CN116549712A - Degradable healing-promoting medical adhesive and preparation method thereof - Google Patents
Degradable healing-promoting medical adhesive and preparation method thereof Download PDFInfo
- Publication number
- CN116549712A CN116549712A CN202310448042.0A CN202310448042A CN116549712A CN 116549712 A CN116549712 A CN 116549712A CN 202310448042 A CN202310448042 A CN 202310448042A CN 116549712 A CN116549712 A CN 116549712A
- Authority
- CN
- China
- Prior art keywords
- sodium alginate
- component
- degradable
- medical adhesive
- reaction
- 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
- 230000001070 adhesive effect Effects 0.000 title claims abstract description 76
- 239000000853 adhesive Substances 0.000 title claims abstract description 74
- 238000002360 preparation method Methods 0.000 title claims description 17
- 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 82
- 239000000661 sodium alginate Substances 0.000 claims abstract description 81
- 235000010413 sodium alginate Nutrition 0.000 claims abstract description 81
- 229940005550 sodium alginate Drugs 0.000 claims abstract description 81
- 108010039918 Polylysine Proteins 0.000 claims abstract description 53
- 229920000656 polylysine Polymers 0.000 claims abstract description 53
- 239000003102 growth factor Substances 0.000 claims abstract description 42
- FHVDTGUDJYJELY-UHFFFAOYSA-N 6-{[2-carboxy-4,5-dihydroxy-6-(phosphanyloxy)oxan-3-yl]oxy}-4,5-dihydroxy-3-phosphanyloxane-2-carboxylic acid Chemical class O1C(C(O)=O)C(P)C(O)C(O)C1OC1C(C(O)=O)OC(OP)C(O)C1O FHVDTGUDJYJELY-UHFFFAOYSA-N 0.000 claims abstract description 30
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 29
- 239000004005 microsphere Substances 0.000 claims abstract description 28
- 229920001661 Chitosan Polymers 0.000 claims abstract description 23
- 125000002057 carboxymethyl group Chemical group [H]OC(=O)C([H])([H])[*] 0.000 claims abstract description 23
- 230000035876 healing Effects 0.000 claims abstract description 15
- JQWHASGSAFIOCM-UHFFFAOYSA-M sodium periodate Chemical compound [Na+].[O-]I(=O)(=O)=O JQWHASGSAFIOCM-UHFFFAOYSA-M 0.000 claims description 52
- 239000000243 solution Substances 0.000 claims description 39
- 238000006243 chemical reaction Methods 0.000 claims description 37
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 claims description 30
- 239000011541 reaction mixture Substances 0.000 claims description 23
- 239000011259 mixed solution Substances 0.000 claims description 21
- HXITXNWTGFUOAU-UHFFFAOYSA-N phenylboronic acid Chemical compound OB(O)C1=CC=CC=C1 HXITXNWTGFUOAU-UHFFFAOYSA-N 0.000 claims description 19
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 16
- 238000004108 freeze drying Methods 0.000 claims description 15
- 239000000725 suspension Substances 0.000 claims description 14
- 230000001737 promoting effect Effects 0.000 claims description 12
- 230000001954 sterilising effect Effects 0.000 claims description 12
- 238000000034 method Methods 0.000 claims description 10
- UXVMQQNJUSDDNG-UHFFFAOYSA-L Calcium chloride Chemical compound [Cl-].[Cl-].[Ca+2] UXVMQQNJUSDDNG-UHFFFAOYSA-L 0.000 claims description 9
- 102000005789 Vascular Endothelial Growth Factors Human genes 0.000 claims description 9
- 108010019530 Vascular Endothelial Growth Factors Proteins 0.000 claims description 9
- 238000001914 filtration Methods 0.000 claims description 8
- DCUFMVPCXCSVNP-UHFFFAOYSA-N methacrylic anhydride Chemical compound CC(=C)C(=O)OC(=O)C(C)=C DCUFMVPCXCSVNP-UHFFFAOYSA-N 0.000 claims description 8
- 238000002156 mixing Methods 0.000 claims description 8
- 238000001035 drying Methods 0.000 claims description 7
- 239000002244 precipitate Substances 0.000 claims description 7
- DPXJVFZANSGRMM-UHFFFAOYSA-N acetic acid;2,3,4,5,6-pentahydroxyhexanal;sodium Chemical compound [Na].CC(O)=O.OCC(O)C(O)C(O)C(O)C=O DPXJVFZANSGRMM-UHFFFAOYSA-N 0.000 claims description 6
- 239000000872 buffer Substances 0.000 claims description 6
- 239000001768 carboxy methyl cellulose Substances 0.000 claims description 6
- 239000007788 liquid Substances 0.000 claims description 6
- 235000019812 sodium carboxymethyl cellulose Nutrition 0.000 claims description 6
- 229920001027 sodium carboxymethylcellulose Polymers 0.000 claims description 6
- 150000001299 aldehydes Chemical class 0.000 claims description 5
- 238000000502 dialysis Methods 0.000 claims description 5
- 239000000178 monomer Substances 0.000 claims description 5
- XIPRTRJDLZVSHO-UHFFFAOYSA-N aminooxy(phenoxy)borinic acid Chemical compound NOB(O)OC1=CC=CC=C1 XIPRTRJDLZVSHO-UHFFFAOYSA-N 0.000 claims description 4
- 239000007853 buffer solution Substances 0.000 claims description 3
- 102000009024 Epidermal Growth Factor Human genes 0.000 claims description 2
- 102100024785 Fibroblast growth factor 2 Human genes 0.000 claims description 2
- 108090000379 Fibroblast growth factor 2 Proteins 0.000 claims description 2
- 108010010803 Gelatin Proteins 0.000 claims description 2
- 229920002907 Guar gum Polymers 0.000 claims description 2
- 101710098940 Pro-epidermal growth factor Proteins 0.000 claims description 2
- 239000007864 aqueous solution Substances 0.000 claims description 2
- 239000001110 calcium chloride Substances 0.000 claims description 2
- 229910001628 calcium chloride Inorganic materials 0.000 claims description 2
- 239000008273 gelatin Substances 0.000 claims description 2
- 229920000159 gelatin Polymers 0.000 claims description 2
- 235000019322 gelatine Nutrition 0.000 claims description 2
- 235000011852 gelatine desserts Nutrition 0.000 claims description 2
- 239000000665 guar gum Substances 0.000 claims description 2
- 235000010417 guar gum Nutrition 0.000 claims description 2
- 229960002154 guar gum Drugs 0.000 claims description 2
- 238000004806 packaging method and process Methods 0.000 claims description 2
- 230000035484 reaction time Effects 0.000 claims description 2
- 230000000844 anti-bacterial effect Effects 0.000 abstract description 9
- 230000004060 metabolic process Effects 0.000 abstract description 2
- 231100000252 nontoxic Toxicity 0.000 abstract description 2
- 230000003000 nontoxic effect Effects 0.000 abstract description 2
- 150000003384 small molecules Chemical class 0.000 abstract description 2
- 239000000843 powder Substances 0.000 description 15
- 230000000052 comparative effect Effects 0.000 description 14
- 210000001519 tissue Anatomy 0.000 description 12
- 239000011521 glass Substances 0.000 description 11
- 238000012360 testing method Methods 0.000 description 11
- 208000027418 Wounds and injury Diseases 0.000 description 10
- 108010073929 Vascular Endothelial Growth Factor A Proteins 0.000 description 8
- 206010052428 Wound Diseases 0.000 description 8
- 239000008213 purified water Substances 0.000 description 8
- 230000015556 catabolic process Effects 0.000 description 7
- 238000004132 cross linking Methods 0.000 description 7
- 238000006731 degradation reaction Methods 0.000 description 7
- 238000002474 experimental method Methods 0.000 description 7
- 238000011049 filling Methods 0.000 description 7
- 238000005303 weighing Methods 0.000 description 7
- UTHULKKJYXJZLV-UHFFFAOYSA-N (3-aminophenoxy)boronic acid Chemical compound NC1=CC=CC(OB(O)O)=C1 UTHULKKJYXJZLV-UHFFFAOYSA-N 0.000 description 6
- 230000000694 effects Effects 0.000 description 6
- 239000007787 solid Substances 0.000 description 6
- 238000004659 sterilization and disinfection Methods 0.000 description 6
- 239000002253 acid Substances 0.000 description 5
- 239000000463 material Substances 0.000 description 5
- 238000007789 sealing Methods 0.000 description 5
- 238000003756 stirring Methods 0.000 description 5
- 229940072056 alginate Drugs 0.000 description 4
- 235000010443 alginic acid Nutrition 0.000 description 4
- 229920000615 alginic acid Polymers 0.000 description 4
- 230000001112 coagulating effect Effects 0.000 description 4
- 239000000839 emulsion Substances 0.000 description 4
- 239000012535 impurity Substances 0.000 description 4
- 239000002504 physiological saline solution Substances 0.000 description 4
- 229920001223 polyethylene glycol Polymers 0.000 description 4
- 238000009987 spinning Methods 0.000 description 4
- 238000001291 vacuum drying Methods 0.000 description 4
- 108010080379 Fibrin Tissue Adhesive Proteins 0.000 description 3
- 239000002202 Polyethylene glycol Substances 0.000 description 3
- 241000191967 Staphylococcus aureus Species 0.000 description 3
- 239000004830 Super Glue Substances 0.000 description 3
- 125000003172 aldehyde group Chemical group 0.000 description 3
- 239000003242 anti bacterial agent Substances 0.000 description 3
- 238000001816 cooling Methods 0.000 description 3
- 238000001723 curing Methods 0.000 description 3
- 230000006378 damage Effects 0.000 description 3
- 239000012153 distilled water Substances 0.000 description 3
- FGBJXOREULPLGL-UHFFFAOYSA-N ethyl cyanoacrylate Chemical compound CCOC(=O)C(=C)C#N FGBJXOREULPLGL-UHFFFAOYSA-N 0.000 description 3
- 239000000499 gel Substances 0.000 description 3
- 239000008055 phosphate buffer solution Substances 0.000 description 3
- 230000001376 precipitating effect Effects 0.000 description 3
- 238000000967 suction filtration Methods 0.000 description 3
- 230000029663 wound healing Effects 0.000 description 3
- 229920001651 Cyanoacrylate Polymers 0.000 description 2
- 238000001157 Fourier transform infrared spectrum Methods 0.000 description 2
- 241000700159 Rattus Species 0.000 description 2
- 239000002262 Schiff base Substances 0.000 description 2
- 150000004753 Schiff bases Chemical class 0.000 description 2
- 208000031737 Tissue Adhesions Diseases 0.000 description 2
- 241000700605 Viruses Species 0.000 description 2
- 230000009286 beneficial effect Effects 0.000 description 2
- 230000003115 biocidal effect Effects 0.000 description 2
- 230000007547 defect Effects 0.000 description 2
- 239000007857 degradation product Substances 0.000 description 2
- 238000001514 detection method Methods 0.000 description 2
- 208000014674 injury Diseases 0.000 description 2
- 239000000203 mixture Substances 0.000 description 2
- 230000010355 oscillation Effects 0.000 description 2
- 239000008363 phosphate buffer Substances 0.000 description 2
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 2
- 210000004872 soft tissue Anatomy 0.000 description 2
- 238000007711 solidification Methods 0.000 description 2
- 230000008023 solidification Effects 0.000 description 2
- 238000009864 tensile test Methods 0.000 description 2
- 239000003106 tissue adhesive Substances 0.000 description 2
- 208000037816 tissue injury Diseases 0.000 description 2
- DIRRKLFMHQUJCM-UHFFFAOYSA-N (2-aminophenyl)boronic acid Chemical compound NC1=CC=CC=C1B(O)O DIRRKLFMHQUJCM-UHFFFAOYSA-N 0.000 description 1
- ZSKXYSCQDWAUCM-UHFFFAOYSA-N 1-(chloromethyl)-2-dodecylbenzene Chemical compound CCCCCCCCCCCCC1=CC=CC=C1CCl ZSKXYSCQDWAUCM-UHFFFAOYSA-N 0.000 description 1
- OLQJQHSAWMFDJE-UHFFFAOYSA-N 2-(hydroxymethyl)-2-nitropropane-1,3-diol Chemical compound OCC(CO)(CO)[N+]([O-])=O OLQJQHSAWMFDJE-UHFFFAOYSA-N 0.000 description 1
- 206010002091 Anaesthesia Diseases 0.000 description 1
- BTBUEUYNUDRHOZ-UHFFFAOYSA-N Borate Chemical compound [O-]B([O-])[O-] BTBUEUYNUDRHOZ-UHFFFAOYSA-N 0.000 description 1
- 208000003322 Coinfection Diseases 0.000 description 1
- 206010059866 Drug resistance Diseases 0.000 description 1
- 108010073385 Fibrin Proteins 0.000 description 1
- 102000009123 Fibrin Human genes 0.000 description 1
- BWGVNKXGVNDBDI-UHFFFAOYSA-N Fibrin monomer Chemical compound CNC(=O)CNC(=O)CN BWGVNKXGVNDBDI-UHFFFAOYSA-N 0.000 description 1
- 238000005033 Fourier transform infrared spectroscopy Methods 0.000 description 1
- 239000004367 Lipase Substances 0.000 description 1
- 102000004882 Lipase Human genes 0.000 description 1
- 108090001060 Lipase Proteins 0.000 description 1
- MWCLLHOVUTZFKS-UHFFFAOYSA-N Methyl cyanoacrylate Chemical compound COC(=O)C(=C)C#N MWCLLHOVUTZFKS-UHFFFAOYSA-N 0.000 description 1
- 108090000190 Thrombin Proteins 0.000 description 1
- 239000007983 Tris buffer Substances 0.000 description 1
- 206010048038 Wound infection Diseases 0.000 description 1
- 125000003277 amino group Chemical group 0.000 description 1
- ILOJFJBXXANEQW-UHFFFAOYSA-N aminooxy(phenyl)borinic acid Chemical compound NOB(O)C1=CC=CC=C1 ILOJFJBXXANEQW-UHFFFAOYSA-N 0.000 description 1
- 230000037005 anaesthesia Effects 0.000 description 1
- 229940088710 antibiotic agent Drugs 0.000 description 1
- 230000001580 bacterial effect Effects 0.000 description 1
- 239000000227 bioadhesive Substances 0.000 description 1
- 230000005540 biological transmission Effects 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- 210000004204 blood vessel Anatomy 0.000 description 1
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 238000005336 cracking Methods 0.000 description 1
- 238000005520 cutting process Methods 0.000 description 1
- NLCKLZIHJQEMCU-UHFFFAOYSA-N cyano prop-2-enoate Chemical class C=CC(=O)OC#N NLCKLZIHJQEMCU-UHFFFAOYSA-N 0.000 description 1
- 231100000135 cytotoxicity Toxicity 0.000 description 1
- 230000003013 cytotoxicity Effects 0.000 description 1
- 230000034994 death Effects 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 235000019441 ethanol Nutrition 0.000 description 1
- 230000005713 exacerbation Effects 0.000 description 1
- 210000003195 fascia Anatomy 0.000 description 1
- 229950003499 fibrin Drugs 0.000 description 1
- 239000012530 fluid Substances 0.000 description 1
- 239000001963 growth medium Substances 0.000 description 1
- 230000023597 hemostasis Effects 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 230000002779 inactivation Effects 0.000 description 1
- 208000015181 infectious disease Diseases 0.000 description 1
- 230000036512 infertility Effects 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 230000009545 invasion Effects 0.000 description 1
- 150000002500 ions Chemical class 0.000 description 1
- 235000019421 lipase Nutrition 0.000 description 1
- JMZFEHDNIAQMNB-UHFFFAOYSA-N m-aminophenylboronic acid Chemical compound NC1=CC=CC(B(O)O)=C1 JMZFEHDNIAQMNB-UHFFFAOYSA-N 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 210000005036 nerve Anatomy 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- 230000036407 pain Effects 0.000 description 1
- 239000002245 particle Substances 0.000 description 1
- 238000011056 performance test Methods 0.000 description 1
- 238000000016 photochemical curing Methods 0.000 description 1
- 238000006116 polymerization reaction Methods 0.000 description 1
- 229920002635 polyurethane Polymers 0.000 description 1
- 239000004814 polyurethane Substances 0.000 description 1
- 238000001556 precipitation Methods 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 238000011084 recovery Methods 0.000 description 1
- 231100000241 scar Toxicity 0.000 description 1
- 238000007390 skin biopsy Methods 0.000 description 1
- 230000036558 skin tension Effects 0.000 description 1
- CIJQGPVMMRXSQW-UHFFFAOYSA-M sodium;2-aminoacetic acid;hydroxide Chemical compound O.[Na+].NCC([O-])=O CIJQGPVMMRXSQW-UHFFFAOYSA-M 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 238000001356 surgical procedure Methods 0.000 description 1
- 229960004072 thrombin Drugs 0.000 description 1
- 229940075469 tissue adhesives Drugs 0.000 description 1
- 230000000451 tissue damage Effects 0.000 description 1
- 231100000827 tissue damage Toxicity 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 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
- A61L24/00—Surgical adhesives or cements; Adhesives for colostomy devices
- A61L24/04—Surgical adhesives or cements; Adhesives for colostomy devices containing macromolecular materials
- A61L24/08—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
- A61L24/00—Surgical adhesives or cements; Adhesives for colostomy devices
- A61L24/001—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
- A61L24/00—Surgical adhesives or cements; Adhesives for colostomy devices
- A61L24/001—Use of materials characterised by their function or physical properties
- A61L24/0015—Medicaments; Biocides
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L24/00—Surgical adhesives or cements; Adhesives for colostomy devices
- A61L24/001—Use of materials characterised by their function or physical properties
- A61L24/0042—Materials resorbable by the body
-
- 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
- A61L24/00—Surgical adhesives or cements; Adhesives for colostomy devices
- A61L24/04—Surgical adhesives or cements; Adhesives for colostomy devices containing macromolecular materials
- A61L24/046—Surgical adhesives or cements; Adhesives for colostomy devices containing macromolecular materials obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L24/00—Surgical adhesives or cements; Adhesives for colostomy devices
- A61L24/04—Surgical adhesives or cements; Adhesives for colostomy devices containing macromolecular materials
- A61L24/10—Polypeptides; Proteins
- A61L24/104—Gelatin
-
- 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
- A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
- A61L2300/40—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices characterised by a specific therapeutic activity or mode of action
- A61L2300/404—Biocides, antimicrobial agents, antiseptic agents
-
- 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
- A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
- A61L2300/40—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices characterised by a specific therapeutic activity or mode of action
- A61L2300/412—Tissue-regenerating or healing or proliferative agents
-
- 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
- A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
- A61L2300/40—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices characterised by a specific therapeutic activity or mode of action
- A61L2300/412—Tissue-regenerating or healing or proliferative agents
- A61L2300/414—Growth factors
-
- 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
- A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
- A61L2300/60—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices characterised by a special physical form
- A61L2300/602—Type of release, e.g. controlled, sustained, slow
-
- 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
- Y02W—CLIMATE CHANGE MITIGATION TECHNOLOGIES RELATED TO WASTEWATER TREATMENT OR WASTE MANAGEMENT
- Y02W90/00—Enabling technologies or technologies with a potential or indirect contribution to greenhouse gas [GHG] emissions mitigation
- Y02W90/10—Bio-packaging, e.g. packing containers made from renewable resources or bio-plastics
Landscapes
- Health & Medical Sciences (AREA)
- Public Health (AREA)
- Epidemiology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Surgery (AREA)
- Veterinary Medicine (AREA)
- Chemical & Material Sciences (AREA)
- Engineering & Computer Science (AREA)
- Materials Engineering (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Materials For Medical Uses (AREA)
Abstract
The invention discloses a degradable healing-promoting medical adhesive, which comprises an A component and a B component which are independently packaged, wherein the A component comprises oxidized sodium alginate and modified alginate microspheres loaded with growth factors in a mass ratio of 1:1-2:1; the component B comprises the following components in percentage by mass: 2.0 to 4.0 percent of carboxymethyl chitosan, 1.0 to 5.0 percent of modified polylysine, 0.5 to 1.0 percent of tackifier and 90 to 96 percent of water. The degradable healing-promoting medical adhesive provided by the invention has excellent antibacterial property and adhesive property, can slowly release growth factors with healing promotion so as to promote the repair of damaged tissues, and can be biodegraded into nontoxic and harmless small molecules along with metabolism in a body.
Description
Technical Field
The invention belongs to the technical field of medicines, and relates to a degradable healing-promoting medical adhesive and a preparation method thereof.
Background
When injury is severe, it is necessary to seal the skin and other damaged tissue to prevent excessive blood loss, foreign body invasion and exacerbation of wound infection leading to increased injury or death. At present, a common method for closing an incision clinically is mechanical fixation of needle and line suturing and suturing nails, the method needs to be subjected to anesthesia operation, and repeated stitch removal and dressing change not only bring discomfort to a patient, but also easily cause secondary infection of a wound, scar left after healing is not attractive, and tissue damage and even tissue function restoration are more likely to be caused when soft tissue suturing. With the development of surgical techniques, people are continually seeking medical means that can maximally reduce pain to the patient, shorten recovery time, and simultaneously, allow perfect restoration of the damaged area. Thus, the use of bioadhesive materials has evolved.
In recent years, tissue adhesive materials have been rapidly developed, mainly fibrin, cyanoacrylates, polyurethanes, polyethylene glycols, and the like, but these adhesive materials still have various drawbacks such as: thrombin in the fibrin glue is extracted from organisms, the risk of virus transmission exists, the fibrin glue needs to be subjected to virus inactivation treatment, the production cost is high, and the fibrin glue has poor adhesive strength and insufficient body mechanical strength in a wet physiological environment; the cyanoacrylate adhesive has high adhesive strength, but the degradation products of the cyanoacrylate adhesive have high cytotoxicity, and the cyanoacrylate adhesive can emit certain heat due to rapid polymerization when in use, and the cured cyanoacrylate material has certain brittleness, which is not beneficial to the use on soft tissues; polyethylene glycol-based adhesives swell in water environment in a large volume, so that when the polyethylene glycol-based adhesives are applied to tissue sealing or hemostasis, the polyethylene glycol-based adhesives can squeeze blood vessels and nerves around tissues, and cause certain damage to human bodies and the like. In addition, the combined adhesive material has the problems of difficult degradation and poor healing performance of damaged tissues. Therefore, it is important to develop a medical adhesive which is biodegradable, has no toxic or side effects as a degradation product, and has the effect of promoting repair of damaged tissues.
Disclosure of Invention
The invention aims to provide a degradable healing-promoting medical adhesive for solving at least one of the technical problems. The degradable healing-promoting medical adhesive provided by the invention has the performances of antibiosis, tissue adhesion, tissue injury repair, tissue filling, biodegradability and the like, can promote the repair of injured tissues by slowly releasing growth factors with healing promotion, and can be biodegraded into nontoxic and harmless small molecules along with metabolism in a body.
The invention aims to provide a preparation method of the degradable healing-promoting medical adhesive, so as to solve at least one of the technical problems.
According to one aspect of the present invention, there is provided a degradable healing promoting medical adhesive comprising an a-component and a B-component, which are individually packaged, wherein,
the component A comprises oxidized sodium alginate and modified alginate microspheres loaded with growth factors in a mass ratio of 1:1-2:1;
the component B comprises the following components in percentage by mass: 2.0 to 4.0 percent of carboxymethyl chitosan, 1.0 to 5.0 percent of modified polylysine, 0.5 to 1.0 percent of tackifier and 90 to 96 percent of water.
In some embodiments, the growth factor may be selected from one or both of VEGF, EGF, bFGF.
In some embodiments, the viscosity increasing agent may be selected from one or more of gelatin, sodium carboxymethyl cellulose, guar gum.
In some embodiments, the method of preparing oxidized sodium alginate may comprise the steps of:
dispersing sodium alginate in absolute ethyl alcohol to prepare sodium alginate suspension, then adding sodium periodate solution to react for 18-32 h under the condition of light shielding, adding ethylene glycol to terminate the reaction to obtain a reaction mixture, purifying the reaction mixture, and freeze-drying to obtain the sodium alginate suspension.
In some embodiments, the M/G ratio of sodium alginate may be 1:1 to 1:3; the molecular weight may be 8-12 kDa.
In some embodiments, the mass to volume ratio of sodium alginate to absolute ethanol is 1:4 to 1:6g/mL.
In some embodiments, the concentration of the sodium periodate solution may be from 6 to 20wt%.
In some embodiments, the molar ratio of sodium periodate to sodium alginate monomer units may be 20 to 100%; for example, the content may be 20%, 40%, 60%, 80%, or 100%.
In some embodiments, ethylene glycol equimolar to sodium periodate is added and the reaction is terminated after 15 minutes.
In some embodiments, purifying the reaction mixture, freeze drying may include the steps of:
adding the reaction mixture into absolute ethyl alcohol, separating out precipitate, filtering, drying the precipitate, dialyzing with water for 24-72 h to remove unreacted sodium periodate, ethylene glycol and other small molecular impurities, and finally freeze-drying the liquid in the dialysis bag.
In some embodiments, the volume ratio of the reaction mixture to absolute ethanol may be 1:4 to 1:6.
In some embodiments, the precipitation may be dried by vacuum drying at a temperature of 35-45 ℃.
In some embodiments, the method of preparing the growth factor loaded modified alginate microspheres may comprise the steps of:
dissolving oxidized sodium alginate in water, adding aminophenylboric acid according to the mass ratio of the aminophenylboric acid to the oxidized sodium alginate of 1:5-1:10 for reaction, and adding a growth factor after the reaction is finished to obtain a mixed solution; and (3) dripping the mixed solution into a calcium chloride solution, and finally filtering and freeze-drying to obtain the calcium chloride aqueous solution.
In some embodiments, the concentration of the oxidized sodium alginate solution prepared by dissolving oxidized sodium alginate in water may be 3 to 5wt%.
In some embodiments, the final concentration of growth factor in the mixed liquor may be 0.5 to 1.0wt%.
In some embodiments, the concentration of the calcium chloride solution may be 2 to 4wt%.
In some embodiments, the aminophenylboronic acid may be one or a mixture of two of 2-aminophenylboronic acid, 3-aminophenylboronic acid, and 4-aminophenylboronic acid.
In some embodiments, the particle size of the growth factor loaded modified alginate microspheres may be 10 to 200 μm.
In some embodiments, the method of preparing modified polylysine may include the steps of:
and (3) dissolving polylysine in an alkaline buffer solution, then adding methacrylic anhydride for reaction, adding aldehyde phenylboronic acid for continuous reaction after the reaction is finished, and purifying and drying the reaction mixture after the reaction is finished to obtain the modified poly-lysine.
In some embodiments, the alkaline buffer is a buffer having a pH of 8 to 10, and may be, for example, a borate buffer having a pH of 8 to 10, glycine-sodium hydroxide buffer, phosphate Buffer (PBS), trimethylol nitromethane buffer (Tris), or the like.
In some embodiments, polylysine is dissolved in an alkaline buffer solution, and the concentration of the resulting polylysine solution can be 4-6 wt%.
In some embodiments, the mass ratio of methacrylic anhydride to polylysine may be 1:1 to 1:10, the reaction temperature may be 40 to 60 ℃, and the reaction time may be 2 to 6 hours.
In some embodiments, the aldehydephenylboronic acid may be one or a combination of two of 2-aldehydephenylboronic acid, 3-aldehydephenylboronic acid, and 4-aldehydephenylboronic acid; the mass ratio of the aldehyde phenylboronic acid to the polylysine can be 1:2-1:10.
The modified polylysine prepared by modifying polylysine by using methacrylic anhydride and aldehyde phenylboronic acid has photocuring performance, and when the modified polylysine is applied to preparing medical adhesives together with oxidized sodium alginate, modified alginate microspheres loaded with growth factors and the like, the prepared medical adhesives have instantaneous curing performance, so that the curing time of the tissue adhesives can be obviously shortened; on the other hand, the phenylboronic acid group of the modified polylysine and the phenylboronic acid group of the modified alginate microsphere loaded with the growth factor can interact, so that the strength of the medical adhesive is improved; on the other hand, the modified polylysine has excellent antibacterial performance, can be used as a high molecular antibacterial agent to replace antibiotics, and avoids the drug resistance caused by the use of antibiotic antibacterial agents.
According to another aspect of the present invention, there is provided a method for preparing a degradable healing promoting medical adhesive, comprising the steps of:
mixing oxidized sodium alginate and modified alginate microspheres loaded with growth factors in proportion to obtain a component A;
firstly, adding carboxymethyl chitosan and modified polylysine into water, dissolving to obtain a carboxymethyl chitosan and modified polylysine mixed solution, and then dissolving a tackifier into the carboxymethyl chitosan and modified polylysine mixed solution to obtain a component B;
packaging the component A and the component B independently, and sterilizing.
In some embodiments, the a-component may be sterilized by irradiation sterilization, and the B-component may be sterilized by wet sterilization to achieve sterility.
When the degradable healing-promoting medical adhesive is used, physiological saline and the A component in a freeze-dried powder state are mixed to form suspension emulsion, then the A component suspension emulsion and the B component are respectively injected into the syringes, the two syringes are respectively connected onto a gel mixing head, and the medical adhesive is extruded to a required position according to the volume ratio of 1:1, so that the effect of adhesion or filling can be achieved.
Compared with the prior art, the invention has the following beneficial effects:
(1) Aldehyde groups of multi-aldehyde oxidized sodium alginate obtained through sodium periodate oxidation can react with amino groups on the surface of a tissue to generate Schiff base reaction, so that a chemical bonding effect is generated; compared with unmodified sodium alginate, the oxidized sodium alginate used in the invention has the characteristic of biodegradability;
(2) In the degradable healing-promoting medical adhesive, the carboxyl of the oxidized sodium alginate is easy to generate electrostatic ion crosslinking with the amino of the carboxymethyl chitosan, the aldehyde group of the oxidized sodium alginate and the amino of the carboxymethyl chitosan form Schiff base reaction, and the phenylboronic acid group of the modified polylysine can also react with the modified alginate microsphere loaded with the growth factor, so that gel with good mechanical property and good application property can be formed when the medical adhesive is used, and the medical adhesive is not easy to crack due to cracking caused by skin tension and the like after being cured;
(3) The modified alginate microspheres loaded with the growth factors can fill the tissue defect part better, and the growth factors loaded by the modified alginate can be released slowly to reach the tissue defect part along with the degradation of the modified alginate by organism tissue fluid, so that the repair of tissue injury is promoted;
(4) The degradable healing-promoting medical adhesive has excellent antibacterial property and adhesive property.
Drawings
FIG. 1 is a Fourier transform infrared spectrum of oxidized sodium alginate prepared in example 1 of the invention; wherein SA represents sodium alginate, and OSA represents oxidized sodium alginate.
Detailed Description
The present invention will be described in further detail with reference to the following embodiments. The examples are for illustration only and are not intended to limit the invention in any way. The raw materials and reagents used in the examples were conventional products which were obtained commercially, unless otherwise specified; the experimental methods for which specific conditions are not specified in the examples are generally in accordance with the conditions conventional in the art or in accordance with the manufacturer's recommendations.
The sodium alginate powder used in the examples was derived from commercial sources with a purity of 85% sodium alginate, wherein the content of paleo Luo Tangquan acid was 80-50%. In the following examples, "vigorous stirring" means stirring at a rotational speed of 1200 to 1800rpm.
Example 1
The degradable healing-promoting medical adhesive comprises a component A, a component B and a component B, wherein the component A comprises oxidized sodium alginate and modified alginate microspheres loaded with growth factors in a mass ratio of 1:1; the component B comprises the following components in percentage by mass: carboxymethyl chitosan 4.0%, modified polylysine 5.0%, sodium carboxymethyl cellulose 0.8%, and water in balance.
The preparation method comprises the following steps:
(1) Preparation of oxidized sodium alginate: dispersing 10g of sodium alginate powder in 50mL of absolute ethyl alcohol to prepare sodium alginate suspension; 10g of sodium periodate is dissolved in 50mL of water to prepare sodium periodate solution; adding sodium periodate solution into sodium alginate suspension according to the molar ratio of sodium periodate to sodium alginate monomer unit of 60%, magnetically stirring for about 24 hours at room temperature in dark place, then adding ethylene glycol which is equimolar with sodium periodate, and stopping the reaction after about 15 minutes to obtain a reaction mixture;
pouring the obtained reaction mixture into vigorously stirred absolute ethyl alcohol, wherein the volume ratio of the reaction mixture to the absolute ethyl alcohol is 1:5, precipitating a precipitate, then carrying out suction filtration and vacuum drying at 40 ℃ to obtain solid powder, dialyzing the obtained solid powder with distilled water for 24 hours to remove unreacted sodium periodate, ethylene glycol and other small molecular impurities, and finally carrying out liquid cooling and freeze drying in a dialysis bag to obtain oxidized sodium alginate;
the prepared oxidized sodium alginate iS subjected to Fourier transform infrared spectrum detection by adopting a Fourier transform infrared spectrometer (instrument model: nicolet iS 50), the detection result iS shown in figure 1, and as can be seen from figure 1, the oxidized sodium alginate iS 1735cm compared with pure sodium alginate -1 Detecting a stretching vibration peak of C=O double bond in aldehyde group, which shows that oxidized sodium alginate is successfully prepared;
(2) Preparing modified alginate microspheres loaded with growth factors: weighing 5g of oxidized sodium alginate, dissolving the oxidized sodium alginate in purified water to prepare 4wt% of oxidized sodium alginate solution, adding 3-aminophenylboric acid into the oxidized sodium alginate solution according to the mass ratio of the 3-aminophenylboric acid to the oxidized sodium alginate solution of 1:6 for reaction, and adding VEGF (vascular endothelial growth factor) after the reaction is finished to obtain a mixed solution, wherein the final concentration of the growth factor in the mixed solution is 1.0wt%; then dripping the mixed solution into a 4wt% calcium chloride solution in a coagulating bath by using a micropump, and finally filtering and freeze-drying to obtain modified alginate microspheres loaded with growth factors;
(3) Preparation of modified polylysine: weighing 5g of polylysine, dissolving in 100mL of phosphate buffer solution with pH=8 to obtain a polylysine solution with 5wt%, adding 1g of methacrylic anhydride into the polylysine solution, reacting at 40 ℃ for 6 hours, adding 1g of 2-aldehyde phenylboronic acid into the polylysine solution after the reaction is finished, continuing the reaction, purifying and drying the reaction mixture after the reaction is finished to obtain modified polylysine;
(4) And (3) preparing a component A: uniformly mixing oxidized sodium alginate freeze-dried powder and modified alginate microspheres loaded with growth factors according to the mass ratio of 1:1, filling into a glass bottle, sealing, and finally sterilizing by irradiation to achieve a sterile state;
(5) And (3) preparing a component B: according to the components of 4.0wt% of carboxymethyl chitosan, 5.0wt% of modified polylysine and 0.8wt% of tackifier, the carboxymethyl chitosan and the modified polylysine are firstly dissolved in purified water, then the tackifier is dissolved in the solution, and the solution is filled into a glass bottle and sealed, and finally the sterile state is achieved through wet sterilization.
When in use, firstly, the physiological saline is taken according to the mass ratio of the component A to the physiological saline of 1:50, the physiological saline is injected into a glass bottle filled with the component A until the suspension emulsion is formed, the suspension emulsion of the component A and the component B are respectively sucked out by syringes, the two syringes are respectively connected onto a gel mixing head, and then the medical adhesive is extruded to the needed position according to the volume ratio of 1:1, thus achieving the effect of bonding or filling.
Example 2
The degradable healing-promoting medical adhesive comprises a component A, a component B and a component B, wherein the component A comprises oxidized sodium alginate and modified alginate microspheres loaded with growth factors in a mass ratio of 1:1; the component B comprises the following components in percentage by mass: carboxymethyl chitosan 4.0%, modified polylysine 5.0%, sodium carboxymethyl cellulose 0.8%, and water in balance.
The preparation method comprises the following steps:
(1) Preparation of oxidized sodium alginate: dispersing 10g of sodium alginate powder in 50mL of absolute ethyl alcohol to prepare sodium alginate suspension; 10g of sodium periodate is dissolved in 50mL of water to prepare sodium periodate solution; adding sodium periodate solution into sodium alginate suspension according to the molar ratio of sodium periodate to sodium alginate monomer unit of 60%, magnetically stirring for about 24 hours at room temperature in dark place, then adding ethylene glycol which is equimolar with sodium periodate, and stopping the reaction after about 15 minutes to obtain a reaction mixture;
pouring the obtained reaction mixture into vigorously stirred absolute ethyl alcohol, wherein the volume ratio of the reaction mixture to the absolute ethyl alcohol is 1:5, precipitating a precipitate, then carrying out suction filtration and vacuum drying at 40 ℃ to obtain solid powder, dialyzing the obtained solid powder with distilled water for 24 hours to remove unreacted sodium periodate, ethylene glycol and other small molecular impurities, and finally carrying out liquid cooling and freeze drying in a dialysis bag to obtain oxidized sodium alginate;
(2) Preparing modified alginate microspheres loaded with growth factors: weighing 5g of oxidized sodium alginate, dissolving the oxidized sodium alginate in purified water to prepare 4wt% of oxidized sodium alginate solution, adding 3-aminophenylboric acid into the oxidized sodium alginate solution according to the mass ratio of the 3-aminophenylboric acid to the oxidized sodium alginate solution of 1:8 for reaction, and adding VEGF (vascular endothelial growth factor) after the reaction is finished to obtain a mixed solution, wherein the final concentration of the growth factor in the mixed solution is 1.0wt%; then dripping the mixed solution into a 4wt% calcium chloride solution in a coagulating bath by using a micropump, and finally filtering and freeze-drying to obtain modified alginate microspheres loaded with growth factors;
(3) Preparation of modified polylysine: weighing 5g of polylysine, dissolving in 100mL of phosphate buffer solution with pH=8 to obtain a polylysine solution with 5wt%, adding 1g of methacrylic anhydride into the polylysine solution, reacting for 2 hours at 40 ℃, adding 1g of 2-aldehyde phenylboronic acid into the solution after the reaction is finished, continuing the reaction, purifying and drying the reaction mixture after the reaction is finished to obtain modified polylysine;
(4) And (3) preparing a component A: uniformly mixing oxidized sodium alginate freeze-dried powder and modified alginate microspheres loaded with growth factors according to the mass ratio of 1:1, filling into a glass bottle, sealing, and finally sterilizing by irradiation to achieve a sterile state;
(5) And (3) preparing a component B: according to the components of 4.0wt% of carboxymethyl chitosan, 5.0wt% of modified polylysine and 0.8wt% of tackifier, the carboxymethyl chitosan and the modified polylysine are firstly dissolved in purified water, then the tackifier is dissolved in the solution, and the solution is filled into a glass bottle and sealed, and finally the sterile state is achieved through wet sterilization.
Method of use reference is made to example 1.
Example 3
The degradable healing-promoting medical adhesive comprises a component A, a component B and a component B, wherein the component A comprises oxidized sodium alginate and modified alginate microspheres loaded with growth factors in a mass ratio of 1:1; the component B comprises the following components in percentage by mass: carboxymethyl chitosan 4.0%, modified polylysine 2.5%, sodium carboxymethyl cellulose 0.8%, and water in balance.
The preparation method comprises the following steps:
(1) Preparation of oxidized sodium alginate: dispersing 10g of sodium alginate powder in 50mL of absolute ethyl alcohol to prepare sodium alginate suspension; 10g of sodium periodate is dissolved in 50mL of water to prepare sodium periodate solution; adding sodium periodate solution into sodium alginate suspension according to the mole ratio of sodium periodate to sodium alginate monomer unit of 40%, magnetically stirring for about 24 hours at room temperature in dark place, then adding ethylene glycol which is equimolar with sodium periodate, and stopping the reaction after about 15 minutes to obtain a reaction mixture;
pouring the obtained reaction mixture into vigorously stirred absolute ethyl alcohol, wherein the volume ratio of the reaction mixture to the absolute ethyl alcohol is 1:5, precipitating a precipitate, then carrying out suction filtration and vacuum drying at 40 ℃ to obtain solid powder, dialyzing the obtained solid powder with distilled water for 24 hours to remove unreacted sodium periodate, ethylene glycol and other small molecular impurities, and finally carrying out liquid cooling and freeze drying in a dialysis bag to obtain oxidized sodium alginate;
(2) Preparing modified alginate microspheres loaded with growth factors: weighing 5g of oxidized sodium alginate, dissolving the oxidized sodium alginate in purified water to prepare 4wt% of oxidized sodium alginate solution, adding 3-aminophenylboric acid into the oxidized sodium alginate solution according to the mass ratio of the 3-aminophenylboric acid to the oxidized sodium alginate solution of 1:6 for reaction, and adding VEGF (vascular endothelial growth factor) after the reaction is finished to obtain a mixed solution, wherein the final concentration of the growth factor in the mixed solution is 0.5wt%; then dripping the mixed solution into a 4wt% calcium chloride solution in a coagulating bath by using a micropump, and finally filtering and freeze-drying to obtain modified alginate microspheres loaded with growth factors;
(3) Preparation of modified polylysine: weighing 5g of polylysine, dissolving in 100mL of phosphate buffer solution with pH=8 to obtain a polylysine solution with 5wt%, adding 0.5g of methacrylic anhydride into the polylysine solution, reacting at 50 ℃ for 4 hours, adding 0.5g of 2-aldehyde phenylboronic acid into the polylysine solution after the reaction is finished, continuing the reaction, purifying and drying the reaction mixture after the reaction is finished to obtain modified polylysine;
(4) And (3) preparing a component A: uniformly mixing oxidized sodium alginate freeze-dried powder and modified alginate microspheres loaded with growth factors according to the mass ratio of 1:1, filling into a glass bottle, sealing, and finally sterilizing by irradiation to achieve a sterile state;
(5) And (3) preparing a component B: according to the components of 4.0wt% of carboxymethyl chitosan, 5.0wt% of modified polylysine and 0.8wt% of tackifier, the carboxymethyl chitosan and the modified polylysine are firstly dissolved in purified water, then the tackifier is dissolved in the solution, and the solution is filled into a glass bottle and sealed, and finally the sterile state is achieved through wet sterilization.
Method of use reference is made to example 1.
Comparative example 1
The medical adhesive of the comparative example comprises a component A comprising sodium alginate and alginate microspheres loaded with growth factors in a mass ratio of 1:1; the component B comprises the following components in percentage by mass: carboxymethyl chitosan 4.0%, sodium carboxymethyl cellulose 0.8%, and water in balance.
The preparation method comprises the following steps:
(1) Preparing alginate microspheres loaded with growth factors: weighing 5g of sodium alginate, dissolving the sodium alginate in purified water to prepare a sodium alginate solution with the concentration of 4wt%, adding VEGF to obtain a mixed solution, and adding the growth factor into the mixed solution, wherein the final concentration of the growth factor is 0.5wt%; then dripping the mixed solution into a 4wt% calcium chloride solution of a coagulating bath by using a micropump, and finally filtering and freeze-drying to obtain the alginate microspheres loaded with the growth factors;
(2) And (3) preparing a component A: uniformly mixing the sodium alginate freeze-dried powder and the alginate microspheres loaded with the growth factors and prepared in the step (1) according to the mass ratio of 1:1, filling the mixture into a glass bottle, sealing the glass bottle, and finally sterilizing the glass bottle by irradiation to achieve a sterile state;
(3) And (3) preparing a component B: according to the weight percent of carboxymethyl chitosan 4.0 and the weight percent of tackifier 0.8, the components are taken, the carboxymethyl chitosan is firstly dissolved in purified water, then the tackifier is dissolved in the solution, and then the solution is filled into a glass bottle and sealed, and finally the sterile state is achieved through wet sterilization.
Method of use reference is made to example 1.
To verify whether the degradable healing-promoting medical adhesive of the present invention achieves the intended effect, the medical adhesives prepared in examples 1 to 3 and comparative example 1 were subjected to an antibacterial test, an adhesive force test, a degradation test, a healing-promoting test, etc.
1. Antibacterial experiments
The medical adhesives prepared in the different examples were respectively added into sterile conical flasks and after solidification 70mL of 0.03mol/L phosphate buffer and 5mL of 10 were respectively added 8 After cfu/mL of staphylococcus aureus bacterial liquid is permeated into the culture medium, the culture is carried out for 8 hours, 12 hours and 24 hours at 37 ℃ for colony counting.
The calculation formula of the bacteriostasis rate: x= (a-B)/a×100%, where X is the antibacterial rate, a is the average colony count before sample oscillation, and B is the average colony count after sample oscillation. The results are shown in Table 1.
Table 1 antibacterial ratio of staphylococcus aureus of medical adhesives of different examples
| 8h | 12h | 24h | |
| Example 1 | 84％ | 89％ | 94％ |
| Example 2 | 87％ | 92％ | 97％ |
| Example 3 | 83％ | 87％ | 92％ |
| Comparative example 1 | 71％ | 75％ | 82％ |
As can be seen from Table 1, the medical adhesive prepared by the invention has good antibacterial performance, and the antibacterial rate of 24h staphylococcus aureus is more than 90%.
2. Tissue adhesion test experiment
Cutting a piece of pigskin into small pieces according to the size of 5cm multiplied by 2.5cm, butting the two small pieces of pigskin together, then dripping the medical adhesive of the embodiment 1 at the butting position of the two pieces of pigskin, waiting for solidification, and placing the connected pigskin on a clamp of a universal testing machine (10 ST of the Maillard precision instruments Co., ltd.) for tensile test.
The medical adhesives prepared in examples 2-3 and comparative example 1 were subjected to tensile force test in the same manner. The experimental results are shown in table 2.
TABLE 2 tensile test results of medical adhesives prepared in examples 1-3 and comparative example 1
| Example 1 | Example 2 | Example 3 | Comparative example 1 | |
| Adhesive force (kPa) | 33.43±0.18 | 37.56±0.25 | 29.27±0.38 | 15.29±0.49 |
As can be seen from Table 2, the medical adhesives prepared in examples 1 to 3 all had an adhesive force of 25kPa or more, wherein the medical adhesives prepared in example 1 and example 3 had an adhesive force of 30kPa or more, and the medical adhesive prepared in comparative example 1 had an adhesive force of less than 20kPa, thus indicating that the medical adhesives prepared in the present invention had a strong adhesive force.
3. Degradation Performance test experiment
200. Mu.L of the cured samples of the medical adhesives prepared in the different examples were placed in 5mL of PBS solution containing 100U/mL lipase, and the in vivo environment was simulated in a constant temperature shaker at 37℃to test the in vitro degradation rate of the medical adhesives. The mass loss rates for each sample at day 5, day 10 and day 15 are shown in table 3.
TABLE 3 mass loss rate after degradation of medical adhesives
| Sample of | Mass loss rate on day 5 | Mass loss rate on day 10 | Mass loss rate on day 15 |
| Example 1 | 53％ | 76％ | 90％ |
| Example 2 | 50％ | 73％ | 86％ |
| Example 3 | 46％ | 68％ | 80％ |
| Comparative example 1 | 26％ | 40％ | 49％ |
From the results of Table 3, it can be seen that the medical adhesives prepared in examples 1-3 have good degradation properties.
4. Crosslinking time test experiment
The medical adhesives prepared in examples 1 to 3 and comparative example 1 were mixed with the A and B components, and then immediately timed until the medical adhesive was no longer flowing, the timing was stopped, and the crosslinking time was recorded. The crosslinking time for each sample is shown in Table 4.
TABLE 4 crosslinking time test results for medical adhesives prepared in examples 1-3 and comparative example 1
| Example 1 | Example 2 | Example 3 | Comparative example 1 | |
| Crosslinking time(s) | 103±7 | 78±5 | 127±9 | 318±16 |
From the results of Table 4, it can be seen that the medical adhesives prepared in examples 1-3 have shorter crosslinking times, meeting the instantaneous curing requirements.
5. Test experiment for healing promoting performance
Rats were anesthetized by injection, back sheared, skin was sterilized by wiping with 75% alcohol, a 1cm x 1cm circular wound was formed in the back of the rats at a position 4cm from the mid-line behind the ear with a 1cm diameter skin biopsy device, the excision was performed as deep as fascia, and the wound was treated as follows.
Control group: the wound surface is sprayed with the medical adhesive of the comparative example 1, and is covered with double-layer spinning and bandaged.
Experiment group one: the wound surface is sprayed with the medical adhesive of the example 1, and covered with double-layer spinning and binding.
Experimental group two: the wound surface is sprayed with the medical adhesive of the example 2, and covered with double-layer spinning and binding.
Experimental group three: the wound surface is sprayed with the medical adhesive of the example 3, and covered with double-layer spinning and binding.
Each time the wound is cleaned, recorded and dressing changed again. The healing rate on day 7 is shown in table 5.
TABLE 5 wound healing Rate promotion on day 7 medical adhesive
| Sample of | Promoting wound healing rate |
| Example 1 | 91％ |
| Example 2 | 95％ |
| Example 3 | 75％ |
| Comparative example 1 | 72％ |
As can be seen from Table 5, the medical adhesives prepared in examples 1-2 have better wound healing properties.
What has been described above is merely some embodiments of the present invention. It will be apparent to those skilled in the art that various modifications and improvements can be made without departing from the spirit of the invention.
Claims (10)
1. The degradable healing promoting medical adhesive is characterized by comprising an A component and a B component which are packaged independently, wherein,
the component A comprises oxidized sodium alginate and modified alginate microspheres loaded with growth factors in a mass ratio of 1:1-2:1;
the component B comprises the following components in percentage by mass: 2.0 to 4.0 percent of carboxymethyl chitosan, 1.0 to 5.0 percent of modified polylysine, 0.5 to 1.0 percent of tackifier and 90 to 96 percent of water.
2. The degradable healing-promoting medical adhesive according to claim 1, wherein the preparation method of the modified alginate microspheres loaded with the growth factors comprises the following steps:
dissolving oxidized sodium alginate in water, adding aminophenylboric acid according to the mass ratio of the aminophenylboric acid to the oxidized sodium alginate of 1:5-1:10 for reaction, and adding a growth factor after the reaction is finished to obtain a mixed solution; and (3) dripping the mixed solution into a calcium chloride solution, and finally filtering and freeze-drying to obtain the calcium chloride aqueous solution.
3. The degradable healing promoting medical adhesive according to claim 2, wherein the final concentration of the growth factor in the mixed solution is 0.5-1.0 wt%; the growth factor is selected from one or two of VEGF, EGF, bFGF.
4. A degradable healing promoting medical adhesive according to any one of claims 1 to 3, wherein the preparation method of the oxidized sodium alginate comprises the following steps:
dispersing sodium alginate in absolute ethyl alcohol to prepare sodium alginate suspension, then adding sodium periodate solution to react for 18-32 hours under the condition of light shielding, adding ethylene glycol to terminate the reaction to obtain a reaction mixture, purifying the reaction mixture, and freeze-drying to obtain the sodium alginate suspension;
wherein the molar ratio of the sodium periodate to the sodium alginate monomer unit is 20-100%.
5. The degradable healing-promoting medical adhesive according to claim 4, wherein the purifying and freeze-drying the reaction mixture comprises the steps of:
adding the reaction mixture into absolute ethyl alcohol, separating out precipitate, filtering, drying the precipitate, dialyzing with water for 24-72 h, and freeze-drying the liquid in the dialysis bag.
6. The degradable healing-promoting medical adhesive according to claim 1, wherein the preparation method of the modified polylysine comprises the following steps:
and (3) dissolving polylysine in an alkaline buffer solution, then adding methacrylic anhydride for reaction, adding aldehyde phenylboronic acid for continuous reaction after the reaction is finished, and purifying and drying the reaction mixture after the reaction is finished to obtain the modified poly-lysine.
7. The degradable healing promoting medical adhesive according to claim 6, wherein the pH of the alkaline buffer is 8-10; the mass ratio of the aldehyde phenylboronic acid to the polylysine is 1:2-1:10.
8. The degradable healing promoting medical adhesive according to claim 6 or 7, wherein the mass ratio of methacrylic anhydride to polylysine is 1:1-1:10, the reaction temperature is 40-60 ℃, and the reaction time is 2-6 h.
9. The degradable healing promoting medical adhesive according to claim 1, wherein the tackifier is selected from one or more of gelatin, sodium carboxymethyl cellulose, guar gum.
10. The method for preparing the degradable healing promoting medical adhesive according to any one of claims 1 to 9, comprising the steps of:
mixing oxidized sodium alginate and modified alginate microspheres loaded with growth factors in proportion to obtain a component A;
firstly, adding carboxymethyl chitosan and modified polylysine into water, dissolving to obtain a carboxymethyl chitosan and modified polylysine mixed solution, and then dissolving a tackifier into the carboxymethyl chitosan and modified polylysine mixed solution to obtain a component B;
packaging the component A and the component B independently, and sterilizing.
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