砜（DMSO），在酶标仪490波长测定吸光度，吸光度值的结果如图4所示。
由图4可以看出：本发明水凝胶浸提液在培养细胞时，第一天时浸提液的细胞存活率与空白组相比更高，第二天溶质质量分数2.5%和5%的浸提液细胞存活依然高于空白组，10%细胞存活略低于空白组，第三天时所有实验组细胞存活率基本和空白组一致。证实本发明水凝胶无细胞毒性，有利于细胞生长，细胞相容性好。
水凝胶的细胞封装及活细胞染色成像实验：
1）将实施例3中制备的改性肝素粉末、改性海藻酸钠粉末分别用PBS缓冲液溶解配制质量分数10%的溶液，0.22μm滤膜过滤，得到无菌的肝素预聚液和海藻酸钠预聚液，备用；
2）将提前培养好的L929细胞收集，细胞量调整至1×106/ml，用微量PBS缓冲液混匀细胞后加入提前制备好的肝素预聚液中，混合均匀，然后用注射器吸取等体积的海藻酸钠预聚液和带细胞的肝素预聚液，同时注入24孔板中，每孔500μl，1min成胶后放入培养箱37℃静置1h，取出，每孔加入150μl的DMEM培养基培养24h，然后吸去培养基加入0.5ml配制好的FDA（二乙酸荧光素）工作液（10 μg/ml），暗处染色5min后，在共聚焦显微镜下成像，结果见图5。
由图5所示的FDA荧光染色图片可以看出：细胞在封装入本发明水凝胶后24h依然存活很好，与水凝胶浸提液MTT实验相印证，说明本发明水凝胶具有很好的细胞相容性。
综上说明：本发明选用动物体内提取的肝素和具有高度生物相容性的海藻酸钠为原料，制备所得水凝胶具有原位可注射和高生物相容性的特点，反应体系为水溶液，反应凝胶稳定；水凝胶为常温下自发反应成胶方式，成胶时间可在几十秒到几小时自行调节，成胶时间可控且成胶时没有副产物；可以用于药物载体，细胞培养及伤口敷料等。
Claims (8)
1.一种具有生物相容性的可注射肝素水凝胶的制备方法，其特征在于，包括如下步骤：
1）将肝素溶于水中，加入己二酸二酰肼、碳化二亚胺和1-羟基苯并三唑混匀，然后调节pH至6.0-7.5，搅拌反应9-15h，经透析、冷冻干燥，获得改性肝素；
2）将海藻酸钠与无水乙醇搅拌混合形成混悬液，加入高碘酸钠避光搅拌反应5-10h，再加入等摩尔量或过量乙二醇终止反应，静置，收集沉淀物，经透析、冷冻干燥，获得改性海藻酸钠；
3）将步骤1）获得的改性肝素、步骤2）获得的改性海藻酸钠分别溶于水或PBS缓冲液中，混合，即得。
2.如权利要求1所述具有生物相容性的可注射肝素水凝胶的制备方法，其特征在于，步骤1）中，所述肝素、己二酸二酰肼、碳化二亚胺和1-羟基苯并三唑的摩尔比为1：1-35：1：1。
3.如权利要求1所述具有生物相容性的可注射肝素水凝胶的制备方法，其特征在于，步骤1）和步骤2）中，所述透析所用透析袋的截留分子量为3-4 kDa，透析时间为2-5天。
4.如权利要求1所述具有生物相容性的可注射肝素水凝胶的制备方法，其特征在于，步骤1）和步骤2）中，所述冷冻干燥为-1~ -2℃干燥40-50h。
5.如权利要求1所述具有生物相容性的可注射肝素水凝胶的制备方法，其特征在于，步骤2）中，高碘酸钠与海藻酸钠的摩尔比为0.2-1：1。
6.如权利要求1所述具有生物相容性的可注射肝素水凝胶的制备方法，其特征在于，步骤1）中，使用盐酸或氢氧化钠水溶液调节pH为至6.0-7.8。
7.如权利要求1所述具有生物相容性的可注射肝素水凝胶的制备方法，其特征在于，步骤3）所得水凝胶中溶质的质量分数为2.5-10%，所述溶质为改性肝素和改性海藻酸钠。
8.采用权利要求1至7任一所述方法制备得到的具有生物相容性的可注射肝素水凝胶。
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202310210212.1A CN116284857B (zh) | 2023-03-07 | 2023-03-07 | 一种具有生物相容性的可注射肝素水凝胶的制备方法 |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202310210212.1A CN116284857B (zh) | 2023-03-07 | 2023-03-07 | 一种具有生物相容性的可注射肝素水凝胶的制备方法 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN116284857A true CN116284857A (zh) | 2023-06-23 |
| CN116284857B CN116284857B (zh) | 2023-11-17 |
Family
ID=86831872
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202310210212.1A Active CN116284857B (zh) | 2023-03-07 | 2023-03-07 | 一种具有生物相容性的可注射肝素水凝胶的制备方法 |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN116284857B (zh) |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110498936A (zh) * | 2019-07-15 | 2019-11-26 | 北京化工大学 | 一种透明质酸钠/海藻酸钠注射型复合水凝胶的制备方法 |
| CN112538171A (zh) * | 2019-09-20 | 2021-03-23 | 天津大学 | 一种可注射可降解肝素水凝胶及其制备方法和应用 |
| WO2021223756A1 (zh) * | 2020-05-08 | 2021-11-11 | 四川大学 | 具有抗炎及促修复功能的可注射水凝胶及其制备方法和在心脏修复中的应用 |
-
2023
- 2023-03-07 CN CN202310210212.1A patent/CN116284857B/zh active Active
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110498936A (zh) * | 2019-07-15 | 2019-11-26 | 北京化工大学 | 一种透明质酸钠/海藻酸钠注射型复合水凝胶的制备方法 |
| CN112538171A (zh) * | 2019-09-20 | 2021-03-23 | 天津大学 | 一种可注射可降解肝素水凝胶及其制备方法和应用 |
| WO2021223756A1 (zh) * | 2020-05-08 | 2021-11-11 | 四川大学 | 具有抗炎及促修复功能的可注射水凝胶及其制备方法和在心脏修复中的应用 |
Also Published As
| Publication number | Publication date |
|---|---|
| CN116284857B (zh) | 2023-11-17 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| Eivazzadeh-Keihan et al. | Alginate hydrogel-polyvinyl alcohol/silk fibroin/magnesium hydroxide nanorods: A novel scaffold with biological and antibacterial activity and improved mechanical properties | |
| Darge et al. | Polysaccharide and polypeptide based injectable thermo-sensitive hydrogels for local biomedical applications | |
| EP3412313B1 (en) | Temperature sensitive hydrogel composition including nucleic acid and chitosan | |
| Liu et al. | Preparation and applications of peptide-based injectable hydrogels | |
| Muzzarelli | Genipin-crosslinked chitosan hydrogels as biomedical and pharmaceutical aids | |
| EP1898881B1 (en) | Bioresorbable polymer matrices and methods of making and using the same | |
| CN100478032C (zh) | 一种可注射型pH及葡萄糖敏感水凝胶的制备方法 | |
| CN108888610B (zh) | 响应性壳聚糖微球/纤维素水凝胶载药复合膜的制备及产品 | |
| JPH03502704A (ja) | 水不溶性バイオ適合性ゲルの製造方法 | |
| CA2662924A1 (en) | Hyaluronic acid derivatives obtained via "click chemistry" crosslinking | |
| Xing et al. | Biomedical applications of chitosan/silk fibroin composites: A review | |
| CN112480434B (zh) | 一种铜离子抗菌水凝胶及制备方法和应用 | |
| CN111494709B (zh) | 兼具抗肿瘤和抑菌功能的促组织修复水凝胶的制备及应用 | |
| JP5907489B2 (ja) | キトサン誘導体から得られるヒドロゲル | |
| KR20140075772A (ko) | 면역 내성을 증가시킨 이식 의료 장비, 및 그의 제조 및 이식 방법 | |
| US20210015966A1 (en) | Antibacterial Cellulose Hydrogels and Preparation Method therefor | |
| JP2007516323A (ja) | 分解時間を調整可能なステレオコンプレックスヒドロゲル | |
| Liu et al. | Bacterial cellulose/chitosan composite materials for biomedical applications | |
| KR100889593B1 (ko) | 생체고분자와 생체세라믹의 이종복합체 및 그 제조 방법 | |
| CN101928355A (zh) | 一种氨基化海藻酸及其制备方法 | |
| CN116284857B (zh) | 一种具有生物相容性的可注射肝素水凝胶的制备方法 | |
| Mehrabi et al. | Evaluation of inherent properties of the carboxymethyl cellulose (CMC) for potential application in tissue engineering focusing on bone regeneration | |
| Qu et al. | Current status of development and biomedical applications of peptide-based antimicrobial hydrogels | |
| CN113929792B (zh) | 一种醛基化修饰的透明质酸(钠)及其合成方法和应用 | |
| Magagula et al. | Biopolymer-based biodegradable biomaterials for in vivo and in vitro biomedical applications |
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 | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant |